Berkhemer PDF

The n e w e ng l a n d j o u r na l of m e dic i n e
original article
A Randomized Trial of Intraarterial

Treatment for Acute Ischemic Stroke
O.A. Berkhemer, P.S.S. Fransen, D. Beumer, L.A. van den Berg, H.F. Lingsma, A.J. Yoo,
W.J. Schonewille, J.A. Vos, P.J. Nederkoorn, M.J.H. Wermer, M.A.A. van Walderveen,
J. Staals, J. Hofmeijer, J.A. van Oostayen, G.J. Lycklama à Nijeholt, J. Boiten,
P.A. Brouwer, B.J. Emmer, S.F. de Bruijn, L.C. van Dijk, L.J. Kappelle, R.H. Lo,
E.J. van Dijk, J. de Vries, P.L.M. de Kort, W.J.J. van Rooij, J.S.P. van den Berg,
B.A.A.M. van Hasselt, L.A.M. Aerden, R.J. Dallinga, M.C. Visser, J.C.J. Bot,
P.C. Vroomen, O. Eshghi, T.H.C.M.L. Schreuder, R.J.J. Heijboer, K. Keizer,
A.V. Tielbeek, H.M. den Hertog, D.G. Gerrits, R.M. van den Berg-Vos, G.B. Karas,
E.W. Steyerberg, H.Z. Flach, H.A. Marquering, M.E.S. Sprengers, S.F.M. Jenniskens,
L.F.M. Beenen, R. van den Berg, P.J. Koudstaal, W.H. van Zwam, Y.B.W.E.M. Roos,
A. van der Lugt, R.J. van Oostenbrugge, C.B.L.M. Majoie, and D.W.J. Dippel,
for the MR CLEAN Investigators*
A BS T R AC T
Background
In patients with acute ischemic stroke caused by a proximal intracranial arterial The authors’ full names, academic de-
occlusion, intraarterial treatment is highly effective for emergency revasculariza- grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
tion. However, proof of a beneficial effect on functional outcome is lacking. Dippel at the Department of Neurology
Methods H643, Erasmus MC University Medical
Center, PO Box 2040, Rotterdam 3000
We randomly assigned eligible patients to either intraarterial treatment plus usual CA, the Netherlands, or at d.dippel@
care or usual care alone. Eligible patients had a proximal arterial occlusion in the erasmusmc.nl.
anterior cerebral circulation that was confirmed on vessel imaging and that could
Drs. Berkhemer, Fransen, and Beumer and
be treated intraarterially within 6 hours after symptom onset. The primary out- Drs. van Zwam, Roos, van der Lugt, van
come was the modified Rankin scale score at 90 days; this categorical scale mea- Oostenbrugge, Majoie, and Dippel con-
sures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). tributed equally to this article.
The treatment effect was estimated with ordinal logistic regression as a common *A complete list of investigators in the
odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds Multicenter Randomized Clinical Trial
ratio measured the likelihood that intraarterial treatment would lead to lower mod- of Endovascular Treatment for Acute
Ischemic Stroke in the Netherlands
ified Rankin scores, as compared with usual care alone (shift analysis). (MR CLEAN) is provided in the Supple-
Results mentary Appendix, available at NEJM.org.
We enrolled 500 patients at 16 medical centers in the Netherlands (233 assigned to in- This article was published on December
traarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 17, 2014, at NEJM.org.
23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before ran- DOI: 10.1056/NEJMoa1411587
domization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to Copyright © 2014 Massachusetts Medical Society.
intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence
interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points
(95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score,
0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differ-
ences in mortality or the occurrence of symptomatic intracerebral hemorrhage.
Conclusions
In patients with acute ischemic stroke caused by a proximal intracranial occlusion
of the anterior circulation, intraarterial treatment administered within 6 hours af-
ter stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and
others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current
Controlled Trials number, ISRCTN10888758.)
n engl j med nejm.org 1
The New England Journal of Medicine
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I
ntravenous alteplase administered Me thods
within 4.5 hours after symptom onset is the
only reperfusion therapy with proven efficacy Study Design
in patients with acute ischemic stroke.1 However, MR CLEAN was a pragmatic, phase 3, multicenter
well-recognized limitations of this therapy in- clinical trial with randomized treatment-group
clude the narrow therapeutic time window and assignments, open-label treatment, and blinded
contraindications such as recent surgery, coagu- end-point evaluation. Intraarterial treatment (in-
lation abnormalities, and a history of intracrani- traarterial thrombolysis, mechanical treatment,
A Quick Take
al hemorrhage.2 Moreover, intravenous alteplase or both) plus usual care (which could include in-
is available at
NEJM.org appears to be much less effective at opening travenous administration of alteplase) was com-
proximal occlusions of the major intracranial ar- pared with usual care alone (control group) in pa-
teries, which account for more than one third of tients with acute ischemic stroke and a proximal
cases of acute anterior-circulation stroke.3,4 Early intracranial arterial occlusion of the anterior cir-
recanalization after intravenous alteplase is seen culation that was confirmed on vessel imaging.
in only about one third of patients with an occlu- The study protocol (available with the full text
sion of the internal-carotid-artery terminus,5 and of this article at NEJM.org) was approved by a cen-
the prognosis without revascularization is gener- tral medical ethics committee and the research
ally poor for such patients.6 For these reasons, board of each participating center. All patients or
intraarterial treatment is regarded as a poten- their legal representatives provided written in-
tially important component of the therapeutic formed consent before randomization.
armamentarium. Members of the executive committee and the
Intraarterial therapy can be broadly divided local investigators designed the study, collected
into chemical dissolution of clots with locally and analyzed the data, wrote the manuscript,
delivered thrombolytic agents and clot retrieval and made the decision to submit the manuscript
or thrombectomy with mechanical devices. Al- for publication. The authors vouch for the accu-
though early randomized trials and subsequent racy and completeness of the data and for the fidel-
meta-analyses7 showed a benefit of treatment with ity of this report to the study protocol. The study
prourokinase8,9 or urokinase,10 their results are sponsors were not involved in the study design,
not directly applicable to current decision making study conduct, protocol review, or manuscript
about treatment because the control groups did preparation or review.
not include intravenous alteplase, and mechani-
cal approaches have largely replaced locally ap- Patients and Participating Centers
plied thrombolytic agents as first-line therapy.11 The study was conducted at 16 centers in the
The neutral results of the recent randomized, Netherlands. Patients were 18 years of age or
controlled trials of intraarterial treatment have older (no upper age limit) with acute ischemic
contributed to uncertainty regarding the efficacy stroke caused by an intracranial occlusion in the
of the catheter-based approach.12-14 Numerous anterior circulation artery. Initiation of intraarte-
questions have been raised concerning the design rial treatment had to be possible within 6 hours
and conduct of these trials, including a relatively after stroke onset. Eligible patients had an occlu-
long interval before intraarterial treatment, the sion of the distal intracranial carotid artery, mid-
absence of pretreatment vascular imaging to con- dle cerebral artery (M1 or M2), or anterior cere-
firm a proximal intracranial occlusion, and the bral artery (A1 or A2), established with computed
limited use of third-generation mechanical throm- tomographic (CT) angiography (CTA), magnetic
bectomy devices such as retrievable stents. In the resonance angiography (MRA), or digital-subtrac-
Multicenter Randomized Clinical Trial of Endo- tion angiography (DSA), and a score of 2 or higher
vascular Treatment for Acute Ischemic Stroke in on the National Institutes of Health Stroke Scale
the Netherlands (MR CLEAN), we assessed wheth- (NIHSS; range, 0 to 42, with higher scores indi-
er intraarterial treatment plus usual care would cating more severe neurologic deficits). Inclusion
be more effective than usual care alone in patients of patients with an additional extracranial inter-
with a proximal arterial occlusion in the anterior nal-carotid-artery occlusion or dissection was left
cerebral circulation that could be treated intra- to the judgment of the treating physician. Detailed
arterially within 6 hours after symptom onset. inclusion and exclusion criteria are listed in the
2 n engl j med nejm.org

Intr a arterial Treatment for Acute Ischemic Stroke
study protocol. We did not keep a log of patients hours and the final infarct volume on noncon-
who were screened for eligibility. trast CT at 5 to 7 days.
Safety variables included hemorrhagic com-
Randomization plications, progression of ischemic stroke, new
The randomization procedure was Web-based, with ischemic stroke into a different vascular territo-
the use of permuted blocks. We stratified random- ry, and death. If neurologic deterioration devel-
ization according to medical center, use of intrave- oped, additional neuroimaging was required.
nous alteplase (yes or no), planned treatment Symptomatic intracranial hemorrhage was de-
method (mechanical or other), and stroke sever- fined as neurologic deterioration (an increase of
ity (NIHSS score of ≤14 or >14). 4 or more points in the score on the NIHSS) and
evidence of intracranial hemorrhage on imaging
Intervention studies. Local neurologists were aware of the
Intraarterial treatment consisted of arterial cath- treatment-group assignments and reported seri-
eterization with a microcatheter to the level of ous adverse events through our Web-based data-
occlusion and delivery of a thrombolytic agent, base or by fax or e-mail.
mechanical thrombectomy, or both. The method
of intraarterial treatment was left to the discre- Clinical and Radiologic Assessment
tion of the local interventionist. All patients underwent clinical assessment (in-
The use of alteplase or urokinase for intraar- cluding determination of the NIHSS score) at
terial thrombolysis was allowed in this trial, baseline, after 24 hours, and at 5 to 7 days or at
with a maximum dose of 90 mg of alteplase or discharge if earlier. A single experienced trial in-
1,200,000 IU of urokinase. The dose was re- vestigator, who was unaware of the treatment-
stricted to 30 mg of alteplase or 400,000 IU of group assignments, conducted the follow-up in-
urokinase if intravenous alteplase was given. terviews at 90 days by telephone with the patient,
Mechanical treatment could involve thrombus re- proxy, or health care provider. This interview
traction, aspiration, wire disruption, or use of a provided reports for the assessment of the modi-
retrievable stent. fied Rankin score by reviewers who remained
Only devices that had received U.S. Food and unaware of the treatment-group assignments.16-18
Drug Administration approval or a Conformité The imaging committee evaluated the find-
Européenne (CE) marking and were approved by ings on baseline noncontrast CT for the Alberta
the steering committee could be used in the Stroke Program Early Computed Tomography
trial. One or more members of each intervention Score (ASPECTS; range, 0 to 10, with 1 point
team had to have completed at least five full subtracted for any evidence of early ischemic
procedures with a particular type of device.15 change in each defined region on the CT scan),19
baseline vessel imaging (CTA, MRA, or DSA) for
Outcome and Safety Measures the location of the occlusion, and follow-up CTA
The primary outcome was the score on the mod- or MRA at 24 hours for vessel recanalization.
ified Rankin scale at 90 days. The modified Recanalization was classified as complete or not
Rankin scale is a 7-point scale ranging from 0 complete and was further evaluated with the use
(no symptoms) to 6 (death). A score of 2 or less of the modified Arterial Occlusive Lesion score
indicates functional independence.16 (see the Supplementary Appendix, available at
Secondary outcomes included the NIHSS NEJM.org, for details about scales).20,21 Follow-
score at 24 hours and at 5 to 7 days or discharge up CT scans obtained at 5 days were assessed for
if earlier, activities of daily living measured with the presence of intracranial hemorrhage.22 All
the Barthel index, and the health-related quality neuroimaging studies were evaluated by two neu-
of life measured with the EuroQol Group 5-Dimen- roradiologists who were unaware of the treat-
sion Self-Report Questionnaire at 90 days.17,18 ment-group assignments. The final infarct vol-
We examined the following prespecified dichoto- ume on the follow-up CT scan was assessed with
mizations of the modified Rankin score: 0 or 1 the use of an automated, validated algorithm.23
versus 2 to 6, 0 to 2 versus 3 to 6, and 0 to 3 versus An independent core laboratory assessed angio-
4 to 6. Imaging outcomes included arterial re- graphic outcomes on DSA imaging, using the
canalization measured with CTA or MRA at 24 modified Thrombolysis in Cerebral Infarction

(TICI) score, which ranges from 0 (no reperfu- Assuming a 10% crossover rate,26 we calcu-
sion) to 3 (complete reperfusion). 21 lated that a sample of 500 patients (250 patients
in each group) would yield a power of 82%, at a
Statistical Analysis significance level of 0.05, to detect a treatment
All analyses were based on the intention-to-treat effect that resulted in an absolute increase of 10
principle. The primary effect variable was the ad- percentage points in the proportion of patients
justed common odds ratio for a shift in the direc- with a modified Rankin score of 0 to 3 in the
tion of a better outcome on the modified Rankin intervention group as compared with the pro-
scale; this ratio was estimated with multivariable portion in the control group.
ordinal logistic regression.24 We calculated an
adjusted odds ratio for all possible cutoff values R e sult s
on the modified Rankin scale to assess the con-
sistency of effect and the plausibility of propor- Randomization and Baseline Characteristics
tionality of the odds ratio. The adjusted common Between December 2010 and March 2014, a total
odds ratio and all secondary effect variables were of 502 patients underwent randomization in 16
adjusted for potential imbalances in the follow- Dutch centers. Two patients, whose representatives
ing major prognostic variables between the inter- withdrew consent immediately after randomization
vention group and the control group: age; stroke and assignment to the control group, could not be
severity (NIHSS score) at baseline; time from included in the intention-to-treat analysis.
stroke onset to randomization; status with re- The mean age of the 500 study participants was
spect to previous stroke, atrial fibrillation, and 65 years (range, 23 to 96); 292 participants
diabetes mellitus; and occlusion of the internal- (58.4%) were men. Risk factors for a poor out-
carotid-artery terminus (yes vs. no).25 We imput- come, clinical risk factors for stroke, and aspects
ed missing values of baseline variables that were of prerandomization treatment were evenly dis-
used to adjust the regression models of treatment tributed between the two treatment groups (Table
effect on primary and secondary outcomes with 1, and Table S1 in the Supplementary Appendix).
mean or mode, as applicable. No outcomes were
imputed, except for single missing values of Treatment Assignments and Crossovers
items on the NIHSS at 24 hours and at 5 to 7 days In total, 233 patients (46.6%) were assigned to
or discharge. Patients who died were not assigned the intervention group and 267 patients (53.4%)
NIHSS scores and were not included in analyses were assigned to the control group. One patient
of such scores. received intraarterial treatment after being as-
The adjusted and unadjusted common odds ra- signed to the control group. Intraarterial treat-
tios are reported with 95% confidence intervals to ment was never initiated in 17 patients (7.3%)
indicate statistical precision. Binary outcomes were assigned to the intervention group (Fig. S1 in the
analyzed with logistic regression and are reported Supplementary Appendix).
as adjusted and unadjusted odds ratios with 95%
confidence intervals. All P values are two-sided. Intervention Details
Treatment-effect modification was explored Actual intraarterial therapy (with or without me-
in prespecified subgroups of patients, defined by chanical thrombectomy) was performed in 196 of
NIHSS score (2 to 15, 16 to 19, or ≥20), age (≥80 the 233 patients in the intervention group (84.1%).
years or <80 years), occlusion of the internal- In 88 patients (37.8%), general anesthesia was used.
carotid-artery terminus (yes or no), additional A simultaneous second revascularization proce-
extracranial internal-carotid-artery occlusion (yes dure (acute cervical carotid stenting) was per-
or no), time from stroke onset to randomization formed in 30 patients (12.9%).
(≤120 minutes or >120 minutes), and ASPECTS Mechanical treatment was performed in 195
(0 to 4, 5 to 7, or 8 to 10). The statistical sig- of the 233 patients (83.7%). Retrievable stents were
nificance of possible differences between sub- used in 190 patients (81.5%), and other devices were
groups in the treatment effect was tested with used in 5 patients (2.1%) (Table S2 in the Supple-
interaction terms. No adjustments for multiple mentary Appendix). Additional intraarterial throm-
tests were made. All analyses were performed bolytic agents were given to 24 patients (10.3%).
with the use of the Stata/SE statistical package, Intraarterial thrombolytic agents were used
version 13.1 (StataCorp). as monotherapy in 1 of the 233 patients (0.4%).

Table 1. Baseline Characteristics of the 500 Patients.*
Intervention Control
Characteristic (N = 233) (N = 267)
Age — yr
Median 65.8 65.7
Interquartile range 54.5–76.0 55.5–76.4
Male sex — no. (%) 135 (57.9) 157 (58.8)
NIHSS score†
Median (interquartile range) 17 (14–21) 18 (14–22)
Range 3–30 4–38
Location of stroke in left hemisphere — no. (%) 116 (49.8) 153 (57.3)
History of ischemic stroke — no. (%) 29 (12.4) 25 (9.4)
Atrial fibrillation — no. (%) 66 (28.3) 69 (25.8)
Diabetes mellitus — no. (%) 34 (14.6) 34 (12.7)
Prestroke modified Rankin scale score — no. (%)‡
0 190 (81.5) 214 (80.1)
1 21 (9.0) 29 (10.9)
2 12 (5.2) 13 (4.9)
<2 10 (4.3) 11 (4.1)
Systolic blood pressure — mm Hg§ 146±26.0 145±24.4
Treatment with IV alteplase — no. (%) 203 (87.1) 242 (90.6)
Time from stroke onset to start of IV alteplase — min
Median 85 87
Interquartile range 67–110 65–116
ASPECTS — median (interquartile range)¶ 9 (7–10) 9 (8–10)
Intracranial arterial occlusion — no./total no. (%)‖
Intracranial ICA 1/233 (0.4) 3/266 (1.1)
ICA with involvement of the M1 middle cerebral artery segment 59/233 (25.3) 75/266 (28.2)
M1 middle cerebral artery segment 154/233 (66.1) 165/266 (62.0)
M2 middle cerebral artery segment 18/233 (7.7) 21/266 (7.9)
A1 or A2 anterior cerebral artery segment 1/233 (0.4) 2/266 (0.8)
Extracranial ICA occlusion — no./total no. (%)‖** 75/233 (32.2) 70/266 (26.3)
Time from stroke onset to randomization — min††
Median 204 196
Interquartile range 152–251 149–266
Time from stroke onset to groin puncture — min
Median 260 NA
Interquartile range 210–313
* The intervention group was assigned to intraarterial treatment plus usual care, and the control group was assigned to
usual care alone. Plus–minus values are means ±SD. ICA denotes internal carotid artery, IV intravenous, and NA not
applicable.
† Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating
more severe neurologic deficits. The NIHSS is a 15-item scale, and values for 30 of the 7500 items were missing
(0.4%). The highest number of missing items for a single patient was 6.
‡ Scores on the modified Rankin scale of functional disability range from 0 (no symptoms) to 6 (death). A score of 2 or
less indicates functional independence.
§ Data on systolic blood pressure at baseline were missing for one patient assigned to the control group.
¶ The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of stroke.
Scores ranges from 0 to 10, with higher scores indicating fewer early ischemic changes. Scores were not available for
four patients assigned to the control group: noncontrast computed tomography was not performed in one patient,
and three patients had strokes in the territory of the anterior cerebral artery.
‖ Vessel imaging was not performed in one patient in the control group, so the level of occlusion was not known.
** Extracranial ICA occlusions were reported by local investigators.
†† Data were missing for two patients in the intervention group.

No intervention was given in 37 patients (15.9%) tion. The adjusted common odds ratio was 1.67
(Fig. S1 in the Supplementary Appendix). (95% confidence interval [CI], 1.21 to 2.30) (Ta-
ble 2). The shift toward better outcomes in favor
Primary Outcome of the intervention was consistent for all catego-
Data on the primary outcome (the score on the ries of the modified Rankin scale, except for
modified Rankin scale at 90 days) were com- death (Fig. 1). The absolute between-group dif-
plete. There was a shift in the distribution of the ference in the proportion of patients who were
primary-outcome scores in favor of the interven- functionally independent (modified Rankin score,
Table 2. Primary and Secondary Outcomes and Treatment Effects.*
Intervention Control Effect Unadjusted Adjusted

Outcome (N = 233) (N = 267) Variable Value (95% CI) Value (95% CI)†
Primary outcome: modified Rankin scale 3 (2 to 5) 4 (3 to 5) Common 1.66 (1.21 to 2.28) 1.67 (1.21 to 2.30)
score at 90 days — median odds ratio
(interquartile range)
Secondary outcomes
Clinical outcomes
Modified Rankin score of 0 or 1 27 (11.6) 16 (6.0) Odds ratio 2.06 (1.08 to 3.92) 2.07 (1.07 to 4.02)
at 90 days — no. (%)
Modified Rankin score of 0–2 76 (32.6) 51 (19.1) Odds ratio 2.05 (1.36 to 3.09) 2.16 (1.39 to 3.38)
Modified Rankin score of 0–3 119 (51.1) 95 (35.6) Odds ratio 1.89 (1.32 to 2.71) 2.03 (1.36 to 3.03)
NIHSS score after 24 hr — median 13 (6 to 20) 16 (12 to 21) Beta 2.6 (1.2 to 4.1) 2.3 (1.0 to 3.5)
(interquartile range)‡
NIHSS score at 5–7 days or dis- 8 (2 to 17) 14 (7 to 18) Beta 3.2 (1.7 to 4.7) 2.9 (1.5 to 4.3)
charge — median (inter-
quartile range)§
Barthel index of 19 or 20 at 90 days 99/215 (46.0) 73/245 (29.8) Odds ratio 2.0 (1.3 to 2.9) 2.1 (1.4 to 3.2)
— no./total no. (%)¶
EQ-5D score at 90 days — median 0.69 (0.33 to 0.85) 0.66 (0.30 to 0.81) Beta 0.08 (0.00 to 0.15) 0.06 (−0.01 to 0.13)
(interquartile range)‖
Imaging outcomes
No intracranial occlusion on fol- 141/187 (75.4) 68/207 (32.9) Odds ratio 6.27 (4.03 to 9.74) 6.88 (4.34 to 10.94)
low-up CT angiography —
no./total no. (%)**
Final infarct volume on CT††
Patients evaluated — no. (%) 138 (59.2) 160 (59.9)
Median (interquartile range) — 49 (22 to 96) 79 (34 to 125) Beta 20 (3 to 36) 19 (3 to 34)
ml
* CT denotes computed tomography.

† Values were adjusted for age; NIHSS score at baseline; time from stroke onset to randomization; status with respect to previous stroke,
atrial fibrillation, and diabetes mellitus; and occlusion of the internal-carotid-artery terminus (yes vs. no).
‡ The NIHSS score was determined for survivors only. The score was not available for 20 patients: 12 died before assessment was finished,
and 8 had missing scores.
§ The NIHSS score was determined for survivors only. The score was not available for 74 patients: 56 died before assessment was finished,
and 18 had missing scores.
¶ The Barthel index is an ordinal scale for measuring performance of activities of daily living. Scores ranges from 0 to 20, with 0 indicating
severe disability and 19 or 20 indicating no disability that interferes with daily activities.
‖ The EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) is a standardized instrument for the measurement of health status.
Scores range from −0.33 to 1.00, with higher scores indicating a better quality of life.
** Data for follow-up CT angiography were not available for 106 patients owing to imminent death or death (24 patients), decreased kidney
function (13 patients), insufficient scan quality (5 patients), and other reasons (64 patients).
†† Data for final infarct volume on noncontrast CT (performed at 3 to 9 days) were missing for 202 patients because of death (52 patients),
hemicraniectomy (21 patients), technical errors with automated assessment (14 patients), or insufficient scan quality (5 patients) or be-
cause CT was not performed for reasons other than death (110 patients).

0 to 2) was 13.5 percentage points (95% CI, 5.9 to

21.2) in favor of the intervention (32.6% vs. 19.1%), Modified Rankin Scale Score
with an adjusted odds ratio of 2.16 (95% CI, 1.39 0 1 2 3 4 5 6
No symptoms Death
to 3.38) (Table 2).
Secondary Outcomes Intervention

3 9 21 18 22 6 21
(N=233)
All clinical and imaging secondary outcomes fa-
vored the intervention (Table 2, and Table S3 in
Control
the Supplementary Appendix). The NIHSS score (N=267)
6 13 16 30 12 22
after 5 to 7 days was, on average, 2.9 points (95%
CI, 1.5 to 4.3) lower in the intervention group 0 20 40 60 80 100
than in the control group. Patients (%)
Data on recanalization after 24 hours, as- Figure 1. Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat
sessed by means of CTA, were available for 394 Population.
patients. An absence of residual occlusion at the Shown is the distribution of scores on the modified Rankin scale. Scores
target site was more common in the intervention range from 0 to 6, with 0 indicating no symptoms, 1 no clinically signifi-
group (141 of 187 patients [75.4%]) than in the cant disability, 2 slight disability (patient is able to look after own affairs
control group (68 of 207 patients [32.9%]) (Table without assistance but is unable to carry out all previous activities), 3 mod-
erate disability (patient requires some help but is able to walk unassisted),
2). Data on infarct volume were available for 298 4 moderately severe disability (patient is unable to attend to bodily needs
of 500 patients; the between-group difference in without assistance and unable to walk unassisted), 5 severe disability (pa-
volume (19 ml; 95% CI, 3 to 34) favored the in- tient requires constant nursing care and attention), and 6 death. There was
tervention group (Table 2). Good reperfusion a significant difference between the intervention group and the control
(modified TICI score, 2b or 3) was achieved in 115 group in the overall distribution of scores in an analysis with univariable
ordinal regression (common odds ratio, 1.66; 95% CI, 1.21 to 2.28), as well
of 196 patients (58.7%) in the intervention group as after adjustment of the treatment effect for age; National Institutes of
(Table S4 in the Supplementary Appendix). Health Stroke Scale score at baseline; time from stroke onset to random-
ization; status with respect to previous stroke, atrial fibrillation, and diabe-
Safety tes mellitus; and occlusion of the internal-carotid-artery terminus (yes vs.
There was no significant between-group differ- no) in an analysis with multivariable regression (adjusted common odds
ratio, 1.67; 95% CI, 1.21 to 2.30). In the control group, only 1 patient
ence in the occurrence of serious adverse events (0.4%) had a modified Rankin score of 0.
during the 90-day follow-up period (P =
0.31)
(Table 3). However, 13 of the 233 patients (5.6%)
in the intervention group had clinical signs of a
new ischemic stroke in a different vascular terri- estimate for treatment effect in the subgroup
tory within 90 days, whereas only 1 of the 267 with ASPECTS of 0 to 4 was close to unity but with
patients (0.4%) in the control group did so. There a wide confidence interval (adjusted common
was no significant difference in mortality at 7, odds ratio, 1.09; 95% CI, 0.14 to 8.46).
30, or 90 days of follow-up.
Procedure-related complications in the inter- Discussion
vention group included embolization into new
territories outside the target downstream terri- Our results show that patients with acute ischemic
tory of the occluded vessel in 20 of the 233 pa- stroke caused by a proximal intracranial arterial
tients (8.6%), procedure-related vessel dissec- occlusion of the anterior circulation have a ben-
tions in 4 patients (1.7%), and vessel perforations efit with respect to functional recovery when in-
in 2 patients (0.9%). traarterial treatment is administered within 6 hours
after stroke onset. This treatment leads to a clin-
Subgroup Analyses ically significant increase in functional indepen-
There were no significant interactions between dence in daily life by 3 months, without an in-
subgroups and treatment effect. The treatment crease in mortality.
effect remained consistent in all predefined sub- Our findings stand in clear distinction to those
groups, including those based on age (<80 years of recent randomized, controlled trials that failed
or ≥80 years), NIHSS score (2 to 15, 16 to 19, or to show a benefit of intraarterial treatment.12,13
≥20), and ASPECTS (0 to 4, 5 to 7, or 8 to 10) (Fig. Approximately 90% of patients in each treatment
S2 in the Supplementary Appendix). The point group of MR CLEAN received intravenous al-

have led to the inclusion of more patients who

Table 3. Safety Variables and Serious Adverse Events within 90 Days
after Randomization. had a favorable response to intravenous alteplase
than in MR CLEAN, which had a median time
Intervention Control from the start of intravenous alteplase to random-
Variable (N = 233) (N = 267)
ization that was considerably longer than the
no. of patients (%)
maximum time in the IMS III trial. It is likely that
Safety variables intraarterial treatment will not alter the natural
Death history of acute ischemic stroke in the absence of
Within 7 days 27 (11.6) 33 (12.4) a proximal arterial occlusion. Unlike the IMS III
Within 30 days 44 (18.9) 49 (18.4) trial and the Local versus Systemic Thrombolysis
Hemicraniectomy 14 (6.0) 13 (4.9)
for Acute Ischemic Stroke (SYNTHESIS Expan-
sion) trial,13 MR CLEAN required a radiologi-
Serious adverse events*
cally proven intracranial occlusion for study eli-
Any serious adverse event 110 (47.2) 113 (42.3) gibility. When the IMS III trial was designed, the
Symptomatic intracerebral hemorrhage availability of CTA was still limited, and the
Any type 18 (7.7) 17 (6.4) presence of a proximal arterial occlusion was
Parenchymal hematoma† therefore uncertain in a subgroup of patients in
Type 1 0 2 (0.7) that trial (47% of the study population).12
Our study benefited from the widespread
Type 2 14 (6.0) 14 (5.2)
availability of retrievable stents, which were used
Hemorrhagic infarction‡
in 82% of the patients in the intervention group.
Type 1 1 (0.4) 0 These devices were recently shown to be supe-
Type 2 1 (0.4) 1 (0.4) rior to the first-generation Merci device for both
Subarachnoid hemorrhage 2 (0.9) 0 revascularization and clinical outcomes.27,28
New ischemic stroke in a different 13 (5.6) 1 (0.4) Previous trials have been criticized because
vascular territory§ investigators could have treated many patients
Progressive ischemic stroke 46 (19.7) 47 (17.6) outside the trials. This was reflected in the low
Pneumonia 25 (10.7) 41 (15.4) recruitment rates in the IMS III trial and the
Mechanical Retrieval and Recanalization of
Other infection 16 (6.9) 9 (3.4)
Stroke Clots Using Embolectomy (MR RESCUE)
Cardiac ischemia 1 (0.4) 4 (1.5)
trial,14 which had an average enrollment of 1 to
Extracranial hemorrhage 0 2 (0.7) 2 patients per center per year. In contrast, all
Allergic reaction 1 (0.4) 0 stroke centers in the Netherlands that provided
Other complication 22 (9.4) 33 (12.4) intraarterial treatment during the execution of
MR CLEAN participated in the trial, and from
* Only first events of a type are listed. Patients having multiple events of one 2013 onward, reimbursement by insurance com-
type were counted once.
† For parenchymal hematoma, type 1 was defined by one or more blood clots panies required participation in a trial.
in 30% or less of the infarcted area with a mild space-occupying effect, and Our trial had several limitations. First, ran-
type 2 was defined by blood clots in more than 30% of the infarcted area with domization was slightly unbalanced, resulting in
a clinically significant space-occupying effect.
‡ For hemorrhagic infarction, type 1 was defined by small petechiae along the more patients in the control group than in the
margins of the infarction, and type 2 was defined by more confluent petechiae intervention group. This imbalance was the re-
within the infarction area. sult of block size and multiple stratifications.
§ P<0.001.
Second, the reperfusion rate in MR CLEAN
(modified TICI score of 2b or 3, 58.7%) was
teplase, making our cohort similar to that in the relatively low as compared with the rates in re-
Interventional Management of Stroke (IMS) III cent case series, which were 80% or higher.29,30
trial, in which intravenous alteplase alone was However, the rate of a modified TICI score of 2b
compared with intravenous alteplase plus intra- or 3 in the IMS III trial was 23 to 44%, depend-
arterial treatment.12 However, in the IMS III ing on the location of the occlusion. The two
trial, patients had to be enrolled and undergo recently published phase 2 trials of retrievable
randomization within 40 minutes after the start stents showed reperfusion rates of 61% and
of intravenous alteplase. This requirement may 86%, but these rates were based on end points

of a modified TICI score of 2a to 3 and a Throm- prognosis at baseline. The advantage is a wide
bolysis in Myocardial Ischemia score of 2 or 3, generalizability of our results.
respectively.27,28 Differentiation between a modi- Finally, although the outcome assessment was
fied TICI score of 2a and a score of 2b or 3 is blinded, patients were aware of the treatment-
difficult when lateral DSA images are not avail- group assignments, and this might have influ-
able. This applied to 15 patients in MR CLEAN, enced their opinions about their health and func-
who were subsequently given a modified TICI tional condition. However, modified Rankin scores
score of 2a. This may have led to an underesti- at 90 days were based on assessment by reviewers
mation of the actual reperfusion rate among who were unaware of the treatment-group assign-
patients with a modified TICI score of 2b or 3. ments, to avoid biased assessments, and the re-
Third, despite the positive result of this trial, sults of blinded assessments of neuroimaging
almost 9% of the patients in the intervention corroborated our findings.
group had embolization into new vascular ter- In conclusion, we found that intraarterial
ritories on DSA. A total of 30 patients (13%) treatment in patients with acute ischemic stroke
assigned to intraarterial treatment also under- caused by a proximal intracranial occlusion of
went a simultaneous second revascularization the anterior circulation was effective and safe
procedure (acute cervical carotid stenting), and when administered within 6 hours after stroke
this complexity needs to be considered when onset.
interpreting our trial results. Supported by the Dutch Heart Foundation and by unrestricted
Fourth, a relatively low proportion of patients grants from AngioCare Covidien/ev3, Medac/Lamepro, and Pen-
in the control group had a modified Rankin score umbra.
Dr. Yoo reports receiving grant support from Penumbra; Dr.
of 0 to 2 at the 90-day follow-up assessment. Brouwer, lecture fees and fees for trial management from
This may be explained by our broad inclusion Stryker, lecture fees and fees for proctoring from BALT, lecture
criteria, which allowed contraindications for fees from Toshiba, teaching fees and fees for research and devel-
opment from Codman/DePuy Synthes, and teaching fees from
intravenous alteplase, nonresponse to intravenous Sequent Medical; Dr. de Vries, consulting fees from Stryker and
alteplase, octogenarians and even nonagenarians, grant support from Covidien/ev3; and Dr. René van den Berg,
and patients with extracranial internal-carotid- consulting fees from Codman/DePuy Synthes. No other poten-
tial conflict of interest relevant to this article was reported.
artery occlusions or dissections. Taken together, Disclosure forms provided by the authors are available with
this resulted in a population with a relatively poor the full text of this article at NEJM.org.
Appendix
The authors’ full names and academic degrees are as follows: Olvert A. Berkhemer, M.D., Puck S.S. Fransen, M.D., Debbie Beumer,
M.D., Lucie A. van den Berg, M.D., Hester F. Lingsma, Ph.D., Albert J. Yoo, M.D., Wouter J. Schonewille, M.D., Jan Albert Vos, M.D.,
Ph.D., Paul J. Nederkoorn, M.D., Ph.D., Marieke J.H. Wermer, M.D., Ph.D., Marianne A.A. van Walderveen, M.D., Ph.D., Julie Staals,
M.D., Ph.D., Jeannette Hofmeijer, M.D., Ph.D., Jacques A. van Oostayen, M.D., Ph.D., Geert J. Lycklama à Nijeholt, M.D., Ph.D., Jelis
Boiten, M.D., Ph.D., Patrick A. Brouwer, M.D., Bart J. Emmer, M.D., Ph.D., Sebastiaan F. de Bruijn, M.D., Ph.D., Lukas C. van Dijk,
M.D., L. Jaap Kappelle, M.D., Ph.D., Rob H. Lo, M.D., Ewoud J. van Dijk, M.D., Ph.D., Joost de Vries, M.D., Ph.D., Paul L.M. de Kort,
M.D., Ph.D., Willem Jan J. van Rooij, M.D., Ph.D., Jan S.P. van den Berg, M.D., Ph.D., Boudewijn A.A.M. van Hasselt, M.D., Leo A.M.
Aerden, M.D., Ph.D., René J. Dallinga, M.D., Marieke C. Visser, M.D., Ph.D., Joseph C.J. Bot, M.D., Ph.D., Patrick C. Vroomen, M.D.,
Ph.D., Omid Eshghi, M.D., Tobien H.C.M.L. Schreuder, M.D., Roel J.J. Heijboer, M.D., Koos Keizer, M.D., Ph.D., Alexander V. Tiel-
beek, M.D., Ph.D., Heleen M. den Hertog, M.D., Ph.D., Dick G. Gerrits, M.D., Renske M. van den Berg-Vos, M.D., Ph.D., Giorgos B.
Karas, M.D., Ewout W. Steyerberg, M.D., Ph.D., H. Zwenneke Flach, M.D., Henk A. Marquering, Ph.D., Marieke E.S. Sprengers, M.D.,
Ph.D., Sjoerd F.M. Jenniskens, M.D., Ph.D., Ludo F.M. Beenen, M.D., René van den Berg, M.D., Ph.D., Peter J. Koudstaal, M.D., Ph.D.,
Wim H. van Zwam, M.D., Ph.D., Yvo B.W.E.M. Roos, M.D., Ph.D., Aad van der Lugt, M.D., Ph.D., Robert J. van Oostenbrugge, M.D.,
Ph.D., Charles B.L.M. Majoie, M.D., Ph.D., and Diederik W.J. Dippel, M.D., Ph.D.
The authors’ affiliations are as follows: the Departments of Radiology (O.A.B., H.A.M., M.E.S.S., L.F.M.B., R.B., C.B.L.M.M.), Neu-
rology (L.A.B., P.J.N., Y.B.W.E.M.R.), and Biomedical Engineering and Physics (H.A.M.), Academic Medical Center, the Departments
of Neurology (M.C.V.) and Radiology (J.C.J.B.), VU Medical Center, and the Departments of Neurology (R.M.B.-V.) and Radiology
(G.B.K.), Sint Lucas Andreas Hospital, Amsterdam, the Departments of Neurology (O.A.B., P.S.S.F., D.B., P.J.K., D.W.J.D.), Radiology
(P.S.S.F., P.A.B., B.J.E., A.L.), and Public Health (H.F.L., E.W.S.), Erasmus University Medical Center, Rotterdam, the Department of
Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht (D.B., J.S., R.J.O.) and the Depart-
ment of Radiology, Maastricht University Medical Center (W.H.Z.), Maastricht, the Departments of Neurology (W.J.S.) and Radiology
(J.A.V.), Sint Antonius Hospital, Nieuwegein, the Departments of Neurology (M.J.H.W.) and Radiology (M.A.A.W.), Leiden University
Medical Center, Leiden, the Departments of Neurology (J.H.) and Radiology (J.A.O.), Rijnstate Hospital, Arnhem, the Departments of
Radiology (G.J.L.N.) and Neurology (J.B.), MC Haaglanden, and the Departments of Neurology (S.F.B.) and Radiology (L.C.D.), HAGA
Hospital, The Hague, the Departments of Neurology (L.J.K.) and Radiology (R.H.L.), University Medical Center Utrecht, Utrecht, the
Departments of Neurology (E.J.D.) and Neurosurgery (J.V.), and Radiology (S.F.M.J.), Radboud University Medical Center, Nijmegen,
the Departments of Neurology (P.L.M.K.) and Radiology (W.J.J.R.), Sint Elisabeth Hospital, Tilburg, the Departments of Neurology

(J.S.P.V.) and Radiology (B.A.A.M.H., H.Z.F.), Isala Klinieken, Zwolle, the Departments of Neurology (L.A.M.A.) and Radiology (R.J.D.),
Reinier de Graaf Gasthuis, Delft, the Departments of Neurology (P.C.V.) and Radiology (O.E.), University Medical Center Groningen,
Groningen, the Departments of Neurology (T.H.C.M.L.S.) and Radiology (R.J.J.H.), Atrium Medical Center, Heerlen, the Departments
of Neurology (K.K.) and Radiology (A.V.T.), Catharina Hospital, Eindhoven, and the Departments of Neurology (H.M.H.) and Radiol-
ogy (D.G.G.), Medical Spectrum Twente, Enschede — all in the Netherlands; and the Department of Radiology, Massachusetts Gen-
eral Hospital, Boston (A.J.Y.).
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edi t or i a l
Interventional Thrombectomy for Major Stroke —

A Step in the Right Direction
Werner Hacke, M.D., Ph.D.
Intravenous thrombolytic therapy is the only sible, and use modern thrombectomy devices.9
proven treatment for acute ischemic stroke, but The results of the first such trial now appear in
its use is limited by a brief time window of up to the Journal.10 The Multicenter Randomized Clini-
4.5 hours after the onset of symptoms1 and a cal Trial of Endovascular Treatment of Acute Is-
recanalization rate of less than 50%. Large clots chemic Stroke in the Netherlands (MR CLEAN)
in vessels such as the distal internal carotid ar- included patients with severe stroke and proxi-
tery or the first segment of the middle cerebral mal-vessel occlusion. Almost 90% of the pa-
artery respond poorly to intravenous thromboly- tients received intravenous thrombolysis first,
sis.2 The need for a treatment for patients who and almost all the devices used were of the
do not have a good response to intravenous retrievable-stent variety, which have a track record
treatment alone remains pressing. of successful recanalization. Thrombectomy im-
On the basis of compelling anecdotal experi- proved outcomes, with an absolute difference of
ence, stroke specialists had hoped that transvas- 13.5 percentage points in the rate of functional
cular recanalization would be an alternative to or independence, as assessed with the use of the
a follow-on treatment after intravenous therapy modified Rankin scale. Most other prespecified
for severe strokes with large-vessel occlusion. clinical end points and the rate of recanalization
However, three randomized, controlled trials of favored transvascular treatment, although the re-
intraarterial treatment, all reported in the Journal, canalization rate with transvascular treatment
have had negative or ambiguous results.3-5 These was a little lower than expected. There were no
trials were criticized for their use of older re- significant differences in mortality or the occur-
canalization devices, which were associated with rence of symptomatic intracranial hemorrhage.
lower recanalization rates than those found with Readers may wonder how the trialists from
newer devices such as retrievable stents6; for the a country with only 16.8 million inhabitants
long interval between the onset of stroke and succeeded in enrolling 500 patients in just over
intervention; and for disappointingly low recruit- 3 years, whereas other trials from much larger
ment rates, which suggested that many suitable regions with similarly advanced medical systems
patients had been treated outside the trials. struggled with recruitment. The well-established
Moreover, subgroup analyses suggested that network of investigator-initiated stroke trials in
there was a benefit for patients treated in shorter the Netherlands contributed to the success of
time windows.7,8 Perhaps most important, two the trial, as did the relatively short distances be-
of the trials did not require evidence of an oc- tween the 15 intervention centers in the coun-
cluded vessel before randomization, thereby mak- try. In my view, however, the most important
ing intracerebral treatment futile from the start. reason for success was the decision by the Dutch
The lessons of these studies were that trials government to pay for the use of thrombectomy
of intraarterial treatment should enroll patients devices only in the context of a randomized trial,
with severe strokes, have proof of proximal ves- thereby precluding treatment outside the trial.
sel occlusion, initiate treatment as early as pos- This policy may be difficult to implement in

editorial
other health systems, but imagine what prog- bolysis with alteplase for acute ischaemic stroke: a meta-analysis
of individual patient data from randomised trials. Lancet 2014
ress the medical-device field would see if this August 5 (Epub ahead of print).
strategy were the rule. 2. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R,
Finally, what does this first positive throm- Deuschl G, Jansen O. The importance of size: successful recan-
alization by intravenous thrombolysis in acute anterior stroke
bectomy trial mean for interventional treatment? depends on thrombus length. Stroke 2011;42:1775-7.
Is there any doubt left, or should thrombectomy 3. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular
now become the new standard treatment for se- therapy after intravenous t-PA versus t-PA alone for stroke. N Engl
J Med 2013;368:893-903. [Erratum, N Engl J Med 2013;368:1265.]
vere stroke with proximal large-vessel occlusion 4. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treat-
up to 6 hours after stroke onset? Several similar ment for acute ischemic stroke. N Engl J Med 2013;368:904-13.
trials are ongoing; it is premature to conclude 5. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging
selection and endovascular treatment for ischemic stroke. N Engl
that there is no longer equipoise regarding J Med 2013;368:914-23.
thrombectomy. We need and will get results 6. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration
from other well-designed trials, not only to con- device versus the Merci Retriever in patients with acute ischaemic
stroke (SWIFT): a randomised, parallel-group, non-inferiority
firm or refute the results of MR CLEAN but also trial. Lancet 2012;380:1241-9.
to look at effects in subgroups (according to 7. Khatri P, Yeatts SD, Mazighi M, et al. Time to angiographic
stroke severity, occlusion site, or time to treat- reperfusion and clinical outcome after acute ischaemic stroke:
an analysis of data from the Interventional Management of
ment initiation), for which most single trials are Stroke (IMS III) phase 3 trial. Lancet Neurol 2014;13:567-74.
underpowered. MR CLEAN is the first step in 8. Mazighi M, Chaudhry SA, Ribo M, et al. Impact of onset-to-
the right direction. reperfusion time on stroke mortality: a collaborative pooled
analysis. Circulation 2013;127:1980-5.
Disclosure forms provided by the author are available with the 9. Hacke W, Furlan AJ. (Here comes that) razors edge — endo-
full text of this article at NEJM.org. vascular stroke therapy: the end, or only the beginning? Int J
Stroke 2013;8:331-3.
From the Department of Neurology, University Hospital Heidel-
10. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized
berg, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
trial of intraarterial treatment for acute ischemic stroke. N Engl
This article was published on December 17, 2014, at NEJM.org. J Med. DOI: 10.1056/NEJMoa1411587.
1. Emberson J, Lees KR, Lyden P, et al. Effect of treatment de- DOI: 10.1056/NEJMe1413346
lay, age, and stroke severity on the effects of intravenous throm- Copyright © 2014 Massachusetts Medical Society.

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for
acute ischemic stroke. N Engl J Med. DOI: 10.1056/NEJMoa1411587
Supplement)to)“A"randomized*trial*of!
intra#arterial!treatment'for'acute'
ischemic'stroke”!
List!of!MR!CLEAN!investigators!and!affiliations!.........................................................................!2!
Acknowledgements!...................................................................................................................!4!
Data!monitoring!and!safety!board:!.......................................................................................!4!
Advisory!board:!.....................................................................................................................!4!
Research!nurses!/!local!trial!coordinators:!............................................................................!4!
PhD!/!Medical!students:!........................................................................................................!4!
Additional!Methods!..................................................................................................................!6!
Intervention!..........................................................................................................................!6!
Clinical!&!radiological!assessment!........................................................................................!6!
Trial!organization!..................................................................................................................!6!
Supplemental!Results!and!Subgroup!analyses!..........................................................................!8!
Figure!S!1!CONSORT!flow!diagram!............................................................................................!9!
Figure!S!2!Subgroup!analyses!..................................................................................................!10!
Table!S!1!Overview!of!additional!clinical!characteristics!.........................................................!11!
Table!S!2!Number!of!patients!treated!and!treatment!details!by!center!.................................!12!
Table!S!3!Definition!and!distribution!of!modified!Arterial!Occlusive!Lesion!(mAOL)!score!....!13!
Table!S!4!Definition!and!distribution!of!mTICI!score!...............................................................!14!
Table!S!5!Breakdown!of!the!primary!outcome!and!treatment!effect!.....................................!15!
Table!S!6!Number!of!patients!with!imputed!values!................................................................!16!
! !
! 1!
List%of%MR%CLEAN%investigators%and%affiliations%%
Olvert!A.!Berkhemer,!M.D.,*,1,2!Puck!S.S.!Fransen,!M.D.,*,2,3!Debbie!Beumer,!M.D.,*2,4!Lucie!A.!
van!den!Berg,!M.D.,5!Hester!F.!Lingsma,!M.D.,!Ph.D.,7!Albert!J.!Yoo,!M.D.,8!Wouter!J.!
Schonewille,!M.D.,9!Jan!Albert!Vos,!M.D.,!Ph.D.,10!Paul!J.!Nederkoorn,!M.D.,!Ph.D.,5!Marieke!
J.H.!Wermer,!M.D.,!Ph.D.,11!Marianne!A.A.!van!Walderveen,!M.D.,!Ph.D.,12!Julie!Staals,!M.D.,!
Ph.D.,4!Jeannette!Hofmeijer,!M.D.,!Ph.D.,13!Jacques!A.!van!Oostayen,!M.D.,!Ph.D.,14!Geert!J.!
Lycklama!à!Nijeholt,!M.D.,!Ph.D.,15!Jelis!Boiten,!M.D.,!Ph.D.,16!Patrick!A.!Brouwer,!M.D.,3!Bart!
J.!Emmer,!M.D.,!Ph.D.,3!Sebastiaan!F.!de!Bruijn,!M.D.,!Ph.D.,17!Lukas!C.!van!Dijk,!M.D.,18!L.!
Jaap!Kappelle,!M.D.,!Ph.D.,19!Rob!H.!Lo,!M.D.,20!Ewoud!J.!van!Dijk,!M.D.,!Ph.D.,21!Joost!de!
Vries,!M.D.,!Ph.D.,22!Paul!L.M.!de!Kort,!M.D.,!Ph.D.,23!Willem!Jan!J.!van!Rooij,!M.D.,!Ph.D.,24!
Jan!S.P.!van!den!Berg,!M.D.,!Ph.D.,25!Boudewijn!A.A.M.!van!Hasselt,!M.D.,26!Leo!A.M.!Aerden,!
M.D.,!Ph.D.,27!René!J.!Dallinga,!M.D.,28!Marieke!C.!Visser,!M.D.,!Ph.D.,29!Joseph!C.J.!Bot,!M.D.,!
Ph.D.,30!Patrick!C.!Vroomen,!M.D.,!Ph.D.,31!Omid!Eshghi,!M.D.,!32!Tobien!H.C.M.L.!Schreuder,!
M.D.,33!Roel!J.J.!Heijboer,!M.D.,34!Koos!Keizer,!M.D.,!Ph.D.,35!Alexander!V.!Tielbeek,!M.D.,!
Ph.D.,36!Heleen!M.!den!Hertog,!M.D.,!Ph.D.,37!Dick!G.!Gerrits,!M.D.,!38!Renske!M.!van!den!
Berg#Vos,!M.D.,!Ph.D.,39!Giorgos!B.!Karas,!M.D.,40!Ewout!W.!Steyerberg,!M.D.,!Ph.D.,7!H.!
Zwenneke!Flach,!M.D.,26!Henk!A.!Marquering!Ph.D.,41,1!Marieke!E.S.!Sprengers,!M.D.,!Ph.D.,1!
Sjoerd!F.M.!Jenniskens,!M.D.,!Ph.D.,42!Ludo!F.M.!Beenen,!M.D.,1!René!van!den!Berg,!M.D.,!
Ph.D.,1!Peter!J.!Koudstaal,!M.D.,!Ph.D.,2!Wim!H.!van!Zwam,!M.D.,!Ph.D.,#,6!Yvo!B.W.E.M.!
Roos,!M.D.,!Ph.D.,!#,5!Aad!van!der!Lugt,!M.D.,!Ph.D.,!#,3!Robert!J.!van!Oostenbrugge,!M.D.,!
Ph.D.,!#,4!Charles!B.L.M.!Majoie,!M.D.,!Ph.D.,!#,1!and!Diederik!W.J.!Dippel,!M.D.,!Ph.D.!#,2!
*!Berkhemer,!Fransen!and!Beumer!contributed!equally.!
#!van!Zwam,!Roos,!van!der!Lugt,!van!Oostenbrugge,!Majoie!and!Dippel!contributed!equally.!
1!Department!of!Radiology,!Academic!Medical!Center!Amsterdam,!the!Netherlands;!2!
Department!of!Neurology,!Erasmus!MC!University!Medical!Center!Rotterdam,!the!
Netherlands;!3!Department!of!Radiology,!Erasmus!MC!University!Medical!Center!Rotterdam,!
the!Netherlands;!4!Department!of!Neurology,!Maastricht!University!Medical!Center!and!
Cardiovascular!Research!Institute!Maastricht!(CARIM),!the!Netherlands;!5!Department!of!
Neurology,!Academic!Medical!Center!Amsterdam,!the!Netherlands;!6!Department!of!
Radiology,!Maastricht!University!Medical!Center,!the!Netherlands;!7!Department!of!Public!
Health,!Erasmus!MC!University!Medical!Center!Rotterdam,!the!Netherlands;!8!Department!
of!Radiology,!Massachusetts!General!Hospital,!Boston,!United!States!of!America;!9!
! 2!
Department!of!Neurology,!Sint!Antonius!Hospital,!Nieuwegein,!the!Netherlands;!10!
Department!of!Radiology,!Sint!Antonius!Hospital,!Nieuwegein,!the!Netherlands;!11!
Department!of!Neurology,!Leiden!University!Medical!Center,!the!Netherlands;!12!
Department!of!Radiology,!Leiden!University!Medical!Center,!the!Netherlands;!13!
Department!of!Neurology,!Rijnstate!Hospital,!Arnhem,!the!Netherlands;!14!Department!of!
Radiology,!Rijnstate!Hospital,!Arnhem,!the!Netherlands;!15!Department!of!Radiology,!MC!
Haaglanden,!the!Hague,!the!Netherlands;!16!Department!of!Neurology,!MC!Haaglanden,!the!
Hague,!the!Netherlands;!17!Department!of!Neurology,!HAGA!Hospital,!the!Hague,!the!
Netherlands;!18!Department!of!Radiology,!HAGA!Hospital,!the!Hague,!the!Netherlands;!19!
Department!of!Neurology,!University!Medical!Center!Utrecht,!the!Netherlands;!20!
Department!of!Radiology,!University!Medical!Center!Utrecht,!the!Netherlands;!21!
Department!of!Neurology,!Radboud!University!Medical!Center,!Nijmegen,!the!Netherlands;!
22!Department!of!Neurosurgery,!Radboud!University!Medical!Center,!Nijmegen,!the!
Netherlands;!23!Department!of!Neurology,!Sint!Elisabeth!Hospital,!Tilburg,!the!Netherlands;!
24!Department!of!Radiology,!Sint!Elisabeth!Hospital,!Tilburg,!the!Netherlands;!25!
Department!of!Neurology,!Isala!Klinieken,!Zwolle,!the!Netherlands;!26!Department!of!
Radiology,!Isala!Klinieken,!Zwolle,!the!Netherlands;!27!Department!of!Neurology,!Reinier!de!
Graaf!Gasthuis,!Delft,!the!Netherlands;!28!Department!of!Radiology,!Reinier!de!Graaf!
Gasthuis,!Delft,!the!Netherlands;!29!Department!of!Neurology,!VU!Medical!Center,!
Amsterdam,!the!Netherlands;!30!Department!of!Radiology,!VU!Medical!Center,!Amsterdam,!
the!Netherlands;!31!Department!of!Neurology,!University!Medical!Center!Groningen,!the!
Netherlands;!32!Department!of!Radiology,!University!Medical!Center!Groningen,!the!
Netherlands;!33!Department!of!Neurology,!Atrium!Medical!Center,!Heerlen,!the!
Netherlands;!34!Department!of!Radiology,!Atrium!Medical!Center,!Heerlen,!the!Netherlands;!
35!Department!of!Neurology,!Catharina!Hospital,!Eindhoven,!the!Netherlands;!36!
Department!of!Radiology,!Catharina!Hospital,!Eindhoven,!the!Netherlands!37!Department!of!
Neurology,!Medical!Spectrum!Twente,!Enschede,!the!Netherlands;!38!Department!of!
Radiology,!Medical!Spectrum!Twente,!Enschede,!the!Netherlands;!39!Department!of!
Neurology,!Sint!Lucas!Andreas!Hospital,!Amsterdam,!the!Netherlands;!40!Department!of!
Radiology,!Sint!Lucas!Andreas!Hospital,!Amsterdam,!the!Netherlands;!41!Department!of!
Biomedical!Engineering!and!Physics,!Academic!Medical!Center!Amsterdam,!the!Netherlands;!
42!Department!of!Radiology,!Radboud!University!Medical!Center,!Nijmegen,!the!
Netherlands!
! %
! 3!
Acknowledgements%
The!MR!CLEAN!trial!was!funded!by!the!Dutch!Heart!Foundation!and!through!unrestricted!
grants!from!AngioCare!BV,!Covidien/EV3®,!MEDAC!Gmbh/LAMEPRO!and!Penumbra!Inc.!
We!thank!the!following!persons!for!their!help!and!advise!during!the!conduct!of!MR!CLEAN:!
Data%monitoring%and%safety%board:%
Chair:!Martin!M.!Brown,!National!Hospital!for!Neurology!&!Neurosurgery,!London,!
UK.!Member:!Thomas!Liebig,!Med.!Fakultät,!Univ!Köln,!Germany,!Independent!Statistician:!
Theo!Stijnen,!Leiden!University!Medical!Center,!Leiden,!the!Netherlands!
Advisory%board:%
Tommy!Andersson,!neuro!interventionist,!Karolinska!Univeristy!Hospital,!Stockholm,!
Sweden,!Heinrich!Mattle,!neurologist,!University!hospital,!Bern,!Switzerland,!Nils!Wahlgren,!
neurologist,!Karolinska!Hospital,!Stockholm,!Sweden.!
Research%nurses%/%local%trial%coordinators:%
Esther!van!der!Heijden,!Naziha!Ghannouti;!Erasmus!MC!University!Medical!Center!
Rotterdam,!the!Netherlands.!Nadine!Fleitour,!Imke!Hooijenga;!Academic!Medical!Center!
Amsterdam,!the!Netherlands.!Corina!Puppels,!Wilma!Pellikaan;!Sint!Antonius!Hospital,!
Nieuwegein,!the!Netherlands.!Annet!Geerling;!Radboud!University!Nijmegen!Medical!
Center,!the!Netherlands.!Annemieke!Lindl#Velema;!Maastricht!University!Medical!Center,!
the!Netherlands.!Gina!van!Vemde;!Isala!Klinieken,!Zwolle,!The!Netherlands.!Ans!de!Ridder,!
Paut!Greebe,!University!Medical!Center!Utrecht,!the!Netherlands.!José!de!Bont#
Stikkelbroeck,!Sint!Elisabeth!Hospital,!Tilburg,!the!Netherlands.!Joke!de!Meris,!MC!
Haaglanden,!the!Hague,!the!Netherlands.!Kirsten!Janssen,!Leiden!University!Medical!Center,!
the!Netherlands.!Willy!Struijk,!HAGA!Hospital,!the!Hague,!the!Netherlands.!!
PhD%/%Medical%students:%
Silvan!Licher,!Nikki!Boodt,!Adriaan!Ros,!Esmee!Venema,!Ilse!Slokkers,!Raymie#Jayce!Ganpat,!
Maxim!Mulder,!Nawid!Saiedie,!Alis!Heshmatollah,!Stefanie!Schipperen,!Stefan!Vinken,!
Tiemen!van!Boxtel,!Jeroen!Koets;!Erasmus!MC!University!Medical!Center!Rotterdam,!the!
Netherlands.!!
! 4!
Merel!Boers,!Emilie!Santos,!Jordi!Borst,!Ivo!Jansen,!Manon!Kappelhof,!Marit!Lucas,!Ralph!
Geuskens,!Renan!Sales!Barros,!Roeland!Dobbe,!Marloes!Csizmadia;!Academic!Medical!
Center!Amsterdam,!the!Netherlands.! !
! 5!
Additional%Methods%
Intervention%%
The!method!of!IAT!was!left!to!the!discretion!of!the!local!interventionist.!The!same!applied!to!
the!type!of!mechanical!thrombectomy,!and!to!the!choice!for!general!anaesthesia.!
Approval!of!devices!by!the!steering!committee!was!based!on!CE!marking!or!FDA!approval,!
documented!evidence!of!safety!in!experienced!hands,!recanalization!rates!that!were!similar!
to!rates!with!other!mechanical!devices,!and!published!case!series!of!at!least!20!patients!with!
one!particular!type!of!device!in!a!representative!series!of!patients.!
Clinical%&%radiological%assessment%%
An!experienced!investigator!did!primary!outcome!assessment!by!means!of!a!telephonic!
interview.!If!a!patient!was!unavailable!or!unable!to!answer!the!questions,!a!proxy!or!
healthcare!provider!was!interviewed.!Written!reports!of!the!interviews!were!sent!to!two!
members!of!the!outcome!assessment!committee,!which!consisted!of!four!experienced!
vascular!neurologists!who!were!blinded!for!treatment!allocation.!The!score!on!the!90#day!
mRS!was!determined!after!review!of!these!telephone!interviews.!If!there!was!disagreement!
between!the!two!observers,!a!third!independent!observer,!who!was!also!blinded,!resolved!
differences!in!interpretation.!
NIHSS!assessment!was!done!by!the!treating!physicians.!They!received!web#based!video#
training.!
The!ASPECTS!is!a!10#point!quantitative!topographic!CT!scan!score!(range!0#10),!with!1!point!
subtracted!for!evidence!of!ischemic!change!in!each!defined!region.!The!mAOL!score!is!a!4#
point!scale,!original!designed!for!DSA,!but!modified!for!CTA,!which!ranges!from!grade!0!(No!
recanalization)!to!grade!3!(Complete!recanalization!of!the!primary!intracranial!occlusion).!
Trial%organization%
All!decisions!concerning!the!trial!design!and!protocol!had!to!be!approved!by!the!trial!
steering!committee,!which!met!at!least!once!a!year.!The!executive!committee,!consisting!of!
3!neuroradiologists,!3!neurologists,!and!4!PhD!students,!was!responsible!for!the!daily!
conduct!of!the!trial.!Central!and!local!research!nurses!organized!data!retrieval.!
Subcommittees!for!the!blinded!assessment!of!clinical!outcomes,!neuroimaging,!and!adverse!
events!acted!blinded!and!independently!of!the!executive!committee.!A!trial!statistician!had!
! 6!
access!to!all!data!and!prepared!unmasked!reports!for!the!data!monitoring!committee!
(DMC).!The!DMC!consisted!of!a!neurologist,!a!neuro#interventionist,!and!a!biostatistician.!
The!procedures!and!statistical!rules!for!DMC!review!are!described!in!the!trial!protocol!
(available!with!this!article!at!nejm.org).!
! !
! 7!
Supplemental%Results%and%Subgroup%analyses%
Baseline!characteristics!were!evenly!distributed!between!the!intervention!and!control!arms!
of!the!trial.!An!imbalance!existed!in!the!proportion!of!patients!with!left!hemisphere!strokes,!
which!were!more!represented!in!the!control!arm!(7.5%!absolute!difference).!Although!this!
imbalance!could!have!favored!the!intervention,!it!did!not!translate!into!differences!in!NIHSS!
scores!at!baseline.!Treatment!with!IV!alteplase!was!more!prevalent!(3.5%!absolute!
difference)!in!the!control!arm,!which!in!its!turn!may!favor!the!control!patients.!It!is!likely!
that!the!absolute!effect!of!these!imbalances!within!the!trial!population!was!minimal.!
The!point!estimates!for!treatment!effect!favored!intervention!regardless!of!NIHSS!score!
strata,!age!≥80!versus!<80!years,!presence!of!internal!carotid!artery!(ICA)!terminus!occlusion!
or!extracranial!ICA!occlusion,!time!from!randomization!≥120!versus!<120!minutes!and!the!
(non#prespecified)!subgroup!with!and!without!IV!alteplase!treatment!(Figure!S2).!
!!!!In!a!post#hoc!analysis!of!the!adjusted!treatment!effect!on!the!primary!outcome,!we!
replaced!“previous!stroke”!with!“pre#stroke!mRS”.!This!did!not!change!the!estimate!of!
treatment!effect!(acOR!1.62,!95%!CI:!1.18!to!2.23).!
! !
! 8!
Figure!S1.!CONSORT!flow!diagram:!Allocation,!crossovers!and!loss!to!follow#up!in!the!MR!
CLEAN!trial.!
Figure%S%1%CONSORT%flow%diagram%
RANDOMIZED (n=502)
Declined participation immediately after

randomization to control arm. (n=2)
ALLOCATION
Allocated to Intervention arm (n=233) Allocated to control arm (n=267)
Underwent catheter angiography (n=216) Received allocated standard treatment (n=266)
Did not undergo catheter angiography (n=17) Did not receive allocated standard treatment (n=1)
Reasons why intervention was withheld: Reason why allocation was violated:
- Clinical improvement before start of intervention (n=8) - Demanded treatment (n=1)
- Protocol violation from local investigators (n=6)
- No femoral access (n=1)
- Withdrawn consent for IAT (n=1)
- Hemodynamically unstable (n=1)
No IAT at the clot during intervention (n=20):

Reasons:
- ICA (stenosis/occlusion/tortuosity/dissection) (n=10)
- No clot or targetable clot visible for IAT (n=8)
- Other technical problems (n=2)
FOLLOW-UP
Lost to follow-up (n=0) Lost to follow-up (n=0)
ANALYSIS
Analyzed 233 out of 233 Analyzed 267 out of 267
The!overall!crossover!rate!was!18/500!(3.6%).!
! !
! 9!
Figure!S2!Subgroup!analyses!
Adjusted!effects!of!treatment!on!the!overall!distribution!of!the!mRS!in!prespecified!
subgroups.!Adjustment!were!made!for!age,!NIHSS!at!baseline,!time!to!randomization,!
previous!stroke,!atrial!fibrillation,!diabetes!mellitus!and!presence!of!carotid!T!occlusion.!!
Figure%S%2%Subgroup%analyses%
No. of patients acOR (95% CI)
Overall 500 1.67 (1.21 to 2.30)
Age
<80 419 1.60 (1.13 to 2.28)
≥80 81 3.24 (1.22 to 8.62)
NIHSS
2-15 164 1.71 (0.96 to 3.02)
16-19 153 1.50 (0.84 to 2.67)
≥20 183 1.85 (1.06 to 3.21)
Onset to randomization
≥120 min 449 1.69 (1.21 to 2.38)
<120 min 51 1.57 (0.51 to 4.85)
IV alteplase*
no 55 2.06 (0.69 to 6.13)
yes 445 1.71 (1.22 to 2.40)
ICA terminus occlusion

absent 366 1.61 (1.11 to 2.33)
present 134 2.43 (1.24 to 4.77)
ASPECTS
0-4 28 1.09 (0.14 to 8.46)
5-7 92 1.97 (0.89 to 4.35)
8-10 376 1.61 (1.11 to 2.34)
Extracranial ICA occlusion^

absent 354 1.85 (1.26 to 2.72)
present 146 1.43 (0.78 to 2.64)
0 1 2 3 4 5 6 7 8 9 10
Favors Control Favors Intervention
Treatment effect 95% CI

No effect Overall effect
*Exploratory!analysis.!
^Exploratory!analysis!based!on!extracranial!ICA!occlusion!as!reported!by!local!investigator.!
! 10!
!
!
Table!S1.!Overview!of!additional!clinical!characteristics!at!baseline!of!the!500!patients!
included!in!the!MR!CLEAN!trial,!by!treatment!allocation:!intervention!(intra#arterial!
treatment)!or!control!(no!intra#arterial!treatment).!
Table%S%1%Overview%of%additional%clinical%characteristics%
Characteristic! Intervention!(N=233)! Control!(N=267)!
History!of!myocardial!infarction!–!n!(%)! 33!(14.2%)! 42!(15.7%)!
History!of!peripheral!artery!disease!–!n!(%)! 8!(3.5%)! 16!(6.0%)!
Hypertension!–!n!(%)! 98!(42.1%)! 129!(48.3%)!
Hyperlipidemia!–!n!(%)! 58!(24.9%)! 71!(26.6%)!
Current!smoking!!–!n!(%)&! 65!(28.9%)! 78!(31.0%)!
Current!statin!use!–!n!(%)! 65!(27.9%)! 78!(29.2%)!
Current!anticoagulant!treatment!–!n!(%)! 18!(7.7%)! 21!(7.9%)!
Current!antiplatelet!use!–!n!(%)! 64!(27.5%)! 80!(30.0%)!
Location!on!vessel!imaging:!left!hemisphere!–!n!(%)*! 116!(49.8%)! 152!(57.1%)!

&
Current!smoking!status!was!missing!in!23!patients.!
*
Vessel!imaging!was!not!performed!in!1!patient!and!level!of!occlusion!is!not!available!
! 11!
Table S2. Number of patients treated and treatment details by center.
Table S 2 Number of patients treated and treatment details by center
Allocated to Mechanical Retrievable Intra-‐arterial No IAT

Center: Included
intervention treatment stent thrombolytics* treatment%
Academic Medical Center /

74 34 30 30 0 4
VU Medical Center, Amsterdam
Sint Antonius Hospital, Nieuwegein 80 40 35 35 1 4
Atrium MC, Heerlen 1 0 0 0 0 0
Maastricht University Medical Center 58 30 27 27 0 3
Erasmus University Medical Center, Rotterdam 26 15 10 10 0 5
Elisabeth Hospital, Tilburg 16 7 7 7 0 0
HAGA, the Hague 25 11 7 7 0 4
Isala Klinieken, Zwolle 10 6 5& 3 0 0
Leiden University Medical Center 60 25 19 19 0 6
MC Haaglanden, the Hague 50 24 24 24 0 0
St. Radboud University Medical Center, Nijmegen 18 7 6# 4 0 1
Reinier de Graaff Groep, Delft 7 3 3 3 0 0
Rijnstate Hospital, Arnhem 53 21 14 14 0 7
University Medical Center Groningen 3 1 1^ 0 0 0
University Medical Center Utrecht 19 9 7 7 0 2
Total 500 233 195 190 1 37
*Given as exclusive therapy. &Merci retriever was used as exclusive therapy in 2 patients. #In 1 patient wire disruption was used. Navigation with the
guidewire beyond the thrombus was impossible in the other patient. ^Thromboaspiration through guiding catheter as exclusive treatment. %In 17 of 37
patients IAT was never started and no DSAs performed. In the other 20/37 the procedure was prematurely aborted (see Figure S1 for detailed overview).

12
Table!S3.!Definition!and!distribution!of!modified!Arterial!Occlusive!Lesion!(mAOL)!score!on!CT!
angiography!after!24!hours.!
Table&S&3&Definition&and&distribution&of&modified&Arterial&Occlusive&Lesion&(mAOL)&score&
mAOL! Intervention!(N=187)! Control!(N=207)!
0!(No!recanalization!of!the!primary!intracranial!
24!(12.8%)! 68!(32.9%)!
occlusion)!–!n.!(%)!
1!(Incomplete!or!partial!recanalization!of!the!
primary!intracranial!occlusion!without!contrast! 6!(3.2%)! 20!(9.6%)!
passage)!–!n.!(%)!
2!(Incomplete!or!partial!recanalization!with!contrast!
16!(8.6%)! 49!(23.7%)!
passage)!–!n.!(%)!
3!(Complete!recanalization!of!the!primary!
141!(75.4%)! 70!(33.8%)!
intracranial!occlusion)!–!n.!(%)!
! !
! 13!
Table!S4.!Definition!and!distribution!of!modified!Thrombolysis!in!Cerebral!Infarction!(mTICI)!score!in!
patients!allocated!to!the!intervention!arm!(N=233).!If!post!treatment!lateral!DSA!images!were!of!
insufficient!quality!or!missing,!the!highest!score!possible!was!mTICI!2a!(N=15).!
Table&S&4&Definition&and&distribution&of&mTICI&score&
mTICI! Baseline!(N=184)! Post!treatment!(N=196)!
0!(no!reperfusion)!–!n.!(%)! 169!(91.8%)! 27!(13.8%)!
1!(antegrade!flow!past!the!initial!occlusion,!
but!limited!distal!branch!filling!with!little!or! 11!(6.0%)! 11!(5.6%)!
slow!distal!reperfusion)!–!n.!(%)!
2a!(antegrade!reperfusion!of!less!than!half!
of!the!previously!ischemic!territory)!–!n.! 4!(2.2%)! 43!(21.9%)!
(%)!
2b!(antegrade!reperfusion!of!more!than!
half!of!the!previously!ischemic!territory)!–! 0!(0%)! 68!(34.7%)!
n.!(%)!
3!(complete!antegrade!reperfusion!of!the!
previously!ischemic!territory,!with!absence!
0!(0%)! 47!(24.0%)!
of!visualized!occlusion!in!all!distal!
branches)!–!n.!(%)!
! 14!
!
Table!S5.!Breakdown!of!the!primary!outcome!and!treatment!effect!in!the!500!MR!CLEAN!patients.!The!table!lists!numbers!of!patients!and!percentages!in!
each!treatment!group,!type!of!effect!parameter!(OR!or!linear!regression!coefficient),!unadjusted!and!adjusted!for!age,!NIHSS!at!baseline,!time!to!
randomization,!previous!stroke,!atrial!fibrillation,!diabetes!mellitus!and!presence!of!ICA!terminus!occlusion.!
Table&S&5&Breakdown&of&the&primary&outcome&and&treatment&effect&
Intervention&& Control& Effect& Unadjusted&effect& &Adjusted&effect&(95%&CI)&

Outcome& !
(N=233)& (N=267)& parameter& (95%&CI)&
&&&&mRS&0N1&at&90&days&–&n.&(%)& 27!(11.6%)! 16!(6.0%)! OR! 2.06!(1.08!to!3.92)! 2.07!(1.07!to!4.02)!
! 15!
Table!S6.!Number!of!patients!with!imputed!values!and!imputation!method!for!baseline!variables,!used!
for!adjustment!of!treatment!effect.!
Table&S&6&Number&of&patients&with&imputed&values&
variable& & Baseline& 24&hr&& 1&wk&
&
Age! Median! 0! A! A!
NIHSS!total!score*+! ! 0! 0! 0!
!!!Item!1a!LOC!responsiveness! Mode! 1! 0! 0!
!!!Item!1b!LOC!questions! Mode! 1! 0! 3!
!!!Item!1c!LOC!commands! Mode! 2! 0! 1!
!!!Item!2!Horizontal!eye!movement! Mode! 1! 1! 4!
!!!Item!3!Visual!field!test! Mode! 5! 1! 8!
!!!Item!4!Facial!palsy! Mode! 1! 1! 2!
!!!Item!5a!Motor!arm!left! Mode! 0! 0! 0!
!!!Item!5b!Motor!arm!right! Mode! 0! 1! 0!
!!!Item!6a!Motor!leg!left! Mode! 0! 0! 0!
!!!Item!6b!Motor!leg!right! Mode! 0! 1! 0!
!!!Item!7!Limb!ataxia! Mode! 6! 4! 5!
!!!Item!8!Sensory! Mode! 9! 5! 9!
!!!Item!9!Language! Mode! 0! 1! 0!
!!!Item!10!Speech!! Mode! 0! 1! 1!
!!!Item!11!Extinction!and!inattention! Mode! 4! 3! 5!
Time!since!onset!to!randomization!! Median! 2!! A! A!
Previous!stroke! Mode! 0! A! A!
Atrial!fibrillation! Mode! 0! A! A!
Diabetes!mellitus! Mode! 0! A! A!
ICA!terminus!occlusion! Mode! 1! A! A!
*at!24!hours!20!patients!had!completely!missing!NIHSS!assessments;!these!data!were!not!imputed.!
+!
at!5A7!days!74!patients!had!completely!missing!NIHSS!assessments;!these!data!were!not!imputed.!
! 16!
Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute
ischemic stroke. N Engl J Med. DOI: 10.1056/NEJMoa1411587

This supplement contains the following items

1. Protocol
th
a. Original protocol, (first version receiving MAC approval) version 3.0 date February 20 2010
p 2 -‐ 58
th
b. Final protocol, version 3.5 date June 11 2014
p 59 -‐ 121
c. Summary of changes, chronologically displayed in appendix 5 to 9 of the Final protocol
p 106 – 111
i. Original protocol: Version 3.0, date February 20, 2010
ii. Amendment 1: Version 3.1, date March 6, 2012
iii. Amendment 2 : Version 3.2, date December 12, 2012
iv. Amendment 3: Version 3.3, date February 26, 2013
v. Amendment 4: Version 3.4, date September 5, 2013
vi. Amendment 5: Version 3.5, date June 11, 2014

2. Statistical analysis plan
a. Original statistical analysis plan (SAP) is listed in Appendix 10 of the Final protocol
p 112 -‐ 117
1 th
b. Latest version of the statistical analysis plan as published in Trials , version 3.1 July 14 2014
p 122 – 127
c. Summary of changes
p 128

1
Fransen PS, Beumer D, Berkhemer OA, et al. MR CLEAN, a multicenter randomized clinical trial of endovascular treatment
for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Trials 2014;15:343.

Version 3.0 February 20, 2010 MR CLEAN Trial protocol
MR CLEAN-‐Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the
Netherlands.
Protocol ID NTR1804
Short title MR CLEAN
Version 3.0
Date February 20, 2010
Coordinating investigator and executive Diederik WJ Dippel, neurologist Erasmus MC
University Medical Center Rotterdam, PO Box 2040
committee of the trial
3000 CA Rotterdam, The Netherlands. T +31 10
7043979; F +31 10 7044721 E

d.dippel@erasmusmc.nl.
Yvo B Roos, neurologist AMC Amsterdam
Charles Majoie, radiologist, AMC Amsterdam
Aad van der Lugt, radiologist, Erasmus MC
Rotterdam
Robert van Oostenbrugge, neurologist, Maastricht
UMC
Wim van Zwam, radiologist, Maastricht UMC
Sponsor Raad van Bestuur Erasmus MC University Medical
Center Rotterdam.

Participating centers 1. Erasmus MC Rotterdam

2. Amsterdam Medical Center
3. Maastricht Medical center
4. UMC Utrecht
5. LUMC te Leiden
6. UMC Nijmegen
7. Haaglanden Ziekenhuis Den-‐Haag
8. Haga Ziekenhuis Den-‐Haag
9. UMC Groningen
10. St. Elisabeth Zkh Tilburg
11. Isala klinieken Zwolle
12. Catharina Ziekenhuis Eindhoven
13. St. Antonius Nieuwegein
14. Rijstate Ziekenhuis Arnhem
2

Independent physician(s) 1. Prof. dr. R.Q. Hintzen, Erasmus MC

2. Prof. dr. W.A. van Gool, AMC

3. Dr. C.G. Faber, Maastricht MC
4. Prof. dr. J.H.J. Wokke, UMC Utrecht
5. Dr. J.G. van Dijk, LUMC
6. Dr. R.A.J. Esselink, UMC Nijmegen
7. Dr. R. S. Rundervoort, Haaglanden DH
8. Follows……Haga DH
9. Dr. J.J. de Vries UMC Groningen
10. Dr. E.P.J. Arnoldus St Elizabeth Tilburg
11. Dr. A.W.J. van het Hof, Isala Zwolle
12. Dr. de Jonge Catharina ZKH Eindhoven
13. Dr. H.W. Mauser, St Antonius Nieuwegein
14. Dr. E.M. Hoogerwaard, Rijnstate Arnhem

3

PROTOCOL SIGNATURE SHEET

Name Signature Date
Head of Department:

Professor dr PA Sillevis Smitt, neurologist
Coordinating Investigator/Project
leader/Principal Investigator:
Diederik WJ Dippel, neurologist

4

MR CLEAN -‐ PROTOCOL FOR A MULTICENTER

RANDOMIZED CLINICAL TRIAL OF ENDOVASCULAR
TREATMENT FOR ACUTE ISCHEMIC STROKE IN THE
NETHERLANDS (NTR1804)

Diederik W Dippel, Charles B Majoie,3 Aad van der Lugt,2 Wim van Zwam5 Robert J van Oostenbrugge,6
Puck Fransen,1,2 JR2,3,4 JR3,5,6 and Yvo B Roos,4 for the MR CLEAN investigators.*

Departments of Neurology1 and Radiology2 of Erasmus MC University Medical Center Rotterdam,
Radiology3 and Neurology4 of the Academisch Medisch Centrum, Amsterdam, The Netherlands, and
Radiology5 and Neurology6 of the Maastricht University Medical Center, The Netherlands.

* The MR CLEAN investigators are listed in the appendix.
Correspondence:
Diederik WJ Dippel, Dept of Neurology, Erasmus MC University Medical Center Rotterdam, PO Box 2040
3000 CA Roterdam, The Netherlands. T +31 10 7043979; F +31 10 7044721 E d.dippel@erasmusmc.nl.

Version: 3.0
Date February 20, 2010

5


Acknowledgments ............................................................................................................................................................................................................. 12
Summary ............................................................................................................................................................................................................................... 13
1. Introduction and rationale ......................................................................................................................................................................................... 15
1.1 Effectiveness of intra-‐arterial thrombolysis ................................................................................................................................................. 15
1.2 Safety of intravenous and intra-‐arterial thrombolysis. ............................................................................................................................ 16
1.3 Safety and effectiveness of mechanical treatment ................................................................................................................................... 16
1.4 Needed: a randomized clinical trial of endovascular treatment in acute ischemic stroke .......................................................... 16
2. Objectives ........................................................................................................................................................................................................................ 17
3. Study design .................................................................................................................................................................................................................... 17
4. study population ........................................................................................................................................................................................................... 18
4.1 Population ................................................................................................................................................................................................................ 18
4.2 Inclusion and exclusion criteria ........................................................................................................................................................................ 18
4.3 Participating centers and center eligibility ................................................................................................................................................... 19
4.4 Sample size ............................................................................................................................................................................................................... 20
5.Treatment of subjects ................................................................................................................................................................................................... 20
5.1 investigational treatment ................................................................................................................................................................................... 20
6.Methods ............................................................................................................................................................................................................................ 20
6.1 Study outcomes ...................................................................................................................................................................................................... 20
6.2 Randomization ........................................................................................................................................................................................................ 22
6.3 Blinding ...................................................................................................................................................................................................................... 22
6.4 Study procedures ................................................................................................................................................................................................... 23
6.5 Trial organization ................................................................................................................................................................................................... 23
7.Safety reporting. ............................................................................................................................................................................................................. 24
7.1 Adverse events ....................................................................................................................................................................................................... 24
7.2 Safety and data monitoring committee ......................................................................................................................................................... 24
8. Statistical analyses ........................................................................................................................................................................................................ 25
9.Ethical considerations, access to appropriate treatment ................................................................................................................................ 25
9.1 Regulation statement ........................................................................................................................................................................................... 25
9.2 Recruitment and consent .................................................................................................................................................................................... 25
6

9.3 Access to appropriate treatment. .................................................................................................................................................................... 26
9.4 Radiation Exposure ............................................................................................................................................................................................... 26
10. Administrative aspects and publication .............................................................................................................................................................. 26
10.1 Privacy ..................................................................................................................................................................................................................... 26
10.2 Substudies .............................................................................................................................................................................................................. 26
10.3 Publication policy ................................................................................................................................................................................................ 27
References ............................................................................................................................................................................................................................ 28
Tables ..................................................................................................................................................................................................................................... 35
Table 1. Abbreviations ................................................................................................................................................................................................. 35
Table 2: randomized clinical trials of intra-‐arterial thrombolysis ................................................................................................................. 37
Table 3 controlled studies and case series of i.v. + i.a. alteplase ................................................................................................................. 38
Table 4 studies of mechanical treatment in acute ischemic stroke ............................................................................................................ 40
Table 5A. Modified Rankin Scale .......................................................................................................................................................................... 41

66
Table 5B. Thrombolysis in Cerebral Infarction (TICI) scale. ......................................................................................................................... 42
45
Table 5C Clot burden score for CTA and MRA ................................................................................................................................................. 43
46
Table 6A. Schedule of study activities .................................................................................................................................................................... 44
Table 6b. List of study data ........................................................................................................................................................................................ 45
Appendices ........................................................................................................................................................................................................................... 48
Appendix 1. List of collaborating investigators ................................................................................................................................................... 48
Appendix 2. Study committees ................................................................................................................................................................................ 49
Appendix 3 Recommendations of the Steering committee with regard to endovascular treatment procedures, thrombolytic
agents, and type of mechanical thrombectomy. ............................................................................................................................................... 50
Table A1. Optimal Time-‐path for treatment and inclusion in MR CLEAN of patients with acute ischemic stroke and relevant
anterior circulation arterial inclusion ..................................................................................................................................................................... 50
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase .................................. 52
Table A3. List of mechanical thrombectomy devices that are available in The Netherlands, their mode of action and current
status. ................................................................................................................................................................................................................................ 53
Appendix 4 Intervention-‐related angiographic imaging .................................................................................................................................. 54
Figures ................................................................................................................................................................................................................................... 55
Figure 1: Trial logo. ....................................................................................................................................................................................................... 55
Figure 2 ............................................................................................................................................................................................................................. 56
Figure 3. Randomization and inclusion of patients in the trial ...................................................................................................................... 57
7

Figure 4. Patient flow in the trial ............................................................................................................................................................................. 58
Summary ............................................................................................................................................................................................................................... 70
2. Objectives ........................................................................................................................................................................................................................ 74
3. Study design .................................................................................................................................................................................................................... 74
4.1 Population ................................................................................................................................................................................................................ 75
4.4 Sample size ............................................................................................................................................................................................................... 77
6.Methods ............................................................................................................................................................................................................................ 78
6.1 Study outcomes ...................................................................................................................................................................................................... 78
6.2 Randomization ........................................................................................................................................................................................................ 79
6.3 Blinding ...................................................................................................................................................................................................................... 80
7.1 Adverse events ....................................................................................................................................................................................................... 81
8

10.1 Privacy ..................................................................................................................................................................................................................... 83
10.2 Substudies .............................................................................................................................................................................................................. 84
References ............................................................................................................................................................................................................................ 84

66
Table 5B. modifed Thrombolysis in Cerebral Infarction (TICI) scale. ....................................................................................................... 95
45
46
Table 5d Arterial occlusive lesion scale ................................................................................................................................................................. 96
Appendices ......................................................................................................................................................................................................................... 100
Appendix 1. List of collaborating investigators ................................................................................................................................................. 100
Appendix 2. Study committees .............................................................................................................................................................................. 100
agents, and type of mechanical thrombectomy. ............................................................................................................................................. 102
anterior circulation arterial inclusion ................................................................................................................................................................... 102
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase ................................ 104
status. .............................................................................................................................................................................................................................. 105
Appendix 4 Intervention-‐related angiographic imaging ................................................................................................................................ 106
APPENDIX 5: Protocol amendment MR CLEAN trial; substantial Protocol 3.1. ..................................................................................... 106
APPENDIX 6 : PROTCOL AMENDMENT MR CLEAN TRIAL SUBSTANTIAL PROTOCOL 3.2 .................................................................... 107
Appendix 7: PROTCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.3 ..................................................................... 108
Appendix 8: PROToCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.4 .................................................................. 110
9

Appendix 9: PROToCOL AMENDMENT MR CLEAN TRIAL; PROTOCOL 3.5 .............................................................................................. 110
Appendix 10 Statistical analysis protocol (SAP) ................................................................................................................................................ 112
Introduction ....................................................................................................................................................................................................................... 112
Status of the trial .............................................................................................................................................................................................................. 112
Research questions ......................................................................................................................................................................................................... 112
Primary research questions ..................................................................................................................................................................................... 113
Secondary research questions ................................................................................................................................................................................ 113
Trial design ......................................................................................................................................................................................................................... 113
Inclusion and exclusion criteria .............................................................................................................................................................................. 113
Primary and secondary outcomes ......................................................................................................................................................................... 114
Blinding ........................................................................................................................................................................................................................... 114
Statistical analysis proper ............................................................................................................................................................................................. 115
Primary effect analysis .............................................................................................................................................................................................. 115
Primary effect analysis in subgroups .................................................................................................................................................................... 115
Missing data and death ............................................................................................................................................................................................. 116
Time path of the analyses and locking of the database. .................................................................................................................................... 116
References .......................................................................................................................................................................................................................... 117
Figures ................................................................................................................................................................................................................................. 118
Figure 1: Trial logo. ..................................................................................................................................................................................................... 118
Figure 2 ........................................................................................................................................................................................................................... 119
Figure 3. Randomization and inclusion of patients in the trial .................................................................................................................... 120
Figure 4. Patient flow in the trial ........................................................................................................................................................................... 121
Introduction ....................................................................................................................................................................................................................... 122
Trial design ......................................................................................................................................................................................................................... 123
10

Blinding ........................................................................................................................................................................................................................... 124
References .......................................................................................................................................................................................................................... 127

11

ACKNOWLEDGMENTS

MR CLEAN is partly funded by the Netherlands Heart Foundation (2008T030), and by
unrestricted grants from AngioCare BV, EV3®, MEDAC Gmbh/LAMEPRO , Penumbra Inc and
Concentric Medical /TOP Medical BV.
The study is designed, and will be conducted, analyzed, and interpreted by the investigators
independently of all sponsors.

12

SUMMARY
RATIONALE AND AIM

Intra-‐arterial treatment increases the likelihood of recanalization in patients with acute
ischemic stroke caused by proximal intracranial arterial occlusion. The purpose of the
Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in
the Netherlands (MR CLEAN) is to assess the safety and effect on functional outcome of
intra-‐arterial treatment in these patients.
DESIGN
MR CLEAN is a pragmatic phase III multicenter randomized clinical trial with blinded
outcome assessment. The intervention contrast is intra-‐arterial treatment versus no intra-‐
arterial treatment.
STUDY POPULATION
Patients should have a clinical diagnosis of acute ischemic stroke, MRI1 or CT ruling out
intracerebral hemorrhage, a score on the National Institutes of Health Stroke Scale (NIHSS)
of 2 points or more, a relevant intracranial arterial occlusion, demonstrated by neuro-‐
imaging and the possibility to start endovascular treatment within 6 hours after stroke
onset.
INTERVENTION
Endovascular treatment may consist of intra-‐arterial thrombolysis with urokinase or
alteplase, mechanical treatment or both. Mechanical treatment refers to retraction or
aspiration of the thrombus with a catheter guided device, or stenting. The exact choice of
endovascular treatment modality for each patient is left to the discretion of the local
investigator and treating physicians. The steering committee will provide recommendations
and guidelines for treatment and selection of patients in the study. Background medical
management is delivered according to national standards and guidelines. It may include
intravenous alteplase within the first 4.5 hours after onset.
MAIN STUDY OUTCOMES

The primary outcome is the score on the modified Rankin scale (mRS) 90 days after inclusion
in the study. Secondary outcomes are the NIHSS score at 24 hours, vessel patency at 24
hours and infarct size at day 5-‐7and the occurrence of major bleeding.
The randomization will be stratified for use of intravenous alteplase, planned treatment
modality (intra-‐arterial thrombolysis, mechanical thrombectomy or both) and center. We
will estimate the effect of treatment by means of the ordinal logistic regression (shift
analysis), which considers the whole range of the mRS. In total, 500 patients will be included.

1
All abbreviations are listed in Table 1.
13

BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION.

All patients that participate in the trial will undergo a second CTA within 24 hours after
admission and a CT scan at day 5-‐7. All patients will have a telephone interview at three
months. Patients who are randomized for intra-‐arterial treatment sometimes need sedation
or anesthesia, and intubation during the procedure. Finally, endovascular treatment is
associated with increased risk of intra-‐cerebral hemorrhage.
DISCUSSION
MR CLEAN is a pragmatic trial. Inclusion of patients will take 4 years, and starts early in 2010.
Key words: alteplase, endovascular treatment, acute ischemic stroke, randomized controlled
trial

14

1. INTRODUCTION AND RATIONALE

In Western Europe and the US, the annual incidence of ischemic stroke is 1-‐2 per 1000.1, 2
Half of all patients with stroke die or remain severely handicapped. Stroke is one of the
major causes of death and the first cause of dependency in the western world. Treatment
with intravenous alteplase, aiming at early reperfusion has been proven effective for these
patients, when they are treated within 4.5 hours, and when there are no contra-‐
indications.3-‐5 The absolute reduction in the chance of poor outcome in patients treated with
i.v. alteplase within 3 hours from onset amounts to 10%; the number needed to treat is 10.6
For the patients treated within 3 to 4.5 hours, this effect was reduced to 7%, for a number
needed to treat of 14.4
In general, the number of patients eligible for treatment with intravenous alteplase is limited
because of the restricted time window. In about 25% of the patients with acute anterior
circulation ischemic stroke, symptoms are caused by a proximal occlusion of one of the
major intracranial arteries, i.e. the distal intracranial internal carotid artery, the proximal
segments of the middle cerebral artery and the anterior cerebral artery.7, 8 The likelihood of
a proximal occlusion increases with severity of the neurological deficit at presentation.9-‐11
The effect in these patients with a symptomatic intracranial arterial occlusion is limited.
Treatment with i.v. alteplase leads to recanalization in up to 33% of treated patients only.12
In those without recanalization, outcome is generally poor.13, 14
1.1 EFFECTIVENESS OF INTRA-‐ARTERIAL THROMBOLYSIS

Four randomized clinical trials that assessed the effectiveness of intra-‐arterial thrombolysis
in patients with acute ischemic stroke due to intracranial occlusion IAO have been reported
(Table 2). The PROACT I and PROACT II were randomized controlled trials that compared
intra-‐arterial thrombolysis by means of pro-‐urokinase with treatment with heparin in
patients with angiographically demonstrated M1 of M2 segment occlusion, within 6 hours
from onset of symptoms. Recanalization rates were high and recanalization occurred more
often in the active treatment group than in controls.15, 16 The results of the PROACT-‐II study
indicated an improved functional outcome on day 90; 40% of the patients had a score on the
modified Rankin Scale (mRS) of less than 3). In total, 11% to 15% of the patients in the
PROACT studies had a symptomatic intracranial hemorrhage after treatment with intra-‐
arterial thrombolysis. A third randomized clinical trial from Japan (MELT) compared intra-‐
arterial urokinase with standard treatment (but not intravenous alteplase) within 6 hours
from onset was terminated prematurely. For a secondary endpoint, (mRS >2 at 90 days, a
significant effect was observed.17 The results of these trials have to be interpreted with care
and cannot be extrapolated to the current clinical situation. In the three trials, intravenous
alteplase was not an option, neither as pre-‐treatment nor as part of the control treatment.
In MELT, mechanical treatment was allowed, but not in PROACT I and II. MELT was an open
label randomized trial with blind outcome assessment, which implies that the treatment
effect could have been known at the time the decision was made to prematurely stop the
trial. In PROACT I and II the control treatment included intravenous heparin, which can now
be considered obsolete.18 Finally, a fourth, Italian RCT (SYNTHESIS) compared intra-‐arterial
alteplase with intravenous alteplase. The trial started in 2004, and was stopped after 50
15

patients had been included. More patients with intra-‐arterial treatment than patients with
intravenous treatment showed recanalization and good outcome, but the effect was not
statistically significant.19 Several non-‐randomized studies with historical controls,20 or
controls in other centers,21 suggested a benefit of intra-‐arterial thrombolysis.
1.2 SAFETY OF INTRAVENOUS AND INTRA-‐ARTERIAL THROMBOLYSIS.

The combination of intravenous and intra-‐arterial rt-‐PA was compared with intravenous
placebo followed by intra-‐arterial alteplase in the EMS Bridging trial (Table 3). The risk of
hemorrhagic transformation was increased in patients who received the combination
treatment.22 In two observational studies, patients were treated within 5 hours from onset
of symptoms. The intravenous dose was adjusted to 0.6 mg/kg, with a maximum of 60 mg.
The incidence of hemorrhages was not larger than in studies of treatment with intravenous
thrombolysis only.23, 24 Similar results have been reported by others.25-‐27 In several case-‐
series, endovascular treatment with low dose i.a. alteplase was preceded by full dose i.v.
alteplase (i.e. 0.9 mg/kg). Risks for sICH ranged from 0 to 13%.28-‐32 These studies suggest that
in patients who have been treated in this way, recanalization rates can be high, without
unacceptable high risks of complications (Table 3).
1.3 SAFETY AND EFFECTIVENESS OF MECHANICAL TREATMENT

Mechanical treatment is a promising technique, either as a secondary in patients who do not
respond quickly to intra-‐arterial thrombolytic treatment, or in patients for whom
thrombolytic agents are contra-‐indicated. The MERCI device is a retractor device. Several
studies of the effect of treatment with the MERCI device have been published (Table 4).33-‐36
The rates of recanalization were similar to observed rates in the intra-‐arterial thrombolytic
treatment studies. However, these studies were not randomized, but used historical controls
derived from the NINDS RTPA stroke trial. The MERCI device has been approved by the FDA.
Several case series describing the treatment of symptomatic occlusion with other devices,
such as the PENUMBRA device and the EKossonic SV have been published.37-‐39 Other
approaches to mechanical treatment include use of aspiration devices, such as the
PENUMBRA device, which has also recently been approved for treatment of acute ischemic
stroke by the FDA, and stents, such as the EV3 stent, and the Wingspan stent.39-‐41 The
Wingspan stent itself is FDA approved for elective treatment of intracranial arterial stenosis
but not for treatment of acute ischemic stroke.
The results of these uncontrolled studies of mechanical thrombectomy are difficult to
compare, because of differences in case mix, pretreatment and patient selection, severity of
intracranial occlusions, and definitions of revascularization. However, these studies suggest
that in experienced hands, mechanical thrombectomy could be safe and may lead to
substantial recanalization rates. A recent AHA guideline therefore stated that “…. Although
the Concentric MERCI device can be useful for extraction of intra-‐arterial thrombi in
appropriately selected patients, the utility of the device in improving outcomes after stroke
remains unclear. “ and “The usefulness of other endovascular devices is not yet established,
but they may be beneficial.”18
1.4 NEEDED: A RANDOMIZED CLINICAL TRIAL OF ENDOVASCULAR TREATMENT IN ACUTE
ISCHEMIC STROKE
16

We conclude from this overview that intra-‐arterial treatment, either with a thrombolytic
agent or by mechanical means is able to recanalize acutely occluded cerebral arteries in
selected patients, within reasonable safety margins. Whether this is the case in an
unselected sample of patients with acute ischemic stroke caused by occlusion is likely, but
unproven. A randomized clinical trial addressing the question whether intra-‐arterial
treatment improves neurological outcome in patients with a relevant occlusion in the
intracranial proximal anterior circulation is therefore needed.
For the trial results to be generalizable and representative of what is state of the art
approach in intra-‐arterial treatment, the trial design should accommodate the possibility to
use local fibrinolytics and or mechanical thrombectomy devices, for a broad range of
patients with acute ischemic stroke caused by a proximal thrombo-‐embolic occlusion of one
of the intracranial arteries belonging to the anterior circulation.
Important subgroups to whom this question of effectiveness and safety applies are patients
who have been treated unsuccessfully with intravenous thrombolysis, patients who can be
treated within 6 hours, but do not meet the time window requirements for intravenous
thrombolysis, and patients with contra-‐indications for intravenous and/or intra-‐arterial
thrombolytic treatment (thrombectomy only). To answer this question, we initiated a large
multicenter pragmatic trial of intra-‐arterial treatment (by means of alteplase and or
mechanical treatment) versus standard medical treatment, in patients with acute ischemic
stroke of less than 6 hours of onset, the MR CLEAN study.
The trial applies the grey area principle: when a patient’s clinical profile meets inclusion and
exclusion criteria, and according to investigator and treating physician there is sufficient
uncertainty concerning the question whether the patient should receive intra-‐arterial
treatment, the patient is eligible for inclusion in the trial.
2. OBJECTIVES
The primary objective of this study is to estimate the effect of endovascular treatment on
overall functional outcome after acute ischemic stroke of less than six hour duration, in
patients with a symptomatic occlusion. The secondary objectives are to assess the safety of
endovascular treatment with regard to the occurrence of hemorrhagic and ischemic
complications, the efficacy with regard to obtaining recanalization, and to evaluate
predictors of recanalization, including imaging aspects and hemostatic parameters.
Moreover, we want to assess the safety and efficacy of different types of endovascular
treatment (i.e. mechanical treatment, intra-‐arterial thrombolysis) different combinations of
treatment (i.e. with intravenous alteplase) and different timings of treatment. Tertiary
objectives are to carry out case studies of implementation strategies and loco-‐regional
solutions for barriers to the delivery of endovascular treatment for acute ischemic stroke
and to collect data for cost-‐effectiveness analysis of endovascular treatment compared with
standard treatment.
3. STUDY DESIGN
This is a multicenter clinical trial with randomized treatment allocation, open label
treatment and blinded endpoint evaluation (PROBE design).
17

The intervention contrast is endovascular treatment (alteplase or urokinase, and/or
mechanical treatment) versus no endovascular treatment. The treatment is provided in
addition to best medical management, including intravenous thrombolysis.
The study will run in at least 10 large hospitals in the Netherlands for a period of five years (4
years of patient inclusion), and starts in 2010.
4. STUDY POPULATION
4.1 POPULATION
Patients over 18 years old, with acute ischemic stroke, a symptomatic anterior proximal
artery occlusion which can be treated within 6 hours after stroke onset are eligible for
participation in this trial.
4.2 INCLUSION AND EXCLUSION CRITERIA
INCLUSION CRITERIA
• A clinical diagnosis of acute stroke, with a deficit on the NIH stroke scale of 2 points
or more.
• CT or MRI scan ruling out intracranial hemorrhage.
• Intracranial arterial occlusion of the distal intracranial carotid artery or middle
(M1/M2) or anterior (A1/A2) cerebral artery, demonstrated with CTA, MRA, DSA or
transcranial Doppler/duplex (TCD).
• The possibility to start treatment within 6 hours from onset.
• Informed consent given.
• Age 18 or over.

GENERAL EXCLUSION CRITERIA
• Arterial blood pressure > 185/110 mmHg.

• Blood glucose < 2.7 or > 22.2 mmol/L.
• Intravenous treatment with thrombolytic therapy in a dose exceeding 0.9 mg/kg
alteplase or 90 mg.
• Intravenous treatment with thrombolytic therapy despite contra-‐indications, i.e.
major surgery, gastrointestinal bleeding or urinary tract bleeding within the previous
2 weeks, or arterial puncture at a non-‐compressible site within the previous 7 days.
SPECIFIC EXCLUSION CRITERIA FOR INTENDED MECHANICAL THROMBECTOMY
• Laboratory evidence of coagulation abnormalities, i.e. platelet count <40 x 109/L,
APTT>50 sec or INR >3.0.

18

SPECIFIC EXCLUSION CRITERIA FOR INTENDED INTRA-‐ARTERIAL THROMBOLYSIS
• Cerebral infarction in the distribution of the relevant occluded artery in the previous
6 weeks.
• History of intracerebral hemorrhage.
• Severe head injury (contusion) in the previous 4 weeks.
• Clinical or laboratory evidence of coagulation abnormalities, i.e. platelet count <90 x
109/L, APTT>50
sec or INR >1.7.

4.3 PARTICIPATING CENTERS AND CENTER ELIGIBILITY

To be fully eligible for participation in the trial and to include patients in the trial, centers
should meet the following minimum criteria:
• The center should have experience in conducting acute stroke trials.
• The intervention team should have ample experience with endovascular interventions
for cerebrovascular disease (carotid stenting or aneurysm coiling), peripheral artery
disease, or coronary artery disease.
• At least one member of the intervention team should have sufficient experience with
intra-‐arterial thrombolysis.
In order to include and randomize patients who may be treated with mechanical
thrombectomy centers should meet the following additional criteria:
• The intervention team should make use of one or more of the devices that have been
approved by the trial steering committee. Other devices are not allowed into the trial.
• At least one member of the intervention team should have sufficient experience with
the particular device.
Sufficient experience is defined as the completion of at least 5 full procedures with het
particular device. Procedures that have been carried out by two team members (for
example, in a training setting) do count. Procedures do not need to be successful, nor
uncomplicated. Procedures consisting of mechanical thrombectomy combined with intra-‐
arterial thrombolysis count for both.
Centers that do not comply with the third criterion may participate in the registration phase
of the study. In these centers, patients cannot be included and randomized. However,
patients who undergo intra-‐arterial treatment will be registered and data will be processed.
The center can apply for a status as fully participating center when criterion 3 is met.
Note that patients may only be included in the trial when the intervention team that will
actually treat the patient includes at least one member with sufficient experience when one
of the treating interventionists. For this reason, the possibility of treatment by an
interventionist with sufficient experience is listed as an inclusion criterion.
Training sessions for intra-‐arterial thrombolysis and mechanical treatment will be held, draft
guidelines and recommendations for endovascular procedures and general management of
included patients, on paper and on video will be issued by the steering committee and
distributed among participating centers.
19

4.4 SAMPLE SIZE

The effect of the intervention on the primary outcome (the mRS, a 7-‐point ordered
categorical scale) will be assessed with ordinal logistic regression. We assume a moderate
effect of 10% absolute increase in the cumulative proportion of patients with mRS 0-‐3 in the
intervention group, compared with controls. We based the distribution of outcome
categories on the results of the PROACT II trial.15 Figure 2 shows the expected distributions
of mRS categories. A total study size of 500 patients (2x250 pts) provides a power (1-‐beta) of
82% at a significance level of 0.05. 42[taking into account 10% cross over rate].
This sample size is also sufficient to assess the effect of the intervention on secondary
endpoints: Analysis of a meaningful reduction on NIH stroke scale at one week of 3-‐4 points
(Cohen’s d=0.33) would require a sample of 400 patients, assuming that at 24-‐48 hours
mean NIH would be 12, with a standard deviation of 10. A doubling of the recanalization rate
from 30% to 60% would require 126 patients to achieve a power of 0.90.
Simulation studies have indicated that ordinal logistic regression is a more powerful method
for analysis of trials with ordered categorical outcome data, and have proven its robustness
against violations of the proportional odds assumption.43
5.TREATMENT OF SUBJECTS
5.1 INVESTIGATIONAL TREATMENT

Endovascular treatment will consist of arterial catheterisation with a microcatheter to the
level of occlusion and delivery of a thrombolytic agent and/ or mechanical thrombectomy.
Both alteplase and urokinase for intra-‐arterial thrombolysis is allowed into the trial, a dose
of 1 mg alteplase is considered to be equivalent to 10.000-‐15.000 U urokinase.44
Mechanical treatment may consist of mechanical thrombectomy, aspiration, or stenting.
Specific recommendations with regards to procedures and devices will be issued regularly by
the trial steering committee.
The steering committee will make recommendations for dosages of thrombolytic agents,
procedures, and for devices that will be allowed in the trial based on proposals by the
executive committee or local investigators. The requirements for a device being allowed for
use in the trial are: documented evidence of safety in experienced hands, and recanalization
rates that are similar to rates with other mechanical devices. Devices that are currently
allowed in the trial are listed in Appendix 4. Evidence on safety or efficacy of particular
devices from other studies, or recommendations made by the DMC on the basis of
monitoring results, or both, may lead the steering committee to decide to discontinue
allowance into the trial of a particular device. Proposals will be prepared by the executive
committee, and should be approved by a majority of the steering committee.
6.METHODS
6.1 S TUDY OUTCOMES
PRIMARY OUTCOME
The primary outcome is the score on the modified Rankin scale at 90 days (Table 5a).
20

SECONDARY OUTCOMES
IMAGING PARAMETERS
• Vessel recanalization at 24 hours after treatment, assessed by CTA or MRA. The
criteria for recanalization on CTA or MRA are based on a simplified TICI score (Table
5b),45 and the clot burden score, proposed by Puetz et al (Table 5c)46.
• Infarct size assessed by CT on day 5-‐7, using standard methods, including manual
tracing of the infarct perimeter and semiautomated pixel thresholding.47, 48 Infarct
size at day 5-‐7 will be compared with plain CT and perfusion CT results (if available) at
baseline.
• CTA or MRA at 24 hours will be compared with baseline vessel imaging data, to
estimate the recanalization rate. Perfusion CT at baseline is optional, but available at
most centers. Clinical parameters
CLINICAL PARAMETERS
• NIHSS 49, including NIH supplemental motor score,50 at 24 hours.
• NIHSS at 1 week or at discharge.
FUNCTIONAL OUTCOME
• Score on the EQ5D at 90 days,51
• Barthel index at 90 days.52
• Score on the Academic Linear Disability Scale at 90 days53.
• Score on the Telephone Interview for Cognitive Status (TICS) 54, 54-‐57
The 90-‐days follow-‐up will be conducted by telephone interview, through the central trial
office.
SAFETY PARAMETERS
Safety is an issue of concern, as the experience with the intervention, overall, and within the
participating centers, is limited. Safety parameters include hemorrhagic complications, and
short term outcome (mortality, Barthel index and NIHSS at 24 hours and at one week or
discharge). As we will make use of web-‐based data-‐entry, these data will be available on
short notice.
The primary safety parameter will be neurologic deterioration within 24 hours from inclusion
in the study. Neurological deterioration is defined as any decline in NIHSS of more than 2
points. In these patients, urgent brain CT is mandatory. This serious adverse event will be
further classified as due to intracranial hemorrhage, ischemia or other (undetermined)
cause. A full list of serious adverse events is provided in section 7.1 Adverse events.
21

If the local investigator, or other member of the team at a trial centre has a concern about
the outcome of their trial procedures, they should inform the MR CLEAN trial office, which
will organize a blinded assessment of the relevant outcome events. This will be submitted by
the central office to the chairman of the data monitoring committee, who may recommend
further action, such as suspending randomization at the centre. Similarly, the database
manager at the trial office will monitor outcome events and if there are three consecutive
deaths or three consecutive serious adverse events at a single centre within 30 days of
treatment in the same arm of the study, then assessment of the events will be triggered. A
cumulative death rate of more than 50% or a cumulative serious adverse event rate
exceeding 20% over 10 cases during hospital admission would also trigger careful
assessment of the relevant outcome events.
DATA FOR COST-‐EFFECTIVENESS ANALYSIS

A limited amount of health and medical costs data will be collected, in a piggy-‐back fashion
i.e. during the registration of other data, and will include length of stay. Measurement of
health care costs will be based on international and national guidelines.58, 59 Analysis of these
data however, and the modeling for the cost-‐effectiveness study is outside the scope of the
current study.
6.2 RANDOMIZATION
The randomization procedure will be computer-‐ and web-‐based, using permuted blocks.
Back-‐up by telephone will be provided. Randomization is allowed when the occlusion has
been established by CTA, MRA, DSA or TCD. Selection of patients for randomization follows
the grey area principle. Randomization will be stratified for center, use of intravenous
alteplase, planned treatment modality (mechanical thrombectomy or not) and stroke
severity,(NIHSS >14 or not).
Patients with contra-‐indications for intravenous thrombolysis are allowed into the trial. This
concerns patients who cannot be treated within 4.5 hours from onset, but only in the 4.5 to
6 hour interval, and patients with either major surgery, gastrointestinal bleeding or urinary
tract bleeding within the previous 2 weeks, or arterial puncture at a non-‐compressible site
within the previous 7 days.
Patients with exclusion criteria for intra-‐arterial thrombolysis are also allowed into the trial .
They can be included and randomized for endovascular treatment or no endovascular
treatment.Treatment with mechanical thrombectomy is allowed, but intra-‐arterial
thrombolysis is not allowed in these patients. The treating physicians are free to change the
actual mode of treatment during the procedure, as long as they comply with the treatment-‐
specific exclusion criteria and recommended devices.
6.3 BLINDING
It will not be possible to view the treatment allocation before the patient is registered in the
study database, nor will it be possible to remove the patient from the study base after
treatment assignment has become known. Both patient and treating physician will be aware
of the treatment assignment. Information on outcome at three months will be assessed
through standardized forms and procedures. Assessment of outcome on the modified
Rankin scale will be based on this information, by assessors who are blind to the treatment
22

allocation. Results of neuroimaging will be also assessed in a blinded manner. Information on
treatment allocation will be kept separate from the main study database. The steering
committee will be kept unaware of the results of interim analyses of efficacy and safety. The
trial statistician will combine data on treatment allocation with the clinical data in order to
report to the data monitoring committee (DMC).
6.4 STUDY PROCEDURES
BASELINE DATA OBTAINED AT ADMISSION

Clinical data, neuro-‐imaging data and procedure-‐related data that might be related to
treatment effect or to adverse events caused by the intervention, as well as several stroke
risk factors, in order to illustrate the representativeness of the study population will be
recorded (Table 6).
INCLUSION AND RANDOMIZATION

A minimal amount of data has to be entered before randomization, as randomization will be
stratified. The trial office will be notified when a new patient is entered into the web based
database. A treatment allocation will be provided by the web-‐based computer system.
Personal data will be sent to the trial office separately, through scrambled email.
FOLLOW-‐UP DATA
At 24 hours, a clinical examination including NIH stroke scale assessment will be carried out.
Also, all patients will undergo CTA or MRA imaging. At day 5-‐7 all patients will undergo CT or
MRI. Raw data will be forwarded to the trial office for blind evaluation. At 1 week, clinical
status, NIH stroke scale score and adverse events will be reported as well as discharge
destination, in order to enable the trial office to conduct the final 3-‐month follow-‐up by
telephone interview.
The standardized telephone interview will include a short questionnaire based on the three
simple questions, assessment of modified Rankin Scale, Academic Linear Disability Scale,
Barthel Index, TICS and Euroqol5D.51-‐53, 60-‐62.
WITHDRAWAL
Patients can leave the study at any time for any reason if they wish to do so without any
consequences. The investigator can decide to withdraw a subject from the study or stop the
allocated intervention for urgent medical reasons. Every attempt will be made to complete
follow-‐up in these patients.
6.5 TRIAL ORGANIZATION

The steering committee will make decisions regarding continuation of the trial and protocol
changes. Decisions will be prepared by the executive committee. The chairman of the
steering committee will be advised by the independent data monitoring and safety
committee, see section 7.2 Safety and data monitoring committee. The steering committee
consists of the local investigators from each center, a neurologist and a neuro-‐
interventionist, and the executive committee. The executive committee consists of the six
23

co-‐principal investigators, and study-‐coordinator. The post of study coordinator will be
manned by each of three junior-‐researchers, taking turns. The study-‐coordinator is
responsible for running the trial on a day-‐to-‐day basis, and will report to the executive
committee. The executive committee will meet on a bi-‐monthly basis. The steering
committee will meet at least annually. The steering committee meeting is chaired by the
principal investigator (DD). Other important committees are the neuro-‐imaging assessment
committee, the functional outcome adjudication committee and the serious adverse event
adjudication committee.
The trial office is located in Rotterdam, Erasmus MC University Medical Center. The neuro-‐
imaging assessment unit is located in AMC, Amsterdam.
7.SAFETY REPORTING.
7.1 ADVERSE EVENTS

Adverse events are undesirable experiences occurring to a subject during the study, whether
or not they are considered to be related to the experimental treatment. All adverse events
reported spontaneously by the subject or observed by the investigator or his staff will be
recorded.
A serious adverse event is any untoward medical occurrence or effect that can cause
mortality, is life-‐threatening, requires prolonged hospitalization, or results in persistent
significant disability.
Expected serious adverse events are neurologic deterioration, symptomatic intracranial
hemorrhage, extracranial hemorrhage, technical complications or vascular damage at the
target lesion such as perforation or dissection and mortality in the first week of stroke,
aspiration pneumonia, allergic reaction towards contrast fluid, death from any cause within
the study period.
A cumulative log will be kept of all serious adverse events, for review by the DMC.
7.2 SAFETY AND DATA MONITORING COMMITTEE

In order to increase the safety of the intervention, the trial will be monitored by an
independent data monitoring committee (DMC). The data monitoring committee will be
chaired by a neurologist, and include a neuro-‐interventionist and an independent
methodologist/statistician. The DMC will meet frequently and assess the occurrence of
unwanted effects by center and by procedure. During the period of intake to the study,
interim analyses of mortality and of any other information that is available on major
endpoints (including serious adverse events believed to be due to treatment) will be
supplied, in strict confidence, to the chairman of the Data Monitoring Committee, along with
any other analyses that the Committee may request. In the light of these analyses, the Data
Monitoring Committee will advise the chairman of the Steering Committee if, in their view,
the randomized comparisons in MR CLEAN have provided both (i) "proof beyond reasonable
doubt" that for all, or for some specific types of patients, one particular treatment is clearly
indicated or clearly contraindicated in terms of a net difference in outcome, and (ii) evidence
that might reasonably be expected to influence materially patient management. Appropriate
criteria of proof beyond reasonable doubt cannot be specified precisely, but a difference of
at least 3 standard deviations in an interim analysis of a major endpoint may be needed to
24

justify halting, or modifying, the study prematurely. This criterion has the practical
advantage that the number of interim analyses is of little importance.
8. STATISTICAL ANALYSES
Baseline characteristics will be summarized by means of simple descriptive statistics. The
main analysis of this trial consists of a single comparison between the trial treatment groups
of the primary outcome after 90 days. The analysis will be based on the intention-‐to-‐treat
principle. The primary effect parameter should take the whole range of the modified Rankin
scale (mRS) into account and is defined as the relative risk for improvement on the mRS
estimated as an odds ratio with ordinal logistic regression.63
Multivariable regression analysis will be used to adjust for chance imbalances in main
prognostic variables between intervention and control group, such as age, stroke severity
(NIHSS), time since onset, ischemic stroke subtype (lacunar vs non-‐lacunar) previous stroke,
atrial fibrillation and diabetes mellitus. Secondary effect parameters will be the
improvement according to the classical dichotomizations of the modified Rankin scale at 0-‐1
vs 2-‐6 and 0-‐2 vs 3-‐6, the presence of vessel patency on CTA, MRA or DSA at 24 hours, and
the score on the NIHSS at 24 hours and 1 week or discharge.
With regard to the range of secondary outcome parameters we will use simple 2x2 tables,
two-‐group t-‐tests, Mann-‐Whitney tests, and multivariable linear and logistic regression
models, where appropriate. In all analyses, statistical uncertainty will be quantified by
means of 95% confidence intervals. Subgroup analyses will be carried out to estimate the
effect intra-‐arterial thrombolysis, mechanical treatment and combination therapy. Although
the size of this study will not allow for precise estimates of treatment effect in subgroups,
we will assess heterogeneity of effects, and analyze consistency of effects on secondary
outcomes.

9.ETHICAL CONSIDERATIONS, ACCESS TO APPROPRIATE TREATMENT
9.1 REGULATION STATEMENT

The trial will be conducted in accordance with the principles of the Declaration of Helsinki, as
amendended by the World Medical Association General Assembly in October 2008, and with
the guidelines for Good Clinical Practice.
9.2 RECRUITMENT AND CONSENT

Written informed consent will be obtained from all patients and a copy must be retained by
the randomizing centre. All patients will be provided with a written explanation of the study.
Because of the urgent character of the treatment informed consent is subdivided in an
informed consent form with a short description of the procedure for immediate use, and an
extensive version which will be discussed with the patient after the procedure.
After approval by the patient or his/her legal representative, the patient’s treating physician
will inform a study physician of the presence of a patient with acute ischemic stroke who is
potentially eligible for the present study. The study physician will inform the patient orally
and in writing and will obtain his/her written informed consent. In case the patient is legally
incompetent, for example because of aphasia or anosognosia, written informed consent will
25

be obtained from a legal representative. Because the study physicians are also involved in
the clinical care of patients with acute ischemic stroke, it appears inevitable that in some
occasions the study physician will also be the patient’s treating physician.
As this is an acute stroke trial with a narrow time window for the start of treatment, and
because of time-‐consuming study-‐related procedures after informed consent will be
obtained, the time for consideration of participation in the trial will be limited to the first
few hours after stroke onset. Even within this time frame, a decision on participation should
preferably be taken as soon as possible, at least within 30 minutes.
Especially patients with large cortical infarcts may not be able to judge the pros and cons of
participation in the trial sufficiently, most often because of aphasia. As aphasia is present in
approximately 25% of the patients with acute stroke and because patients with large cortical
infarcts may benefit most from intra-‐arterial treatment on theoretical grounds, it may be
considered inappropriate to exclude these patients from the trial. Incapacitated patients in
the control group are treated according to current standards and participation in the trial
does therefore not carry a risk; the burden caused by the additional investigations is
considered minimal.
9.3 ACCESS TO APPROPRIATE TREATMENT.

The design of MR CLEAN allows that all patients with an indication for intravenous alteplase
will be treated accordingly. All patients will be managed according to local stroke care
protocols, which have to be in agreement with national guidelines.
9.4 RADIATION EXPOSURE

All participants in the trial will undergo CTA at 24-‐28 hours to assess TICI score after
treatment. Radiation exposure for CTA is an attributable 3.5-‐3.6 mSV (millisievert). At day 5-‐
7 all patients will undergo a CT scan to assess infarct size. Radiation exposure for this CT scan
is an attributable 2.1-‐2.3 mSV.
For CTA patients need to be injected with contrast fluid. We believe the indication for this
CTA justifies the extra contrast load.
10. ADMINISTRATIVE ASPECTS AND PUBLICATION
10.1 PRIVACY
All included patients will be assigned a unique number. Name and address will be stored
separately from the study data. Consent with participation in the study will be asked from all
patients after presenting them with standard written forms. The information describes the
purpose of the study, interventions, potential hazards and benefits and the procedures for
recording of clinical information and three month follow up.
10.2 SUBSTUDIES
Substudies will be carried out on the role of hemostatic factors as effect modifiers in
endovascular treatment (van Oostenbrugge), on costs and cost-‐effectiveness of
endovascular treatment (Roos), and on clinical and radiological predictors of recanalization
(Majoie) and functional outcome after treatment (Dippel). Interobserver and validation
studies of rapid reperfusion scores will be carried out. The MR CLEAN investigators share a
26

positive attitude towards the conductance of substudies in general. Proposals for substudies
will be discussed within the executive committee and decisions will be made by the steering
committee.
10.3 PUBLICATION POLICY

The writing committee for the main publication consists of members of the executive
committee. Publication of the main study results, substudies described in this protocol and
of future substudies will be on behalf of the MR CLEAN investigators. All investigators will
have the opportunity to read and comment on a manuscript before it will be submitted for
publication.

27


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34

TABLES
TABLE 1. ABBREVIATIONS
Abbreviation Description
ASPECTS Alberta Stroke Program Early CT score
BI Barthel index
CT Computed tomography
CTA Computed tomography angiography
DMC Data Monitoring Committee
EQ5D EuroQol 5 dimensions scale
GCS Glasgow Coma Score
ICH Intracerebral hemorrhage
MI Myocardial infarction
MRA Magnetic Resonance Angiography
MRI Magnetic Resonance Imaging
mRS Modified Rankin Scale
NIHSS National Institutes of Health Stroke Scale
PAD Peripheral arterial disease
TICI Thrombolysis in Cerebral infarction
TICS Telephone Interview for Cognitive 35

Status


TIMI Thrombolysis in Myocardial Infarction
36

TABLE 2: RANDOMIZED CLINICAL TRIALS OF INTRA-‐ARTERIAL THROMBOLYSIS

Poor outcome
Intervention-‐contrast N Recanalization ARR RR
Study mRS >2
15
PROACT I IA r-‐pro-‐UK + heparin vs heparin 42 15/26 vs 2/14 18/26 vs 11/14 9% 0.9 (0.6-‐1.3)
58% vs 14%
16
PROACT II IA r-‐pro-‐UK + heparin vs heparin 180 66% vs 18% 73/121 vs 14% 0.8 (0.7-‐1.0)
44/59
17
MELT Ia urokinase +/-‐ mechanical thrombectomy vs 114 53% vs (n.r.)* 29/57 vs 35/57 11% 0.8 (0.6 –
control 1.2)
19
SYNTHESIS IA alteplase w/wo MERCI vs I.V. alteplase, both 54 NR 52% vs72% 19% 0.7 (0.5 -‐1.1)
0.9 mg/kg
ARR=absolute risk reduction; RR= relative risk; mRS= modified Rankin Scale score. Recanalization: TIMI 2+3

37

TABLE 3 CONTROLLED STUDIES AND CASE SERIES OF I.V. + I.A. ALTEPLASE

Intervention (dose, mode) Design NIHSS N SICH Recanalization Poor
Study or (%) (N,%) outcome
author mRS >2
(N,(%)
22
EMS I.V. alteplase 0.6 mg/kg followed by i.a. alteplase vs RCT -‐ 35 6% 9/11 (82%) NR
i.a. alteplase alone
11% 5/10 (50%)
27
Wolfe I.V. alteplase 0.6 mg/kg followed by i.a. alteplase vs Cohort -‐ 96 12% 27/41 (66%) 22/41
i.a. alteplase alone (54%)
33/55 (60%)
35/55
(64%)
25
Ernst I.V. alteplase 0.6 mg/kg followed by i.a. Cohort 16 5% 11/16 (69%) 6/16 (38%)
alteplase
26
Suarez I.V. alteplase 0.6 mg/kg followed by i.a. alteplase / Cohort 45 0% 18/24 (67%) 5/24 (21%)
urokinase
29
Hill I.V. alteplase 0.9 mg/kg followed by i.a. alteplase Cohort 6 0% 3/6 (50%) NR
28
Shaltoni I.V. alteplase 0.9 mg/kg followed by i.a. Cohort 69 6% 50/69 (73%) 45%
thrombolytics
30
Burns I.v. alteplase 0.9 mg/kg followed by i.a. reteplase Cohort 33 12% 24/33 (73%) NR
w/wo mechanical thrombectomy
64
Keris IA alteplase 25mg followed by i.v. alteplase 25 mg RCT 45 0% 6/12 (50%) 2/12(17%)
versus no thrombolysis
0% NR 22/33
(67%)
65
IMS I I.V. alteplase 0.6 mg/kg followed by angiography and Cohort 80 6.3% 35/62 (56%) 46/80
endovascular treatment (ia alteplase, heparin) when (58%)
indicated

24
IMS II I.V. alteplase 0.6 mg/kg followed by angiography and Cohort 81 9.9% 33/55 (60%) 44/81
endovascular treatment (ia alteplase, heparin and i.a. (54%)
ultrasonography (MicroLysUS device)
31
Sohn I.v. alteplase, followed by i.a. urokinase and/or Cohort 14 157 12.7% NR NR
mechanical thrombectomy
38

32
Kim I.v. alteplase followed by urokinase Cohort 16 18 5.6% 16/18 (89%) 9/18 (50%)

39

TABLE 4 STUDIES OF MECHANICAL TREATMENT IN ACUTE ISCHEMIC STROKE

Device/ Therapeutic NIHSS N Recanalization Symptomatic Poor
Study Intervention Window (TIMI2,3) haemorrhages outcome
2 (N,%) (mRS >2)
(N,%)
(N,%)
33
MERCI –II MERCI retriever, i.a. alteplase 8 hrs 20 141 69 (46%) 11 (7%) 94/130
(72%)
Multi MERCI MERCI retriever, i.a. alteplase, 8 h 19 164 112 (68%) 16 (10%) 102/160
34
final 3 (68%)
preceded by i.v. alteplase
35
Devlin MERCI retriever, i.a. alteplase, 8h 18 25 14 (56%) 1 (4%) 19 (76%)
36
Kim MERCI retriever, i.a. alteplase, 8h 21 24 12 (50%) 2 (8%) 18 (75%)
37
Bose PENUMBRA device 8h 23 21 21 (93%) 2 (10%) ?
38
McDougall PENUMBRA device 8h 18 125 102 (82%) 14 (11%) 94 (75%)
40
Zaidat Wingspan-‐Neuroform stents w 8 h 18 9 8 (89%) 0 3 (33%)
or w/o i.a. or i.v. alteplase
41
Brekenfeld Wingspan stents after failed i.v. 8 hrs 14 12 11 (92%) 0 9 (75%)
treatment w or w/o i.v. or i.a.
alteplase

2
Recanalization and outcome rates, but not SICH rates were recalculated according to intent to treat principle, assuming that not-‐reported
patients (i.e. patients without intervention) had no recanalization and poor outcome.
3
In most studies, patients treated within 3 hrs received i.v. alteplase, and a small percentage was treated with i.a. thrombolytic.
40

TABLE 5A. MODIFIED RANKIN SCALE 6 6

Category Short description Long description
0 No symptoms No symptoms
1 Symptoms, no Minor symptoms that do not interfere with lifestyle
disability
2 Slight disability Slight disability, symptoms that lead to some restriction in lifestyle,
but do not interfere with the patient's capacity to look after himself.
3 Moderate Moderate disability, symptoms that significantly restrict lifestyle and

disability prevent totally independent existence
4 Moderately severe Moderately severe disability, symptoms that clearly prevent

disability independent existence though not needing constant attention
5 Severe disability Severe disability, totally dependent patient requiring constant

attention day and night.
6 Dead Death

41

TABLE 5B. THROMBOLYSIS IN CEREBRAL INFARCTION (TICI) SCALE. 4 5

Grade Short Long description
description
0 No Perfusion. No antegrade flow beyond the point of occlusion
1 Penetration The contrast material passes beyond the area of obstruction but fails to
With Minimal opacify the entire cerebral bed distal to the obstruction for the duration of
Perfusion. the angiographic run.
2 Partial The contrast material passes the obstruction and opacifies the arterial bed distal
perfusion. to the obstruction. However, the rate of entry of contrast into the vessel distal to
the obstruction and/or its rate of clearance from the distal bed are perceptibly
slower than its entry into and/or clearance from comparable areas not perfused
by the previously occluded vessel, eg the opposite cerebral artery or the arterial
bed proximal to the obstruction.
2a Partial filling Only partial filling of the entire vascular territory is visualized
only
2b Slow complete Filling of all of the expected vascular territory is visualized, but the filling is
filling slower than normal
3 Complete Antegrade flow into the bed distal to the obstruction occurs as promptly
perfusion as into the obstruction and clearance of contrast material from the
involved bed is as rapid as from an uninvolved other bed of the same
vessel of the opposite cerebral artery

42

TABLE 5C CLOT BURDEN SCORE FOR CTA AND MRA 4 6

Absence of contrast opafication at Score
Supraclinoid internal carotid artery 2
Proximal M1 2
Distal M1 2
Infraclinoid internal carotid artery 1

A1 branch 1
M2 brances 1
Total score: 10 – Sum Sum

43

TABLE 6A. SCHEDULE OF STUDY ACTIVITIES

Inclusion 24 hrs day 5-‐7 3 months
Clinical evaluation x x X x
NIHSS x x X
Laboratory x x
Neuroimaging x x X
Barthel index x X x
Modified Rankin Scale x
TICS x
EQ5D x
Academic Linear Dis. Scale x

44

TABLE 6B. LIST OF STUDY DATA

Screening
Inclusion criteria
Exclusion criteria

Baseline
Demographics Age, gender
Clinical NIHSS, NIHSS supplemental motor score, pre-‐stroke mRS, blood pressure,
GCS, weight, height, body temperature.
Medical history Previous stroke, previous MI, PAD, diabetes mellitus
Medication Antiplatelet agents, coumarines, heparin(oids), statines
Vascular risk factors Hypertension, atrial fibrillation, diabetes mellitus, smoking,

hypercholesterolemia
Laboratory parameters INR, kreatinine, GFR (Cockroft-‐Gault), serum glucose, CRP.
Neuro imaging4 CT: location, ASPECTS score, hemorrhagic transformation (NINDS/ECASS

classification), hyperdense artery sign.
CTA: location, clot burden score/collateral score
If possible CTP: location, infarct core size, penumbra size,

penumbra/infarct index.
Treatment Intended mode of endovascular treatment

4
Neuro-‐imaging parameters will be assessed by a central subcommittee.
45

Intervention
Modalities Actual treatment: i.a. thrombolysis (urokinase, alteplase, other),

mechanical treatment (device /type).
Timing Time of: onset (last seen well), admission, plain CT, CT angiography, (CTP)
start of i.v. alteplase, end of i.v. alteplase, start of endovascular
procedure (needle in groin), first i.a. bolus, end of revascularization, end
of procedure.
Dosages of Dose of urokinase, alteplase, other agent.

thrombolytics
Effect of intervention TICI score at start of procedure, TICI score at end of procedure
Complications Procedure-‐related complications
Neurological deterioration

Follow-‐up
Clinical assessment at 24 NIH Stroke Scale, NIHS supplemental motor scale,
hours
Complications
Neuro-‐imaging at 24 Plain CT: location, ASPECTS score, hemorrhagic transformation
hours (NINDS/ECASS classification), hyperdense artery sign.
CT angiography: location, Clot Burden Score/Collateral score
CT Perfusion: location, infarct core size, penumbra size,

penumbra/infarct index
Neuro imaging at 5-‐7 Plain CT: location, ASPECTS score, hemorrhagic transformation
days (NINDS/ECASS classification), hyperdense artery sign.
Clinical assessment at 1 NIH stroke scale; Barthel Index; Global assessment of improvement or
wk or discharge deterioration; clinical complications: hemorrhages; Laboratory: GFR.
Clinical assessment at 90 Modified Rankin score, NIH stroke scale, Barthel index, EQ5D, Academic
46

days. Linear Disability Scale, TICS

47

APPENDICES

APPENDIX 1. LIST OF COLLABORATING INVESTIGATORS
COORDINATING INVESTIGATORS
Puck Fransen, Dept of Neurology, Erasmus MC Rotterdam; JR2, AMC Amsterdam (vacancy),
JR3, Dept of Neurology, UMC Maastricht (vacancy).
PRINCIPAL INVESTIGATORS
Diederik Dippel, neurologist, Erasmus MC Rotterdam, Charles B Majoie, neuroradiologist,
AMC Amsterdam, Yvo Roos, neurologist, AMC Amsterdam, Robert van Oostenbrugge,
neurologist, UMC Maastricht, Aad van der Lugt, neuroradiologist, Erasmus MC Rotterdam.
LOCAL INVESTIGATORS:
More than 20 centers will join the pre-‐trial phase. A definite selection of 10-‐12 centers will
be made at the beginning of the year 2010.

48

APPENDIX 2. STUDY COMMITTEES
DATA MONITORING COMMITTEE

Chair: Professor Martin Brown, National Hospital for Neurology & Neurosurgery, London,
UK.
Member: Thomas Liebig
Independent Statistician: Theo Stijnen
EXECUTIVE AND WRITING COMMITTEE

AMC Amsterdam, Yvo Roos, neurologist, AMC Amsterdam, Wim van Zwam,
neuroradiologist, UMC Maastricht, Robert van Oostenbrugge, neurologist, UMC Maastricht,
Aad van der Lugt, neuroradiologist, Erasmus MC Rotterdam,
Puck Fransen, research coordinator, Erasmus MC Rotterdam.
Junior researchers at AMC Amsterdam and Maastricht UMC.
IMAGING ASSESSMENT COMMITTEE

Charles B Majoie, neuroradiologist, AMC Amsterdam, Aad van der Lugt, neuroradiologist,
Erasmus MC Rotterdam, , Wim van Zwam, neuroradiologist, UMC Maastricht, Rene van den
Berg, neuroradiologist, AMC Amsterdam, Geert Lyclama a Nijeholt, neuroradiologist, MC
Haaglanden, Den Haag, Trude Leertouwer, neuroradiologist, Erasmus MC Rotterdam, Henk
Marquering, medical physicist, AMC Amsterdam.
OUTCOME ASSESSMENT COMMITTEE

Yvo Roos neurologist, AMC Amsterdam (chair) Peter J Koudstaal, neurologist, Erasmus MC
Rotterdam, vacancies.
ADVERSE EVENT ADJUDICATION COMMITTEE

Robert van Oostenbrugge neurologist, UMC Maastricht (chair) vacancies
TRIAL STATISTICIANS
Hester Lingsma, methodologist, Erasmus MC Rotterdam, Ewoud Steyerberg, methodologist,
Erasmus MC Rotterdam
ADVISORY BOARD
Peter Koudstaal, neurologist, Erasmus MC Rotterdam, Tommy Andersson, neuro
interventionist, Karolinska Hospital, Stockholm, Sweden, Heinrich Mattle, neurologist,
University hospital, Bern, Switzerland, Nils Wahlgren, neurologist, Karolinska Hospital,
Stockholm, Sweden.

49

APPENDIX 3 RECOMMENDATIONS OF THE STEERING COMMITTEE WITH REGARD TO

ENDOVASCULAR TREATMENT PROCEDURES, THROMBOLYTIC AGENTS, AND TYPE OF
MECHANICAL THROMBECTOMY.

GENERAL
Randomization, inclusion in the trial and subsequent endovascular treatment should be
started as soon as possible after presentation in all eligible patients. The time-‐path below
gives an indication about how soon the following steps need to take place.
TABLE A1. OPTIMAL TIME-‐PATH FOR TREATMENT AND INCLUSION IN MR CLEAN OF
PATIENTS WITH ACUTE ISCHEMIC STROKE AND RELEVANT ANTERIOR CIRCULATION
ARTERIAL INCLUSION

Procedure Tx with i.v. alteplase No tx with i.v. alteplase
Arrival at ER 0 0
Start neuroimaging 20 min 20
Start iv-‐alteplase 30 min -‐
Randomization 60 min 30
Start endovascular treatment 90 min (since ER) 60

The selection process is shown in Figure 3 of the protocol. Three clinical situations can be
distinguished:
1 “No response to i.v. alteplase”: in these patients, there is no favorable response to
treatment with intravenous alteplase. Vascular neuroimaging (CTA, MRA, TCD) may follow
treatment with i.v. alteplase, but the steering committee recommends that vascular
neuroimaging is done at the start of i.v. treatment. The exact definition of favorable
response is left to the discretion of the local investigator, but the steering committee
suggests the following: neurological recovery to a level that would obviate the indication for
i.v. alteplase would the patient present with these symptoms. No minimum time period
between assessment of the response to i.v. alteplase and end of treatment is required, but
the steering committee recommends that randomization and inclusion into the trial,
andsubsequent endovascular treatment should be started as soon as possible.
2 “Outside therapeutic window for i.v. alteplase”: these patients present in the 4.5 to 6 hour
window. They can be included in the study, and randomized for endovascular treatment or
no endovascular treatment.
50

3 “ Contra-‐indications for i.v. alteplase”: these patients have contraindications for i.v.
alteplase that do not apply to mechanical thrombectomy, for example a recent cerebral
infarction in a different vascular area, previous cerebral hemorrhage, treatment with
coumarines leading with INR 1.7 to 3.0). They can be included in the study, and randomized
for endovascular treatment or no endovascular treatment. Intra-‐arterial thrombolysis is not
recommended for these patients, but mechanical thrombectomy ís.
NEUROIMAGING
Neuroimaging studies to assess vessel patency should preferably be done before or
simultaneously with treatment with i.v. alteplase, in order not to lose time and brain.
Especially, the delay between end of i.v. infusion and start of endovascular treatment should
be minimized to less than 1 hour.
THROMBOLYTIC AGENTS, DOSE AND TYPE

For intra-‐arterial thrombolysis urokinase or alteplase may be used. A dose of 1 mg alteplase
is considered to be equivalent to 12.500 U (10.000-‐15.000 U) urokinase. 44
Patients who have been pre-‐treated with iv alteplase should not receive more than 30 mg
alteplase during intra-‐arterial treatment, or an equivalent dose of 400,000 U urokinase. The
steering committee recommends that the thrombolytic agent is delivered in shots of 5 mg
alteplase or 50.000 – 100.000 U urokinase , in 5-‐10 minutes time intervals. Vessel patency
should be checked after each shot. Before the last i.a. shot is given, the interventionist has to
decide to go for mechanical thrombectomy. After mechanical thrombectomy the last 5mg
alteplase can be given, in order to prevent distal re-‐occlusion.
Patients should be treated with intra-‐arterial thrombolyis until recanalization is reached or
the maximum cumulative dose is reached. When intra-‐arterial treatment will be delivered
directly (i.e. within 30 minutes) after intravenous alteplase, the clinical investigator may
consider giving only 2/3 of the total i.v. alteplase dose. The safety of these dosing schedules
is discussed in section 1.2 of the protocol.
51

TABLE A2-‐A: DOSING SCHEME FOR INTRAVENOUS AND INTRA ARTERIAL THROMBOLYSIS
WITH ALTEPLASE OR UROKINASE

Weight Alteplase Alteplase Alteplase Alteplase N of
(kg) Bolus i.v 2/3 dose 1/3 dose Total i.v. i.a. shots
(mg) (mg) (mg) dose(mg) 5 mg alteplase or
or 60,000 U
urokinase
50 5 25 15 45 3
55 5 28 17 50 3
60 5 31 18 54 4
65 6 34 19 59 4
70 6 36 21 63 4
75 7 38 23 68 5
80 7 41 24 72 5
85 8 43 26 77 5
90 8 46 27 81 5
95 9 48 29 86 6
100 9 51 30 90 6
>100 9 51 30 90 6
MECHANICAL THROMBECTOMY
Randomized clinical trials of devices for mechanical thrombectomy have not been done.
General criteria for the use of devices in MR CLEAN are publication of a case series at least
20 patients treated with the device, with an acceptable rate of complications and a TIMI 2/3
recanalization rate of more than 50%.
Currently, two devices for mechanical thrombectomy (MERCI and PENUMBRA), specifically
designed for treatment of acute intracranial arterial occlusions have been evaluated in case
series, and have been FDA approved for this purpose. One catheter system, EKossonics SV,
designed for delivery of ultrasound-‐waves to the occluding thrombus, has been evaluated in
IMS2 and will be evaluated together with the MERCI system in IMS3. These devices have
been shown to be capable of recanalization, with an acceptable rate of complications.39
Therefore, Currently the MERCI, Penumbra, Solitaire and Ekossonics SV devices fulfill the
requirements as formulated by the steering committee (Table A3).
Two stent devices have been approved for intracranial treatment, but not for treatment of
patients with acute ischemic stroke, moreover published experience with treatment is
limited. The steering committee of MR CLEAN will be actively seeking evidence that will
make specific stenting devices acceptable for use in the trial.

52

TABLE A3. LIST OF MECHANICAL THROMBECTOMY DEVICES THAT ARE AVAILABLE IN THE
NETHERLANDS, THEIR MODE OF ACTION AND CURRENT STATUS.

6
Device Mode of
action
5
Manufacturer NL Dealer Approval Evaluation
7
studies

Allowed
Merci retriever R,A Concentric Medical Top Medical FDA CS
Penumbra System A,F Penumbra Incm US Penumbra FDA CS
Solitaire Stent (ev3) S EV3 Ev3 CE CS
EKossonic SV U EKOS Bothell Wash Angiocare CE CR

Pending
8
Wingspan stent A Boston Scientific Boston sci FDA CS
CATCH device R,A Balt Extrusion Angiocare CE CR
Revasc S Micrus Angiocare CE ?
Moses S Micrus Angiocare CE ?
Fast A Micrus Angiocare CE ?
Vasco+35ASPI A Balt Angiocare CE ?

5
R=retraction, A=aspiration, S=Stenting, F=Fragmentation, U= ultrasound enhanced lysis
6
FDA = Federal Drugs Agency, CE = Conformité Européenne, which means in concordance with European
legislation.
7
U=unpublished studies only, CR=case reports, CS=case series
8
Approved only for elective treatment of intracranial stenosis.

53

APPENDIX 4 INTERVENTION-‐RELATED ANGIOGRAPHIC IMAGING
WHEN
1) The pre-‐intervention angiogram should be performed via the guiding catheter to evaluate
the site of vessel occlusion, extent of thrombus, territories involved, concomittant
pathologies and to assess collateral flow. 45
2) After passing the occlusion site a microcatheter injection should be performed to assess
the distal vascular bed.
3) After each bolus of thrombolytic agent a control angiogram via a microcatheter injection
and/or guiding catheter injection should be performed to assess vessel patency.
4) After each passage of a mechanical device, a control angiogram should be performed via
the guiding catheter to assess vessel patency.
5) At the end of the procedure the angiogram should be repeated via the guiding catheter to
assess the final angiographic outcome
HOW
1. Pre-‐intervention and end-‐of-‐procedure angiogram:
The angiogram should include the internal carotid artery (or common carotid in case of
occlusion or severe stenosis of internal carotid) feeding the target vessel as demonstrated
on CTA.
To completely assess the collateral circulation, injections of the contralateral internal carotid
artery (or common carotid in case of occlusion or severe stenosis of internal) and the
dominant vertebral artery are preferred. However, they are not necessary for inclusion in
the study.
AP views and lateral views of the intracranial arteries are obtained. It is essential that the
angiograms include both the arterial and venous phases of the injection to evaluate the
collateral pathways and perfusion of the distal vascular bed.
The angiograms should be performed via the guiding catheter with the same catheter
position, contrast injection volume and rate (6-‐8ml with 4ml/s for internal carotid, 8-‐10ml
with 4-‐6ml/s for common carotid and 6-‐8ml with 4-‐5ml/s for vertebral artery), and
angiographic views before, after the procedures to adequately assess the results of therapy.
2. After passing the occlusion site, after each bolus of thrombolytic agent and after each
pass of a mechanical device:
At least one view, at the discretion of the interventionalist.

The complete series of the angiograms and microcatheter injections should be saved
according to the DICOM standard and a copy should be sent to the imaging assessment
committee.

54

FIGURES
FIGURE 1: TRIAL LOGO.

55

FIGURE 2
Assumed distribution of the primary outcome, according to the modified Rankin scale in
group receiving no intra-‐arterial treatment (mRS-‐C) (control) and the group receiving intra-‐
arterial treatment (mRS-‐I). THe cumulative proportion of patients in mRS 0-‐3 has increased
with 10%.

30%
25%
20%
proportion
15% mRS_C
mRS_I
10%
5%
0%
0 1 2 3 4 5 6
mRS score
56

FIGURE 3. RANDOMIZATION AND INCLUSION OF PATIENTS IN THE TRIAL

57

FIGURE 4. PATIENT FLOW IN THE TRIAL

58

Version 3.5 June 11 , 2014 MR CLEAN Trial protocol

MR CLEAN-‐Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the
Netherlands.
Protocol ID NTR1804 / ISRCTN10888758
Short title MR CLEAN
Version 3.5
Date June 11, 2014
Coordinating investigator and executive Diederik WJ Dippel, neurologist Erasmus MC
University Medical Center Rotterdam, PO Box 2040
committee of the trial
3000 CA Rotterdam, The Netherlands. T +31 10
7043979; F +31 10 7044721 E

d.dippel@erasmusmc.nl.
Yvo B Roos, neurologist AMC Amsterdam
Charles Majoie, radiologist, AMC Amsterdam
Aad van der Lugt, radiologist, Erasmus MC Rotterdam
Robert van Oostenbrugge, neurologist, Maastricht
UMC
Wim van Zwam, radiologist, Maastricht UMC
Sponsor Raad van Bestuur Erasmus MC University Medical
Center Rotterdam.

Participating centers 15. Erasmus MC Rotterdam

16. Amsterdam Medical Center
17. Maastricht Medical center
18. UMC Utrecht
19. LUMC te Leiden
20. UMC Nijmegen
21. Haaglanden Ziekenhuis Den-‐Haag
22. Haga Ziekenhuis Den-‐Haag
23. UMC Groningen
24. St. Elisabeth Zkh Tilburg
25. Isala klinieken Zwolle
26. Catharina Ziekenhuis Eindhoven
27. St. Antonius Nieuwegein
28. Rijnstate Ziekenhuis Arnhem
29. VUmc Amsterdam
59

30. Reinier de Graaf Groep Delft

31. Atrium Heerlen
32. Medisch Spectrum Twente Enschede
33. Sint Lucas Andreas Ziekenhuis Amsterdam
Independent physician(s) 15. Prof. dr. R.Q. Hintzen, Erasmus MC

16. Prof. dr. W.A. van Gool, AMC

17. Dr. C.G. Faber, Maastricht MC
18. Prof. dr. J.H.J. Wokke, UMC Utrecht
19. Dr. J.G. van Dijk, LUMC
20. Dr. R.A.J. Esselink, UMC Nijmegen
21. Dr. R. S. Rundervoort, Haaglanden DH
22. Dr. F. van Kooten, Erasmus MC Rotterdam
23. Dr. J.J. de Vries UMC Groningen
24. Dr. E.P.J. Arnoldus St Elizabeth Tilburg
25. Dr. A.W.J. van het Hof, Isala Zwolle
26. Dr. de Jonge Catharina ZKH Eindhoven
27. Dr. H.W. Mauser, St Antonius Nieuwegein
28. Dr. E.M. Hoogerwaard, Rijnstate Arnhem
29. Dr. J.C. Reijneveld, VUmc Amsterdam
30. Dr. F. van Kooten, ErasmusMC Rotterdam
31. Drs. van Vliet, Atrium Heerlen
32. Dr. L. Dorresteijn, Medisch Spectrum Twente
33. Drs. E.J. Wouda, Sint Lucas Andreas
Ziekenhuis Amsterdam

60

PROTOCOL SIGNATURE SHEET

Name Signature Date
Head of Department:

Professor dr PA Sillevis Smitt, neurologist
Coordinating Investigator/Project
leader/Principal Investigator:
Diederik WJ Dippel, neurologist

61

MR CLEAN -‐ PROTOCOL FOR A MULTICENTER

RANDOMIZED CLINICAL TRIAL OF ENDOVASCULAR
TREATMENT FOR ACUTE ISCHEMIC STROKE IN THE
NETHERLANDS (NTR1804/ISRCTN10888758)

Diederik W Dippel, Charles B Majoie,3 Aad van der Lugt,2 Wim van Zwam5 Robert J van Oostenbrugge,6
Puck Fransen,1,2 Debbie Beumer,1,6 Olvert A Berkhemer,1,3 Lucie A van den Berg4 and Yvo B Roos4 for the
MR CLEAN investigators.*

Departments of Neurology1 and Radiology2 of Erasmus MC University Medical Center Rotterdam,
Radiology3 and Neurology4 of the Academisch Medisch Centrum, Amsterdam, The Netherlands, and
Radiology5 and Neurology6 of the Maastricht University Medical Center, The Netherlands.

* The MR CLEAN investigators are listed in the appendix.
Correspondence:
Diederik WJ Dippel, Dept of Neurology, Erasmus MC University Medical Center Rotterdam, PO Box 2040
3000 CA Roterdam, The Netherlands. T +31 10 7043979; F +31 10 7044721 E d.dippel@erasmusmc.nl.

Original protocol : Version 3.0, date February 20, 2010
Amendment 1:Version 3.1, date March 6 ,2012
Amendment 2 :Version 3.2, date December 12, 2012
Amendment 3:Version : 3.3, date February 26, 2013
Amendment 4:Version 3.4, date September 5, 2013
Amendment 5:Version 3.5, date June 11, 2014

62


Summary ............................................................................................................................................................................................................................... 13
2. Objectives ........................................................................................................................................................................................................................ 17
3. Study design .................................................................................................................................................................................................................... 17
4.1 Population ................................................................................................................................................................................................................ 18
4.4 Sample size ............................................................................................................................................................................................................... 20
6.Methods ............................................................................................................................................................................................................................ 20
6.1 Study outcomes ...................................................................................................................................................................................................... 20
6.2 Randomization ........................................................................................................................................................................................................ 22
6.3 Blinding ...................................................................................................................................................................................................................... 22
7.1 Adverse events ....................................................................................................................................................................................................... 24
63

10.1 Privacy ..................................................................................................................................................................................................................... 26
10.2 Substudies .............................................................................................................................................................................................................. 26
References ............................................................................................................................................................................................................................ 28
Tables ..................................................................................................................................................................................................................................... 35

66
Table 5B. Thrombolysis in Cerebral Infarction (TICI) scale. ......................................................................................................................... 42
45
46
Appendices ........................................................................................................................................................................................................................... 48
Appendix 1. List of collaborating investigators ................................................................................................................................................... 48
Appendix 2. Study committees ................................................................................................................................................................................ 49
agents, and type of mechanical thrombectomy. ............................................................................................................................................... 50
anterior circulation arterial inclusion ..................................................................................................................................................................... 50
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase .................................. 52
status. ................................................................................................................................................................................................................................ 53
Appendix 4 Intervention-‐related angiographic imaging .................................................................................................................................. 54
Figures ................................................................................................................................................................................................................................... 55
Figure 1: Trial logo. ....................................................................................................................................................................................................... 55
Figure 2 ............................................................................................................................................................................................................................. 56
Figure 3. Randomization and inclusion of patients in the trial ...................................................................................................................... 57
64

Figure 4. Patient flow in the trial ............................................................................................................................................................................. 58
Summary ............................................................................................................................................................................................................................... 70
2. Objectives ........................................................................................................................................................................................................................ 74
3. Study design .................................................................................................................................................................................................................... 74
4.1 Population ................................................................................................................................................................................................................ 75
4.4 Sample size ............................................................................................................................................................................................................... 77
6.Methods ............................................................................................................................................................................................................................ 78
6.1 Study outcomes ...................................................................................................................................................................................................... 78
6.2 Randomization ........................................................................................................................................................................................................ 79
6.3 Blinding ...................................................................................................................................................................................................................... 80
7.1 Adverse events ....................................................................................................................................................................................................... 81
65

10.1 Privacy ..................................................................................................................................................................................................................... 83
10.2 Substudies .............................................................................................................................................................................................................. 84
References ............................................................................................................................................................................................................................ 84

66
Table 5B. modifed Thrombolysis in Cerebral Infarction (TICI) scale. ....................................................................................................... 95
45
46
Table 5d Arterial occlusive lesion scale ................................................................................................................................................................. 96
Appendices ......................................................................................................................................................................................................................... 100
Appendix 1. List of collaborating investigators ................................................................................................................................................. 100
Appendix 2. Study committees .............................................................................................................................................................................. 100
agents, and type of mechanical thrombectomy. ............................................................................................................................................. 102
anterior circulation arterial inclusion ................................................................................................................................................................... 102
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase ................................ 104
status. .............................................................................................................................................................................................................................. 105
Appendix 4 Intervention-‐related angiographic imaging ................................................................................................................................ 106
APPENDIX 5: Protocol amendment MR CLEAN trial; substantial Protocol 3.1. ..................................................................................... 106
APPENDIX 6 : PROTCOL AMENDMENT MR CLEAN TRIAL SUBSTANTIAL PROTOCOL 3.2 .................................................................... 107
Appendix 7: PROTCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.3 ..................................................................... 108
Appendix 8: PROToCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.4 .................................................................. 110
66

Appendix 9: PROToCOL AMENDMENT MR CLEAN TRIAL; PROTOCOL 3.5 .............................................................................................. 110
Appendix 10 Statistical analysis protocol (SAP) ................................................................................................................................................ 112
Introduction ....................................................................................................................................................................................................................... 112
Trial design ......................................................................................................................................................................................................................... 113
Blinding ........................................................................................................................................................................................................................... 114
References .......................................................................................................................................................................................................................... 117
Figures ................................................................................................................................................................................................................................. 118
Figure 1: Trial logo. ..................................................................................................................................................................................................... 118
Figure 2 ........................................................................................................................................................................................................................... 119
Figure 3. Randomization and inclusion of patients in the trial .................................................................................................................... 120
Figure 4. Patient flow in the trial ........................................................................................................................................................................... 121
Introduction ....................................................................................................................................................................................................................... 122
Trial design ......................................................................................................................................................................................................................... 123
67

Blinding ........................................................................................................................................................................................................................... 124
References .......................................................................................................................................................................................................................... 127

68

ACKNOWLEDGMENTS

MR CLEAN is partly funded by the Netherlands Heart Foundation (2008T030), and by
unrestricted grants from AngioCare BV, EV3®, MEDAC Gmbh/LAMEPRO, Penumbra Inc and
Concentric Medical /TOP Medical BV.
The study is designed, and will be conducted, analyzed, and interpreted by the investigators
independently of all sponsors.

69

SUMMARY
RATIONALE AND AIM

Intra-‐arterial treatment increases the likelihood of recanalization in patients with acute
ischemic stroke caused by proximal intracranial arterial occlusion. The purpose of the
Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in
the Netherlands (MR CLEAN) is to assess the safety and effect on functional outcome of
intra-‐arterial treatment in these patients.
DESIGN
MR CLEAN is a pragmatic phase III multicenter randomized clinical trial with blinded
outcome assessment. The intervention contrast is intra-‐arterial treatment versus no intra-‐
arterial treatment.
STUDY POPULATION
Patients should have a clinical diagnosis of acute ischemic stroke, MRI9 or CT ruling out
intracerebral hemorrhage, a score on the National Institutes of Health Stroke Scale (NIHSS)
of 2 points or more, a relevant intracranial arterial occlusion, demonstrated by neuro-‐
imaging and the possibility to start endovascular treatment within 6 hours after stroke
onset.
INTERVENTION
Endovascular treatment may consist of intra-‐arterial thrombolysis with urokinase or
alteplase, mechanical treatment or both. Mechanical treatment refers to retraction or
aspiration of the thrombus with a catheter guided device, or stenting. The exact choice of
endovascular treatment modality for each patient is left to the discretion of the local
investigator and treating physicians. The steering committee will provide recommendations
and guidelines for treatment and selection of patients in the study. Background medical
management is delivered according to national standards and guidelines. It may include
intravenous alteplase within the first 4.5 hours after onset.
MAIN STUDY OUTCOMES

The primary outcome is the score on the modified Rankin scale (mRS) 90 days after inclusion
in the study. Secondary outcomes are the NIHSS score at 24 hours, vessel patency at 24
hours and infarct size at day 5-‐7 and the occurrence of major bleeding.
The randomization will be stratified for use of intravenous alteplase, planned treatment
modality (intra-‐arterial thrombolysis, mechanical thrombectomy or both) and center. We
will estimate the effect of treatment by means of the ordinal logistic regression (shift
analysis), which considers the whole range of the mRS. In total, 500 patients will be included.

9
All abbreviations are listed in Table 1.
70

BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION.

All patients that participate in the trial will undergo a second CTA within 24 hours after
admission and a CT scan at day 5-‐7. All patients will have a telephone interview at three
months. Patients who are randomized for intra-‐arterial treatment sometimes need sedation
or anesthesia, and intubation during the procedure. Finally, endovascular treatment is
associated with increased risk of intra-‐cerebral hemorrhage.
DISCUSSION
MR CLEAN is a pragmatic trial. Inclusion of patients will take 4 years, and starts early in 2010.
Key words: alteplase, endovascular treatment, acute ischemic stroke, randomized controlled
trial

71

1. INTRODUCTION AND RATIONALE

In Western Europe and the US, the annual incidence of ischemic stroke is 1-‐2 per 1000.1, 2
Half of all patients with stroke die or remain severely handicapped. Stroke is one of the
major causes of death and the first cause of dependency in the western world. Treatment
with intravenous alteplase, aiming at early reperfusion has been proven effective for these
patients, when they are treated within 4.5 hours, and when there are no contra-‐
indications.3-‐5 The absolute reduction in the chance of poor outcome in patients treated with
i.v. alteplase within 3 hours from onset amounts to 10%; the number needed to treat is 10.6
For the patients treated within 3 to 4.5 hours, this effect was reduced to 7%, for a number
needed to treat of 14.4
In general, the number of patients eligible for treatment with intravenous alteplase is limited
because of the restricted time window. In about 25% of the patients with acute anterior
circulation ischemic stroke, symptoms are caused by a proximal occlusion of one of the
major intracranial arteries, i.e. the distal intracranial internal carotid artery, the proximal
segments of the middle cerebral artery and the anterior cerebral artery.7, 8 The likelihood of
a proximal occlusion increases with severity of the neurological deficit at presentation.9-‐11
The effect in these patients with a symptomatic intracranial arterial occlusion is limited.
Treatment with i.v. alteplase leads to recanalization in up to 33% of treated patients only.12
In those without recanalization, outcome is generally poor.13, 14
1.1 EFFECTIVENESS OF INTRA-‐ARTERIAL THROMBOLYSIS

Four randomized clinical trials that assessed the effectiveness of intra-‐arterial thrombolysis
in patients with acute ischemic stroke due to intracranial occlusion have been reported
(Table 2). The PROACT I and PROACT II were randomized controlled trials that compared
intra-‐arterial thrombolysis by means of pro-‐urokinase with treatment with heparin in
patients with angiographically demonstrated M1 of M2 segment occlusion, within 6 hours
from onset of symptoms. Recanalization rates were high and recanalization occurred more
often in the active treatment group than in controls.15, 16 The results of the PROACT-‐II study
indicated an improved functional outcome on day 90; 40% of the patients had a score on the
modified Rankin Scale (mRS) of less than 3). In total, 11% to 15% of the patients in the
PROACT studies had a symptomatic intracranial hemorrhage after treatment with intra-‐
arterial thrombolysis. A third randomized clinical trial from Japan (MELT) compared intra-‐
arterial urokinase with standard treatment (but not intravenous alteplase) within 6 hours
from onset was terminated prematurely. For a secondary endpoint, (mRS >2 at 90 days, a
significant effect was observed.17 The results of these trials have to be interpreted with care
and cannot be extrapolated to the current clinical situation. In the three trials, intravenous
alteplase was not an option, neither as pre-‐treatment nor as part of the control treatment.
In MELT, mechanical treatment was allowed, but not in PROACT I and II. MELT was an open
label randomized trial with blind outcome assessment, which implies that the treatment
effect could have been known at the time the decision was made to prematurely stop the
trial. In PROACT I and II the control treatment included intravenous heparin, which can now
be considered obsolete.18 Finally, a fourth, Italian RCT (SYNTHESIS) compared treatment
with intra-‐arterial alteplase with intravenous alteplase. The trial started in 2004, and was
stopped after 50 patients had been included. More patients with intra-‐arterial treatment
than patients with intravenous treatment showed recanalization and good outcome, but the
72

effect was not statistically significant.19 Several non-‐randomized studies with historical
controls,20 or controls in other centers,21 suggested a benefit of intra-‐arterial thrombolysis.

1.2 SAFETY OF INTRAVENOUS AND INTRA-‐ARTERIAL THROMBOLYSIS.

The combination of intravenous and intra-‐arterial rt-‐PA was compared with intravenous
placebo followed by intra-‐arterial alteplase in the EMS Bridging trial (Table 3). The risk of
hemorrhagic transformation was increased in patients who received the combination
treatment.22 In two observational studies, patients were treated within 5 hours from onset
of symptoms. The intravenous dose was adjusted to 0.6 mg/kg, with a maximum of 60 mg.
The incidence of hemorrhages was not larger than in studies of treatment with intravenous
thrombolysis only.23, 24 Similar results have been reported by others.25-‐27 In several case-‐
series, endovascular treatment with low dose i.a. alteplase was preceded by full dose i.v.
alteplase (i.e. 0.9 mg/kg). Risks for sICH ranged from 0 to 13%.28-‐32 These studies suggest that
in patients who have been treated in this way, recanalization rates can be high, without
unacceptable high risks of complications (Table 3).
1.3 SAFETY AND EFFECTIVENESS OF MECHANICAL TREATMENT

Mechanical treatment is a promising technique, either as a secondary in patients who do not
respond quickly to intra-‐arterial thrombolytic treatment, or in patients for whom
thrombolytic agents are contra-‐indicated. The MERCI device is a retractor device. Several
studies of the effect of treatment with the MERCI device have been published (Table 4).33-‐36
The rates of recanalization were similar to observed rates in the intra-‐arterial thrombolytic
treatment studies. However, these studies were not randomized, but used historical controls
derived from the NINDS RTPA stroke trial. The MERCI device has been approved by the FDA.
Several case series describing the treatment of symptomatic occlusion with other devices,
such as the PENUMBRA device and the EKossonic SV have been published.37-‐39 Other
approaches to mechanical treatment include use of aspiration devices, such as the
PENUMBRA device, which has also recently been approved for treatment of acute ischemic
stroke by the FDA, and stents, such as the EV3 stent, and the Wingspan stent.39-‐41 The
Wingspan stent itself is FDA approved for elective treatment of intracranial arterial stenosis
but not for treatment of acute ischemic stroke.
The results of these uncontrolled studies of mechanical thrombectomy are difficult to
compare, because of differences in case mix, pretreatment and patient selection, severity of
intracranial occlusions, and definitions of revascularization. However, these studies suggest
that in experienced hands, mechanical thrombectomy could be safe and may lead to
substantial recanalization rates. A recent AHA guideline therefore stated that “….Although
the Concentric MERCI device can be useful for extraction of intra-‐arterial thrombi in
appropriately selected patients, the utility of the device in improving outcomes after stroke
remains unclear. “ and “The usefulness of other endovascular devices is not yet established,
but they may be beneficial.”18
1.4 NEEDED: A RANDOMIZED CLINICAL TRIAL OF ENDOVASCULAR TREATMENT IN ACUTE
ISCHEMIC STROKE
73

We conclude from this overview that intra-‐arterial treatment, either with a thrombolytic
agent or by mechanical means is able to recanalize acutely occluded cerebral arteries in
selected patients, within reasonable safety margins. Whether this is the case in an
unselected sample of patients with acute ischemic stroke caused by occlusion is likely, but
unproven. A randomized clinical trial addressing the question whether intra-‐arterial
treatment improves neurological outcome in patients with a relevant occlusion in the
intracranial proximal anterior circulation is therefore needed.
For the trial results to be generalizable and representative of what is state of the art
approach in intra-‐arterial treatment, the trial design should accommodate the possibility to
use local fibrinolytics and or mechanical thrombectomy devices, for a broad range of
patients with acute ischemic stroke caused by a proximal thrombo-‐embolic occlusion of one
of the intracranial arteries belonging to the anterior circulation.
Important subgroups to whom this question of effectiveness and safety applies are patients
who have been treated unsuccessfully with intravenous thrombolysis, patients who can be
treated within 6 hours, but do not meet the time-‐window requirements for intravenous
thrombolysis, and patients with contra-‐indications for intravenous and/or intra-‐arterial
thrombolytic treatment (thrombectomy only). To answer this question, we initiated a large
multicenter pragmatic trial of intra-‐arterial treatment (by means of alteplase and or
mechanical treatment) versus standard medical treatment, in patients with acute ischemic
stroke of less than 6 hours of onset, the MR CLEAN study.
The trial applies the grey area principle: when a patient’s clinical profile meets inclusion and
exclusion criteria, and according to investigator and treating physician there is sufficient
uncertainty concerning the question whether the patient should receive intra-‐arterial
treatment, the patient is eligible for inclusion in the trial.
2. OBJECTIVES
overall functional outcome after acute ischemic stroke of less than six hour duration, in
patients with a symptomatic occlusion. The secondary objectives are to assess the safety of
endovascular treatment with regard to the occurrence of hemorrhagic and ischemic
complications, the efficacy with regard to obtaining recanalization, and to evaluate
predictors of recanalization, including imaging aspects and hemostatic parameters.
Moreover, we want to assess the safety and efficacy of different types of endovascular
treatment (i.e. mechanical treatment, intra-‐arterial thrombolysis) different combinations of
treatment (i.e. with intravenous alteplase) and different timings of treatment. Tertiary
objectives are to carry out case studies of implementation strategies and loco-‐regional
solutions for barriers to the delivery of endovascular treatment for acute ischemic stroke
and to collect data for cost-‐effectiveness analysis of endovascular treatment compared with
standard treatment.
3. STUDY DESIGN
74

The intervention contrast is endovascular treatment (alteplase or urokinase, and/or
mechanical treatment) versus no endovascular treatment. The treatment is provided in
addition to best medical management, including intravenous thrombolysis.
The study will run in at least 10 large hospitals in the Netherlands for a period of five years (4
years of patient inclusion), and starts in 2010.
4. STUDY POPULATION
4.1 POPULATION
Patients over 18 years old, with acute ischemic stroke, a symptomatic anterior proximal
artery occlusion which can be treated within 6 hours after stroke onset are eligible for
participation in this trial.

4.2 INCLUSION AND EXCLUSION CRITERIA
INCLUSION CRITERIA
• A clinical diagnosis of acute stroke, with a deficit on the NIH stroke scale of 2 points or more.
(M1/M2) or anterior (A1/A2) cerebral artery, demonstrated with CTA, MRA or DSA.
• Age 18 or over.

GENERAL EXCLUSION CRITERIA

• Intravenous treatment with thrombolytic therapy in a dose exceeding 0.9 mg/kg alteplase or 90 mg.
• Intravenous treatment with thrombolytic therapy despite contra-‐indications, i.e. major surgery,
gastrointestinal bleeding or urinary tract bleeding within the previous 2 weeks, or arterial puncture at
a non-‐compressible site within the previous 7 days.
• Cerebral infarction in the distribution of the relevant occluded artery in the previous 6 weeks.
SPECIFIC EXCLUSION CRITERIA FOR INTENDED MECHANICAL THROMBECTOMY

9
• Laboratory evidence of coagulation abnormalities, i.e. platelet count <40 x 10 /L, APTT>50 sec or INR
>3.0.
SPECIFIC EXCLUSION CRITERIA FOR INTENDED INTRA-‐ARTERIAL THROMBOLYSIS

75

9
• Clinical or laboratory evidence of coagulation abnormalities, i.e. platelet count <90 x 10 /L, APTT>50
sec or INR >1.7. Current treatment with oral thrombin antagonists, such as argatroban and dabigatran
or treatment with oral selective Factor Xa inhibitors, such as rivaroxaban.

4.3 PARTICIPATING CENTERS AND CENTER ELIGIBILITY

To be fully eligible for participation in the trial and to include patients in the trial, centers
should meet the following minimum criteria:
• The center should have experience in conducting acute stroke trials.
• The intervention team should have ample experience with endovascular interventions for
cerebrovascular disease (carotid stenting or aneurysm coiling), peripheral artery disease, or coronary
artery disease.
• At least one member of the intervention team should have sufficient experience with intra-‐arterial
thrombolysis.
In order to include and randomize patients who may be treated with mechanical
thrombectomy centers should meet the following additional criteria:
• The intervention team should make use of one or more of the devices that have been approved by the
trial steering committee. Other devices are not allowed into the trial.
• At least one member of the intervention team should have sufficient experience with the particular
device.
Sufficient experience is defined as the completion of at least 5 full procedures with het
particular device. Procedures that have been carried out by two team members (for
example, in a training setting) do count. Procedures do not need to be successful, nor
uncomplicated. Procedures consisting of mechanical thrombectomy combined with intra-‐
arterial thrombolysis count for both.
Centers that do not comply with the third criterion may participate in the registration phase
of the study. In these centers, patients cannot be included and randomized. However,
patients who undergo intra-‐arterial treatment will be registered and data will be processed.
The center can apply for a status as fully participating center when criterion 3 is met.
Note that patients may only be included in the trial when the intervention team that will
actually treat the patient includes at least one member with sufficient experience when one
of the treating interventionists. For this reason, the possibility of treatment by an
interventionist with sufficient experience is listed as an inclusion criterion.
Training sessions for intra-‐arterial thrombolysis and mechanical treatment will be held, draft
guidelines and recommendations for endovascular procedures and general management of
included patients, on paper and on video will be issued by the steering committee and
distributed among participating centers.
Three centers will be added as ‘randomization centers’. These centers do not have an
intervention team, but are in close range to an approved and active MR-‐CLEAN participating
center with a neurointerventional team. If a patient presents in a randomization center, who
is eligible for inclusion in the MR CLEAN trial, the neurologist will contact the closest MR
CLEAN center with an active interventional team. If the interventional team is available, the
neurologist will proceed to randomize the patient. Either the patient will be included in the
treatment arm and will be transferred to the center with the interventional team or the
76

patient will be assigned to the standard arm and will remain at the randomization center.
Follow up will be monitored in this center until discharge. 10
4.4 SAMPLE SIZE

The effect of the intervention on the primary outcome (the mRS, a 7-‐point ordered
categorical scale) will be assessed with ordinal logistic regression. We assume a moderate
effect of 10% absolute increase in the cumulative proportion of patients with mRS 0-‐3 in the
intervention group, compared with controls. We based the distribution of outcome
categories on the results of the PROACT II trial.15 Figure 2 shows the expected distributions
of mRS categories. A total study size of 500 patients (2x250 pts) provides a power (1-‐beta) of
82% at a significance level of 0.05, taking into account 10% cross over rate. 42
This sample size is also sufficient to assess the effect of the intervention on secondary
endpoints: Analysis of a meaningful reduction on NIH stroke scale at one week of 3-‐4 points
(Cohen’s d=0.33) would require a sample of 400 patients, assuming that at 24-‐48 hours
mean NIH would be 12, with a standard deviation of 10. A doubling of the recanalization rate
from 30% to 60% would require 126 patients to achieve a power of 0.90.
Simulation studies have indicated that ordinal logistic regression is a more powerful method
for analysis of trials with ordered categorical outcome data, and have proven its robustness
against violations of the proportional odds assumption.43
5.TREATMENT OF SUBJECTS
5.1 INVESTIGATIONAL TREATMENT

Endovascular treatment will consist of arterial catheterization with a microcatheter to the
level of occlusion and delivery of a thrombolytic agent and/ or mechanical thrombectomy.
Both alteplase and urokinase for intra-‐arterial thrombolysis is allowed into the trial, a dose
of 1 mg alteplase is considered to be equivalent to 10.000-‐15.000 U urokinase.44
Mechanical treatment may consist of mechanical thrombectomy, aspiration, or stenting.
Specific recommendations with regards to procedures and devices will be issued regularly by
the trial steering committee.
The steering committee will make recommendations for dosages of thrombolytic agents,
procedures, and for devices that will be allowed in the trial based on proposals by the
executive committee or local investigators. The requirements for a device being allowed for
use in the trial are: documented evidence of safety in experienced hands, and recanalization
rates that are similar to rates with other mechanical devices. Devices that are currently
allowed in the trial are listed in Appendix 4. Evidence on safety or efficacy of particular
devices from other studies, or recommendations made by the DMC on the basis of
monitoring results, or both, may lead the steering committee to decide to discontinue

10
One of the randomization centers (Reinier de Graaf) has the available resources to treat
patients with intra-‐arterial therapy (equipment and supporting staff) but there is a shortage
of neurointerventionalist. Instead of transferring the patient to the closest MR CLEAN center
(HAGA) the members of the neurointerventional team will visit the Reinier de Graaf hospital.

77

allowance into the trial of a particular device. Proposals will be prepared by the executive
committee, and should be approved by a majority of the steering committee.
6.METHODS
6.1 S TUDY OUTCOMES
PRIMARY OUTCOME
The primary outcome is the score on the modified Rankin scale at 90 days (Table 5a).

SECONDARY OUTCOMES
IMAGING PARAMETERS
• Vessel recanalization at 24 hours after treatment, assessed by CTA or MRA. The criteria for
recanalization on CTA or MRA are based on the Arterial Occlusive Lesion (AOL) scale, and the Clot
46
Burden Score, proposed by Puetz et al (Table 5c) .
• Infarct size assessed by CT on day 5-‐7, using standard methods, including manual tracing of the infarct
47, 48
perimeter and semi-‐automated pixel thresholding. Infarct size at day 5-‐7 will be compared with
plain CT and perfusion CT results (if available) at baseline.
• CTA or MRA at 24 hours will be compared with baseline vessel imaging data, to estimate the
recanalization rate. Perfusion CT at baseline is optional, but available at most centers. Clinical
parameters
CLINICAL PARAMETERS
• NIHSS 49, including NIH supplemental motor score,50 at 24 hours.
• NIHSS at 1 week or at discharge.
FUNCTIONAL OUTCOME
• Score on the EQ5D at 90 days,51
• Barthel index at 90 days.52

The 90-‐days follow-‐up will be conducted by telephone interview, through the central trial
office.
SAFETY PARAMETERS
Safety is an issue of concern, as the experience with the intervention, overall, and within the
participating centers, is limited. Safety parameters include hemorrhagic complications, and
short term outcome (mortality, Barthel index and NIHSS at 24 hours and at one week or
78

discharge). As we will make use of web-‐based data-‐entry, these data will be available on
short notice.
The primary safety parameter will be neurologic deterioration within 24 hours from inclusion
in the study. Neurological deterioration is defined as any decline in NIHSS of more 4 points
or more. In these patients, urgent brain CT is mandatory. This serious adverse event will be
cause. A full list of serious adverse events is provided in section 7.1 Adverse events.
If the local investigator or other member of the team at a trial centre has a concern about
the outcome of their trial procedures, they should inform the MR CLEAN trial office, which
will organize a blinded assessment of the relevant outcome events. This will be submitted by
the central office to the chairman of the data monitoring committee, who may recommend
further action, such as suspending randomization at the centre. Similarly, the database
manager at the trial office will monitor outcome events and if there are three consecutive
deaths or three consecutive serious adverse events at a single centre within 30 days of
treatment in the same arm of the study, then assessment of the events will be triggered. A
cumulative death rate of more than 50% or a cumulative serious adverse event rate
exceeding 20% over 10 cases during hospital admission would also trigger careful
assessment of the relevant outcome events.
DATA FOR COST-‐EFFECTIVENESS ANALYSIS

A limited amount of health and medical costs data will be collected, in a piggy-‐back fashion
i.e. during the registration of other data, and will include length of stay. Measurement of
health care costs will be based on international and national guidelines.58, 59 Analysis of these
data however, and the modeling for the cost-‐effectiveness study is outside the scope of the
current study. Therefore a separate substudy on cost-‐effectiveness will be carried out (see
10.2 substudies and the separate substudy protocol for more detailed information).
6.2 RANDOMIZATION
The randomization procedure will be computer-‐ and web-‐based, using permuted blocks.
Back-‐up by telephone will be provided. Randomization is allowed when the occlusion has
been established by CTA, MRA, DSA or TCD. Selection of patients for randomization follows
the grey area principle. Randomization will be stratified for center, use of intravenous
alteplase, planned treatment modality (mechanical thrombectomy or not) and stroke
severity, (NIHSS >14 or not).
Patients with contra-‐indications for intravenous thrombolysis are allowed into the trial. This
concerns patients who cannot be treated within 4.5 hours from onset, but only in the 4.5 to
6 hour interval, and patients with either major surgery, gastrointestinal bleeding or urinary
tract bleeding within the previous 2 weeks, or arterial puncture at a non-‐compressible site
within the previous 7 days.
Patients with exclusion criteria for intra-‐arterial thrombolysis are also allowed into the trial.
They can be included and randomized for endovascular treatment or no endovascular
treatment. Treatment with mechanical thrombectomy is allowed, but intra-‐arterial
thrombolysis is not allowed in these patients. The treating physicians are free to change the
actual mode of treatment during the procedure, as long as they comply with the treatment-‐
specific exclusion criteria and recommended devices.
79

6.3 BLINDING
It will not be possible to view the treatment allocation before the patient is registered in the
study database, nor will it be possible to remove the patient from the study base after
treatment assignment has become known. Both patient and treating physician will be aware
of the treatment assignment. Information on outcome at three months will be assessed
through standardized forms and procedures. Assessment of outcome on the modified
Rankin scale will be based on this information, by assessors who are blind to the treatment
allocation. Results of neuroimaging will be also assessed in a blinded manner. Information on
treatment allocation will be kept separate from the main study database. The steering
committee will be kept unaware of the results of interim analyses of efficacy and safety. The
trial statistician will combine data on treatment allocation with the clinical data in order to
report to the data monitoring committee (DMC).

6.4 STUDY PROCEDURES
BASELINE DATA OBTAINED AT ADMISSION

Clinical data, neuro-‐imaging data and procedure-‐related data that might be related to
treatment effect or to adverse events caused by the intervention, as well as several stroke
risk factors, in order to illustrate the representativeness of the study population will be
recorded (Table 6).
INCLUSION AND RANDOMIZATION

A minimal amount of data has to be entered before randomization, as randomization will be
stratified. The trial office will be notified when a new patient is entered into the web-‐based
database. A treatment allocation will be provided by the web-‐based computer system.
Personal data will be sent to the trial office separately, through scrambled email.
FOLLOW-‐UP DATA
At 24 hours, a clinical examination including NIH stroke scale assessment will be carried out.
Also, all patients will undergo CTA or MRA imaging. At day 5-‐7 all patients will undergo CT or
MRI. Raw data will be forwarded to the trial office for blind evaluation. At 1 week, clinical
status, NIH stroke scale score and adverse events will be reported as well as discharge
destination, in order to enable the trial office to conduct the final 3-‐month follow-‐up by
telephone interview.
The standardized telephone interview will include a short questionnaire based on the three
simple questions, assessment of modified Rankin Scale, Barthel Index, and Euroqol5D.51-‐53, 60-‐
62
.
WITHDRAWAL
80

Patients can leave the study at any time for any reason if they wish to do so without any
consequences. The investigator can decide to withdraw a subject from the study or stop the
allocated intervention for urgent medical reasons. Every attempt will be made to complete
follow-‐up in these patients.
6.5 TRIAL ORGANIZATION

The steering committee will make decisions regarding continuation of the trial and protocol
changes. Decisions will be prepared by the executive committee. The chairman of the
steering committee will be advised by the independent data monitoring and safety
committee, see section 7.2 Safety and data monitoring committee. The steering committee
consists of the local investigators from each center, a neurologist and a neuro-‐
interventionist, and the executive committee. The executive committee consists of the six
co-‐principal investigators, and study-‐coordinator. The post of study-‐coordinator will be taken
by each of three junior-‐researchers, taking turns. The study-‐coordinator is responsible for
running the trial on a day-‐to-‐day basis, and will report to the executive committee. The
executive committee will meet on a bi-‐monthly basis. The steering committee will meet at
least annually. The steering committee meeting is chaired by the principal investigator (DD).
Other important committees are the neuro-‐imaging assessment committee, the functional
outcome adjudication committee and the serious adverse event adjudication committee.
The trial office is located in Rotterdam, Erasmus MC University Medical Center. The neuro-‐
imaging assessment unit is located in AMC, Amsterdam.
7.SAFETY REPORTING.
7.1 ADVERSE EVENTS

Adverse events are undesirable experiences occurring to a subject during the study, whether
or not they are considered to be related to the experimental treatment. All adverse events
reported spontaneously by the subject or observed by the investigator or his staff will be
recorded.
A serious adverse event is any untoward medical occurrence or effect that can cause
mortality, is life-‐threatening, requires prolonged hospitalization, or results in persistent
significant disability.
Expected serious adverse events are neurologic deterioration, symptomatic intracranial
hemorrhage, extracranial hemorrhage, technical complications or vascular damage at the
target lesion such as perforation or dissection and mortality in the first week of stroke,
aspiration pneumonia, allergic reaction towards contrast fluid, death from any cause within
the study period.
A cumulative log will be kept of all serious adverse events, for review by the DMC.
7.2 SAFETY AND DATA MONITORING COMMITTEE

In order to increase the safety of the intervention, the trial will be monitored by an
independent data monitoring committee (DMC). The data monitoring committee will be
chaired by a neurologist, and include a neuro-‐interventionist and an independent
methodologist/statistician. The DMC will meet frequently and assess the occurrence of
unwanted effects by center and by procedure. During the period of intake to the study,
81

interim analyses of mortality and of any other information that is available on major
endpoints (including serious adverse events believed to be due to treatment) will be
supplied, in strict confidence, to the chairman of the Data Monitoring Committee, along with
any other analyses that the Committee may request. In the light of these analyses, the Data
Monitoring Committee will advise the chairman of the Steering Committee if, in their view,
the randomized comparisons in MR CLEAN have provided both (i) "proof beyond reasonable
doubt" that for all, or for some specific types of patients, one particular treatment is clearly
indicated or clearly contraindicated in terms of a net difference in outcome, and (ii) evidence
that might reasonably be expected to influence materially patient management. Appropriate
criteria of proof beyond reasonable doubt cannot be specified precisely, but a difference of
at least 3 standard deviations in an interim analysis of a major endpoint may be needed to
justify halting, or modifying, the study prematurely. This criterion has the practical
advantage that the number of interim analyses is of little importance.
8. STATISTICAL ANALYSES
Baseline characteristics will be summarized by means of simple descriptive statistics. The
main analysis of this trial consists of a single comparison between the trial treatment groups
of the primary outcome after 90 days. The analysis will be based on the intention-‐to-‐treat
principle. The primary effect parameter should take the whole range of the modified Rankin
scale (mRS) into account and is defined as the relative risk for improvement on the mRS
estimated as an odds ratio with ordinal logistic regression.63
Multivariable regression analysis will be used to adjust for chance imbalances in main
prognostic variables between intervention and control group, such as age, stroke severity
(NIHSS), time since onset, previous stroke, atrial fibrillation and diabetes mellitus. Secondary
effect parameters will be the improvement according to the classical dichotomizations of the
modified Rankin scale at 0-‐1 vs 2-‐6 and 0-‐2 vs 3-‐6, the presence of vessel patency on CTA,
MRA or DSA at 24 hours, and the score on the NIHSS at 24 hours and 1 week or discharge.
With regard to the range of secondary outcome parameters we will use simple 2x2 tables,
two-‐group t-‐tests, Mann-‐Whitney tests, and multivariable linear and logistic regression
models, where appropriate. In all analyses, statistical uncertainty will be quantified by
means of 95% confidence intervals. Subgroup analyses will be carried out to estimate the
effect intra-‐arterial thrombolysis, mechanical treatment and combination therapy. Although
the size of this study will not allow for precise estimates of treatment effect in subgroups,
we will assess heterogeneity of effects, and analyze consistency of effects on secondary
outcomes.
9.ETHICAL CONSIDERATIONS, ACCESS TO APPROPRIATE TREATMENT
9.1 REGULATION STATEMENT

The trial will be conducted in accordance with the principles of the Declaration of Helsinki, as
amendended by the World Medical Association General Assembly in October 2008, and with
the guidelines for Good Clinical Practice.
9.2 RECRUITMENT AND CONSENT
82

Written informed consent will be obtained from all patients and a copy must be retained by
the randomizing centre. All patients will be provided with a written explanation of the study.
Because of the urgent character of the treatment informed consent is subdivided in an
informed consent form with a short description of the procedure for immediate use, and an
extensive version which will be discussed with the patient after the procedure.
After approval by the patient or his/her legal representative, the patient’s treating physician
will inform a study physician of the presence of a patient with acute ischemic stroke who is
potentially eligible for the present study. The study physician will inform the patient orally
and in writing and will obtain his/her written informed consent. In case the patient is legally
incompetent, for example because of aphasia or anosognosia, written informed consent will
be obtained from a legal representative. Because the study physicians are also involved in
the clinical care of patients with acute ischemic stroke, it appears inevitable that in some
occasions the study physician will also be the patient’s treating physician.
As this is an acute stroke trial with a narrow time window for the start of treatment, and
because of time-‐consuming study-‐related procedures after informed consent will be
obtained, the time for consideration of participation in the trial will be limited to the first
few hours after stroke onset. Even within this time frame, a decision on participation should
preferably be taken as soon as possible, at least within 30 minutes.
Especially patients with large cortical infarcts may not be able to judge the pros and cons of
participation in the trial sufficiently, most often because of aphasia. As aphasia is present in
approximately 25% of the patients with acute stroke and because patients with large cortical
infarcts may benefit most from intra-‐arterial treatment on theoretical grounds, it may be
considered inappropriate to exclude these patients from the trial. Incapacitated patients in
the control group are treated according to current standards and participation in the trial
does therefore not carry a risk; the burden caused by the additional investigations is
considered minimal.
9.3 ACCESS TO APPROPRIATE TREATMENT.

The design of MR CLEAN allows that all patients with an indication for intravenous alteplase
will be treated accordingly. All patients will be managed according to local stroke care
protocols, which have to be in agreement with national guidelines.
9.4 RADIATION EXPOSURE

All participants in the trial will undergo CTA at 24-‐28 hours to assess recanalization after
treatment. Radiation exposure for CTA is an attributable 3.5-‐3.6 mSV (milliSievert). At day 5-‐
7 all patients will undergo a CT scan to assess infarct size. Radiation exposure for this CT scan
is an attributable 2.1-‐2.3 mSV.
For CTA patients need to be injected with contrast fluid. We believe the indication for this
CTA justifies the extra contrast load.
10. ADMINISTRATIVE ASPECTS AND PUBLICATION
10.1 PRIVACY
All included patients will be assigned a unique number. Name and address will be stored
separately from the study data. Consent with participation in the study will be asked from all
83

patients after presenting them with standard written forms. The information describes the
purpose of the study, interventions, potential hazards and benefits and the procedures for
recording of clinical information and three month follow up.
10.2 SUBSTUDIES
Substudies will be carried out on the role of hemostatic factors as effect modifiers in
endovascular treatment (van Oostenbrugge). The hematological substudy is called: SMARTIS
(the study of haemostatic markers in intra arterial treatment for acute ischemic stroke). We
refer to a separate study protocol for this. A second substudy will be carried out to
investigate the role of MRI (DWI sequence). This sequence is conducted to identify the
infarct core (see separate substudy protocol: DIANE; (“Value of Diffusion-‐Weighted MRI for
Selection of Patients for IA Treatment for Acute Ischemic Stroke in the NEtherlands”).
Furthermore we will carry out a third substudy on long term follow-‐up and cost-‐
effectiveness of endovascular treatment (Roos) . For this study the follow-‐up will be
extended to two years. We refer to a separate substudy protocol for a detailed description (
‘CLOT-‐MR CLEAN: Cost-‐effectiveness analyses and LOng Term follow-‐up in patients
randomised in a multicenter randomized clinical trial of endovascular treatment for acute
ischemic stroke in The Netherlands’).
A substudy on clinical and radiological predictors of recanalization (Majoie) and functional
outcome after treatment (Dippel) as well as interobserver and validation studies of rapid
reperfusion scores will be carried out. The MR CLEAN investigators share a positive attitude
towards the conductance of substudies in general. Proposals for substudies will be discussed
within the executive committee and decisions will be made by the steering committee.
10.3 PUBLICATION POLICY

The writing committee for the main publication consists of members of the executive
committee. Publication of the main study results, substudies described in this protocol and
of future substudies will be on behalf of the MR CLEAN investigators. All investigators will
have the opportunity to read and comment on a manuscript before it will be submitted for
publication.

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90

Tables
TABLE 1. ABBREVIATIONS

Abbreviation Description
ALDS Academic Medical Center Linear Disability Scale
ASPECTS Alberta Stroke Program Early CT score
BI Barthel index
CT Computed tomography
CTA Computed tomography angiography
DMC Data Monitoring Committee
DWI Diffusion Weighted Imaging
EQ5D EuroQol 5 dimensions scale
GCS Glasgow Coma Score
ICH Intracerebral hemorrhage
MI Myocardial infarction
MRA Magnetic Resonance Angiography
MRI Magnetic Resonance Imaging
mRS Modified Rankin Scale
NIHSS National Institutes of Health Stroke Scale
PAD Peripheral arterial disease
TICI Thrombolysis in Cerebral infarction
TICS Telephone Interview for Cognitive Status
TIMI Thrombolysis in Myocardial Infarction
91

TABLE 2: RANDOMIZED CLINICAL TRIALS OF INTRA-‐ARTERIAL THROMBOLYSIS

Poor outcome
Intervention-‐contrast N Recanalization ARR RR
Study mRS >2
15
PROACT I IA r-‐pro-‐UK + heparin vs heparin 42 15/26 vs 2/14 18/26 vs 11/14 9% 0.9 (0.6-‐1.3)
58% vs 14%
16
PROACT II IA r-‐pro-‐UK + heparin vs heparin 180 66% vs 18% 73/121 vs 14% 0.8 (0.7-‐1.0)
44/59
17
MELT Ia urokinase +/-‐ mechanical thrombectomy vs 114 53% vs (n.r.)* 29/57 vs 35/57 11% 0.8 (0.6 –
control 1.2)
19
SYNTHESIS IA alteplase w/wo MERCI vs I.V. alteplase, both 54 NR 52% vs72% 19% 0.7 (0.5 -‐1.1)
0.9 mg/kg
ARR=absolute risk reduction; RR= relative risk; mRS= modified Rankin Scale score. Recanalization: TIMI 2+3

92

TABLE 3 CONTROLLED STUDIES AND CASE SERIES OF I.V. + I.A. ALTEPLASE

Intervention (dose, mode) Design NIHSS N SICH Recanalization Poor
Study or (%) (N,%) outcome
author mRS >2
(N,(%)
22
EMS I.V. alteplase 0.6 mg/kg followed by i.a. alteplase vs RCT -‐ 35 6% 9/11 (82%) NR
i.a. alteplase alone 11% 5/10 (50%)
27
Wolfe I.V. alteplase 0.6 mg/kg followed by i.a. alteplase vs Cohort -‐ 96 12% 27/41 (66%) 22/41
i.a. alteplase alone 33/55 (60%) (54%)
35/55
(64%)
25
Ernst I.V. alteplase 0.6 mg/kg followed by i.a. Cohort 16 5% 11/16 (69%) 6/16 (38%)
alteplase
26
Suarez I.V. alteplase 0.6 mg/kg followed by i.a. alteplase / Cohort 45 0% 18/24 (67%) 5/24 (21%)
urokinase
29
Hill I.V. alteplase 0.9 mg/kg followed by i.a. alteplase Cohort 6 0% 3/6 (50%) NR
28
Shaltoni I.V. alteplase 0.9 mg/kg followed by i.a. Cohort 69 6% 50/69 (73%) 45%
thrombolytics
30
Burns I.v. alteplase 0.9 mg/kg followed by i.a. reteplase Cohort 33 12% 24/33 (73%) NR
w/wo mechanical thrombectomy
64
Keris IA alteplase 25mg followed by i.v. alteplase 25 mg RCT 45 0% 6/12 (50%) 2/12(17%)
versus no thrombolysis 0% NR 22/33
(67%)
65
IMS I I.V. alteplase 0.6 mg/kg followed by angiography and Cohort 80 6.3% 35/62 (56%) 46/80
endovascular treatment (ia alteplase, heparin) when (58%)
indicated
24
IMS II I.V. alteplase 0.6 mg/kg followed by angiography and Cohort 81 9.9% 33/55 (60%) 44/81
endovascular treatment (ia alteplase, heparin and i.a. (54%)
ultrasonography (MicroLysUS device)
31
Sohn I.v. alteplase, followed by i.a. urokinase and/or Cohort 14 157 12.7% NR NR
mechanical thrombectomy
32
Kim I.v. alteplase followed by urokinase Cohort 16 18 5.6% 16/18 (89%) 9/18 (50%)

93

TABLE 4 STUDIES OF MECHANICAL TREATMENT IN ACUTE ISCHEMIC STROKE

Device/ Therapeutic NIHSS N Recanalization Symptomatic Poor
Study Intervention Window (TIMI2,3) haemorrhages outcome
11
(N,%) (N,%) (mRS >2)
(N,%)
33
MERCI –II MERCI retriever, i.a. alteplase 8 hrs 20 141 69 (46%) 11 (7%) 94/130
(72%)
Multi MERCI MERCI retriever, i.a. alteplase, 8 h 19 164 112 (68%) 16 (10%) 102/160
34 12
final preceded by i.v. alteplase (68%)
35
Devlin MERCI retriever, i.a. alteplase, 8h 18 25 14 (56%) 1 (4%) 19 (76%)
36
Kim MERCI retriever, i.a. alteplase, 8h 21 24 12 (50%) 2 (8%) 18 (75%)
37
Bose PENUMBRA device 8h 23 21 21 (93%) 2 (10%) ?
38
McDougall PENUMBRA device 8h 18 125 102 (82%) 14 (11%) 94 (75%)
40
Zaidat Wingspan-‐Neuroform stents w 8 h 18 9 8 (89%) 0 3 (33%)
or w/o i.a. or i.v. alteplase
41
Brekenfeld Wingspan stents after failed i.v. 8 hrs 14 12 11 (92%) 0 9 (75%)
treatment w or w/o i.v. or i.a.
alteplase

TABLE 5A. MODIFIED RANKIN SCALE 6 6

Category Short Long description
description
0 No symptoms No symptoms
1 Symptoms, no Minor symptoms that do not interfere with lifestyle
disability
2 Slight disability Slight disability, symptoms that lead to some restriction in
lifestyle, but do not interfere with the patient's capacity to look

11
Recanalization and outcome rates, but not SICH rates were recalculated according to intent to treat principle, assuming that not-‐
reported patients (i.e. patients without intervention) had no recanalization and poor outcome.
12
In most studies, patients treated within 3 hrs received i.v. alteplase, and a small percentage was treated with i.a. thrombolytic.
94

after himself.
3 Moderate Moderate disability, symptoms that significantly restrict lifestyle
disability and prevent totally independent existence
4 Moderately Moderately severe disability, symptoms that clearly prevent
severe independent existence though not needing constant attention
disability
5 Severe Severe disability, totally dependent patient requiring constant
disability attention day and night.
6 Dead Death

TABLE 5B. MODIFED THROMBOLYSIS IN CEREBRAL INFARCTION (TICI) SCALE. 4 5

Grade Short Long description
description
0 No perfusion.
1 Antegrade reperfusion past the initial occlusion, but limited distal
branch filling with little or slow distal reperfusion.

2a Antegrade reperfusion of less than half of the previously occluded
target artery ischemic territory (eg, in 1 major division of the MCA
and its territory).
2b Antegrade reperfusion of more than half of the previously occluded
target artery ischemic territory (eg, in 2 major divisions of the MCA
and their territories).
3 Complete antegrade reperfusion of the previously occluded target
artery ischemic territory, with absence of visualized occlusion in all
distal branches.

95

TABLE 5C CLOT BURDEN SCORE FOR CTA AND MRA 4 6

Absence of contrast opafication at Score
Supraclinoid internal carotid artery 2
Proximal M1 2
Distal M1 2
Infraclinoid internal carotid artery 1
A1 branch 1
M2 branch 1 1
M2 branch 2 1
Total score: 10 – Sum Sum

TABLE 5D ARTERIAL OCCLUSIVE LESION SCALE

AOL Grades Definitions
Grade 0 Complete occlusion of the target artery.
Grade 1 Incomplete occlusion of the partial local recanalization at the target artery
with no distal flow.
Grade 2 Incomplete occlusion of the partial local recanalization at the target artery
with any distal flow.
Grade 3 Complete recanalization and restoration of the target artery with any distal
flow.

96

TABLE 6A. SCHEDULE OF STUDY ACTIVITIES

Inclusion 24 hrs day 5-‐7 3 months
Clinical evaluation x x X x
NIHSS x x X
Laboratory x x x
Neuroimaging x x X
Barthel index X x
Modified Rankin Scale x
EQ5D x

97

TABLE 6B. LIST OF STUDY DATA

Screening
Inclusion criteria
Exclusion criteria

Baseline
Demographics Age, gender
Clinical NIHSS, NIHSS supplemental motor score, pre-‐stroke mRS, blood
pressure, GCS, weight, height, body temperature.
Medical history Previous stroke, previous MI, PAD, diabetes mellitus
Medication Antiplatelet agents, coumarines, heparin(oids), oral thrombin
antagonists and oral factor Xa inhibitors., statines
Vascular risk factors Hypertension, atrial fibrillation, diabetes mellitus, smoking,
hypercholesterolemia
Laboratory INR, kreatinine, GFR (Cockroft-‐Gault), serum glucose, CRP.
parameters SMARTIS substudy: 5x9 cc venous blood sample (before
randomization)
Neuro imaging13 CT: location, ASPECTS score, hemorrhagic transformation
(NINDS/ECASS classification), hyperdense artery sign.
CTA: location, clot burden score/collateral score
If possible CTP: location, infarct core size, penumbra size,
penumbra/infarct index.
If possible DWI: location and infarct core size.
Treatment Intended mode of endovascular treatment

13
Neuro-‐imaging parameters will be assessed by a central subcommittee.
98

Intervention
Modalities Actual treatment: i.a. thrombolysis (urokinase, alteplase, other),
mechanical treatment (device /type).
Timing Time of: onset (last seen well), admission, plain CT, CT
angiography, (CTP), DWI start of i.v. alteplase, end of i.v. alteplase,
start of endovascular procedure (needle in groin), first i.a. bolus,
end of revascularization, end of procedure.
Dosages of Dose of urokinase, alteplase, other agent.
thrombolytics
Effect of intervention mTICI score at start of procedure, mTICI score at end of procedure
Complications Procedure-‐related complications
Neurological deterioration

Follow-‐up
Clinical assessment at NIH Stroke Scale, NIHS supplemental motor scale,
24 hours Complications
Laboratory parameters SMARTIS substudy: 5x9 cc venous blood sample
Neuro-‐imaging at 24 Plain CT: location, ASPECTS score, hemorrhagic transformation
hours (NINDS/ECASS classification), hyperdense artery sign.
CT angiography: location, Clot Burden Score/Collateral score
CT Perfusion: location, infarct core size, penumbra size,
penumbra/infarct index
Neuro imaging at 5-‐7 Plain CT: location, ASPECTS score, hemorrhagic transformation
days (NINDS/ECASS classification), hyperdense artery sign.

Clinical assessment at NIH stroke scale; Barthel Index; Global assessment of
1 wk or discharge improvement or deterioration; clinical complications:
hemorrhages; Laboratory: GFR.
Clinical assessment at Modified Rankin score, Barthel index, EQ5D.
90 days.
Laboratory parameters SMARTIS substudy: 5x9cc venous blood

99

APPENDICES

APPENDIX 1. LIST OF COLLABORATING INVESTIGATORS
COORDINATING INVESTIGATORS
Puck Fransen, Dept of Neurology, Erasmus MC Rotterdam.
Debbie Beumer, Dept of Neurology, UMC Maastricht.
Olvert Berkhemer, Dept of Radiology, AMC Amsterdam.
Lucie van den berg, Dept of Neurology, AMC Amsterdam.
PRINCIPAL INVESTIGATORS
AMC Amsterdam, Yvo Roos, neurologist, AMC Amsterdam, Robert van Oostenbrugge,
neurologist, UMC Maastricht, Aad van der Lugt, neuroradiologist, Erasmus MC Rotterdam.
LOCAL PRINCIPAL INVESTIGATORS:

No Center Neurologist Interventionist
1 Erasmus MC Rotterdam D. Dippel P.A. Brouwer
2 Amsterdam Medical Center Y. Roos C. Majoie
3 Maastricht Medical center R. v Oostenbrugge W. van Zwam
4 UMC Utrecht J. Kappelle R. Lo
5 LUMC te Leiden M. Wermer M. van Walderveen
6 UMC Nijmegen E. van Dijk J. de Vries
7 Haaglanden Ziekenhuis Den-‐Haag J. Boiten G. Lycklama
8 HAGA Ziekenhuis Den-‐Haag S. de Bruyn L. van Dijk
9 UMC Groningen P. Vroomen O. Eshgi
10 St. Elisabeth Zkh Tilburg P. de Kort W. van Rooy
11 Isala klinieken Zwolle P. van den Bergh B. van Hasselt
12 Catharina Ziekenhuis Eindhoven K. Keizer X. Tielbeek
13 St. Antonius Nieuwegein W. Schonewille J. de Vos
14 Rijnstate Ziekenhuis Arnhem J. Hofmeijer J. van Oostayen
15 VU Medisch Centrum Amsterdam M. Visser Randomisation only
16 Reinier de Graaf Delft L. Aerden Randomisation only*
17 Atrium Heerlen T. Schreuder R. Heijboer
18 Medisch Spectrum Twente H. den Hertog D. Gerrits
19 Sint Lucas Andreas Ziekenhuis R. van den Berg-‐Vos Randomisation only
* patients may be treated locally by the team from HAGA ziekenhuis.

APPENDIX 2. STUDY COMMITTEES
DATA MONITORING COMMITTEE
100

Chair: Professor Martin Brown, National Hospital for Neurology & Neurosurgery, London,
UK.
Member: Thomas Liebig
Independent Statistician: Theo Stijnen
EXECUTIVE AND WRITING COMMITTEE

AMC Amsterdam, Yvo Roos, neurologist, AMC Amsterdam, Wim van Zwam,
neuroradiologist, UMC Maastricht, Robert van Oostenbrugge, neurologist, UMC Maastricht,
Aad van der Lugt, neuroradiologist, Erasmus MC Rotterdam,
Puck Fransen, research coordinator, Erasmus MC Rotterdam.
Debbie Beumer, research coordinator, Maastricht UMC.
Olvert Berkhemer, research coordinator, AMC Amsterdam.
Lucie van den Berg, research coordinator on the economic evaluation and long-‐term follow-‐
up, AMC Amsterdam.
Hester Lingsma, methodologist, Erasmus MC Rotterdam.
IMAGING ASSESSMENT COMMITTEE

Charles B Majoie, neuroradiologist, AMC Amsterdam, Aad van der Lugt, neuroradiologist,
Erasmus MC Rotterdam, , Wim van Zwam, neuroradiologist, UMC Maastricht, Rene van den
Berg, neuroradiologist, AMC Amsterdam, Geert Lyclama a Nijeholt, neuroradiologist, MC
Haaglanden, Den Haag, Sjoerd Jenniskens, neuroradiologist, UMC Nijmegen, Henk
Marquering, medical physicist, AMC Amsterdam, Ludo Beenen, ED radiologist, AMC
Amsterdam, Marianne van Walderveen, radiologist LUMC, Leiden, Olvert Berkhemer, PhD
student, AMC Amsterdam.
OUTCOME ASSESSMENT COMMITTEE

Yvo Roos neurologist, AMC Amsterdam (chair) Peter J Koudstaal, neurologist, Erasmus MC Rotterdam, Ewoud
van Dijk, neurologist UMC St. Radboud, Nijmegen , Jelis Boiten, neurologist MC Haaglanden, Den Haag.

ADVERSE EVENT ADJUDICATION COMMITTEE

Robert van Oostenbrugge, neurologist, UMC Maastricht (chair) .
Zwenneke Flach, Radiologist, Isala Kliniek Zwolle, Marieke Wermer, Neurologist, LUMC Leiden.

TRIAL STATISTICIANS
Hester Lingsma, methodologist, Erasmus MC Rotterdam, Ewout Steyerberg, methodologist,
Erasmus MC Rotterdam.
INDEPENDENT (ANGIOGRAPHIC) CORE LAB

Albert Yoo (chair), Massachusetts General Hospital Boston, USA
ADVISORY BOARD
101

Peter Koudstaal, neurologist, Erasmus MC Rotterdam, Tommy Andersson, neuro

interventionist, Karolinska Hospital, Stockholm, Sweden, Heinrich Mattle, neurologist,
University hospital, Bern, Switzerland, Nils Wahlgren, neurologist, Karolinska Hospital,
Stockholm, Sweden.

APPENDIX 3 RECOMMENDATIONS OF THE STEERING COMMITTEE WITH REGARD TO

ENDOVASCULAR TREATMENT PROCEDURES, THROMBOLYTIC AGENTS, AND TYPE OF
MECHANICAL THROMBECTOMY.

GENERAL
Randomization, inclusion in the trial and subsequent endovascular treatment should be
started as soon as possible after presentation in all eligible patients. The time-‐path below
gives an indication about how soon the following steps need to take place.

TABLE A1. OPTIMAL TIME-‐PATH FOR TREATMENT AND INCLUSION IN MR CLEAN OF
PATIENTS WITH ACUTE ISCHEMIC STROKE AND RELEVANT ANTERIOR CIRCULATION
ARTERIAL INCLUSION

Procedure Tx with i.v. alteplase No tx with i.v. alteplase
0 0
Arrival at ER
20 min 20
Start neuroimaging
30 min -‐
Start iv-‐alteplase
60 min 30
Randomization
90 min (since ER) 60

Start endovascular treatment

The selection process is shown in Figure 3 of the protocol. Three clinical situations can be
distinguished:
1 “No response to i.v. alteplase”: in these patients, there is no favorable response to
treatment with intravenous alteplase. Vascular neuroimaging (CTA, MRA, TCD) may follow
treatment with i.v. alteplase, but the steering committee recommends that vascular
neuroimaging is done at the start of i.v. treatment. The exact definition of favorable
response is left to the discretion of the local investigator, but the steering committee
suggests the following: neurological recovery to a level that would obviate the indication for
i.v. alteplase would the patient present with these symptoms. No minimum time period
between assessment of the response to i.v. alteplase and end of treatment is required, but
102

the steering committee recommends that randomization and inclusion into the trial,
andsubsequent endovascular treatment should be started as soon as possible.
2 “Outside therapeutic window for i.v. alteplase”: these patients present in the 4.5 to 6 hour
window. They can be included in the study, and randomized for endovascular treatment or
no endovascular treatment.
3 “ Contra-‐indications for i.v. alteplase”: these patients have contraindications for i.v.
alteplase that do not apply to mechanical thrombectomy, for example a recent cerebral
infarction in a different vascular area, previous cerebral hemorrhage, treatment with
coumarines leading with INR 1.7 to 3.0). They can be included in the study, and randomized
for endovascular treatment or no endovascular treatment. Intra-‐arterial thrombolysis is not
recommended for these patients, but mechanical thrombectomy ís.
NEUROIMAGING
Neuroimaging studies to assess vessel patency should preferably be done before or
simultaneously with treatment with i.v. alteplase, in order not to lose time and brain.
Especially, the delay between end of i.v. infusion and start of endovascular treatment should
be minimized to less than 1 hour.
THROMBOLYTIC AGENTS, DOSE AND TYPE

For intra-‐arterial thrombolysis urokinase or alteplase may be used. A dose of 1 mg alteplase
is considered to be equivalent to 12.500 U (10.000-‐15.000 U) urokinase. 44
Patients who have been pre-‐treated with i.v. alteplase should not receive more than 30 mg
alteplase during intra-‐arterial treatment, or an equivalent dose of 400,000 U urokinase. The
steering committee recommends that the thrombolytic agent is delivered in shots of 5 mg
alteplase or 50.000 – 100.000 U urokinase , in 5-‐10 minutes time intervals. Vessel patency
should be checked after each shot. Before the last i.a. shot is given, the interventionist has to
decide to go for mechanical thrombectomy. After mechanical thrombectomy the shot can be
given, in order to prevent distal re-‐occlusion.
Patients should be treated with intra-‐arterial thrombolyis until recanalization is reached or
the maximum cumulative dose is reached. When intra-‐arterial treatment will be delivered
directly (i.e. within 30 minutes) after intravenous alteplase, the clinical investigator may
consider giving only 2/3 of the total i.v. alteplase dose. The safety of these dosing schedules
is discussed in section 1.2 of the protocol.

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TABLE A2-‐A: DOSING SCHEME FOR INTRAVENOUS AND INTRA ARTERIAL THROMBOLYSIS
WITH ALTEPLASE OR UROKINASE

Weight Alteplase Alteplase Alteplase Urokinase Alteplase Urokinase
(kg) Bolus i.v 2/3 dose 1/3 dose equivalent Max total equivalent max
(mg) (mg) (mg) 1/3 Dose dose (mg)* total dose (kU)
(U)
50 5 25 15 200 45 600
55 5 28 17 200 50 600
60 5 31 18 225 54 675
65 6 34 19 250 59 750
70 6 36 21 250 63 750
75 7 38 23 275 68 825
80 7 41 24 300 72 900
85 8 43 26 325 77 975
90 8 46 27 350 81 1,050
95 9 48 29 375 86 1,125
100 9 51 30 400 90 1,200
>100 9 51 30 400 90 1,200
*urokinase dose is rounded 25,000 U.
MECHANICAL THROMBECTOMY
Randomized clinical trials of devices for mechanical thrombectomy have not been done.
General criteria for the use of devices in MR CLEAN are publication of a case series at least
20 patients treated with the device, with an acceptable rate of complications and a TIMI 2/3
recanalization rate of more than 50%.
Currently, two devices for mechanical thrombectomy (MERCI and PENUMBRA), specifically
designed for treatment of acute intracranial arterial occlusions have been evaluated in case
series, and have been FDA approved for this purpose. One catheter system, EKossonics SV,
designed for delivery of ultrasound-‐waves to the occluding thrombus, has been evaluated in
IMS2 and will be evaluated together with the MERCI system in IMS3. These devices have
been shown to be capable of recanalization, with an acceptable rate of complications.39
Therefore, Currently the MERCI, Penumbra, Solitaire and Ekossonics SV devices, fulfill the
requirements as formulated by the steering committee (Table A3).
Two stent devices have been approved for intracranial treatment, but not for treatment of
patients with acute ischemic stroke, moreover published experience with treatment is
limited. The steering committee of MR CLEAN will be actively seeking evidence that will
make specific stenting devices acceptable for use in the trial.

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TABLE A3. LIST OF MECHANICAL THROMBECTOMY DEVICES THAT ARE AVAILABLE IN THE
NETHERLANDS, THEIR MODE OF ACTION AND CURRENT STATUS.
15
Device Mode of Manufacturer NL Dealer Approval Evaluation
14 16
action studies
Allowed
Merci retriever R,A Concentric Medical Top Medical FDA CS
Penumbra System A,F Penumbra Incm US Penumbra FDA CS
Solitaire Stent (ev3) S EV3 Ev3 CE CS
EKossonic SV U EKOS Bothell Wash Angiocare CE CR
Pending
17
Wingspan stent A Boston Scientific Boston sci FDA CS
CATCH device R,A Balt Extrusion Angiocare CE CR
Revasc S Micrus Angiocare CE ?
Moses S Micrus Angiocare CE ?
Fast A Micrus Angiocare CE ?
Vasco+35ASPI A Balt Angiocare CE ?

14
R=retraction, A=aspiration, S=Stenting, F=Fragmentation, U= ultrasound enhanced lysis
15
FDA = Federal Drugs Agency, CE = Conformité Européenne, which means in concordance with European
legislation.
16
U=unpublished studies only, CR=case reports, CS=case series
17
Approved only for elective treatment of intracranial stenosis.

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APPENDIX 4 INTERVENTION-‐RELATED ANGIOGRAPHIC IMAGING
WHEN
1) The pre-‐intervention angiogram should be performed via the guiding catheter to evaluate
the site of vessel occlusion, extent of thrombus, territories involved, concomittant
pathologies and to assess collateral flow. 45
2) After passing the occlusion site a microcatheter injection should be performed to assess
the distal vascular bed.
3) After each bolus of thrombolytic agent a control angiogram via a microcatheter injection
and/or guiding catheter injection should be performed to assess vessel patency.
4) After each passage of a mechanical device, a control angiogram should be performed via
the guiding catheter to assess vessel patency.
5) At the end of the procedure the angiogram should be repeated via the guiding catheter to
assess the final angiographic outcome
HOW
3. Pre-‐intervention and end-‐of-‐procedure angiogram:
The angiogram should include the internal carotid artery (or common carotid in case of
occlusion or severe stenosis of internal carotid) feeding the target vessel as demonstrated
on CTA.
To completely assess the collateral circulation, injections of the contralateral internal carotid
artery (or common carotid in case of occlusion or severe stenosis of internal) and the
dominant vertebral artery are preferred. However, they are not necessary for inclusion in
the study.
AP views and lateral views of the intracranial arteries are obtained. It is essential that the
angiograms include both the arterial and venous phases of the injection to evaluate the
collateral pathways and perfusion of the distal vascular bed.
The angiograms should be performed via the guiding catheter with the same catheter
position, contrast injection volume and rate (6-‐8ml with 4ml/s for internal carotid, 8-‐10ml
with 4-‐6ml/s for common carotid and 6-‐8ml with 4-‐5ml/s for vertebral artery), and
angiographic views before, after the procedures to adequately assess the results of therapy.
4. After passing the occlusion site, after each bolus of thrombolytic agent and after each pass of a
mechanical device:
At least one view, at the discretion of the interventionalist.

The complete series of the angiograms and microcatheter injections should be saved
according to the DICOM standard and a copy should be sent to the imaging assessment
committee.
APPENDIX 5: PROTOCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.1.
Amendment 1:
Add under Add under Specific exclusion criteria for intended intra-‐arterial thrombolysis:
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“ Current treatment with oral thrombin antagonists, such as argatroban and dabigatran or
treatment with rivaroxaban, a selective Factor Xa inhibitor.”
Rationale: the new oral factor Xa inhibitors and thrombin antagonsists provide a level of
anticoagulation that is comparable with cumarines or heparin. It is very likely that
concomittant treatment with alteplase of urokinase leads to an increased risk of (local)
hemorrhage. The risk of treatment with mechanical devices is likely to be unchanged.

Amendment 2:
Add under substudies:
‘’SMARTIS: study of haemostatic markers in intra-‐arterial treatment for acute ischemic
stroke’’.
Rationale: the study was planned to be carried out on the role of heamostatic factors as
effect modifiers in endovascular treatment

Amendment 3:
Replace vacancy under after AMC Amsterdam under appendix 1, coordinating investigators
by: Olvert Berkhemer

Amendment 4:
Replace vacancy under after UMC Maastricht under appendix 1, coordinating investigators
by: Debbie Beumer

Amendment 5:
Replace Trude Leertouwer by Sjoerd Jenniskens, neuroradiologist, UMC Nijmegen
under appendix 2,Imaging assessment committee

Amendment 6:
Replace vacancy under appendix 2, outcome assessment committee by Ewoud van Dijk,
neurologist UMC St. Radboud, Nijmegen , Jelis Boiten, neurologist MC Haaglanden, Den
Haag.

Amendment 7:
Replace vacancy under appendix 2, adverse event committee by Zwenneke Flach, Radiologist, Isala Kliniek
Zwolle, Marieke Wermer, Neurologist, LUMC Leiden

APPENDIX 6 : PROTCOL AMENDMENT MR CLEAN TRIAL SUBSTANTIAL PROTOCOL 3.2

Amendment 1: Add on page 2/3 under participating centers and independent physicians
three new centers (listed above). Added corrected one independent physicians. The newly
added centers will only randomize patients since there is no interventional radiologist
present. For further explanation see Amendment 3.
Amendment 2: Added and replaced under “List of authors under the main title”: JR2 was
changed into Debbie Beumer. JR3 was changed into Olvert A Berkhemer.
Amendment 3: Add under 4.3 Participating centers and center eligibility. Three new centers
are added where patients can be randomized. Prior to randomization the neurologist of that
center will contact the closet center MEC approved MR CLEAN center. If there is a possibility
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for intra arterial treatment in that particular center the so called ‘randomization center’ will
continue to randomize the patients. If the patient is randomized in the intra arterial
treatment arm, the patient will be transferred to the MEC approved MR CLEAN center. If the
patient is randomized in the control arm the patient will be monitored in this randomization
center.
Amendment 4: Add under substudies: “DIANE: Value of Diffusion-‐Weighted MRI for
Selection of Patients for IA Treatment for Acute Ischemic Stroke in the NEtherlands.” For
further explanation we refer to the separate protocol.
Amendment 5: Add under Tables, “Table 1 Abbreviations”: DWI “Diffusion Weighted
Imaging”
Amendment 6: Added M2 branche 2 and adjusted M2 branche 1 under “Table 5c CLOT
BURDEN SCORE’. Sum score is now 10.
Amendment 7: Add under Tables, Table 6b. List of study data, Baseline: “If possible DWI:
location and infarct core size. And under intervention: DWI
Amendment 8: Deleted under Tables, Table 6b: List of study data, Follow-‐up: Deleted NIHSS
stroke scale at 90 days.
Amendment 9: Appendix 1, coordinating investigators: Formatting and hierarchy of names
was changed. Added Dept of Radiology to Olvert Berkhemer
Amendment 10: Added three local principal investigators changed two others, to the table in
APPENDIX 1 LIST OF COLLABORATIONG INVESTIGATORS. Table “Local principal
investigators”.
Amendment 11: Added 2 members to the imagine committee in Appendix 2 “Imaging
Assessment Committee”
APPENDIX 7: PROTCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.3

Substantial changes:

Amendment 1: Added under “List of authors under the main title”: junior researcher 4 :
Lucie A. van den Berg was added,
Rationale of change: this junior researcher is added to investigate the economic evaluation
and long-‐term follow up of the MR CLEAN trial.

Amendment 2: On page 18 under paragraph 6. Methods, under Functional Outcome,
removed from the original text: Score on the Academic Medical Centre Linear Disability Scale
at 90 Days and Score of Telephone Interview on Cognitive Status (TICS) at 90 days.
Rationale of change: two measurements were removed due to practical problems of
implementing the Academic Medical Centre Linear Disability Scale and time management
problems during the telephone interview at three months.

Amendment 3: On page 18 under paragraph 6. Methods, under Data for cost-‐effectiveness
analysis, added to the original text: Therefore a separate substudy on cost-‐effectiveness will
be carried out (see 10.2 substudies and the separate substudy protocol for more detailed
information).
Rationale of change: sentence was added to announce a substudy on economic evaluation.

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Amendment 4: On page 20 under paragraph 6.4 Study procedures, removed from the
original text: Academic Medical Centre Linear Disability Scale and TICS.
Rationale of change: see Amendment 2.

Amendment 5: On page 23 under paragraph 10 Administrative aspects and publication,
under 10.2 substudies, added to the original text: Furthermore we will carry out a third
substudy on long term follow-‐up and cost-‐effectiveness of endovascular treatment (Roos) .
For this study the follow-‐up will be extended to two years. We refer to a separate substudy
protocol for a detailed description ( ‘CLOT-‐MR CLEAN: Cost-‐effectiveness analyses and LOng
Term follow-‐up in patients randomised in a multicenter randomized clinical trial of
endovascular treatment for acute ischemic stroke in The Netherlands’).
Rationale of change: The MR CLEAN trial is an ideal setting for measuring the societal costs
related to endovascular treatment after stroke , thereby enabling a full economic evaluation
of cerebral endovascular treatment against standard care. The time horizon will be two
years. Within this time horizon the MR CLEAN trial itself will answer the question whether
higher recanalization rates improve functional outcome and quality of life (see separate
substudy protocol CLOT-‐MR CLEAN).

Amendment 6: On page 36, under TABLE 6A. Schedule of study activities, removed from
table: Academic Medical Centre Linear Disability Scale and TICS.
Rationale of change: see Amendment 2.

Amendment 7: On page 38, under TABLE 6B. List of study data, removed from table:
Academic Medical Centre Linear Disability Scale and TICS. Rationale of change: see
Amendment 2.

Non substantial administrative changes:
Non substantial amendment 1: On page 23 under paragraph 10 Administrative aspects and
publication, under 10.2 substudies, the original text : replaced Another for A second

Non substantial amendment 2: On page 23 under paragraph 10 Administrative aspects and
publication, under 10.2 substudies, The original text A substudy on costs and cost-‐
effectiveness of endovascular treatment (Roos), and on clinical and radiological predictors of
recanalization (Majoie) and functional outcome after treatment (Dippel). Interobserver and
validation studies of rapid reperfusion scores will be carried out, was replaced by: A substudy
on clinical and radiological predictors of recanalization (Majoie) and functional outcome
after treatment (Dippel) as well as interobserver and validation studies of rapid reperfusion
scores will be carried out.

Non substantial amendment 3: On page 39, under Appendix 1. List of collaborating
investigators, under Coordinating investigators, one new junior researcher was added: Lucie
van den berg, Dept of Neurology, AMC Amsterdam, see .

Non substantial amendment 4 : On page 39, under Appendix 1. List of collaborating
investigators, under local principal investigators J. de Vries was replaced by J. van Dijk as
interventionist at the HAGA Ziekenhuis Den Haag.
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Non substantial amendment 5: On page 40, under Appendix 2. Study committees, under
Executive and Writing committee, one new junior researcher was added : Lucie van den
Berg, research coordinator on the economic evaluation and long-‐term follow-‐up, AMC
Amsterdam and one methodologist: Hester Lingsma, methodologist, Erasmus MC
Rotterdam,was added.
APPENDIX 8: PROTOCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.4
Substantial changes:
Amendment 1: Added two new centers. One center, Medisch Spectrum Twente, will be a MR
CLEAN intervention center and will start patient treatment after complying with the protocol
guidelines. The other center, Sint Lucas Andreas, will only randomize patients; intra-‐arterial
treatment will be provided by the Academic Medical Center Amsterdam. (Adjustments can
be found on page 2, 3 and 39)
Amendment 2: Moved the exclusion criterion: “Cerebral infarction in the distribution of the relevant occluded
artery in the previous 6 weeks” from “specific exclusion criteria for intended intra-‐aterial thrombolysis” to
“general exclusion criteria”. Rationale; this criterion was accidently placed under specific instead of general.
Amendment 3: Changed on page 39, the status of the Atrium MC to active MR CLEAN
treatment center. The Atrium MC may start treatment after complying with the protocol
guidelines. Treatment of patients is done in close collaboration with Maastricht University
Medical Center.
Non substantial changes administrative changes:
Non substantial amendment 1: Correction of table 5C “Clot Burden score for CTA and MRA’
on page 35. Added an extra M2 branch in the table, this was a typo in the original table.
Non substantial amendment 2: Added in Appendix 2 “Study Committees”. Added O.A.
Berkhemer to the Imaging Assessment committee.
APPENDIX 9: PROTOCOL AMENDMENT MR CLEAN TRIAL; PROTOCOL 3.5

(Non) substantial changes / administrative changes:
Non substantial amendment 1: Correction of the word amendment on title page and
correction and added one amendment date on page 5.
Non substantial amendment 2: Corrected neurological decline on the NIHSS scale to 4 or
more points (page 18).
Substantial amendment 3: We removed the option for use of transcranial Doppler
ultrasound to confirm the intracranial arterial occlusion from the inclusion criteria.
Rationale: this option was not operationalized, and transcranial Doppler was not used in the
trial (page 15).
Non substantial amendment 4: We updated the TICI scale to the modified TICI scale and are
following the definitions as formulated in “Recommendations on Angiographic
Revascularization Grading Standards for Acute Ischemic Stroke: A Consensus Statement”
published in Stroke. 2013;44:2650-‐2663 to grade reperfusion on the DSA's acquired during
the intervention. (page 34). We replaced the term TICI with m(odified) TICI throughout the
manuscript.
110

Non substantial amendment 5: Added APPENDIX 10: (predefined) Statiscal Analysis Plan
(SAP). Rationale: SAP was added as an appendix to the manuscript we submitted to Trials,
which now has been provisionally accepted. The SAP defines our prespecified subgroup
analyses before closure of the database and deblinding (page 50).

111

APPENDIX 10 STATISTICAL ANALYSIS PROTOCOL (SAP)
MR CLEAN SAP (STATISTICAL

ANALYSIS PLAN).
Diederik Dippel, Hester Lingsma, Olvert Berkhemer.
for the MR CLEAN steering committee.
V 3.0 May 14, 2014.
INTRODUCTION
The purpose of the Multi Center Randomized Clinical trial of Endovascular treatment in The
Netherlands (MR CLEAN) is to assess the safety and effect on functional outcome of intra-‐
arterial treatment in patients with acute ischemic stroke caused by intracranial arterial,
anterior circulation occlusion.
Here we will summarize the statistical analysis of the data. We will describe how missing
data will be handled and subgroup analyses will be performed. Moreover, we will describe
the time path of the analyses and the process of deblinding, as well as reporting to the Data
Monitoring and Safety Committee (DMSC).
Although we list an extensive number of analyses, we do not imply that all these will be
described in the main paper, because of space restrictions.
STATUS OF THE TRIAL

The trial is running well. Inclusion has ended on March 16, 2014. In total, 502 patients have
been randomized, but 2 patients have withdrawn consent, leaving 500 patients who have
been registered in the database.
RESEARCH QUESTIONS
112

PRIMARY RESEARCH QUESTIONS

functional outcome after acute ischemic anterior circulation stroke of less than six hours
duration, in patients with a symptomatic intracranial occlusion.
SECONDARY RESEARCH QUESTIONS

The secondary objectives are to assess the safety of endovascular treatment with regard to
the occurrence of hemorrhagic and ischemic complications, the efficacy with regard to
obtaining recanalization, and to evaluate predictors of recanalization, including imaging
aspects and hemostatic parameters. Moreover, we want to assess the safety and efficacy of
different types of endovascular treatment (i.e. mechanical treatment, intra-‐arterial
thrombolysis) different combinations of treatment (i.e. with intravenous alteplase) and
different timings of treatment.
TRIAL DESIGN
The intervention contrast is intra-‐arterial treatment (alteplase or urokinase, and/or
mechanical treatment) versus no intra-‐arterial treatment. The treatment is provided in
addition to best medical management, which may include intravenous alteplase.
Randomization was stratified for center, dichotomized score on the National Institutes of
Health Stroke Scale (NIHSS),[1] treatment with iv alteplase and intended mechanical
treatment.
INCLUSION AND EXCLUSION CRITERIA

Inclusion criteria are:
• A clinical diagnosis of acute stroke, with a deficit on the NIH stroke scale of 2 points
or more.
(M1/M2) or anterior (A1/A2) cerebral artery, demonstrated with CTA, MRA, DSA.
• Age 18 or over.
General exclusion criteria are:

• Intravenous treatment with thrombolytic therapy in a dose exceeding 0.9 mg/kg
alteplase or 90 mg.
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• Intravenous treatment with thrombolytic therapy despite contra-‐indications, i.e.

major surgery, gastrointestinal bleeding or urinary tract bleeding within the previous
2 weeks, or arterial puncture at a non-‐compressible site within the previous 7 days.
• Cerebral infarction in the distribution of the relevant occluded artery in the previous
6 weeks.
Specific exclusion Criteria for intended mechanical thrombectomy are:
Laboratory evidence of coagulation abnormalities, i.e. platelet count <40 x 109/L,
•
APTT>50 sec or INR >3.0.

Specific exclusion criteria for intended intra-‐arterial thrombolysis are:

• Clinical or laboratory evidence of coagulation abnormalities, i.e. platelet count <90 x
109/L, APTT>50 sec or INR >1.7.
PRIMARY AND SECONDARY OUTCOMES

The primary outcome is the score on the modified Rankin Scale at 90 days. Secondary
outcomes concern imaging parameters, clinical parameters and safety parameters.

Imaging parameters are:
• Vessel recanalization at 24 hours after treatment, assessed by CTA or MRA. The
criteria for recanalization on CTA or MRA are based on the Arterial Occlusive Lesion
(AOL) scale,[2] and the Clot Burden Score.[3]
• Infarct size assessed by CT on day 5-‐7, using standard methods, including manual
tracing of the infarct perimeter and semiautomated pixel thresholding.[4, 5]
Clinical parameters are:
• Score on the National Institutes of Health Stroke Scale (NIHSS) at 24 hours.
• Score on the NIHSS at 1 week or at discharge.
• Score on the EQ5D at 90 days,[6]
• Barthel index at 90 days.[7]
The primary safety parameter was neurologic deterioration within 24 hours from inclusion
in the study. Neurological deterioration was defined as any decline in NIHSS of more than 4
points. In these patients, urgent brain CT is mandatory. This serious adverse event was
cause.
BLINDING
114

It was not possible to view the treatment allocation before the patient was registered in the
study database, nor was it possible to remove the patient from the study base after
treatment assignment has become known. Both patient and treating physician were aware
of the treatment assignment. Information on outcome at three months was assessed
through standardized forms and procedures by a dedicated research nurse. Assessment of
outcome on the modified Rankin scale was based on this information, by assessors who
were blind to the treatment allocation. Results of neuroimaging were also assessed in a
blinded manner. Information on treatment allocation and 90-‐day outcome was kept
separate from the main study database. The steering committee members were kept
unaware of the results of interim analyses of efficacy and safety. The trial statistician
combined data on treatment allocation with the clinical data in order to report to the data
monitoring and safety committee (DMSC) in a closed session.
STATISTICAL ANALYSIS PROPER
PRIMARY EFFECT ANALYSIS

The main analysis of this trial consists of a single comparison between the trial treatment
groups of the primary outcome after 90 days. The analysis is based on the intention-‐to-‐treat
principle. The primary effect parameter takes the whole range of the modified Rankin scale
(mRS) into account and is defined as the relative risk for improvement on the mRS estimated
as an odds ratio with ordinal logistic regression.[8] Multivariable regression analysis will be
used to adjust for chance imbalances in main prognostic variables between intervention and
control group in the primary effect analysis, but also in all secondary analyses and subgroup
analyses.[9] These key variables are:
• age,
• stroke severity (NIHSS) at baseline
• time to randomization
• previous stroke,
• atrial fibrillation,
• diabetes mellitus and
• carotid top occlusion versus no carotid top occlusion
PRIMARY EFFECT ANALYSIS IN SUBGROUPS

The effect of intervention on the modified Rankin scale will be analyzed in the following
subgroups:
• Age 80 or over versus age less than 80

• NIHSS in tertiles (2-‐15, 16-‐19 and 20 or higher)
• Carotid top occlusion present versus no carotid top occlusion
• Time since onset to randomization 120 minutes or less versus more than 120
minutes.
115

• Extracranial >50% carotid stenosis or occlusion versus no >50% carotid stenosis or
occlusion
• ASPECTS 0-‐4 / 5-‐7 / 8-‐10
• Thrombus length >7mm versus 7 mm or less.
Secondary effect parameters will be the improvement according to the classical
dichotomizations of the modified Rankin scale, neurological deficit at 24 hours and 1 week
measured with the NIHSS, quality of life at 90 days measured with EQ5D and vessel patency
at 24 hours as well as infarct size at 5-‐7 days on CT or MRI.
1. mRS 0-‐1 versus 2-‐6 at 90 days

3. mRS at 0-‐3 versus 4-‐6 at 90 days
4. Barthel index 19-‐20 versus <19 at 90 days
5. Score on the EQ5D at 90 days
6. Score on the NIHSS at 24 hours
7. Score on the NIHSS at 7 days or discharge
8. Vessel patency (clot burden score) on CTA at 24 hours
9. Infarct size (automated volume measurement) on CT at 5-‐7 days.
Effect parameter in these first four analyses will be the odds ratio, estimated with multiple
logistic regression. The effect parameter on the fourth to sixth outcome (EQ5D and NIHSS)
will be a regression parameter beta, estimated with multiple linear regression models.
Outcome data may have to be log-‐transformed. The clot burden score will be dichotomized
into 10 or less than 10 and the effect parameter will be the odds ratio, estimated with
multiple logistic regression. The effect on infarct size will be estimated with a multiple linear
regression model.

In all analyses, statistical uncertainty will be expressed by means of 95% confidence
intervals. Although the size of this study does not allow for precise estimates of treatment
effect in subgroups, we assess heterogeneity of effects, and analyze consistency of effects
on secondary outcomes.
MISSING DATA AND DEATH

Patients who die within the study period will be assigned the worst score on all outcome
measures and taken into the analysis. Proportions of missing values for all variables will be
reported. Variables that will be used to adjust the primary and secondary effect analyses
(age, NIHSS at baseline, time to randomization, previous stroke, atrial fibrillation, diabetes
mellitus and site of intracranial occlusion are designated as key variables. Missing values for
these variables (if any) will be analysed for randomness and imputed with standard
methods.
TIME PATH OF THE ANALYSES AND LOCKING OF THE DATABASE.

116

To maximize time for analysis and interpretation of the results and allow presentation of the
final results at the World Stroke Conference by the end of October 2014, a soft-‐lock and
preliminary analysis will be performed once the last patients have had their final outcome
recorded and the data has been reviewed by the DMSC by mid July 2014. Following final
data cleaning on the last patients to be recruited, a hard-‐lock will be performed by mid
September. The results of this analysis will be considered by the Trial Steering Committee by
the end of September, 2014. The preliminary interpretation will be performed after soft-‐lock
by DD, CM and HL; they will not be involved in resolving any final queries to maintain the
integrity and blinding of the final database. The approach of soft-‐lock then hard-‐lock is a
standard approach in large trials and allows more time to be spent on considering the results
of a trial, their interpretation and presentation for publication.
REFERENCES

1. Brott T, Adams HP, Jr., Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R,
Hertzberg V et al: Measurements of acute cerebral infarction: a clinical examination scale. Stroke
1989, 20(7):864-‐870.
2. Higashida RT, Furlan AJ: Trial Design and Reporting Standards for Intra-‐Arterial Cerebral
Thrombolysis for Acute Ischemic Stroke. Stroke 2003, 34(8):e109-‐e137.
3. Puetz V, Dzialowski I, Hill MD, Subramaniam S, Sylaja PN, Krol A, O'Reilly C, Hudon ME, Hu WY, Coutts
SB et al: Intracranial thrombus extent predicts clinical outcome, final infarct size and hemorrhagic
transformation in ischemic stroke: the clot burden score. International journal of stroke : official
journal of the International Stroke Society 2008, 3(4):230-‐236.
4. van der Worp HB, Claus SP, Bar PR, Ramos LM, Algra A, van GJ, Kappelle LJ: Reproducibility of
measurements of cerebral infarct volume on CT scans. Stroke 2001, 32(2):424-‐430.
5. Gavin CM, Smith CJ, Emsley HC, Hughes DG, Turnbull IW, Vail A, Tyrrell PJ: Reliability of a semi-‐
automated technique of cerebral infarct volume measurement with CT. CerebrovascDis 2004,
18(3):220-‐226.
6. EuroQol Group T: EuroQol-‐a new facility for the measurement of health-‐related quality of life.
Health Policy 1990, 16(3):199-‐208.
7. Mahoney FI, Barthel DW: Functional Evaluation: The Barthel Index. Md State Med J 1965, 14:61-‐65.
8. McHugh GS, Butcher I, Steyerberg EW, Marmarou A, Lu J, Lingsma HF, Weir J, Maas AI, Murray GD: A
simulation study evaluating approaches to the analysis of ordinal outcome data in randomized
controlled trials in traumatic brain injury: results from the IMPACT Project. Clin Trials 2010, 7(1):44-‐
57.
9. Hernandez AV, Steyerberg EW, Butcher I, Mushkudiani N, Taylor GS, Murray GD, Marmarou A, Choi SC,
Lu J, Habbema JD et al: Adjustment for strong predictors of outcome in traumatic brain injury trials:
25% reduction in sample size requirements in the IMPACT study. J Neurotrauma 2006, 23(9):1295-‐
1303.

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FIGURES
FIGURE 1: TRIAL LOGO.

118

FIGURE 2
Assumed distribution of the primary outcome, according to the modified Rankin scale in
group receiving no intra-‐arterial treatment (mRS-‐C) (control) and the group receiving intra-‐
arterial treatment (mRS-‐I). THe cumulative proportion of patients in mRS 0-‐3 has increased
with 10%.

proportion
mRS_C
mRS_I
mRS score
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Version 3.5 June 11 , 2014 MR CLEAN Trial
protocol
FIGURE 3. RANDOMIZATION AND INCLUSION OF PATIENTS IN THE TRIAL

120

Version 3.5 June 11 , 2014 MR CLEAN Trial
protocol
FIGURE 4. PATIENT FLOW IN THE TRIAL

1. Zaidat
OO, Yoo AJ,
Khatri P, Tomsick
TA, von Kummer
R, Saver JL, et al.
Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a
consensus statement. Stroke; a journal of cerebral circulation. 2013;44(9):2650-‐63.

121

MR CLEAN SAP (STATISTICAL

ANALYSIS PLAN).
Diederik Dippel, Hester Lingsma, Olvert Berkhemer.
for the MR CLEAN steering committee.
V 3.1 July 14, 2014.
INTRODUCTION
The purpose of the Multi Center Randomized Clinical trial of Endovascular treatment
in The Netherlands (MR CLEAN) is to assess the safety and effect on functional
outcome of intra-‐arterial treatment in patients with acute ischemic stroke caused by
intracranial arterial, anterior circulation occlusion.
Here we will summarize the statistical analysis of the data. We will describe how
missing data will be handled and subgroup analyses will be performed. Moreover,
we will describe the time path of the analyses and the process of deblinding, as well
as reporting to the Data Monitoring and Safety Committee (DMSC).
Although we list an extensive number of analyses, we do not imply that all these
will be described in the main paper, because of space restrictions.
STATUS OF THE TRIAL

The trial is running well. Inclusion has ended on March 16, 2014. In total, 502
patients have been randomized, but 2 patients have withdrawn consent, leaving 500
patients who have been registered in the database.
RESEARCH QUESTIONS
PRIMARY RESEARCH QUESTIONS

The primary objective of this study is to estimate the effect of endovascular
treatment on functional outcome after acute ischemic anterior circulation stroke of
less than six hours duration, in patients with a symptomatic intracranial occlusion.
SECONDARY RESEARCH QUESTIONS

The secondary objectives are to assess the safety of endovascular treatment with
regard to the occurrence of hemorrhagic and ischemic complications, the efficacy
122

with regard to obtaining recanalization, and to evaluate predictors of recanalization,
including imaging aspects and hemostatic parameters. Moreover, we want to assess
the safety and efficacy of different types of endovascular treatment (i.e. mechanical
treatment, intra-‐arterial thrombolysis) different combinations of treatment (i.e. with
intravenous alteplase) and different timings of treatment.
TRIAL DESIGN
The intervention contrast is intra-‐arterial treatment (alteplase or urokinase, and/or
mechanical treatment) versus no intra-‐arterial treatment. The treatment is provided
in addition to best medical management, which may include intravenous alteplase.
Randomization was stratified for center, dichotomized score on the National
Institutes of Health Stroke Scale (NIHSS),[1] treatment with iv alteplase and intended
mechanical treatment.
INCLUSION AND EXCLUSION CRITERIA

Inclusion criteria are:
• A clinical diagnosis of acute stroke, with a deficit on the NIH stroke scale of 2
points or more.
• Intracranial arterial occlusion of the distal intracranial carotid artery or
middle (M1/M2) or anterior (A1/A2) cerebral artery, demonstrated with CTA,
MRA, DSA.
• Age 18 or over.
General exclusion criteria are:

• Intravenous treatment with thrombolytic therapy in a dose exceeding 0.9
mg/kg alteplase or 90 mg.
• Intravenous treatment with thrombolytic therapy despite contra-‐indications,
i.e. major surgery, gastrointestinal bleeding or urinary tract bleeding within
the previous 2 weeks, or arterial puncture at a non-‐compressible site within
the previous 7 days.
• Cerebral infarction in the distribution of the relevant occluded artery in the
previous 6 weeks.
Specific exclusion Criteria for intended mechanical thrombectomy are:
123

•Laboratory evidence of coagulation abnormalities, i.e. platelet count <40 x

109/L, APTT>50 sec or INR >3.0.

Specific exclusion criteria for intended intra-‐arterial thrombolysis are:

• Clinical or laboratory evidence of coagulation abnormalities, i.e. platelet
count <90 x 109/L, APTT>50 sec or INR >1.7.
PRIMARY AND SECONDARY OUTCOMES

The primary outcome is the score on the modified Rankin Scale at 90 days.
Secondary outcomes concern imaging parameters, clinical parameters and safety
parameters.

Imaging parameters are:
• Vessel recanalization at 24 hours after treatment, assessed by CTA or MRA.
The criteria for recanalization on CTA or MRA are based on the Arterial
Occlusive Lesion (AOL) scale,[2] and the Clot Burden Score.[3]
• Infarct size assessed by CT on day 5-‐7, using standard methods, including
manual tracing of the infarct perimeter and semiautomated pixel
thresholding.[4, 5]
Clinical parameters are:
• Score on the National Institutes of Health Stroke Scale (NIHSS) at 24 hours.
• Score on the NIHSS at 1 week or at discharge.
• Score on the EQ5D at 90 days,[6]
• Barthel index at 90 days.[7]
The primary safety parameter was neurologic deterioration within 24 hours from
inclusion in the study. Neurological deterioration was defined as any decline in
NIHSS of more than 4 points. In these patients, urgent brain CT is mandatory. This
serious adverse event was further classified as due to intracranial hemorrhage,
ischemia or other (undetermined) cause.
BLINDING
It was not possible to view the treatment allocation before the patient was
registered in the study database, nor was it possible to remove the patient from the
study base after treatment assignment has become known. Both patient and
treating physician were aware of the treatment assignment. Information on
outcome at three months was assessed through standardized forms and procedures
by a dedicated research nurse. Assessment of outcome on the modified Rankin scale
124

was based on this information, by assessors who were blind to the treatment
allocation. Results of neuroimaging were also assessed in a blinded manner.
Information on treatment allocation and 90-‐day outcome was kept separate from
the main study database. The steering committee members were kept unaware of
the results of interim analyses of efficacy and safety. The trial statistician combined
data on treatment allocation with the clinical data in order to report to the data
monitoring and safety committee (DMSC) in a closed session.
STATISTICAL ANALYSIS PROPER
PRIMARY EFFECT ANALYSIS

The main analysis of this trial consists of a single comparison between the trial
treatment groups of the primary outcome after 90 days. The analysis is based on the
intention-‐to-‐treat principle. The primary effect parameter takes the whole range of
the modified Rankin scale (mRS) into account and is defined as the relative risk for
improvement on the mRS estimated as an odds ratio with ordinal logistic
regression.[8] Multivariable regression analysis will be used to adjust for chance
imbalances in main prognostic variables between intervention and control group in
the primary effect analysis, but also in all secondary analyses and subgroup
analyses.[9] These key variables are:
• age,
• stroke severity (NIHSS) at baseline
• time to randomization
• previous stroke,
• atrial fibrillation,
• diabetes mellitus and
• carotid top occlusion versus no carotid top occlusion
PRIMARY EFFECT ANALYSIS IN SUBGROUPS

The effect of intervention on the modified Rankin scale will be analyzed in the
following subgroups:
• Age 80 or over versus age less than 80

• NIHSS in tertiles (2-‐15, 16-‐19 and 20 or higher)
• Carotid top occlusion present versus no carotid top occlusion
• Time since onset to randomization 120 minutes or less versus more than 120
minutes.
• Extracranial >50% carotid stenosis or occlusion versus no >50% carotid
stenosis or occlusion
• ASPECTS 0-‐4 / 5-‐7 / 8-‐10
• Thrombus length >7mm versus 7 mm or less.
125

Secondary effect parameters will be the improvement according to the classical
dichotomizations of the modified Rankin scale, neurological deficit at 24 hours and 1
week measured with the NIHSS, quality of life at 90 days measured with EQ5D and
vessel patency at 24 hours as well as infarct size at 5-‐7 days on CT or MRI.

12. mRS at 0-‐3 versus 4-‐6 at 90 days
13. Barthel index 19-‐20 versus <19 at 90 days
14. Score on the EQ5D at 90 days
15. Score on the NIHSS at 24 hours
16. Score on the NIHSS at 7 days or discharge
17. Vessel patency (clot burden score) on CTA at 24 hours
18. Infarct size (automated volume measurement) on CT at 5-‐7 days.
Effect parameter in these first four analyses will be the odds ratio, estimated with
multiple logistic regression. The effect parameter on the fourth to sixth outcome
(EQ5D and NIHSS) will be a regression parameter beta, estimated with multiple
linear regression models. Outcome data may have to be log-‐transformed. The clot
burden score will be dichotomized into 10 or less than 10 and the effect parameter
will be the odds ratio, estimated with multiple logistic regression. The effect on
infarct size will be estimated with a multiple linear regression model.

In all analyses, statistical uncertainty will be expressed by means of 95% confidence
intervals. Although the size of this study does not allow for precise estimates of
treatment effect in subgroups, we assess heterogeneity of effects, and analyze
consistency of effects on secondary outcomes.
MISSING DATA AND DEATH

Patients who die within the study period will be assigned the worst score on all
outcome measures and taken into the analysis. Proportions of missing values for all
variables will be reported. Variables that will be used to adjust the primary and
secondary effect analyses (age, NIHSS at baseline, time to randomization, previous
stroke, atrial fibrillation, diabetes mellitus and site of intracranial occlusion are
designated as key variables. Missing values for these variables (if any) will be
analysed for randomness and imputed with standard methods.
TIME PATH OF THE ANALYSES AND LOCKING OF THE DATABASE.

To maximize time for analysis and interpretation of the results and allow
presentation of the final results at the World Stroke Conference by the end of
October 2014, a soft-‐lock and preliminary analysis will be performed once the last
patients have had their final outcome recorded and the data has been reviewed by
the DMSC by end of July 2014. Following final data cleaning on the last patients to be
recruited, a hard-‐lock will be performed by mid September. The results of this
126

analysis will be considered by the Trial Steering Committee by the end of September,
2014. The preliminary interpretation will be performed after soft-‐lock by DD, CM and
HL; they will not be involved in resolving any final queries to maintain the integrity
and blinding of the final database. The approach of soft-‐lock then hard-‐lock is a
standard approach in large trials and allows more time to be spent on considering
the results of a trial, their interpretation and presentation for publication.
REFERENCES

1. Brott T, Adams HP, Jr., Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle
R, Hertzberg V et al: Measurements of acute cerebral infarction: a clinical examination
scale. Stroke 1989, 20(7):864-‐870.
2. Higashida RT, Furlan AJ: Trial Design and Reporting Standards for Intra-‐Arterial Cerebral
Thrombolysis for Acute Ischemic Stroke. Stroke 2003, 34(8):e109-‐e137.
3. Puetz V, Dzialowski I, Hill MD, Subramaniam S, Sylaja PN, Krol A, O'Reilly C, Hudon ME, Hu
WY, Coutts SB et al: Intracranial thrombus extent predicts clinical outcome, final infarct size
and hemorrhagic transformation in ischemic stroke: the clot burden score. International
journal of stroke : official journal of the International Stroke Society 2008, 3(4):230-‐236.
4. van der Worp HB, Claus SP, Bar PR, Ramos LM, Algra A, van GJ, Kappelle LJ: Reproducibility
of measurements of cerebral infarct volume on CT scans. Stroke 2001, 32(2):424-‐430.
5. Gavin CM, Smith CJ, Emsley HC, Hughes DG, Turnbull IW, Vail A, Tyrrell PJ: Reliability of a
semi-‐automated technique of cerebral infarct volume measurement with CT.
CerebrovascDis 2004, 18(3):220-‐226.
6. EuroQol Group T: EuroQol-‐a new facility for the measurement of health-‐related quality of
life. Health Policy 1990, 16(3):199-‐208.
7. Mahoney FI, Barthel DW: Functional Evaluation: The Barthel Index. Md State Med J 1965,
14:61-‐65.
8. McHugh GS, Butcher I, Steyerberg EW, Marmarou A, Lu J, Lingsma HF, Weir J, Maas AI,
Murray GD: A simulation study evaluating approaches to the analysis of ordinal outcome
data in randomized controlled trials in traumatic brain injury: results from the IMPACT
Project. Clin Trials 2010, 7(1):44-‐57.
9. Hernandez AV, Steyerberg EW, Butcher I, Mushkudiani N, Taylor GS, Murray GD, Marmarou
A, Choi SC, Lu J, Habbema JD et al: Adjustment for strong predictors of outcome in
traumatic brain injury trials: 25% reduction in sample size requirements in the IMPACT
study. J Neurotrauma 2006, 23(9):1295-‐1303.
127

Summary of changes between original and last version (3.1) of the Statistical Analysis Plan:

The original text of the predefined SAP is displayed on the left side of the table. On the right,
the text as can be found in the last version of the SAP. Changes between the versions are in
bold typography.

Original Changed
Vessel recanalization at 24 hours after treatment, Vessel recanalization at 24 hours after treatment,
assessed by CTA or MRA. The criteria for assessed by CTA or MRA. The criteria for
recanalization on CTA or MRA are based on a recanalization on CTA or MRA are based on the
simplified TICI score,[2] and the clot burden Arterial Occlusive Lesion (AOL) scale,[2] and the
score.[3] Clot Burden Score.[3]

To maximize time for analysis and interpretation To maximize time for analysis and interpretation
of the results and allow presentation of the final of the results and allow presentation of the final
results at the World Stroke Conference by the results at the World Stroke Conference by the
end of October 2014, a soft-‐lock and preliminary end of October 2014, a soft-‐lock and preliminary
analysis will be performed once the last patients analysis will be performed once the last patients
have had their final outcome recorded and the have had their final outcome recorded and the
data has been reviewed by the DMSC by mid July data has been reviewed by the DMSC by end of
2014. July 2014.

128

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The n e w e ng l a n d j o u r na l of m e dic i n e

A Randomized Trial of Intraarterial

2 n engl j med nejm.org

The New England Journal of Medicine

n engl j med nejm.org 3

4 n engl j med nejm.org

The New England Journal of Medicine

Table 1. Baseline Characteristics of the 500 Patients.*

n engl j med nejm.org 5

Table 2. Primary and Secondary Outcomes and Treatment Effects.*

Intervention Control Effect Unadjusted Adjusted

* CT denotes computed tomography.

6 n engl j med nejm.org

The New England Journal of Medicine

0 to 2) was 13.5 percentage points (95% CI, 5.9 to

Secondary Outcomes Intervention

n engl j med nejm.org 7

have led to the inclusion of more patients who

8 n engl j med nejm.org

The New England Journal of Medicine

n engl j med nejm.org 9

10 n engl j med nejm.org

The New England Journal of Medicine

Interventional Thrombectomy for Major Stroke —

n engl j med nejm.org 1

2 n engl j med nejm.org

The New England Journal of Medicine

Declined participation immediately after

No IAT at the clot during intervention (n=20):

No. of patients acOR (95% CI)

Overall 500 1.67 (1.21 to 2.30)

≥80 81 3.24 (1.22 to 8.62)

16-19 153 1.50 (0.84 to 2.67)

≥20 183 1.85 (1.06 to 3.21)

<120 min 51 1.57 (0.51 to 4.85)

yes 445 1.71 (1.22 to 2.40)

ICA terminus occlusion

present 134 2.43 (1.24 to 4.77)

5-7 92 1.97 (0.89 to 4.35)

8-10 376 1.61 (1.11 to 2.34)

Extracranial ICA occlusion^

present 146 1.43 (0.78 to 2.64)

Favors Control Favors Intervention

Treatment effect 95% CI

Characteristic! Intervention!(N=233)! Control!(N=267)!

History!of!myocardial!infarction!–!n!(%)! 33!(14.2%)! 42!(15.7%)!

History!of!peripheral!artery!disease!–!n!(%)! 8!(3.5%)! 16!(6.0%)!

Hypertension!–!n!(%)! 98!(42.1%)! 129!(48.3%)!

Hyperlipidemia!–!n!(%)! 58!(24.9%)! 71!(26.6%)!

Current!smoking!!–!n!(%)&! 65!(28.9%)! 78!(31.0%)!

Current!statin!use!–!n!(%)! 65!(27.9%)! 78!(29.2%)!

Current!anticoagulant!treatment!–!n!(%)! 18!(7.7%)! 21!(7.9%)!

Current!antiplatelet!use!–!n!(%)! 64!(27.5%)! 80!(30.0%)!

Location!on!vessel!imaging:!left!hemisphere!–!n!(%)*! 116!(49.8%)! 152!(57.1%)!

Allocated to Mechanical Retrievable Intra-­‐arterial No IAT

Academic Medical Center /

mAOL! Intervention!(N=187)! Control!(N=207)!

mTICI! Baseline!(N=184)! Post!treatment!(N=196)!

0!(no!reperfusion)!–!n.!(%)! 169!(91.8%)! 27!(13.8%)!

Intervention&& Control& Effect& Unadjusted&effect& &Adjusted&effect&(95%&CI)&

&&&&mRS&0N1&at&90&days&–&n.&(%)& 27!(11.6%)! 16!(6.0%)! OR! 2.06!(1.08!to!3.92)! 2.07!(1.07!to!4.02)!

&&&&mRS&0N2&at&90&days&–&n.&(%)& 76!(32.6%)! 51!(19.1%)! OR! 2.05!(1.36!to!3.09)! 2.16!(1.39!to!3.38)!

&&&&mRS&0N3&at&90&days&–&n.&(%)& 119!(51.1%)! 95!(35.6%)! OR! 1.89!(1.32!to!2.71)! 2.03!(1.36!to!3.03)!

Allocated to Mechanical Retrievable Intra-‐arterial No IAT

MR CLEAN -‐ PROTOCOL FOR A MULTICENTER

1.1 Effectiveness of intra-‐arterial thrombolysis ................................................................................................................................................. 15

1.2 Safety of intravenous and intra-‐arterial thrombolysis. ............................................................................................................................ 16

Appendix 4 Intervention-‐related angiographic imaging .................................................................................................................................. 54

1.1 Effectiveness of intra-‐arterial thrombolysis ................................................................................................................................................. 72

1.2 Safety of intravenous and intra-‐arterial thrombolysis. ............................................................................................................................ 73