CLINICAL TRIALS

SECTION EDITOR: ANNE S. LINDBLAD, PhD

ONLINE FIRST

Dexamethasone Intravitreal Implant for Noninfectious Intermediate or Posterior Uveitis

Careen Lowder, MD, PhD; Rubens Belfort Jr, MD; Sue Lightman, MD; C. Stephen Foster, MD; Michael R. Robinson, MD; Rhett M. Schiffman, MD, MS, MHSA; Xiao-Yan Li, MD; Harry Cui, PhD; Scott M. Whitcup, MD; for the Ozurdex HURON Study Group

Objective: To evaluate the safety and efficacy of 2 doses

of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis.
Methods: In this 26-week trial, eyes with noninfectious intermediate or posterior uveitis were randomized to a single treatment with a 0.7-mg DEX implant (n=77), 0.35-mg DEX implant (n=76), or sham procedure (n=76). Main Outcome Measure: The main outcome measure was the proportion of eyes with a vitreous haze score of 0 at week 8. Results: The proportion of eyes with a vitreous haze score of 0 at week 8 was 47% with the 0.7-mg DEX implant, 36% with the 0.35-mg DEX implant, and 12% with the sham (P .001); this benefit persisted through week 26. A gain of 15 or more letters from baseline best-corrected visual acuity was seen in significantly more eyes in the DEX implant groups than the sham group at all study visits. The percentage of eyes with intraocular pressure of 25 mm Hg

or more peaked at 7.1% for the 0.7-mg DEX implant, 8.7% for the 0.35-mg DEX implant, and 4.2% for the sham (P .05 at any visit). The incidence of cataract reported in the phakic eyes was 9 of 62 (15%) with the 0.7-mg DEX implant, 6 of 51 (12%) with the 0.35-mg DEX implant, and 4 of 55 (7%) with the sham (P .05).
Conclusions: In patients with noninfectious intermediate or posterior uveitis, a single DEX implant significantly improved intraocular inflammation and visual acuity persisting for 6 months. Application to Clinical Practice: Dexamethasone intravitreal implant may be used safely and effectively for treatment of intermediate and posterior uveitis. Trial Registration : clinicaltrials.gov Identifier:

NCT00333814. Arch Ophthalmol. 2011;129(5):545-553. Published online January 10, 2011. doi:10.1001/archophthalmol.2010.339 Part of the reason that many patients are resistant to systemic anti-inflammatory therapy for intraocular disease is because of the physiological properties of the bloodretinal barrier. Similar to the blood-brain barrier, the blood-retinal barrier is maintained by tight junctions of endothelial cells that restrict the passage of medications into the eye.7 Over the past decade, the intravitreal administration of corticosteroids has helped to control uveitis in patients with previously recalcitrant disease.6,8 For example, intravitreal injections of triamcinolone have been effective in many forms of uveitis, but repeated injections every 2 to 3 months are often required and this treatment has been associated with adverse effects, such as cataract formation, increased intraocular pressure (IOP), and steroid-induced glaucoma, often requiring medication or surgery.6,9

Author Affiliations: Cole Eye Institute, Cleveland, Ohio (Dr Lowder); Vision Institute, Federal University of Sa o Paulo, Sa o Paulo, Brazil (Dr Belfort); Clinical Ophthalmology, Moorfields Eye Hospital, London, England (Dr Lightman); Massachusetts Eye Research and Surgery Institution and Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts (Dr Foster); and Allergan, Inc, Irvine, California (Drs Robinson, Schiffman, Li, Cui, and Whitcup). Group Information: The Ozurdex HURON Study Group members are listed at the end of this article.

of intraocular inflammatory diseases that cause 10% to 15% of blindness in the developed world.1-4 Despite advances in immunosuppressive treatments, corticosteroids remain the mainstay of therapy.5,6 Many patients, however, are intolerant of or resistant to systemic steroids. Topical corticosteroids administered as eye drops are better tolerated than systemic corticosteroids but are typically only effective for anterior uveitis.5 Unfortunately, most of the severe vision loss related to uveitis occurs in patients with intermediate or posterior uveitis, in which the inflammation involves the vitreous and retina.5 Previously, these patients required systemic therapy, either with corticosteroids or other immunosuppressive agents, to control their ocular inflammation.5

VEITIS REFERS TO A GROUP

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 545

WWW.ARCHOPHTHALMOL.COM

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

Macula

Implant

Applicator

100 m

Figure 1. Dexamethasone intravitreal implant. A, Placement of the dexamethasone intravitreal implant in the vitreous. B, Degradation of the implant over time: at administration (left) and after 3 weeks (right).

Advances in nanotechnology have led to the development of sustained-release intravitreal implants that can release corticosteroids directly into the back of the eye. A surgically placed nonbioerodible implant that releases fluocinolone (fluocinolone acetonide intravitreal implant [FA implant]) into the vitreous has been shown to be effective in the treatment of intermediate and posterior uveitis.8,10 A single FA implant (0.59-mg dose) can control inflammation for up to 3 years but leads to the need for cataract surgery in almost all patients and is associated with glaucoma that requires surgery in 10.9% of patients after 1 year and 32% after 3 years.8,11 More recently, an intravitreal, bioerodible, sustainedrelease implant has been developed that gradually delivers dexamethasone to the posterior chamber (Figure 1A) (DEX implant Ozurdex; Allergan, Inc, Irvine, California). This implant is composed of a mix of polylactic acid and polyglycolic acid polymers and can be implanted into the eye using an office-based procedure. As the implant erodes, dexamethasone is released into the eye (Figure 1B). Studies demonstrate a several-fold higher dexamethasone concentration in the retina with this implant (mean [SD] maximum concentration, 1110 [284] ng/g) in nonhuman primates compared with dexamethasone drug levels in the subretinal fluid following oral (mean [SEM] maximum concentration, 12.3 [1.61] ng/mL) and peribulbar (mean [SEM] maximum concentration, 82.2 [17.6] ng/mL) administrations in humans.12,13

The DEX implant has been shown to be effective in the treatment of macular edema associated with retinal vein occlusions and has been approved by the US Food and Drug Administration for this indication.14 In this study, we examine the efficacy and safety of the DEX implant in the treatment of noninfectious intermediate and posterior uveitis.
METHODS

STUDY DESIGN
This 26-week, prospective, multicenter, masked, randomized, parallel-group, sham-controlled clinical trial was approved by the institutional review board at each investigational site. All patients signed a written consent form before initiation of the study-specific procedures. The study was conducted in compliance with regulations of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki.

PATIENT POPULATION
Patients with a diagnosis of noninfectious intermediate or posterior uveitis were enrolled in this study if they were at least 18 years of age, had a vitreous haze score of at least 1.5 (on a scale of 0-4), and a best-corrected visual acuity (BCVA) of 10 to 75 letters (20/630 to 20/32). Only 1 eye was designated as the study eye. If both eyes were eligible for the study, the right eye was designated as the study eye. Patients were allowed to use the following medications under specified con-

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 546

WWW.ARCHOPHTHALMOL.COM

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

ditions: (1) topical corticosteroids and nonsteroidal antiinflammatory agents if doses were stable for at least 2 weeks prior to screening and remained stable through the treatment day on day 0, (2) systemic corticosteroids if doses were 20 mg/d or less for oral prednisone (or equivalent for other corticosteroids), were stable for at least 1 month prior to screening, remained stable through the treatment day on day 0, and were expected to remain stable through week 8, and (3) systemic immunosuppressors (eg, cyclosporine and methotrexate) if doses were stable for at least 3 months prior to screening, remained stable through the treatment day on day 0, and were expected to remain stable through week 8. Key exclusion criteria included any active ocular disease or infection; uveitis unresponsive to prior corticosteroid treatment; the use of IOP-lowering medications within the last month and a history of glaucoma, ocular hypertension, or clinically significant IOP elevation in response to corticosteroid treatment; IOP more than 21 mm Hg at baseline; BCVA less than 34 letters in the nonstudy eye; or any uncontrolled systemic disease. Patients were also excluded if they had participated in a previous clinical trial of the DEX implant, had used the FA implant in the study eye, had periocular corticosteroid injections in the study eye 8 weeks or less prior to the treatment visit on day 0, had history of any intravitreal drug injection to the study eye 26 weeks or less prior to the treatment visit unless it was triamcinolone acetonide at the dose of 4 mg or less injected 26 weeks or more prior to the treatment visit on day 0, or there was an anticipation to initiate or change current doses of systemic corticosteroids or systemic immunosuppressors during the first 8 weeks of the study.

travitreal, or topical) was prohibited. The criteria for the use of anti-inflammatory agents were an increase from baseline in vitreous haze score of 1 or more units from week 3 to just prior to week 8 and a vitreous haze score of 1.5 or more from week 8 to week 26. The use of either of these therapies was recorded as a rescue treatment. Other prohibited treatments included nonstudy procedures or surgery on the study eye and the use of anticoagulant agents within 2 weeks of receiving study treatment.

OUTCOME MEASURES
The primary outcome measure was based on the amount of vitreous haze that obscured visualization and the proportion of patients with a vitreous haze score of 0 at week 8. Vitreous haze was measured using a standardized photographic scale ranging from 0 to 4, with 0=no inflammation, 0.5=trace inflammation (slight blurring of the optic disc margins and/or loss of the nerve fiber layer reflex), 1=mild blurring of the retinal vessels and optic nerve, 1.5=optic nerve head and posterior retina view obscuration greater than 1 but less than 2, 2=moderate blurring of the optic nerve head, 3=marked blurring of the optic nerve head, and 4=optic nerve head not visible. In clinical practice, the majority of patients with uveitis have a vitreous haze score less than 2. A vitreous haze score of 1.5 was used to categorize patients with a vitreous haze score greater than 1 but less than 2. Other outcome measures included the time to a vitreous haze score of 0, the proportion of patients achieving at least 2 units of improvement in vitreous haze score, mean change from baseline in vitreous haze scores through week 26, BCVA measured using a standardized Early Treatment Diabetic Retinopathy Study protocol,15 central macular thickness measured by optical coherence tomography (at selected sites), and safety parameters. Safety parameters included adverse events, IOP assessments, slitlamp biomicroscopy, and ophthalmoscopy. Patients were evaluated at baseline and days 1 and 7 and weeks 3, 6, 8, 12, 16, 20, and 26 posttreatment.

RANDOMIZATION AND MASKING

On study entry, patients were randomized to either a sham procedure or treatment with the 0.7-mg or 0.35-mg DEX implant using a 1:1:1 allocation ratio. Randomization was performed centrally (using an interactive voice/web response system) by the study sponsor and was stratified by baseline vitreous haze (scores of 1.5 or 2 in one stratum and scores of 3 or 4 in the other). The treatment investigator performed the implant placement and other treatment procedures and was responsible for the overall safety of study participants but kept all study medication information confidential and did not collect efficacy information. Patients were masked with regard to study treatment, and the key efficacy variables were collected and evaluated by follow-up investigators who were also masked with regard to study treatment.

DATA ANALYSIS AND STATISTICAL METHODS

The primary efficacy analysis was performed using all patients who were randomized to treatment (intention-to-treat analysis). Any missing data from weeks 2 through 26 were imputed using the last observation carried forward method. For any patients who received a rescue medication, the efficacy scores for all efficacy end points were set as missing for any visits after the rescue medication, and the last observation was carried forward. The primary efficacy analysis was performed using the Pearson 2 test. A gate-keeping procedure was used to control the overall type I error rate at 5% for comparisons between the DEX implant groups and the sham group. In addition, 2-sided 95% confidence intervals were constructed for the between-group difference in the proportion of patients with a vitreous haze score of 0 using the normal approximation of binary variables. The treatment investigator interaction was assessed using the Breslow-Day test at the significance level of .10. Any investigator with fewer than 2 patients enrolled under any treatment group was excluded from this analysis. The Pearson 2 test was used to analyze the proportion of patients achieving 2 units of improvement in vitreous haze score. Treatment-group comparisons for the time to vitreous haze score of 0 were analyzed using the log-rank test. Change from baseline in vitreous haze score was analyzed using a 1-way analysis of variance model with fixed effect of treatment. Between-group comparisons were performed in a pairwise fashion using contrasts from the analysis of variance model. A sample size of 73 patients for each treatment group was deter-

STUDY TREATMENT
Prior to each treatment, the study eye was anesthetized with topical and subconjunctival anesthetics and prepared according to standard clinical practice for eyes undergoing intravitreal injection. The DEX implant was inserted into the vitreous cavity through the pars plana using a customized, single-use, 22-gauge applicator. The sham procedure followed the same protocol but used a needleless applicator. All patients were treated with a topical ophthalmic antibiotic 4 times daily starting 3 days prior to the day of their study procedure (day 0) and continuing for 3 days after the procedure.

NONSTUDY TREATMENTS
Nonstudy treatments considered necessary for the best care of the patient could be given at the discretion of the investigator. Unless required for patient care, the use of systemic immunosuppressive therapy or corticosteroids (systemic, periocular, in-

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 547

WWW.ARCHOPHTHALMOL.COM

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

Enrollment

331 Assessed for eligibility 102 Excluded 86 Not meeting inclusion criteria 10 Refused to participate 6 Other reasons

229 Randomized Allocation

77 Randomized to 0.7-mg DEX implant 76 Received treatment 2 Discontinued week 8 1 Adverse event 1 Other

76 Randomized to 0.35-mg DEX implant 74 Received treatment 2 Discontinued week 8 2 Other

76 Randomized to sham procedure 75 Received procedure 2 Discontinued week 8 1 Lost to follow-up 1 Other 3 Discontinued > week 8 1 Lost to follow-up 2 Other

Follow-up

2 Discontinued > week 8 1 Adverse event 1 Other

1 Discontinued > week 8 1 Lack of efficacy

73 Completed 26 wks

73 Completed 26 wks

71 Completed 26 wks

Figure 2. Flowchart of patient disposition. DEX implant indicates dexamethasone intravitreal implant.

mined to have a 93% power to detect a between-group difference of 23% (DEX implant minus sham) in the proportion of patients with a vitreous haze score of 0 (assuming 10% of patients in the sham group would have a vitreous haze score of 0). RESULTS

A total of 229 patients from 46 study sites in 18 countries were randomized to receive the 0.7-mg DEX implant (n=77), the 0.35-mg DEX implant (n=76), or the sham (n=76) between May 2006 and October 2008 and followed up through April 2009. Nearly all (217 of 229; 95%) completed the 26-week study (Figure 2). Only 2 patients discontinued because of adverse events (0.7-mg DEX implant group) and only 1 patient discontinued because of lack of efficacy (0.35-mg DEX implant group). Patient demographics and baseline characteristics are listed in the Table. Mean patient age was approximately 45 years, more than 60% of patients were female, and more than 60% of patients were white. The overwhelming majority (81%) of patients enrolled had intermediate uveitis. There were no notable between-group differences in any demographic or baseline characteristic. VITREOUS HAZE At baseline, the mean vitreous haze score was approximately 2 in all treatment groups. The percentage of eyes with a vitreous haze score of 0 at week 8 (primary end point) was significantly greater in both the 0.7-mg DEX implant group (47%; 36 of 77; P .001) and the 0.35-mg DEX implant group (36%; 27 of 76; P .001) than the sham group (12%; 9 of 76) (Figure 3A). The percentage of eyes with a vitreous haze score of 0 was also significantly greater in the 0.7-mg DEX implant group than the sham group at weeks 6 through 26 (P .014) and in the 0.35-mg DEX implant group at weeks 6 through 12 and weeks 20 and 26 (P .030). There was no statisti-

cally significant difference between the 0.7-mg and 0.35-mg DEX implant groups. At week 8, a significantly lower percentage of patients in the 0.7-mg and 0.35-mg DEX implant groups had 1 or more cells in the anterior chamber compared with patients in the sham group (14.5% and 20.3% vs 38.7%, respectively; P =.002). When patients with 1 or more cells in the anterior chamber were excluded from analysis of the primary efficacy end point, a significantly higher percentage of patients in the 0.7-mg and 0.35-mg DEX implant groups than those in the sham group had a vitreous haze score of 0 at week 8 (51.5% [34 of 66] and 41.0% [25 of 61] vs 17.0% [8 of 47], respectively; P .007), indicating that the reduction of anterior chamber inflammation due to DEX implant use did not significantly contribute to the reduction of vitreous haze at week 8. At baseline, the majority of eyes had vitreous haze score of 1.5 or 2 (Table). In this strata, the percentage of eyes with a vitreous haze score of 0 was significantly greater in both DEX implant groups than the sham group at all study visits (P .05), with the exception of the 0.35-mg DEX implant group at week 16 (Figure 3B). At week 8, 48.4% (31 of 64) of the 0.7-mg DEX implant eyes, 40% (24 of 60) of the 0.35-mg DEX implant eyes, and 12.1% (8 of 66) of the sham eyes had a vitreous haze score of 0 (P .001 for both implant groups compared with the sham group). There was no statistically significant difference between the 0.7-mg and 0.35-mg DEX implant groups. The percentage of eyes whose baseline vitreous haze score of 3 or 4 decreased to 0 was numerically greater in both DEX implant groups than the sham group at all study visits, except weeks 3 and 26 (Figure 3C). At week 8, 41.7% (5 of 12) of the 0.7-mg DEX implant eyes, 18.8% (3 of 16) of the 0.35-mg DEX implant eyes, and 10% (1 of 10) of the sham eyes had a vitreous haze score of 0. In this strata, between-group differences were statistically insignificant, likely because of the small number of eyes in each group.
WWW.ARCHOPHTHALMOL.COM

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 548

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

Table. Patient Demographics and Baseline Characteristics

No. (%) DEX Implant Characteristic Age, y, mean (SD) Female Race White Black Asian Hispanic Other Iris color Dark Light Diagnosis in study eye Intermediate uveitis Posterior uveitis Baseline visual acuity, letters, mean (SD) Severity of vitreous haze at baseline Score of 1.5 or 2 Score of 3 or 4 Baseline vitreous haze score, mean (SD) Duration of uveitis, mo, mean (SD) Phakic lens at baseline Cataract in phakic eyes at baseline Patients taking systemic anti-inflammatory or immunosuppressant medication at baseline 0.7 mg (n = 77) 44 (14.8) 46 (59.7) 47 (61) 8 (10) 18 (23) 2 (3) 2 (3) 33 (43) 44 (57) 63 (82) 14 (18) 58 (15.2) 65 (84) 12 (16) 2.06 (0.55) 50.5 (54.2) 62 (81) 20 (32) 20 (26) 0.35 mg (n = 76) 46 (13.6) 48 (63) 46 (61) 10 (13) 12 (16) 1 (1) 7 (9) 27 (36) 49 (64) 64 (84) 12 (16) 57 (17.2) 60 (79) 16 (21) 2.12 (0.50) 43.9 (48.9) 51 (67) 32 (63) 22 (29) Sham Procedure (n = 76) 44 (15.0) 51 (67) 46 (61) 9 (12) 15 (20) 2 (3) 4 (5) 32 (42) 44 (58) 58 (76) 18 (24) 63 (15.2) 66 (87) 10 (13) 2.01 (0.54) 61.2 (62.5) 55 (72) 27 (49) 18 (24) Between-Group P Value

.997

.597

.48 .071 .407 .427 .154 .194 .108 .761

Abbreviation: DEX implant, dexamethasone intravitreal implant.

The primary efficacy end point was also analyzed by the study regions (North America [n=50], Brazil [n=29], Europe [n = 79], Australia [n = 19], Israel [n = 7], India [n=32], and South Africa [n=10]). The proportion of patients with a vitreous haze score of 0 at week 8 in each region was similar to that of overall population, and there was no significant treatment investigator interaction (P =.46 for the 0.7-mg DEX implant vs sham and P =.828 for the 0.35-mg DEX implant vs sham). There was a statistically significant difference between the sham group and both the 0.7-mg DEX implant group (P .023) and the 0.35-mg DEX implant group (P .034) in the percentage of eyes that achieved at least 2 units of improvement in vitreous haze score (Figure 4). The response in the 0.7-mg DEX implant group peaked at week 8 (44.2%) and was maintained up to week 26 (33.8%). VISUAL ACUITY Of 229 patients, 48 patients (21%) had a baseline BCVA of more than 70 letters (20/40). These patients were considered as nonresponders for the 15-letter improvement (3 lines on standard visual acuity chart) even if their BCVA improved to 20/20 at follow-up visits. The proportion of eyes achieving at least a 15-letter improvement from baseline BCVA was 2- to 6-fold greater in the DEX implant groups than the sham group throughout the study period (Figure 5A). This difference from sham was statistically significant at all points for both the 0.7-mg DEX

implant group (P .001) and the 0.35-mg DEX implant group (P .027). The mean improvement from baseline BCVA was also significantly greater in the DEX implant groups than the sham group throughout the study period (Figure 5B). This difference was statistically significant at all points for the 0.7-mg DEX implant group (P .002) and at all points except week 26 for the 0.35-mg DEX implant group (P .010). CENTRAL MACULAR THICKNESS At baseline, the mean (SD) central macular thickness was 344.0 (141.6) m in the 0.7-mg DEX implant group (n=39), 338.9 (162.4) m in the 0.35-mg DEX implant group (n=48), and 324.6 (145.5) m in the sham group (n=43). At weeks 8 and 26, both DEX implant groups had significantly lower central macular thickness compared with their corresponding baseline (P .004) while changes in the central macular thickness of the sham group were not significantly different from the baseline (P .092). The mean (SD) decrease from baseline central macular thickness was significantly greater in the 0.7-mg and 0.35-mg DEX implant groups compared with the sham group at week 8 (99.4 [151.8] m and 91.0 [132.8] m vs 12.4 [123.7] m, respectively; P .004) but not at week 26 (50.2 [102.9] m and 68.1 [138.8] m vs 35.5 [134.9] m, respectively; P .227). The mean change from baseline central macular thickness was not statistically different between the DEX implant groups (P .516).
WWW.ARCHOPHTHALMOL.COM

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 549

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

A Patients With Vitreous Haze Score of 0, %

100 0.7-mg DEX implant (n = 77) 0.35-mg DEX implant (n = 76) Sham (n = 76)

100

Patients With at Least 2 Units of Improvement in Vitreous Haze Score, %

80

0.7-mg DEX implant 0.35-mg DEX implant Sham

80

60 P <.001 P = .023 20 P <.001 P <.001 P = .002 P <.001 P = .001

60 P <.001 40 P <.001 P <.001 P = .010 P = .009 P = .014

40

20

0 3 0 3 6 8 12 16 20 26 6 8 12 16 20 26

Study Week

Study Week B
100

Patients With Vitreous Haze Score of 0 Who Had a Baseline Vitreous Haze Score of +1.5 or +2, %

80

0.7-mg DEX implant (n = 64) 0.35-mg DEX implant (n = 60) Sham (n = 66)

Figure 4. Eyes with at least 2 units of improvement in vitreous haze score. When significant, P values are shown for the 0.7-mg dexamethasone intravitreal implant (DEX implant) vs sham. The differences between the 0.35-mg DEX implant group and the sham group were statistically significant at week 3 (P = .034) and weeks 6 to 26 (P .003).

60 P <.001 40 P <.001 P <.001 P <.018 P <.017 P <.006

0.7-mg DEX implant 0.35-mg DEX implant Sham P <.001 (21.1%46.2%) P <.001 (23.9%48.7%) P <.001 (15.0%41.8%)

20 50 0 3 6 8 12 16 20 26 45 P <.001 (17.2%39.9%)

Study Week Patients, % C

100

40 35 30 25 20 15 10

P <.001 (12.5%39.1%)

P <.001 (13.8%40.4%)

P <.001 (11.3%37.7%)

Patients With Vitreous Haze Score of 0 Who Had a Baseline Vitreous Haze Score of +3 or +4, %

80

0.7-mg DEX implant (n = 12) 0.35-mg DEX implant (n = 16) Sham (n = 10)

60

5 0 3 6 9 12 16 20 26

40

Study Week
20

0 3 6 8 12 16 20 26

B Study Week Mean Change From Baseline BCVA, Letters

16 14 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 P <.001 P <.001 P <.001 P <.001 P <.001

0.7-mg DEX implant 0.35-mg DEX implant Sham

Figure 3. Eyes with a vitreous haze score of 0. A, All eyes. B, Eyes with a baseline vitreous haze score of 1.5 or 2. C, Eyes with a baseline vitreous haze score of 3 or 4. When significant, P values are shown for the 0.7-mg dexamethasone intravitreal implant (DEX implant) vs sham. *One patient in the 0.7-mg DEX implant group with a baseline vitreous haze score of 1 was excluded from the analysis.

P <.001 P <.010 P <.001

P <.001

P <.001 P = .002

P = .010

P = .008

SAFETY ANALYSIS At the first study visit (week 3), the percentage of eyes requiring rescue medication in the sham and 0.35-mg and 0.7-mg DEX implant groups was 15%, 3%, and 1% (P =.002 vs sham), respectively (Figure 6). At week 26, the corresponding percentages were 38%, 25%, and 22% (P =.030 vs sham). Throughout the study, the percentage of eyes requiring rescue medication was greater in the 0.7-mg DEX implant group compared with the 0.35-mg DEX implant group, except for weeks 3 and 26. This between-group difference, however, was not statistically significant.

18

20

22

24

26

Study Week

Figure 5. Best-corrected visual acuity (BCVA). A, Eyes achieving a 15-letter or more improvement from baseline BCVA. B, Change from baseline BCVA. P .05 for the 0.7-mg vs 0.35-mg dexamethasone intravitreal implant (DEX implant). P values are in comparison with the sham procedure.

Across all treatment groups and all study visits, less than 5% of eyes developed an IOP of 35 mm Hg or greater and less than 10% had an IOP of 25 mm Hg or greater
WWW.ARCHOPHTHALMOL.COM

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 550

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

45 40 35 30 0.7-mg DEX implant 0.35-mg DEX implant Sham P = .027 P = .012 P = .011 P = .002 80 P = .030 P = .026 P = .059 100

No IOP medication 1 IOP medication 2 IOP medications 3 IOP medications

Patients, %

25 20 15 10 5 0 3 6

Patients, %
8 12 16 20 26

60

40

20

Study Week
0 3 12 16 26

Figure 6. Cumulative percentage of eyes requiring rescue medication in the study eye at each visit. P values are for the 0.7-mg dexamethasone intravitreal implant (DEX implant) vs the sham procedure.

Study Week

Figure 8. Intraocular pressure (IOP)lowering medication use in the 0.7-mg dexamethasone intravitreal implant (DEX implant) group only.

A
20 18 16 14 0.7-mg DEX implant 0.35-mg DEX implant Sham

12 10 8 6 4 2 0 0 3 6 8 12 16 20 26

Study Week B
20 18 16 14

12 10 8 6 4 2 0 0 3 6 8 12 16 20 26

Study Week

Figure 7. Percentage of eyes with notable changes in intraocular pressure (IOP). A, Percentage of eyes with IOP of at least 35 mm Hg. B, Percentage of eyes with IOP of at least 25 mm Hg. DEX implant indicates dexamethasone intravitreal implant.

sional surgery, laser trabeculoplasty, or cryotherapy for elevated IOP. At baseline, cataracts were reported in 20 of 62 phakic eyes (32%) in the 0.7-mg DEX implant group, 32 of 51 eyes (63%) in the 0.35-mg DEX implant group, and 27 of 55 eyes (49%) in the sham group (Table). During follow-up, cataracts were reported as adverse events in 9 of 62 phakic eyes (15%) in the 0.7-mg DEX implant group, 6 of 51 phakic eyes (12%) in the 0.35-mg DEX implant group, and 4 of 55 phakic eyes (7%) in the sham group, although the differences were not statistically significant (P =.769). Three patients had a surgical procedure for cataract in the study eye (1 eye in the 0.7-mg DEX implant group and 2 in the sham group). Other common ocular adverse events included conjunctival hemorrhage (0.7-mg DEX implant group: 23 of 76, 30%; 0.35-mg DEX implant group: 12 of 74, 16%; sham group: 16 of 75, 21%), ocular discomfort (0.7-mg DEX implant group: 10 of 76, 13%; 0.35-mg DEX implant group: 3 of 74, 4%; sham group: 6 of 75, 8%), eye pain (0.7-mg DEX implant group: 9 of 76, 12%; 0.35-mg DEX implant group: 8 of 74, 11%; sham group: 10 of 75, 13%), and iridocyclitis (0.7-mg DEX implant group: 7 of 76, 9%; 0.35-mg DEX implant group: 1 of 74, 1%; sham group: 4 of 75, 5%). The between-group differences were not statistically significant for any of these adverse events. There was a single case of possible culture-negative endophthalmitis or uveitis flare (0.7-mg DEX implant group) and 4 retinal detachments (2 in the 0.7-mg DEX implant group and 2 in the sham group). There were no notable changes from baseline in any vital signs or physical findings.
COMMENT

(Figure 7). Throughout the 26-week study, the percentage of eyes in the 0.7-mg DEX implant group requiring IOP-lowering medications was 23% or less (Figure 8). The majority of patients were either observed or treated with only 1 medication. Less than 8% of eyes at any visit required more than 1 medication. Only 1 patient required laser iridotomy for narrow angles (0.35-mg DEX implant group). No eyes required inci-

Patients, %

Patients, %

Current treatment options for intermediate and posterior uveitis are associated with significant limitations. The blood-retinal barrier significantly reduces the ability of topical and systemic medications to achieve effective concentrations in posterior ocular structures. In addition, systemic corticosteroids are often accompanied by a poor
WWW.ARCHOPHTHALMOL.COM

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 551

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

safety profile characterized by multiple adverse effects, such as fluid retention, hypertension, hyperglycemia, greater susceptibility to infections, osteoporosis, mood changes, and psychosis. Achieving adequate vitreous and retinal concentrations of corticosteroids for the treatment of posterior inflammation is achieved ideally with localized therapies without associated systemic adverse effects. The results of the present study demonstrate that the DEX implant has a favorable safety profile and can effectively reduce inflammation and substantially improve vision in eyes with noninfectious intermediate or posterior uveitis. In the current study, almost one-quarter (23%) of eyes treated with the 0.7-mg DEX implant achieved a vitreous haze score of 0 as early as 3 weeks after a single treatment. At week 8, 47% and 36% of eyes treated with the 0.7-mg and 0.35-mg DEX implants, respectively, had a vitreous haze score of 0. Similar efficacy with DEX implants was observed for the eyes with a baseline vitreous haze score of 1.5 or 2. While statistically insignificant because of small sample size, the pattern of proportion of patients who achieved a vitreous haze score of 0 from a baseline score of 3 or 4 was similar to that of the overall population. These findings suggest that the DEX implant may alleviate vitreous haze regardless of the baseline severity of vitreous haze. Patients treated with either doses of DEX implant had a significantly lower mean central macular thickness than the patients in the sham group at week 8. Importantly, improvements in inflammation were accompanied by substantial improvements in vision measured in both mean change in BCVA and the percentage of eyes with a 15-letter gain. The efficacy of the 0.7-mg DEX implant in alleviating vitreous haze and improving BCVA was maintained for up to 26 weeks. However, in a group of patients, the duration of DEX implant efficacy may have been shorter because 22% of patients in the 0.7-mg DEX implant group required rescue medications by week 26. It is difficult to compare the efficacy results of the present 26-week study with those for other intravitreal corticosteroids used to treat uveitis because there are no randomized controlled studies of the effects of intravitreal triamcinolone acetonide in the treatment of uveitis and the controlled studies of the FA implant do not focus on 6-month results. Moreover, the primary efficacy outcome measure in FA implant studies was the recurrence rate for uveitis over a 34-week study period.16 The reported visual improvement of at least 15 letters from baseline BCVA following treatment with the 0.59-mg FA implant was only 21% over 34 weeks compared with 38% at week 26 in the current study.16 The percentage of eyes using rescue medications was similar in both studies, with 22% of the DEX implant eyes receiving rescue medications at week 26 compared with 10.4%, 2.7%, and 12.3% of the 0.59-mg FA implant eyes receiving, respectively, systemic, periocular, and topical corticosteroids/immunosuppressors at week 34.16 Similar to the eyes treated with the 0.35-mg and 0.7-mg DEX implants, the need for rescue medications in eyes treated with the 2.1-mg FA implant was numerically higher than in those treated with the 0.59-mg dose.16 Typically, the most common adverse events associated with intravitreal corticosteroids, which may have im-

pacted use in the past, include increases in IOP11,17,18 and cataract.8,19 On any given follow-up visit in the present study, substantial increases in IOP (to 25 mm Hg) occurred in less than 10% of treated eyes. Those increases in IOP that did occur were typically transient and managed with topical medications or observation. No eye required a glaucoma-related surgical intervention. In contrast, in a pooled analysis from 3 randomized controlled trials of the 0.59-mg FA implant, 4.4% of eyes at 6 months, 10.9% of eyes at 12 months, and 32% of eyes at 36 months required surgical intervention to lower IOP.11 In the present study, only 1 of 62 phakic eyes (1.6%) treated with the 0.7-mg DEX implant required cataract extraction, though this study was only 6 months in duration. In eyes treated with the 0.59-mg FA implant, cataract extraction was performed in 10.9% of phakic eyes after 34 weeks16 and in 87.8% of phakic eyes after 2 years.20 These findings suggest that the DEX implant may provide a higher benefit-risk ratio than the FA implant for the treatment of noninfectious intermediate or posterior uveitis on the basis of a higher rate of visual acuity improvement combined with a lower incidence of IOP elevation requiring surgery and cataract extraction. Head-to-head clinical studies are warranted to directly compare the safety and efficacy of the DEX implant with the FA implant. The major limitation of the present study is that patients were treated with only a single DEX implant and followed up for only a 6-month period, which limits the ability to assess the risk of cataract (cataracts may take longer than 6 months to develop). Future studies will be needed to explore the long-term effects of repeated treatment with the DEX implant in patients with uveitis and evaluate the potential of this therapy in other retinal disorders beyond retinal vein occlusion. In conclusion, the present study demonstrated that in patients with noninfectious intermediate or posterior uveitis, a single dose of the DEX implant was well tolerated and produced significant improvements in intraocular inflammation and visual acuity that persisted for 6 months. Overall, the 0.7-mg DEX implant demonstrated greater efficacy than the 0.35-mg DEX implant, with similar safety. Submitted for Publication: July 20, 2010; final revision received October 8, 2010; accepted October 19, 2010. Published Online: January 10, 2011. doi:10.1001 /archophthalmol.2010.339 Correspondence: Careen Lowder, MD, PhD, Cleveland Clinic Cole Eye Institute, 9500 Euclid Ave, I-32, Cleveland, OH 44195 (lowderc@ccf.org). Author Contributions: The HURON Study Group Writing Committee had full access to all study data and takes responsibility for the integrity of the data and the accuracy of the data analysis. All members of the writing committee participated in the interpretation of the study findings and in either the drafting or critical revision of the manuscript or both. Ozurdex HURON Study Group Members: The HURON Study Group Writing Committee included the following: Drs Belfort, Cui, Foster, Li, Lightman, Lowder, Robinson, Schiffman, and Whitcup. The HURON Study Group Investigators are C. Augusto Moreira, T. BarisaniAsenbauer, Dr Belfort, J. Beniz Neto, J. Biswas, A. Brezin,
WWW.ARCHOPHTHALMOL.COM

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 552

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.

D. Callanan, N. Cassoux, L. R. DeBarge, J. Deschenes, R. Diaz-Rohena, G. Ephraim, A. Feuermannova , J. Forrester, Dr Foster, S. Garg, M. Goldstein, Y. Guex-Crosier, M. Kramer, S. C. Lee, Dr Lightman, Dr Lowder, F. Mackensen, N. Markomichelakis, P. Merrill, R. Nussenblatt, A. Palestine, U. Pleyer, R. Proenca, J. Sheppard, M. Shneck, K. Raczynska, T. Rabinovitch, S. R. Rathinam, E. Rihov, M. Sainz de la Maza, C. M. Samson, V. Sangwan, G. Sartani, M. Stanford, M. L. Tay Kearney, H. Tessler, C. Teitelbaum, J. Thorne, H. Vieira de Moraes, V. VishnevskiaDai, and R. Wang. Financial Disclosure: This study was sponsored by Allergan, Inc, which participated in the design of the study, data analysis, and interpretation and supervised the preparation of the manuscript and approved the final version. Drs Robinson, Schiffman, Li, Cui, and Whitcup are employees of Allergan, Inc. Previous Presentations: A preliminary report of this study was presented at the Association for Research in Vision and Ophthalmology Annual Meeting; May 6, 2010; Fort Lauderdale, Florida. Additional Contributions: Amy Lindsay, PhD, provided professional writing assistance with the preparation of the manuscript.
REFERENCES
1. Darrell RW, Wagener HP, Kurland LT. Epidemiology of uveitis: incidence and prevalence in a small urban community. Arch Ophthalmol. 1962;68:502-514. 2. Durrani OM, Tehrani NN, Marr JE, Moradi P, Stavrou P, Murray PI. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88(9):1159-1162. 3. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol. 1990;14(5-6):303308. 4. ten Doesschate J. Causes of blindness in the Netherlands. Doc Ophthalmol. 1982; 52(3-4):279-285. 5. Janigian RH, Young D. Uveitis, evaluation and treatment. http://emedicine .medscape.com/article/1209123-overview. Accessed January 22, 2010.

6. Couch SM, Bakri SJ. Intravitreal triamcinolone for intraocular inflammation and associated macular edema. Clin Ophthalmol. 2009;3:41-47. 7. Hosoya K, Tachikawa M. Inner blood-retinal barrier transporters: role of retinal drug delivery. Pharm Res. 2009;26(9):2055-2065. 8. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191-1201. 9. van Kooij B, Rothova A, de Vries P. The pros and cons of intravitreal triamcinolone injections for uveitis and inflammatory cystoid macular edema. Ocul Immunol Inflamm. 2006;14(2):73-85. 10. Jaffe GJ, Yang CH, Guo H, Denny JP, Lima C, Ashton P. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci. 2000;41(11):3569-3575. 11. Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthalmol. 2007;125 (11):1478-1485. 12. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of the sustained-release dexamethasone intravitreal implant [published online August 11, 2010]. Invest Ophthalmol Vis Sci. doi:10.1167/iovs.10_5285. 13. Weijtens O, Schoemaker RC, Lentjes EG, Romijn FP, Cohen AF, van Meurs JC. Dexamethasone concentration in the subretinal fluid after a subconjunctival injection, a peribulbar injection, or an oral dose. Ophthalmology. 2000;107(10):19321938. 14. Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010; 117(6):1134-1146. 15. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103(12):1796-1806. 16. Jaffe GJ, Martin D, Callanan D, Pearson PA, Levy B, Comstock T; Fluocinolone Acetonide Uveitis Study Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006;113(6):1020-1027. 17. Armaly MF. Statistical attributes of the steroid hypertensive response in the clinically normal eye, I: the demonstration of three levels of response. Invest Ophthalmol. 1965;4:187-197. 18. Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol. 1965;4:198-205. 19. Butcher JM, Austin M, McGalliard J, Bourke RD. Bilateral cataracts and glaucoma induced by long term use of steroid eye drops. BMJ. 1994;309(6946):43. 20. Pavesio C, Zierhut M, Bairi K, Comstock TL, Usner DW; Fluocinolone Acetonide Study Group. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology. 2010; 117(3):567-575.

Visit www.archophthalmol.com. As an individual subscriber, you may elect to be contacted when a specific article is cited. Receive an e-mail alert when the article you are viewing is cited by any of the journals hosted by HighWire. You will be asked to enter the volume, issue, and page number of the article you wish to track. Your e-mail address will be shared with other journals in this feature; other journals privacy policies may differ from JAMA & Archives Journals. You may also sign up to receive an e-mail alert when articles on particular topics are published.

ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 553

WWW.ARCHOPHTHALMOL.COM

Downloaded from www.archophthalmol.com at HINARI, on June 21, 2011 2011 American Medical Association. All rights reserved.