FULL-LENGTH ORIGINAL RESEARCH

Safety, tolerability, and seizure control during long-term

treatment with adjunctive brivaracetam for partial-onset
seizures
*Manuel Toledo, John Whitesides, Jimmy Schiemann, Martin E. Johnson, Klaus Eckhardt,
Belinda McDonough, Simon Borghs, and **Patrick Kwan

Epilepsia, 57(7):11391151, 2016

doi: 10.1111/epi.13416

Dr. Manuel Toledo is
epilepsy attending
doctor at Vall dHebron
University Hospital,
Barcelona, Spain.
SUMMARY
Objectives: To report pooled safety/tolerability and seizure outcome data from
adults with uncontrolled partial-onset (focal) seizures (POS) receiving adjunctive
brivaracetam (BRV) during phase IIb/III and long-term follow-up (LTFU) studies.
Methods: Seizure outcome data were pooled from phase IIb (NCT00175929
and NCT00175825), III/IIIb (NCT00490035, NCT00464269, NCT00504881,
and NCT01261325) and associated LTFU studies (NCT00175916, NCT00150800, and
NCT01339559). Safety/tolerability data were pooled from these studies plus
NCT01405508, NCT01653262, and NCT01728077 (LTFU). Patients received placebo
(during core studies) or BRV 5200 mg/day. Safety/tolerability and seizure outcomes
(BRV modal doses 50200 mg/day) were assessed until January 17, 2014.
Results: Of 2,186 patients (97.3% with POS and 2.7% with other seizure types) who
received BRV 50200 mg/day, 2,051 (93.8%) completed core studies and continued
in LTFU studies. Total BRV exposure: 5,339.4 patient-years (8.0 years in 41
patients); 6-, 12-, 24-, and 60-month retention: 91.0%, 79.8%, 68.1%, and 54.4%,
respectively. Safety/tolerability data pooled from 2,186 patients: 1 treatment-
emergent adverse event (TEAE) reported by 1,848 (84.5%) patients; 1,184 (54.2%)
reported 1 TEAE considered treatment-related. Most frequent TEAEs (10%):
headache (20.9%), dizziness (17.5%), somnolence (15.2%), nasopharyngitis (13.2%),
fatigue (11.3%), and convulsion (10.6%). Serious TEAEs (SAEs) and treatment-
related SAEs: 401 (18.3%) and 95 (4.3%) patients, respectively. Of 28 (1.3%) deaths,
four (14.3%) were considered possibly treatment related by the investigator. Pooled
seizure outcome data (1,836 patients): median POS frequency/28 days at baseline
was 8.9; on treatment, median percentage reduction from baseline in POS/28 days
was 48.8%, and 50% responder rate was 48.7%. Complete seizure freedom: 4.9%,
4.2%, 3.0%, and 3.3% for 6, 12, 24, and 60 months, respectively. Improvements were
seen in health-related quality of life (HRQoL) from baseline, assessed by Quality of
Life in Epilepsy Inventory-31.
Significance: Adjunctive BRV treatment in adults with POS was effective and generally
well tolerated when administered long-term (8.0 years). Retention was high and
HRQoL improvements were observed.

Accepted April 21, 2016; Early View publication June 6, 2016.

*Vall dHebron University Hospital, Independent University of Barcelona, Barcelona, Spain; UCB Pharma, Raleigh, North Carolina, U.S.A.; UCB
Pharma, Monheim, Germany; UCB Pharma, Slough, United Kingdom; University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria,
Australia; and **Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
Address correspondence to Manuel Toledo, Epilepsy Unit, Neurology Department, Vall dHebron Hospital, Passeig Vall dHebron 119-129, 08035 Bar-
celona, Spain. E-mail: mtoledo@vhebron.net
2016 The Authors. Epilepsia published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution
in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

1139
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M. Toledo et al.
KEY WORDS: Epilepsy, Brivaracetam, Long-term, Safety/tolerability, Seizure con-
trol, Quality of life.
Key Points
We report safety, tolerability, and seizure outcome
data for adjunctive BRV 50200 mg/day from phase
IIb/III and LTFU studies in patients with POS
Of 2,186 BRV-treated patients, 93.8% completed core
studies and continued to be treated in LTFU; some
were treated for >8 years
Long-term safety/tolerability showed no deterioration;
most common TEAEs were headache (20.9%), dizzi-
ness (17.5%), and somnolence (15.2%)
Long-term seizure outcome data (n = 1,836) demon-
strated BRV was effective: median percentage reduc-
tion from baseline in POS/28 days was 48.8%
Long-term QoL measured by QOLIE-31P total score
and subscales improved from baseline.
Despite antiepileptic drug (AED) therapy, 2030% of
patients continue to have seizures. Approximately half of all
treated patients experience mild to moderately severe
adverse reactions.1 This tolerability issue is compounded in
patients who require polytherapy to control their condition.
Thus, effective treatment of epilepsy remains an important
unmet need.
Brivaracetam (BRV) is a selective, high-affinity synaptic
vesicle protein 2A ligand,2 which has been approved by the
European Medicines Agency and U.S. Food and Drug
Administration as adjunctive treatment for adults
(16 years old) with partial-onset (focal) seizures (POS). It
has demonstrated efficacy and acceptable tolerability in
phase IIb3,4 and phase III studies510 with treatment periods
of 16 weeks. However, the chronic nature of epilepsy
requires that medications are administered over substan-
tially longer periods of time; hence, there is a need for AEDs
to demonstrate long-term effectiveness, which is poorly
studied for most new AEDs.
The objective of the current analysis was, therefore, to
assess the long-term safety, tolerability, and seizure out-
come of BRV for adjunctive treatment of patients with POS.
Compared with data from short-term phase IIb and III stud-
ies, reviewing pooled long-term data provides a greater abil-
ity to detect uncommon or rare adverse events (AEs), or
AEs that may manifest only after periods of exposure
greater than the duration of the individual studies. Studying
treatment over a longer period also allows assessment of
sustained improvement in seizure control, which may
Epilepsia, 57(7):11391151, 2016
doi: 10.1111/epi.13416
fluctuate in some patients.11 Effective long-term treatments
can decrease the burden associated with switching from
AED to AED, thereby improving patient quality of life
(QoL)12 and reducing treatment costs in those patients with
stable treatment regimens.13
We report here pooled safety and seizure outcome data
from over 2,000 adult patients with epilepsy who received,
or are currently receiving, BRV (50 200 mg/day) during
the BRV phase IIb and III studies and their associated long-
term follow-up (LTFU) studies, with >8 years of treatment
in some patients.
Methods
Patient population
Adults who took part in the phase IIb and phase III
double-blind, randomized, placebo-controlled trials of
adjunctive BRV were aged 16 years old, had a well-
characterized epilepsy diagnosis, and had POS uncontrolled
on 13 AEDs. A small number of patients (n = 60) with pri-
mary generalized seizures at baseline were also recruited
into two studies and are included in the present safety analy-
ses. At study completion, all patients had the opportunity to
join an open-label, LTFU study. All studies were conducted
according to the International Conference on Harmonisation
notes for Guidance on Good Clinical Practice and the Decla-
ration of Helsinki. All patients gave written informed con-
sent prior to study entry.
Study design
Of the studies included in this analysis, most were ran-
domized, placebo-controlled, double-blind studies with
treatment periods of 716 weeks. Patients were eligible for
entry into the LTFU studies if the investigator believed that
a reasonable benefit could be expected from long-term BRV
administration; the recommended initial dose was 50 mg/
day and a flexible dosing regimen (200 mg/day) was per-
mitted. Table 1 summarizes the studies included in the
analysis.
Assessments and statistical analysis
Safety, tolerability, and seizure outcome assessments
were carried out at protocol-specified time points until Jan-
uary 17, 2014. Data were reported according to modal BRV
dose, which effectively summarizes data from studies con-
taining flexible dosing schedules, such as LTFU studies.
However, any assessment of significant or serious safety
issues was based on the actual dose the patient(s) were
 Table 1. Summary of studies included in safety and efficacy populations

Included in Included in Key inclusion criteria Up-titration/

safety efficacy Age Concomitant dose-finding Maintenance Treatment BRV dosages
Study NCT number population population (years) Seizure type AEDs Design period (weeks) period (weeks) period (weeks) administered (mg/day)
Phase IIb studies
N011144 NCT00175929 Y Y 1665 POS 12 R, DB, PC 3 7 10 50, 150
N011933 NCT00175825 Y Y 1665 POS 12 R, DB, PC 7 5, 20, 50
Phase III studies
N012529 NCT00490035 Y Y 1670 POS 12 R, DB, PC 12 20, 50, 100
N012535 NCT00464269 Y Y 1670 POS 12 R, DB, PC 12 5, 20, 50
N012548 NCT00504881 Y Ya 1670 POS or primary 13 R, DB, PC 8 8 16 Flexible (20150)
generalized
N012586 NCT01405508 Y 1670 POS or primary 12 R, OL 7-day DB 4.5 days 11.5 days 200 (run-in), 200 IV
generalized run-in period
N013587 NCT01261325 Y Y 1680 POS 12 R, DB, PC 12 100, 200
N0139510 NCT01653262 Y 16 Epilepsy 23 OL 12 200
Long-term
follow-up studies
N01125 NCT00175916 Y Y As for feeder studies N01114, N01252, OL, LTFU Flexible (200)
N01254
N01199 NCT00150800 Y Y As for feeder studies N01193, N01252, OL, LTFU Flexible (200)
N01253, N01254
N01372 NCT01728077 Y As for feeder study N01395 OL, LTFU Flexible (200)
N01379 NCT01339559 Y Yb As for feeder studies N01358, N01258 OL, LTFU Flexible (200)
AEDs, antiepileptic drugs; DB, double-blind; IV, intravenous; LTFU, long-term follow-up; OL, open-label; PC, placebo-controlled; POS, partial-onset seizures; R, randomized.
POS includes partial-onset seizures with or without secondary generalization.
a
Patients with POS only.
b
Patients from core study N01358 only.
Long-Term Adjunctive Brivaracetam

Epilepsia, 57(7):11391151, 2016

1141

doi: 10.1111/epi.13416
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M. Toledo et al.
receiving at the time of the event. Modal dose groups of
BRV 5 and 20 mg/day were not included, since the
LTFU studies were constrained to a minimum dose of
50 mg/day. The safety population comprised patients with
focal or generalized epilepsy who received BRV in studies
NCT00175929,4 NCT00175825,3 NCT00490035,9
NCT00464269, NCT00504881, NCT01261325,7 and
5 8
NCT01653262,10 and LTFU studies NCT00175916,
NCT00150800, NCT01339559, and NCT01728077. In
addition, patients from study NCT014055086 were included
if they had received BRV in the LTFU study
NCT01339559.
Treatment-emergent adverse events (TEAEs), including
information on intensity, seriousness, and causality, were
monitored at each study visit. To enable accurate pooling,
all TEAEs were recoded according to the Medical Dic-
tionary for Regulatory Activities version 15.0. Laboratory
assessments, electrocardiography, vital signs, and body
measurements were carried out at protocol-specified inter-
vals. Safety data were collected from the start of treatment
with BRV (either in the core study or the LTFU).
The efficacy population comprised patients with focal
epilepsy from studies NCT00175929, NCT00175825,
NCT00490035, NCT00464269, NCT00504881, and
NCT01261325 who received BRV in the LTFU studies
NCT00175916, NCT00150800, and NCT01339559. Pooled
summaries of seizure outcome data were based on data col-
lected during the LTFU studies, with baseline POS fre-
quency derived from the baseline period of the core studies.
Seizure outcome variables included the percentage reduc-
tion from baseline in POS frequency/28 days, the number
of patients with 50% reduction in POS frequency from
baseline (50% responder rate), and freedom from seizures
(any type). Seizure outcome variables were summarized for
all patients on BRV, at 3-month time intervals from 1 to
60 months during LTFU. The percentage of seizure-free
patients was calculated by two different methods:
1 Number of seizure-free patients in each exposure duration
interval divided by the total number of patients in the effi-
cacy population (N = 1,836), including patients who
were exposed for a shorter duration.
2 Number of seizure-free patients with a specified duration
of seizure freedom (e.g., 6 months, 12 months, and so
on) at any time during the exposure duration interval
divided by the number of patients with each minimum
exposure duration.
Patients were only included in the seizure-free population
if they had completed their seizure diary for 90% of the
seizure-free interval.
The Quality of Life in Epilepsy Inventory-31 (QOLIE-
31P), a patient-reported epilepsy-specific health-related
quality of life (HRQoL) instrument (scored 0100; higher
scores represent better functioning),14,15 was measured at
baseline, at the last maintenance visit of the core study, and
Epilepsia, 57(7):11391151, 2016
doi: 10.1111/epi.13416
at protocol-specified intervals throughout LTFU. QOLIE-
31P data were presented as mean change from baseline and
percentage of patients with clinically meaningful improve-
ment from baseline at each study visit. A clinically mean-
ingful improvement in QOLIE-31P total score was defined
as a change from baseline of greater than 5.19 points.16
The modified safety population, defined for the evalu-
ation of retention, comprised patients from the safety
population and excluded patients from the NCT01405508
and NCT01653262, due to differences in their study
design that may have influenced the assessment of reten-
tion. Retention rate was estimated using Kaplan-Meier
analyses of the modified safety population using data
from BRV modal doses 50200 mg/day. Patients who
discontinued for reasons other than lack of efficacy or
AE were censored.
Due to the observational nature of the LTFU studies, no
formal statistical testing was performed. Data in this manu-
script are presented using descriptive statistics.
Results
Patient disposition
Of 2,186 patients who received BRV, 2,051 (93.86%)
patients completed their core studies and continued in
LTFU studies (Fig. 1A and B). The core studies were con-
ducted between May 2005 and May 2014. Patients were
recruited from Europe (1,055; 49.3%), North America (427;
19.5%), Asia Pacific/other countries (433; 19.8%), and
Latin America (271; 12.4%).
Patient demographics and baseline characteristics
A summary of patient demographics and baseline charac-
teristics in the safety and efficacy populations is given in
Table 2; no major differences were apparent. (Tables S1
and S2 give demographic and baseline characteristics for
BRV 5200 mg/day, and 5 and 20 mg/day.) Patients had a
mean age of 37 years (range 1680 years), with >97% of
the patients having POS. There was an approximately equal
proportion of male and female patients, and the majority
(71%) were white. At entry to the core studies, the most
common concomitant AEDs were carbamazepine (41.2%),
lamotrigine (25.6%), and valproate (22.6% of safety popu-
lation).
Exposure to BRV and retention rate
In the safety population, the total exposure to BRV was
5,339.4 patient-years, ranging from exposure of <1 month
in 43 (2.0%) patients, 8 years in 41 (1.7%) patients, and
8.5 years in 3 (0.1%) patients. In the modified safety popu-
lation, patients from core studies and LTFU studies who
received a modal BRV dose of 50200 mg/day demon-
strated 6-, 12-, 24-, and 60-month retention rates of 91.0%,
79.8%, 68.1%, and 54.4%, respectively, based on Kaplan-
Meier estimates measured from the beginning of exposure.
 1143
Long-Term Adjunctive Brivaracetam

N011144 N011933 N012529 N012535 N012548 N012586 N013587 N0139510

Randomized n = 157 Randomized n = 210 Randomized n = 399 Randomized n = 400 Randomized n = 480 Randomized n = 105 Randomized n = 768 Enrolled n = 29
Completed n = 148 Completed n = 197 Completed n = 367 Completed n = 361 Completed n = 434 Completed n = 103 Completed n = 696 Completed n = 26
Entered LTFU n = 135 Entered LTFU n = 182 Entered LTFU n = 345 Entered LTFU n = 347 Entered LTFU n = 417 Entered LTFU n = 91 Entered LTFU n = 676 Entered LTFU n = 26

BRV
Modal BRV 5 mg/day BRV 20 mg/day BRV 50 mg/day BRV 100 mg/day BRV 150 mg/day BRV 200 mg/day BRV overall
Dose (N = 53) (N = 149) (N = 319) (N = 544) (N = 869) (N = 454) (N = 2388)

Completed study; Completed study; Completed study; Completed study; Completed study; Completed study; Completed study;
did not enter LTFU did not enter LTFU did not enter LTFU did not enter LTFU did not enter LTFU did not enter LTFU did not enter LTFU
n = 6 (11.3%) n = 11 (7.4%) n = 18 (5.6%) n = 67 (12.3%) n = 5 (0.6%) n = 45 (9.9%) n = 152 (6.4%)

Discontinued LTFU Discontinued LTFU Discontinued LTFU Discontinued LTFU Discontinued LTFU Discontinued LTFU Discontinued LTFU
n = 47 n = 124 n = 221 n = 302 n = 455 n = 144 n = 1293
AE 19 (40.4%) AE 52 (41.9%) AE 75 (33.9%) AE 79 (26.2%) AE 74 (16.3%) AE 43 (29.9%) AE 342 (26.5%)
Lack efficacy 10 (21.3%) Lack efficacy 35 (28.2%) Lack efficacy 66 (29.9%) Lack efficacy 127 (42.1%) Lack efficacy 249 (54.7%) Lack efficacy 55 (38.2%) Lack efficacy 542 (41.9%)
Lost to FU 10 (21.3%) Lost to FU 9 (7.3%) Lost to FU 19 (8.6%) Lost to FU 19 (6.3%) Lost to FU 21 (4.6%) Lost to FU 7 (4.9%) Lost to FU 85 (6.6%)
Patient choice 7 (14.9%) Patient choice 17 (13.7%) Patient choice 36 (16.3%) Patient choice 45 (14.9%) Patient choice 72 (15.8%) Patient choice 26 (18.1%) Patient choice 203 (15.7%)
Other 1 (2.1%) Other 11 (8.9%) Other 25 (11.3%) Other 32 (10.6%) Other 39 (8.6%) Other 13 (9.0%) Other 121 (9.4%)

Treatment Treatment Treatment Treatment Treatment Treatment Treatment

ongoing ongoing ongoing ongoing ongoing ongoing ongoing
n = 0 (0%) n = 14 (9.4%) n = 80 (25.1%) n = 175 (32.2%) n = 409 (47.1%) n = 265 (58.4%) n = 943 (39.5%)

Phase IIb studies

Phase III studies
Phase IIIb study

B
N011144 N011933 N012529 N012535 N012548 N013587
Randomized n = 157 Randomized n = 210 Randomized n = 399 Randomized n = 400 Randomized n = 480 Randomized n = 768
Completed n = 148 Completed n = 197 Completed n = 367 Completed n = 361 Completed n = 434 Completed n = 696
Entered LTFU n = 135 Entered LTFU n = 182 Entered LTFU n = 345 Entered LTFU n = 347 Entered LTFU n = 417 Entered LTFU n = 676

BRV overall
(N = 1904)

Discontinued LTFU
n = 1034
AE 211 (20.4%)
Lack efficacy 499 (48.3%)
Lost to FU 58 (5.6%)
Patient choice 168 (16.2%)
Other 98 (9.5%)

Treatment
ongoing
n = 870 (45.7%)

C
100
Percentage of paents remaining on treatment

90

80

70

60

50

40

30

20

10

0 12 24 36 48 60 72 84 96 108
Months

Figure 1.
Patient disposition and reasons for discontinuation in (A) the safety population (N = 2,186) and (B) the efficacy population (N = 1,836).
(C) Kaplan-Meier curve of time to discontinuation (modified safety population; N = 2,051). Patients who discontinued for reasons other
than adverse events or lack of efficacy were censored. Number of patients at risk at given time points are shown in the table. AE, adverse
event; BRV, brivaracetam; FU, follow-up; LTFU, long-term follow-up.
Epilepsia ILAE

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doi: 10.1111/epi.13416
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M. Toledo et al.

In total, 31 patients reported pregnancies. Of these, 14

Table 2. Patient demographics and baseline
underwent early terminations (elective/induced abortions
characteristics for BRV modal dose groups 50200 mg/
day in the safety and efficacy populations n = 8; induced abortion as a consequence of missed abor-
tion n = 2; spontaneous abortion n = 4); no fetal abnormal-
Safety Efficacy ities were reported. Fifteen patients delivered babies
population population
(N = 2,186) (N = 1,836)
(n = 14 delivered healthy babies with two pregnancies
resulting in twins and two in premature births; n = 1 deliv-
Mean (SD) age, years 37.2 (12.6) 37.0 (12.6)
Male gender, n (%) 1,103 (50.5) 937 (51.0)
ered baby with unknown health status), and two patients
Race, n (%) have not yet delivered.
White 1,542 (70.5) 1,288 (70.2) The most frequently reported psychiatric/behavioral side
Asian 416 (19.0) 364 (19.8) effects (1%) were depression (156/2,186; 7.1%), insomnia
Othera 228 (10.4) 184 (10.0) (135/2,186; 6.2%), irritability (114/2,186; 5.2%), anxiety
Seizure type
POS 2,126 (97.3) b
(107/2,186; 4.9%), suicidal ideation (43/2,186; 2.0%),
Other seizure types 60 (2.7) b depressed mood (39/2,186; 1.8%), aggression (38/2,388;
Median (Q1, Q3) POS frequency/ b 8.9 (5.5, 20.1) 1.7%), nervousness (36/2,186; 1.6%), and sleep disorder
28 days at baseline (34/2,186; 1.6%). Thirteen patients (0.6%) attempted sui-
Concomitant AEDs at core study cide. There was no evidence that the incidence of any of
entry, n (%)
Carbamazepine 901 (41.2) 785 (42.8)
these TEAEs increased with dose.
Lamotrigine 559 (25.6) 457 (24.9) Serious TEAEs (SAEs) and SAEs considered to be treat-
Valproate 494 (22.6) 411 (22.4) ment-related by the investigator were reported in 401/2,186
Oxcarbazepine 343 (15.7) 296 (16.1) (18.3%) and 95/2,186 (4.3%) patients, respectively. Over-
Topiramate 340 (15.6) 283 (15.4) all, the most common SAEs (0.5%) were convulsion
Levetiracetam 321 (14.7) 250 (13.6)
Phenytoin 240 (11.0) 197 (10.7)
(56/2,186; 2.6%), status epilepticus (20/2,186; 0.9%), pneu-
monia (12/2,186; 0.5%), epilepsy (13/2,186; 0.6%), suicidal
AED, antiepileptic drug; POS, partial-onset seizure; Q1, first quartile; Q3,
third quartile; SD, standard deviation.
ideation (12/2,186; 0.5%), suicide attempt (12/2,186;
a
Other includes black, other, and missing. 0.5%), and fall (10/2,186; 0.5%).
b
Data not available. There were a total of 28 (1.3%) deaths reported in patients
in the safety population (BRV modal doses 50200 mg/
A Kaplan-Meier curve of time to discontinuation is pre- day). Across doses 5200 mg/day, 33 adult patients died.
sented in Figure 1C. The mortality rate (95% confidence interval [CI]) per 1,000
patient-years for the 33 patients was 5.9 (4.18.3). Cause of
Safety and tolerability death reported in 1 patient included cancer (n = 6), drown-
Of the 2,186 patients in the safety population, 1,848 ing (n = 4), sudden unexpected death in epilepsy (SUDEP;
(84.5%) reported 1 TEAE and 1,184 patients (54.2%) n = 4), myocardial infarction (n = 3), accident (n = 2), and
reported 1 TEAE that was considered by the investigator suicide (n = 2).
to be treatment related (Table 3). (Tables S3 and S4 present Four (14.3%) of the 28 deaths were considered to be
overviews and incidence of TEAEs for BRV 5200 mg/ possibly related to treatment with BRV by the investiga-
day, and 5 and 20 mg/day.) There was no evidence to sug- tor. SUDEP was reported as the cause of death in two
gest that the number of patients reporting TEAEs or treat- patients, a 30-year-old woman who had been on treat-
ment-related TEAEs increased with higher modal doses of ment for 8.2 months and a 50-year-old woman who had
BRV in this pooling of patients. Overall, and at all modal been on treatment for 42.2 months; at the time of death
doses except for 200 mg/day, the most frequently reported both were receiving BRV 50 mg/day. One other patient
TEAE was headache (13.924.8%), with dizziness (15.4%) died as a result of events that were subsequently consid-
the most frequent TEAE in the 200 mg/day modal dose ered to be a potential SUDEP event: a 21-year-old
group. Other TEAEs reported by >10% of the safety popula- woman who had been receiving BRV for 2.7 months
tion were dizziness, somnolence, nasopharyngitis, fatigue, died of brain hypoxia (dosage at time of death: 50 mg/
and convulsion (Table 3). day). The final patient whose death was considered pos-
A total of 264 patients (12.1%) had a TEAE that resulted sibly treatment-related was a 20-year-old man who com-
in permanent discontinuation of BRV. The most frequently mitted suicide after 24.8 months on treatment at a BRV
reported (0.5%) TEAEs leading to discontinuation were dosage of 150 mg/day.
convulsion (31/2,186; 1.4%), pregnancy (19/2,186; 0.9%), Causes of death were further reviewed using SUDEP cri-
somnolence (16/2,186; 0.7%), depression (14/2,186; 0.6%), teria17; this identified an additional 8 potential cases of
dizziness (14/2,186; 0.6%), fatigue (12/2,186; 0.5%), suici- SUDEP, giving 12 potential cases of SUDEP in total. The
dal ideation (11/2,186; 0.5%), and suicide attempt causes of death reported for cases considered as definite
(10/2,186; 0.5%). SUDEP after review were SUDEP (n = 3), hypertensive
Epilepsia, 57(7):11391151, 2016
doi: 10.1111/epi.13416
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Long-Term Adjunctive Brivaracetam

Table 3. Summary of TEAEs and most commonly reported TEAEs for BRV modal dose groups 50200 mg/day (safety
population; N = 2,186)
BRV modal dose (mg/day)
Patients, n (%) BRV overall (N = 2,186) 50 (n = 319) 100 (n = 544) 150 (n = 869) 200 (n = 454)
1 TEAE 1,848 (84.5) 277 (86.8) 469 (86.2) 750 (86.3) 352 (77.5)
TEAEs leading to discontinuation of study drug 264 (12.1) 70 (21.9) 79 (14.5) 73 (8.4) 42 (9.3)
Treatment-related TEAEs 1,184 (54.2) 205 (64.3) 317 (58.3) 475 (54.7) 187 (41.2)
Severe TEAEs 431 (19.7) 70 (21.9) 98 (18.0) 193 (22.2) 70 (15.4)
SAEs 401 (18.3) 66 (20.7) 106 (19.5) 168 (19.3) 61 (13.4)
Treatment-related SAEs 95 (4.3) 19 (6.0) 29 (5.3) 35 (4.0) 12 (2.6)
Deaths 28 (1.3) 7 (2.2) 10 (1.8) 9 (1.0) 2 (0.4)
TEAEs reported by 5% patients in the
overall BRV group
Headache 457 (20.9) 79 (24.8) 119 (21.9) 196 (22.6) 63 (13.9)
Dizziness 382 (17.5) 63 (19.7) 90 (16.5) 159 (18.3) 70 (15.4)
Somnolence 333 (15.2) 53 (16.6) 98 (18.0) 120 (13.8) 62 (13.7)
Nasopharyngitis 288 (13.2) 32 (10.0) 79 (14.5) 143 (16.5) 34 (7.5)
Fatigue 274 (11.3) 37 (11.6) 58 (10.7) 101 (11.6) 51 (11.2)
Convulsion 231 (10.6) 47 (14.7) 56 (10.3) 102 (11.7) 26 (5.7)
Influenza 170 (7.8) 35 (11.0) 45 (8.3) 75 (8.6) 15 (3.3)
Nausea 168 (7.7) 35 (11.0) 40 (7.4) 70 (8.1) 23 (5.1)
Diarrhea 166 (7.6) 27 (8.5) 42 (7.7) 76 (8.7) 21 (4.6)
Depression 156 (7.1) 36 (11.3) 38 (7.0) 61 (7.0) 21 (4.6)
Urinary tract infection 155 (7.1) 24 (7.5) 37 (6.8) 63 (7.2) 31 (6.8)
Back pain 142 (6.5) 26 (8.2) 31 (5.7) 66 (7.6) 19 (4.2)
Upper respiratory tract infection 142 (6.5) 16 (5.0) 37 (6.8) 67 (7.7) 22 (4.8)
Insomnia 135 (6.2) 22 (6.9) 39 (7.2) 56 (6.4) 18 (4.0)
Vomiting 134 (6.1) 17 (5.3) 39 (7.2) 65 (7.5) 13 (2.9)
Irritability 114 (5.2) 21 (6.6) 29 (5.3) 46 (5.3) 18 (4.0)
BRV, brivaracetam; SAE, serious treatment-emergent adverse event; TEAE, treatment-emergent adverse event.

heart disease (n = 1), brain hypoxia (n = 1), pulmonary
congestion (n = 1), and death (n = 1). Probable cases were
reported as SUDEP (n = 1) and sudden death (n = 1). Pos-
sible cases were reported as myocardial infarction (n = 3).
The SUDEP rate in adults (95% CI) per 1,000 patient-years
in the BRV 5200 mg/day group was 1.6 (0.73.1) for defi-
nite or probable SUDEP, and 2.2 (1.13.8) for definite,
probable, or possible SUDEP.
Two deaths resulted from completed suicides. A 22-year-
old man, on BRV for 10.6 months, was receiving BRV
100 mg/day at time of death, with no recent dose changes,
and had a history of depression. He committed suicide by
ingesting pesticides after an altercation with family mem-
bers, assessed by the investigator as unlikely to be related to
study drug. A 20-year-old man, taking BRV for
24.8 months, was receiving BRV 150 mg/day at time of
death, with no recent dose changes, and had begun taking
topiramate 1 month prior to death. This patients seizure
control was said to be poor in the preceding days. The
patient committed suicide by ingesting an unknown poison,
assessed by the investigator as possibly related to study
drug.
Other safety and tolerability assessments, including labo-
ratory tests, did not reveal any issues of clinical concern,
with no dosage-related effects or increases in incidence over
time. Changes in electrocardiography findings were small
and were not clinically meaningful.
Seizure outcomes
Combined data from the 1,836 patients in the efficacy
population showed that the baseline median POS frequency/
28 days was 8.9. The overall median percentage reduction
from baseline in POS/28 days was 48.8%, which increased
over time from 43.1% for the 1,834 patients who received
treatment for 13 months to 77.0% for the 540 patients who
received treatment for 5860 months (Fig. 2A).
The percentage of patients with a 50% reduction in POS
frequency from baseline (50% responder rate) increased
from 43.5% for 13 months to 71.0% at 5860 months
(n = 541) (Fig. 2B).
The percentage of patients who were seizure-free for the
first 6, 12, 24, and 60 months of treatment with BRV were
4.9%, 4.2%, 3.0%, and 3.3%, respectively. The percentage
of patients who were seizure-free during treatment for any
6-, 12-, 24-, and 60-month period were 16.9%, 10.4%,
5.5%, and 1.4%, respectively (Fig. 2C). Among patients
who had received treatment with BRV for 60 months
(n = 518), 32.4%, 22.4%, 13.7%, and 3.3% of patients were
seizure-free for any 6-, 12-, 24-, or 60-month period during
this treatment period. Seizure outcomes for BRV

Epilepsia, 57(7):11391151, 2016

doi: 10.1111/epi.13416
 C
B
A
1146

Al Al
lp lp
Continuous seizure freedom (all seizure types) (%) at 50% responder rate (%) at Median reduction in POS from baseline (%)
ie ie
nt nt
s( s(
N N
100

20
40
60
80

0
5
10
15
20
0
20
40
60
80
100
=
1 = 18 1 18
3 3 3 4)
( n 36) (n

48.7
=

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doi: 10.1111/epi.13416
6
4 = 1 4
8 18
M. Toledo et al.

6 6 34

16.9
( n 36) (n )

43.5
7 = 1 7 =
9 64 9 16
( (n 38
)

50.6
10 n = 0 ) 10 =

4.2
1 14 1 14

12
2 4 2

Epilepsia, 57(7):11391151, 2016

47

10.4
(n )

56.1
1 3 ( n = 9) 13
1
5 1 2 1 = 1
8 5 27

58.5
16 ( n = 0 ) 16 ( n = 8 )

3.5
1 11 1

18
8 51 8 114
( (

7.2
19 n = ) 19 n =
9)
2 1 0 2 10
1 41 1 39

62.5 63.8
22 ( n = )

3.0
22 ( n = )

24
2 95 2 95
4 9 4 7

5.5
25 ( n = ) 25 ( n = )
2
7 8 7 2 87
7 7 5

2.7
28 ( n = ) 28 ( n = )
3

30
81 3
0 7

4.5
0 815

67.3 65.8 66.6

31 ( n = ) 31 ( n = )
3 3 75
3 760 3 8

65.4

3.0
3 4 (n = )

Months
34 ( n = )
3 7

36
73 3
6 2 6

Months
Months
30

3.5
37 ( n = ) 37 ( n = )
3 69 3 69
9 9 9 7

2.7
40 ( n = ) 40 ( n = )
4

42
4 66
2 66 9 2 7

3.1
)

69.3 69.4 67.4

43 ( n = ) 43 ( n
4 65 4 = 6
5 4 5 52
46 ( n = ) 46 ( n = )

2.9
4 4

48
63 62
8 1 8 9

2.4
49 ( n = ) 49 ( n = )
5 61 5 60
1 1 8
52 n = ( 0)
5 2 (n = )

3.0
5 5

54
59 59
4 5 4 3

1.9
5 5 (n = ) 67.3 66.9 68.5 67.9 55 ( n = )

Continuous seizure freedom at any period

5 5 57
7 57 3 7 1
(
70.2

58 ( n = ) 58 n = )

3.3
6 55 6

60
0 0 557

1.4
( n 9) (n )
68.3

= =

Continuous seizure freedom from start of treatment

54 54
1) 0)
71.0

seizure.
Figure 2.

Epilepsia ILAE
modal doses 50200 mg/day;
N = 1,836). POS, partial-onset
responder rate for partial-onset
(A) Median (interquartile range)

seizures from baseline; (B) 50%

freedom rate (all seizure types) for

seizures; and (C) continuous seizure

the efficacy population (brivaracetam

percentage reduction in partial-onset

the initial period and for any period in


5200 mg/day, and 5 and 20 mg/day are presented in Fig-
ures S1 and S2.
Health-related quality of life
Patients who had received BRV for 2 months showed
substantial mean improvements in total QOLIE-31P score
over the first 42 months of treatment (Fig. 3A), with many
patients showing clinically meaningful improvements
(Fig. 3B). The improvements were largest for the seizure
worry and daily activities/social functioning subscales, with
clinically meaningful improvements observed in approxi-
mately 59% and 55% of patients, respectively. QOLIE-31P
data for BRV 5200 mg/day are presented in Figure S3.
Following longer periods of treatment, there was greater
variability in the QoL results, most likely a consequence
of smaller patient numbers, which result in less robust esti-
mations of treatment effect. Month 48 assessed only 40%
of the patients assessed at month 42. The sharp reduction
in number of patients is likely due to the protocol-
specified completion of QOLIE-31P assessment in LTFU
studies, which was limited to 24 months for patients who
enrolled later. Variability might also result from the
change in population composition from patients coming
from phase IIb and phase III core studies, to patients from
phase IIb core studies alone, and consequently of the dif-
ferences in baseline characteristics between patients from
the core studies. For example, at month 48, there is a sharp
decline in the mean change in QOLIE-31P and percent-
ages of patients with a meaningful change (Fig. 3). In the
cognitive functioning, energy/fatigue, medication effects,
and in particular the emotional well-being subscales, there
was no difference, or a worsening, from baseline to month
48. Although only minor differences were observed in
baseline QOLIE-31P total score and subscale scores of the
long-term exposure cohorts, standard deviations (SDs) of
the later exposure cohorts were larger than in earlier
cohorts, especially for subscale scores with a lower mean
change from baseline at month 48 (data not shown). After
month 48, there were increases across the QOLIE-31P
scores to similar or greater levels than seen at month 42
for most subscales.
Discussion
Randomized controlled trials provide vital information
on the efficacy, safety, and tolerability of the investigative
treatment in the study population. However, each study is
limited by the number of patients they can practically
include and the number of different pharmacologic factors
that can be investigated. In terms of safety, a finite study
population can provide only a snapshot of potential safety
and tolerability issues, with limited power to detect rare and
serious effects. The longer duration of LTFU studies, cou-
pled with appropriate pooling of data from across multiple
core and LTFU studies, can broaden the information
1147
Long-Term Adjunctive Brivaracetam
obtained from individual studies by further defining the
drugs safety profile, including identifying rare safety sig-
nals, assessing adverse effects of prolonged treatment,
assessing sustained seizure control, and allowing investiga-
tions of patient subgroups with greater numbers of patients.
This pooled analysis of 9 (for efficacy) or 12 (for safety)
phase IIb, phase III, and LTFU studies provides further evi-
dence of the seizure control, safety, and tolerability of
adjunctive BRV in almost 2,200 patients with POS who had
received treatment for periods of 8.5 years, giving a total
exposure of >5,300 patient-years. The duration of exposure
to BRV reported here is very long, even among LTFU stud-
ies reported by other recently approved AEDs.1822
The safety profile obtained from the pooled dataset
showed that treatment with adjunctive BRV was generally
well tolerated with a low overall incidence of TEAEs and
SAEs, as well as TEAEs considered to be related to BRV
treatment. Findings from a placebo-controlled study have
shown the incidence of somnolence and fatigue to be dose-
related.9
Overall, the tolerability profile of BRV may enable
patients to benefit from flexible dosing of their adjunctive
therapy. In support of this hypothesis is the observation, as
can be seen in Table 1, that one of the phase IIb studies and
four of the phase III studies did not involve uptitration,
allowing adjunctive BRV treatment to be immediately
administered at the target dosage, giving the opportunity for
improved seizure control.
Behavioral and psychiatric TEAEs are of particular con-
cern in patients with epilepsy. Review of events that poten-
tially fall into these categories showed that in this pooled
population, depression (7.1%), insomnia (6.2%), and irri-
tability (5.2%) were reported by 5% of the safety popula-
tion, and incidence of other behavioral and psychiatric
TEAEs was generally low.
A comprehensive evaluation was made of other tolerabil-
ity and safety factors such as measurement of vital signs,
electrocardiograms, and laboratory assessments. These
investigations did not reveal any issues of clinical concern
for long-term administration of BRV.
For BRV doses 5200 mg/day, the mortality rate in
adults reported across these studies of <6 deaths/1,000
patient-years is comparable with other AED drug develop-
ment programs and community-based epidemiologic stud-
ies, as is the SUDEP rate of <2 deaths/1,000 patient-years
for definite or probable SUDEP. Mortality rates (95% CI)
recently published are 5.9 (4.18.2) from a large systematic
review,17 9.1 (7.610.8) from pooled study data taken from
drug applications,23 and 12.3 (8.916.6) from the lamotrig-
ine clinical development program.24 SUDEP rates pub-
lished by others have varied from 0.9 (95% CI 0.22.7) to
3.8 (95% CI 2.95.0).17,23,24 Although deaths from SUDEP
were considered to be possibly related to treatment in three
cases, there is a lack of consistent evidence of specific
AEDs as risk factors for SUDEP.25 The incidence of suicide
Epilepsia, 57(7):11391151, 2016
doi: 10.1111/epi.13416
1148
M. Toledo et al.

A 20
Total score Energy / Overall Seizure Worry
Well-Being Eects Quality of Life

15
QOLIE-31P mean change from baseline

10

Month 2 Month 6 Month 12 Month 18 Month 24 Month 30 Month 36 Month 42 Month 48 Month 54 Month 60
(n = 1299) (n = 1059) (n = 908) (n = 669) (n = 607) (n = 523) (n = 410) (n = 215) (n = 87) (n = 54) (n = 55)

-5

B
70 Total score Energy / Overall Seizure Worry
Well-Being Eects Quality of Life

60

50

40

30

20

10

0
Month 2 Month 6 Month 12 Month 18 Month 24 Month 30 Month 36 Month 42 Month 48 Month 54 Month 60
(n = 1299) (n = 1059) (n = 908) (n = 669) (n = 607) (n = 523) (n = 410) (n = 215) (n = 87) (n = 54) (n = 55)

Meaningful improvement in
QOLIE-31P score
Total score 5.19
4.76
5.00
Seizure Worry 7.42
5.34
5.25
Overall Quality of Life 6.42
3.95

Figure 3.
Quality of Life in Epilepsy Inventory-31 (QOLIE-31P) in the efficacy population (brivaracetam modal doses 50200 mg/day; N = 1,836):
(A) Mean change from baseline to each time point; (B) percentage of patients with meaningful improvements16 from baseline to each time
point.
Epilepsia ILAE

Epilepsia, 57(7):11391151, 2016

doi: 10.1111/epi.13416

and suicidal ideation are important safety concerns when
assessing AEDs, as it has been reported that suicide rates in
patients with chronic epilepsy are 10-fold higher than in
the general population.26 In this pooled population, 13
patients attempted suicide, there were two cases of com-
pleted suicide, and 2% incidence of suicidal ideation.
Across the entire BRV program, incidence of suicidality
was 323.9 per 100,000 patient-years (95% CI 198.8500.8),
which falls within the range reported in community-based
epidemiologic studies.27
The assessment of seizure outcomes was based on the
entire efficacy population (N = 1,836), and results were
analyzed by duration of treatment rather than by dose. Evi-
dence from the individual phase IIb and III studies has sug-
gested that at doses of adjunctive BRV of 5, 20, and 50 mg/
day, there is a doseresponse profile,3,5 although no such
dose response was seen in a study that included both 50 mg/
day and 150 mg/day.4 Another phase III study investigating
dosages of 20, 50, and 100 mg/day9 did not see an improve-
ment in efficacy with dose, and the most recent phase III
study7 saw no doseresponse effect between 100 and
200 mg/day.
When considering the entire pooled efficacy population,
there was an approximate 50% reduction in frequency/
28 days of POS from baseline and a similar percentage of
patients with a 50% responder rate. Assessments by dura-
tion of therapy suggested greater improvements in these
efficacy endpoints over time, although these results need to
be interpreted with a degree of caution as almost half of the
patients in the efficacy population who entered the LTFU
studies ultimately discontinued due to a lack of efficacy.
Thus, at longer time points, there is a bias toward patients
who have benefited most from adjunctive treatment with
BRV, and so increases in efficacy findings over the earlier
assessments might be expected. Nonetheless, the results do
show that in patients who remain on therapy, the high level
of efficacy is maintained.
Improving HRQoL is an important part of epilepsy man-
agement, which should be considered in addition to seizure
prevention.28 Although the occurrence of seizures can con-
tribute to poor HRQoL,29,30 so also can TEAEs associated
with AED treatment,31 depression and anxiety,30,32 per-
ceived stigma of epilepsy,33 and reduced independence.34
Improvements in HRQoL, as assessed by the QOLIE-31P,
were seen for both the total score and the seven subscales.
Meaningful improvements across all the scores were seen
in approximately 45% of patients as early as month 2.
There were trends for larger improvements in patients with
longer-term treatment up to month 42, perhaps because
patients who responded well to BRV remained in the
LTFU studies. The lower improvements at subsequent time
points may have resulted from the changing composition
of LTFU studies over time, as patients who originated in
different studies with different baseline characteristics
entered the study pool. The increased SDs of later exposure
1149
Long-Term Adjunctive Brivaracetam
cohorts appear to support this theory, but further confirma-
tion is needed. The lower improvements observed at later
time points might also arise from lower patient numbers
contributing to the assessments. QOLIE-31P assessment in
LTFU studies was limited to 24 months for patients who
enrolled later.
These long-term QOLIE-31P data are more informative
than short-term data from the pooled phase III pivotal stud-
ies,35 as they demonstrate the maintenance of improved
HRQoL and, therefore, can better inform treatment choices
than can short-term data. The HRQoL data are consistent
with the known safety and efficacy profile of BRV. Positive
efficacy results are reflected in the seizure worry and daily
activities/social functioning subscales, and the low level of
tolerability issues is reflected in the medication effects, cog-
nitive functioning, and energy/fatigue subscales. The great-
est improvement was seen in seizure worry, with mean
improvements of 9.5 and 13.2 points at months 2 and 42; the
percentage of patients with meaningful improvement in sei-
zure worry was 51% and 58%. The population at month 42
is likely to consist of those whose seizures are better con-
trolled than at month 2, perhaps as a result of fine-tuning
AED dosing, and this may contribute to greater patient con-
fidence in their treatment. Daily activities/social function-
ing was also seen to meaningfully improve in
approximately 55% of the patients during 42 months of
treatment. This is an important finding, as reductions in
daily activities can greatly influence QoL and well-being of
patients.36
As with any study that pools data from across several
studies, there will be limitations associated with the analysis
of combined data. Although the studies were largely similar
in design, there will inevitably be some differences between
study populations in the demographics and baseline charac-
teristics but also in differences arising from geographic
study locations. The data presented in this article cannot be
meaningfully used to compare adjunctive treatment with
BRV with other adjunctive therapies. The pooled popula-
tion does not include comparator groups, so there are no
head-to-head data available to make such assessments.
However, results from the pooled core and LTFU studies
have provided good evidence that when BRV was used as a
long-term adjunctive treatment, it was effective and had
HRQoL benefits in adult patients with POS without any
deterioration in safety and tolerability.
The continued monitoring of the patients remaining in the
LTFU studies will provide more robust assessments of effi-
cacy and HRQoL, particularly for treatment durations over
42 months, and provide extra vigilance for the continued
safety and tolerability of BRV.
Acknowledgments
This study was funded by UCB Pharma, which was involved in the
design and conduct of the study; collection, management, and analysis of
Epilepsia, 57(7):11391151, 2016
doi: 10.1111/epi.13416
1150
M. Toledo et al.
the data; and preparation and review of the manuscript. The authors
acknowledge Mark Hughes and Sally Cotterill (QXV Comms, an Ashfield
Business, part of UDG Healthcare plc, Macclesfield, United Kingdom) for
writing assistance, which was funded by UCB Pharma.
Disclosure of Conflicts of
Interest
Manuel Toledo has received personal fees from Bial, Eisai, and UCB
Pharma, and research support from Bial and Eisai. John Whitesides, Klaus
Eckhardt, Belinda McDonough, and Simon Borghs are employees of UCB
Pharma. Martin E. Johnson is an employee of and holds stock options with
UCB Pharma. Jimmy Schiemann was an employee of UCB Pharma at the
time these studies were conducted and this analysis was carried out, and is
now an employee of Teva Pharmaceuticals. Patrick Kwan has received per-
sonal fees from Eisai and Novartis, has received research support from
UCB Pharma, and has served as associate editor for the journal Epilepsy
Research. We confirm that we have read the Journals position on issues
involved in ethical publication and affirm that this report is consistent with
those guidelines.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. (A) Median (interquartile range) percentage
reduction in partial-onset seizures from baseline; (B) 50%
responder rate for partial-onset seizures; and (C) continuous
seizure freedom rate (all seizure types) for the initial period
and for any period in the efficacy population (N = 1,904)
for brivaracetam modal doses of 5200 mg/day.
Figure S2. (A) Median (interquartile range) percentage
reduction in partial-onset seizures from baseline; (B) 50%
responder rate for partial-onset seizures; and (C) continuous
seizure freedom rate (all seizure types) for the initial period
and for any period in the efficacy population (N = 1,904)
for brivaracetam modal doses of 520 mg/day.
Figure S3. Quality of Life in Epilepsy Inventory-31
(QOLIE-31P) in the efficacy population (N = 1,904) for
1151
Long-Term Adjunctive Brivaracetam
brivaracetam modal doses of 5200 mg/day: (A) Mean
change from baseline to each time point; (B) Percentage of
patients with meaningful improvements16 from baseline to
each time point.
Table S1. Patient demographics and baseline characteris-
tics for BRV modal dose groups 5200 mg/day in the safety
and efficacy populations.
Table S2. Demographics and baseline characteristics for
the BRV modal dose groups 5 and 20 mg/day in the safety
and efficacy populations.
Table S3. Summary of TEAEs and most commonly
reported TEAEs for BRV modal dose groups 5200 mg/day
(safety population; N = 2,388).
Table S4. Summary of TEAEs and most commonly
reported TEAEs for the BRV modal dose groups 5 and
20 mg/day (safety population; N = 202).
Epilepsia, 57(7):11391151, 2016
doi: 10.1111/epi.13416