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Clinical Trials  |   July 2013
Vision-Related Functioning Outcomes of Dexamethasone Intravitreal Implant in Noninfectious Intermediate or Posterior Uveitis
Author Affiliations & Notes
  • Susan Lightman
    UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom
  • Rubens Belfort, Jr.
    Department of Ophthalmology, Federal University of Sao Paulo, Sao Paulo, Brazil
  • Rupali K. Naik
    Allergan, Inc., Irvine, California
  • Careen Lowder
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • C. Stephen Foster
    Ophthalmology, Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts
  • Anne M. Rentz
    United BioSource Corporation, Bethesda, Maryland
  • Harry Cui
    Allergan, Inc., Irvine, California
  • Scott M. Whitcup
    Allergan, Inc., Irvine, California
  • Jonathan W. Kowalski
    Allergan, Inc., Irvine, California
  • Dennis A. Revicki
    United BioSource Corporation, Bethesda, Maryland
Investigative Ophthalmology & Visual Science July 2013, Vol.54, 4864-4870. doi:10.1167/iovs.12-10981
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      Susan Lightman, Rubens Belfort, Rupali K. Naik, Careen Lowder, C. Stephen Foster, Anne M. Rentz, Harry Cui, Scott M. Whitcup, Jonathan W. Kowalski, Dennis A. Revicki; Vision-Related Functioning Outcomes of Dexamethasone Intravitreal Implant in Noninfectious Intermediate or Posterior Uveitis. Invest. Ophthalmol. Vis. Sci. 2013;54(7):4864-4870. doi: 10.1167/iovs.12-10981.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To evaluate the effect of a single treatment with dexamethasone intravitreal implant (DEX implant) on patient-reported visual functioning in patients with noninfectious intermediate or posterior uveitis.

Methods.: Patient eyes with noninfectious intermediate or posterior uveitis were randomized to a single treatment with DEX implant 0.70 mg (n = 77), DEX implant 0.35 mg (n = 76), or a sham procedure (n = 76) and followed for 26 weeks. Vision-related functioning was measured using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) assessed at baseline and at weeks 8, 16, and 26 or early exit. Analysis of covariance and mixed model analysis of covariance were used to compare vision-related functioning between the DEX implant 0.70 and 0.35 mg groups and the sham group.

Results.: By 8 weeks, the DEX implant 0.70 mg group demonstrated significant improvements in NEI VFQ-25 subscales near vision (P = 0.031), distance vision (P = 0.023), peripheral vision (P = 0.045), vision-specific social functioning (P = 0.019), and the NEI VFQ-25 composite score (P = 0.007) compared with sham. After 26 weeks, the DEX implant 0.70 mg group reported significant improvements in NEI VFQ-25 subscales distance vision (P = 0.003), vision-specific role difficulties (P = 0.038), vision-specific dependency (P = 0.017), vision-specific social functioning (P = 0.009), vision-specific mental health (P = 0.036), and the composite score (P = 0.001) compared with sham.

Conclusions.: In patients with noninfectious intermediate or posterior uveitis receiving a single treatment of DEX implant 0.70 mg, significant and clinically meaningful improvements in patient-reported visual functioning were observed as early as week 8 and were maintained over 26 weeks. (ClinicalTrials.gov number, NCT00333814.)

Introduction
Uveitis refers to a group of diverse diseases not only affecting the uvea but also involving adjacent tissues including the retina, optic nerve, and vitreous. Patients with uveitis are at significant risk of developing substantial and sometimes permanent loss of vision, and uveitis is estimated to account for 10% to 15% of all cases of total blindness in the United States and the developed world. 13 The risk of severe vision loss is higher in patients with intermediate and posterior uveitis, characterized by inflammation of the vitreous and the retina. 
Vision loss in patients with uveitis is most commonly due to cystoid macular edema (CME), inflammatory vitreous haze and debris, and cataracts. 1,3,4 The CME and inflammatory haze are typically responsive to anti-inflammatory agents such as corticosteroids. 5 Corticosteroids are most often used to treat uveitis, despite the availability of immunosuppressive therapies. 6,7 The low bioavailability of topical corticosteroids within ocular tissues posterior to the iris/lens complex limits their utility. Oral corticosteroid administration often requires extremely high plasma concentrations to achieve therapeutic levels in the eye, and the high drug plasma levels often lead to systemic side effects such as hypertension, hyperglycemia, and increased susceptibility to infection. Advances in nanotechnology have led to the development of sustained-release intravitreal implants, like the dexamethasone intravitreal implant that gradually delivers dexamethasone to the posterior chamber (DEX implant, OZURDEX; Allergan, Inc., Irvine, CA). Studies demonstrate a severalfold higher dexamethasone concentration in the retina with the DEX implant in nonhuman primates 8 compared with dexamethasone drug levels in the subretinal fluid following oral and peribulbar administrations in humans. 9 Lowder et al. 10 have evaluated the safety and efficacy of DEX implant 0.70 and 0.35 mg compared with a sham procedure in a 26-week randomized clinical trial in patients with noninfectious intermediate or posterior uveitis. The proportion of eyes achieving a vitreous haze score of 0 at week 8 was 46.8% with DEX implant 0.70 mg, 35.5% with DEX implant 0.35 mg, and 11.8% with sham (P < 0.001), and these effects were maintained over the course of the study. The proportion of eyes achieving a ≥15-letter improvement from baseline best corrected visual acuity (BCVA) was significantly greater for both the DEX implant 0.70 mg (P < 0.001) and the 0.35 mg group (P ≤ 0.027) compared with sham at all assessment visits. At week 8, the proportion of eyes with a ≥15-letter improvement from baseline BCVA was 43% with DEX implant 0.70 mg, 40% with DEX implant 0.35 mg, and 7% with sham (P < 0.001). Vision-related functioning, as measured by the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), was included as a patient-reported outcome in this clinical trial. Patient-reported outcome (PRO) measures such as the NEI VFQ-25 capture unique aspects of visual functioning that are both relevant and important to patients. This report summarizes the methods and results on vision-related functioning outcomes assessed in the DEX implant clinical trial. 
The primary objective of this study was to evaluate the effect of a single treatment with DEX implant on patient-reported vision-related functioning in patients with noninfectious intermediate or posterior uveitis. 
Methods
Study Design
The vision function outcome data are based on the Phase III multicenter masked, randomized, sham-controlled, parallel-group trial of 0.70 and 0.35 mg DEX implant compared with a sham procedure. Patients were followed for 8 weeks with an 18-week masked extension for a total of 26 weeks. 10 The clinical trial received Institutional Review Board Committee approval and was conducted in compliance with regulations in the Health Insurance Portability and Accountability Act and the Declaration of Helsinki. Written informed consent was received from all patients. This clinical trial is registered at clinicaltrials.gov as NCT00333814. 
Detailed descriptions of the clinical trial and key inclusion and exclusion criteria have been reported elsewhere. 10 Patients were included in the study if they were at least 18 years of age and had a diagnosis of intermediate uveitis (with the vitreous as the primary site of inflammation) or posterior uveitis (with the retina or choroid the primary site of inflammation). Patients were also required to have decreased visual acuity attributable to uveitis, with vitreous haze score at least +1.5 and BCVA between 10 (approximately 20/640 Snellen equivalent) and 75 letters (approximately 20/32 Snellen equivalent) in the study eye measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) method at baseline. Only one eye was designated as the study eye. In patients with both eyes eligible for the study, the right eye was used as the study eye. Patients were allowed to use stable-dose topical corticosteroids, nonsteroidal anti-inflammatory agents, systemic corticosteroids, and systemic immunosuppressors under specified conditions. 10 Patients were excluded if they had uncontrolled systemic disease, any ocular condition in the study eye that would prevent improvement in visual acuity, or any condition or treatment that would otherwise confound the results of the study. 
Study Treatment
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 resulting in no ocular penetration. Unless required for patient care, the use of systemic immunosuppressive therapy or corticosteroids (systemic, periocular, intravitreal, or topical) was not allowed. Rescue therapy could be administered if the clinical investigator considered it necessary for the patient. Rescue therapy was defined as intravitreal/periocular injections of corticosteroids in the study eye or systemic medications taken for uveitis or ocular inflammation that were newly started or increased in dose from treatment day 0. The criteria for the use of anti-inflammatory agents were an increase from baseline in vitreous haze of ≥1 unit from week 3 to just prior to week 8 and a vitreous haze score of ≥+1.5 from week 8 to week 26. 
Vision Function Outcome Measure
The NEI VFQ-25 was used as the vision-related functioning outcome measure for this clinical study. The NEI VFQ-25 was developed to assess vision functioning outcomes across a range of ocular conditions. 1114 The NEI VFQ-25 includes 11 vision-related subscales (general vision, near vision, distance vision, driving, peripheral vision, color vision, ocular pain, vision-specific role difficulties, vision-specific dependency, vision-specific social function, and vision-specific mental health) and one general health item. Each subscale is scored such that 0 represents the lowest and 100 the best possible visual functioning. An overall composite score is calculated as the mean of the subscale scores excluding the general health score. The NEI VFQ-25 was administered at screening and at weeks 8, 16, and 26 or early exit. 
Statistical Analysis
The NEI VFQ-25 analyses were performed using all patients who were randomized to treatment and who had at least a baseline and one follow-up assessment. Missing data, unless otherwise specified, were imputed using the last observation carried forward (LOCF) method. For patients who received rescue medication, the NEI VFQ-25 scores for visits following the use of rescue medication were set as missing and the last observation was carried forward (Supplementary Table S1). Statistical significance was considered at P < 0.05, and clinical significance was predefined as a 5- to 10-point increase in the NEI VFQ-25 subscale and overall composite scores. 1517  
The prespecified primary treatment comparisons were between the DEX implant 0.70 mg and sham groups and between the DEX implant 0.35 mg and sham groups. Group comparisons of absolute scores and mean changes from baseline scores at each visit were performed using analysis of covariance (ANCOVA) and repeated measures mixed model ANCOVA. The former included treatment group as a fixed effect and uveitis type, vitreous haze stratification group, and baseline VFQ-25 score as covariates. The repeated measures mixed model ANCOVA added visit and treatment-by-visit interaction as additional covariates and included the intercept as a random effect. A prespecified per protocol analysis was also conducted to examine the among-group differences in change from baseline to week 26 using the one-way analysis of variance (ANOVA) test; pairwise between-treatment group comparisons were performed if the among-treatment group difference was statistically significant. 
Clinical significance for the NEI VFQ-25 domains was assessed using two different responder definitions. The first responder definition required at least a 5-point improvement from pretreatment baseline for the NEI VFQ-25 subscale and overall composite scores. The second responder definition required at least a 10-point improvement for the NEI VFQ-25 subscale and overall composite scores. For each responder definition, the proportion of patients meeting the criterion was calculated for each NEI VFQ-25 domain by treatment group at each visit. Between-group differences were evaluated using a χ 2 test. 
Results
A total of 229 patients with noninfectious uveitis (80% with intermediate uveitis and 20% with posterior uveitis) were randomized to receive DEX implant 0.70 mg (n = 77), DEX implant 0.35 mg (n = 76), or sham (n = 76). The analytic sample for this study included 95% of the DEX implant 0.70 mg group (n = 73), 96% of the DEX implant 0.35 mg group (n = 73), and 97% of the sham group (n = 74). Demographic and clinical characteristics by treatment group are summarized in Table 1. The mean age was 44.6 years; 65% of the patients were female, and majority of the patients were white (61%). The median visual acuity in the study eye was 62.0 letters, and 84% received treatment in their worse-seeing eye. 
Table 1
 
Demographic and Clinical Characteristics
Table 1
 
Demographic and Clinical Characteristics
DEX Implant 0.70 mg, N = 73 DEX Implant 0.35 mg, N = 73 Sham, N = 74 Total, N = 220
Mean age, y 43.4 46.0 44.5 44.6
Range 18–75 19–82 18–82 18–82
Female, n (%) 45 (61.6) 47 (64.4) 50 (67.6) 142 (64.5)
Caucasian, n (%) 43 (58.9) 45 (61.1) 45 (60.8) 133 (60.5)
Intermediate uveitis, n (%) 59 (80.8) 61 (83.6) 56 (75.7) 176 (80.0)
Median vitreous haze score, measured on a standardized 0–4 scale 2.0 2.0 2.0 2.0
Median visual acuity in ETDRS letters 61.0 59.0 66.5 62.0
Worse-seeing eye, n (%) 63 (86.3) 63 (86.3) 59 (79.7) 185 (84.1)
Descriptive statistics (including n, mean, SD) for all VFQ-25 subscales and the overall composite score at baseline and weeks 8, 16, and 26 are available online for the three study groups (Supplementary Table S2). At baseline, significant differences were found between DEX implant 0.70 mg and sham groups for overall composite score (P = 0.013), color vision (P = 0.036), dependency (P = 0.008), social functioning (P = 0.014), and mental health (P = 0.012) and between DEX implant 0.35 mg and sham groups for overall composite score (P = 0.031), near vision (P = 0.019), distance vision (P = 0.047), role difficulties (P = 0.011), and dependency (P = 0.045) (data not shown). No significant differences were observed in the other seven NEI VFQ-25 subscale scores. For each subscale with significant differences in mean baseline NEI VFQ-25 scores between the three treatment groups, the sham group reported better vision-related functioning scores. 
Mean Change Analyses
From baseline through week 16, the overall composite score increased for all treatment groups. By contrast, from week 16 to week 26, the composite score increased for the DEX implant 0.70 mg group but decreased for the DEX implant 0.35 mg and sham groups (Fig. 1). Mean score by treatment group by visit for the 11 subdomains are available online (Supplementary Table S2). 
Figure 1
 
Mean National Eye Institute Vision Function Questionnaire-25 unadjusted composite score by treatment group.
Figure 1
 
Mean National Eye Institute Vision Function Questionnaire-25 unadjusted composite score by treatment group.
For the ANCOVA models with LOCF, there were statistically significant differences in baseline to week 8 changes between the DEX implant 0.70 mg and sham groups on NEI VFQ-25 overall composite (P = 0.007), near vision (P = 0.031), distance vision (P = 0.023), peripheral vision (P = 0.045), and vision-specific social functioning scores (P = 0.019) (Fig. 2). The improvements in overall composite scores were 9.6 points for the DEX 0.70 mg group compared with 4.2 points in the sham group. After 26 weeks, statistically significant changes from baseline were observed between the DEX implant 0.70 mg and sham groups on NEI VFQ-25 overall composite (P = 0.001), distance vision (P = 0.003), vision-specific role difficulties (P = 0.038), vision-specific dependency (P = 0.017), vision-specific social functioning (P = 0.009), and vision-specific mental health scores (P = 0.036) (Fig. 3). The improvements in the overall composite scores were maintained at 26 weeks in the DEX implant 0.70 mg group, with patients reporting improvement of 10.1 points compared with 2.8 points in the sham group. 
Figure 2
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 8 by treatment group.
Figure 2
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 8 by treatment group.
Figure 3
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 26 by treatment group. BL, baseline.
Figure 3
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 26 by treatment group. BL, baseline.
Compared to the sham group, the DEX implant 0.35 mg group had statistically significant greater improvements in baseline to 8-week changes in NEI VFQ-25 overall composite (P = 0.012), distance vision (P = 0.035), general vision (P = 0.008), peripheral vision (P = 0.014), and vision-specific role difficulties (P = 0.034) scores (Fig. 2). At 8 weeks, the improvements in overall composite scores were 9.2 points for the DEX 0.35 mg group compared with 4.2 points in the sham group. After 26 weeks, statistically significant changes from baseline were observed between the DEX implant 0.35 mg and sham groups on NEI VFQ-25 overall composite score (P = 0.023), near vision (P = 0.032), and distance vision (P = 0.015) (Fig. 3). The improvements in the DEX implant 0.35 mg group were maintained at 26 weeks, with patients reporting changes in the overall composite scores of 8.0 points compared with 2.8 points in the sham group. 
Additional per protocol ANOVA models produced comparable findings (data not shown). From baseline to week 26, the DEX implant 0.70 mg group demonstrated statistically significant improvements, compared with the sham group, in distance vision (P = 0.026), color vision (P = 0.022), vision-specific role difficulties (P = 0.026), vision-specific dependency (P = 0.004), vision-specific social function (P = 0.012), vision-specific mental health (P = 0.012), and the overall composite scores (P = 0.004). During the same period, the DEX 0.35 implant group demonstrated statistically significant improvements in distance vision (P = 0.032) and vision-specific role difficulties (P = 0.027) compared with the sham group. 
Mixed Model Repeated Measures Analyses
In the mixed model repeated measures ANCOVAs, significant treatment-by-visit interactions were observed for the mean NEI VFQ-25 overall composite (P = 0.004), distance vision (P = 0.013), color vision (P = 0.016), vision-specific role difficulties (P = 0.033), vision-specific dependency (P = 0.028), vision-specific social function (P = 0.008), and vision-specific mental health scores (P = 0.05) (data not shown). 
For the adjusted least-square mean changes across all visits in overall composite scores, the DEX implant 0.70 mg and DEX implant 0.35 mg groups reported significantly greater changes (10.0 points [P = 0.008] and 8.8 points [P = 0.037], respectively) compared to the sham groups (4.2 points). Similar magnitudes in improved scores were observed for the DEX implant groups compared to the sham group for mean change in distance vision, color vision, vision-specific role difficulties, vision-specific dependency, vision-specific social function, and vision-specific mental health (data not shown). 
Responder Analyses
Table 2 summarizes the responder analyses for the NEI VFQ-25 subscale and overall composite scores. By 8 weeks, there were significantly more ≥5-point responders for the overall composite score in the DEX implant 0.70 mg (54.8%; P < 0.001) and 0.35 mg (60.3%; P < 0.001) groups compared with the sham group (27.0%). These differences were maintained at 16 (data not shown) and 26 weeks, favoring the DEX implant treatment groups. Statistically significant differences in the proportion of ≥5-point responders at week 8 were observed for the DEX implant 0.70 mg group compared with the sham group for near vision (P < 0.001), distance vision (P = 0.016), general vision (P = 0.003), peripheral vision (P = 0.041), color vision (P = 0.001), ocular pain (P = 0.002), vision-specific role difficulties (P = 0.039), dependency (P = 0.007), vision-specific social functioning (P < 0.001), and mental health (P = 0.026). These differences generally persisted over the course of the study (Table 2). 
Table 2
 
Proportion of Patients With a 5-Point Improvement on National Eye Institute Vision Function Questionnaire-25 Domains (Intent-to-Treat Population)
Table 2
 
Proportion of Patients With a 5-Point Improvement on National Eye Institute Vision Function Questionnaire-25 Domains (Intent-to-Treat Population)
≥5-Point Improvement
DEX Implant 0.70 mg, N = 73 DEX Implant 0.35 mg, N = 73 Sham, N = 74
Near-vision activities
 Week 8, % (n) 58.9 (43)* 57.5 (42)* 31.1 (23)
 Week 26, % (n) 52.1 (28) 61.6 (45)* 37.8 (28)
Distance-vision activities
 Week 8, % (n) 52.1 (38)* 54.8 (40)* 32.4 (24)
 Week 26, % (n) 54.8 (40)* 64.4 (47)* 35.1 (26)
General health
 Week 8, % (n) 21.9 (16) 17.8 (13) 17.6 (13)
 Week 26, % (n) 26.0 (19) 17.8 (13) 21.6 (16)
General vision
 Week 8, % (n) 49.3 (36)* 54.8 (40)* 25.7 (19)
 Week 26, % (n) 49.3 (36)* 46.6 (34)* 28.4 (21)
Driving
 Week 8, % (n) 19.2 (14) 20.5 (15) 16.2 (12)
 Week 26, % (n) 27.4 (20) 21.9 (16) 20.3 (15)
Peripheral vision
 Week 8, % (n) 37.0 (27)* 41.1 (30)* 21.6 (16)
 Week 26, % (n) 35.6 (26) 46.6 (34)* 27.0 (20)
Color vision
 Week 8, % (n) 28.8 (21)* 19.2 (14)* 8.1 (6)
 Week 26, % (n) 26.0 (19)* 15.1 (11) 8.1 (6)
Ocular pain
 Week 8, % (n) 50.7 (37)* 47.9 (35)* 25.7 (19)
 Week 26, % (n) 58.9 (43)* 43.8 (32) 31.1 (23)
VS role difficulties
 Week 8, % (n) 52.1 (38)* 49.3 (36) 35.1 (26)
 Week 26, % (n) 58.9 (43)* 49.3 (36)* 28.4 (21)
VS dependency
 Week 8, % (n) 42.5 (31)* 34.2 (25) 21.6 (16)
 Week 26, % (n) 43.8 (32)* 41.1 (30)* 18.9 (14)
VS social functioning
 Week 8, % (n) 43.8 (32)* 32.9 (24)* 14.9 (11)
 Week 26, % (n) 45.2 (33)* 31.5 (23)* 14.9 (11)
VS mental health
 Week 8, % (n) 56.2 (41)* 60.3 (44)* 37.8 (28)
 Week 26, % (n) 67.1 (49)* 61.6 (45)* 44.6 (33)
Overall composite score
 Week 8, % (n) 54.8 (40)* 60.3 (44)* 27.0 (20)
 Week 26, % (n) 57.5 (42)* 60.3 (44)* 32.4 (24)
Statistically significant differences in the proportion of ≥5-point responders at week 8 were also observed for the DEX implant 0.35 mg group compared with the sham group for near vision (P = 0.001), distance vision (P = 0.006), general vision (P < 0.001), peripheral vision (P = 0.011), color vision (P = 0.050), ocular pain (P = 0.005), vision-specific social functioning (P = 0.010), and vision-specific mental health scores (P = 0.007). These differences were generally maintained over the course of the study. 
Similar patterns for significant differences between the DEX implant and sham groups were observed with responder definition of ≥10 points for the NEI VFQ-25 scores. After 8 weeks, there were significantly more ≥10-point responders for the overall composite score in the DEX implant 0.70 mg (45.2%; P < 0.001) and 0.35 mg (39.7%; P < 0.001) groups compared with the sham group (14.9%). Statistically significant differences in the proportion of ≥10-point responders at week 8 were observed for the DEX implant 0.70 mg group compared with the sham group for distance vision, general vision, peripheral vision, color vision, ocular pain, vision-specific role difficulties, vision-specific dependency, vision-specific social functioning, and vision-specific mental health (all P < 0.05; data not shown). In general, these differences were maintained over the course of the study, and by 26 weeks we observed differences in responders on all NEI VFQ-25 subscales and the composite score except for driving and peripheral vision subscales. Statistically significant differences in the proportion of ≥10-point responders at week 8 were observed for the DEX 0.35 mg group compared with the sham group, and the patterns of effects were similar to those of the DEX implant 0.70 mg groups. These differences persisted over the course of the study for near vision, distance vision, general vision, peripheral vision, vision-specific social functioning, vision-specific mental health, and overall composite score (all P < 0.05; data not shown). 
Discussion
The clinical trial by Lowder et al. 10 demonstrated that the DEX implant has a good safety profile and that it effectively reduced inflammation, improving vision in eyes with noninfectious intermediate or posterior uveitis. We found, based on this clinical trial, 10 that improvement in inflammation and visual acuity result in improvement in vision-related functioning and well-being. With DEX implant treatment, the effects on vision-related functioning were observed as early as 8 weeks for the overall composite score and several of the NEI VFQ-25 subscales. Most of these early effects on vision-related functioning persisted over the 26-week study. 
For patients treated with a single-dose DEX 0.70 mg implant, the earliest improvements were observed in the overall composite score and the near vision, distance vision, peripheral vision, and vision-specific social functioning subscales. These improvements were maintained over the 26-week study for the overall composite score, distance vision, and vision-specific social functioning; and additional improvements were observed for vision-specific role difficulties, vision-specific dependency, and vision-specific mental health outcomes. These findings indicate that a single-dose DEX implant treatment can effectively improve vision-related functioning in patients with noninfectious intermediate or posterior uveitis for at least 6 months. The mixed model results further confirm the effectiveness of DEX implant 0.70 mg on vision-related functioning in uveitis patients. 
The DEX implant 0.35 mg showed fewer effects on vision-related functioning, but improvements in the NEI VFQ-25 overall composite, distance vision, general vision, peripheral vision, and vision-specific role difficulties scores were observed by 8 weeks. These improvements persisted over 26 weeks for the overall composite, near vision, and distance vision scores. The mixed model analyses confirmed the impacts on distance vision, vision-specific role difficulties, and vision-specific dependency. Clearly, the DEX implant 0.70 mg–treated group demonstrated greater improvements in vision-related functioning than the DEX implant 0.35 mg–treated group. 
More important, these improvements in vision-related functioning are clinically meaningful. All of the statistically significant mean changes were greater than 5 points. A 5- to 10-point improvement in NEI VFQ-25 scores has been previously recommended as a clinically significant improvement. 1517 In patients with subfoveal choroidal neovascularization in at least one eye, a 3-line decrease in the visual acuity of the better-seeing eye was associated with a 3.6- to 16.2-point decrease in the overall NEI-VFQ score and nine subscale scores. 17 As evidenced by a population-based prevalence study of eye disease in 5,287 Latinos, for 9 of 11 NEI VFQ-25 subscales, a 5-point change was equivalent to a 1- or 2-line difference in visual acuity. 16 Further, based on psychometric analyses of data from this clinical trial, we estimated a clinically meaningful change in the NEI VFQ-25 scores in uveitis patients using anchor-based and distribution-based analyses. Using the distribution-based methods, a clinically meaningful change for the NEI VFQ-25 composite score was estimated at 3.86 points, and for the NEI VFQ-25 domain scores between 5 and 10 points. 18 Using the anchor-based method, a clinically meaningful change for the NEI VFQ-25 domain scores was estimated at between 4.5 and 16.6 points and at 10.2 for the NEI VFQ-25 composite score. 18  
Psychometric analyses also indicated that BCVA is correlated with vision-related functioning scores. Spearman's product-moment rank correlations between BCVA and NEI VFQ-25 scores ranged from small to moderate at baseline and weeks 8, 16, and 26. Correlations between the NEI VFQ-25 overall composite score and BCVA ranged from 0.45 to 0.50 at weeks 8, 16, and 26. 18  
The responder analysis further confirms and quantifies the effectiveness of the DEX implant 0.70 mg on vision-related functioning compared with the sham group. As early as 8 weeks, twice as many patients treated with DEX implant 0.70 mg (55%) and 0.35 mg (60%) showed 5-point or greater improvements in NEI VFQ-25 overall composite scores compared with the sham group (27%). By 26 weeks, there were more responders in the DEX 0.70 mg (58%) and 0.35 mg (60%) groups compared with the sham group (32%) on the overall composite scores. These early effects, based on the 5-point responder definition, were observed in 10 of the 11 NEI VFQ-25 subscale scores, all favoring the DEX implant 0.70 mg–treated group. Significantly more responders were also observed in the DEX implant 0.35 mg–treated group compared with sham for 8 of 11 subscale scores. Overall, these improvements were maintained over the course of the study in both groups. 
Comparable results were observed when the responder definition was increased to the 10-point criterion. For example, as early as 8 weeks, there was a greater proportion of 10-point responders on the NEI VFQ-25 overall composite score for the DEX implant 0.70 mg (45%) and DEX implant 0.35 mg (40%) groups than for the sham group (15%). These differences increased over the course of the study. Similar differences in 10-point responders were observed between the DEX implant–treated patients and those in the sham group on the other vision-related function outcomes, with significant differences observed in 9 of 11 NEI VFQ-25 subscales and the composite score in the DEX implant 0.70 mg group by 26 weeks. 
Because the NEI VFQ-25 responses are based on vision in both eyes, results are highly influenced by vision in the better-seeing eye. Results presented here are for all patients, regardless of whether their study eye was the better- or worse-seeing eye. It is important to note that DEX implant 0.70 mg and DEX implant 0.35 mg provided clinically meaningful benefit compared to sham treatment, improving patient-reported visual functioning as measured by the NEI VFQ-25 domains, despite the fact that a large majority (84%) of the sample received treatment in their worse-seeing eye. 
Several limitations to this study should be considered in interpreting these findings. First, given the inclusion and exclusion criteria for this clinical study, the vision-related function results may not be generalizable to all patients with noninfectious intermediate and posterior uveitis. Second, study patients were treated in only one eye. BCVA and vision-related functioning outcomes may vary when both eyes are treated as is the case in clinical practice. Differences at baseline in five NEI VFQ-25 subscale scores and the overall score may have affected the interpretation of the results; however, statistically significant treatment benefits were observed after adjustment for differences at baseline in the ANCOVA analyses. 
In conclusion, the current study demonstrated that in patients with noninfectious intermediate or posterior uveitis, a single treatment with the DEX implant significantly improved patient-reported vision function outcomes as early as week 8 and that these improvements were maintained for 6 months. These improvements in vision-related functioning were clinically meaningful, and showed that treatment-related improvements in inflammation and visual acuity resulted in beneficial effects on visual functioning and well-being. The vision-related functioning measures provide the patient's perspective on the outcomes of treatment, and these outcomes are complementary but not identical to visual acuity and other clinical measures. 
Supplementary Materials
Acknowledgments
The authors thank Young Zhu and Rebecca Liu of Allergan, Inc., for providing support for statistical analyses. 
Supported by Allergan, Inc. 
Disclosure: S. Lightman, Allergan (F, C); R. Belfort Jr, Allergan (F, C, R); R.K. Naik, Allergan (E); C. Lowder, Allergan (F, C, R); C.S. Foster, Allergan (F, C, R), Abbott (F, C), Alcon (F, C, R), Eyegate (F, I), LUX (F, C, R), Novartis (F, C), ISTA (C, R), Inspire (R); A.M. Rentz, Allergan (F); H. Cui, Allergan (E); S.M. Whitcup, Allergan (E); J.W. Kowalski, Allergan (E); D.A. Revicki, Allergan (F) 
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Figure 1
 
Mean National Eye Institute Vision Function Questionnaire-25 unadjusted composite score by treatment group.
Figure 1
 
Mean National Eye Institute Vision Function Questionnaire-25 unadjusted composite score by treatment group.
Figure 2
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 8 by treatment group.
Figure 2
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 8 by treatment group.
Figure 3
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 26 by treatment group. BL, baseline.
Figure 3
 
Least-square mean change in National Eye Institute Vision Function Questionnaire-25 scores from baseline to week 26 by treatment group. BL, baseline.
Table 1
 
Demographic and Clinical Characteristics
Table 1
 
Demographic and Clinical Characteristics
DEX Implant 0.70 mg, N = 73 DEX Implant 0.35 mg, N = 73 Sham, N = 74 Total, N = 220
Mean age, y 43.4 46.0 44.5 44.6
Range 18–75 19–82 18–82 18–82
Female, n (%) 45 (61.6) 47 (64.4) 50 (67.6) 142 (64.5)
Caucasian, n (%) 43 (58.9) 45 (61.1) 45 (60.8) 133 (60.5)
Intermediate uveitis, n (%) 59 (80.8) 61 (83.6) 56 (75.7) 176 (80.0)
Median vitreous haze score, measured on a standardized 0–4 scale 2.0 2.0 2.0 2.0
Median visual acuity in ETDRS letters 61.0 59.0 66.5 62.0
Worse-seeing eye, n (%) 63 (86.3) 63 (86.3) 59 (79.7) 185 (84.1)
Table 2
 
Proportion of Patients With a 5-Point Improvement on National Eye Institute Vision Function Questionnaire-25 Domains (Intent-to-Treat Population)
Table 2
 
Proportion of Patients With a 5-Point Improvement on National Eye Institute Vision Function Questionnaire-25 Domains (Intent-to-Treat Population)
≥5-Point Improvement
DEX Implant 0.70 mg, N = 73 DEX Implant 0.35 mg, N = 73 Sham, N = 74
Near-vision activities
 Week 8, % (n) 58.9 (43)* 57.5 (42)* 31.1 (23)
 Week 26, % (n) 52.1 (28) 61.6 (45)* 37.8 (28)
Distance-vision activities
 Week 8, % (n) 52.1 (38)* 54.8 (40)* 32.4 (24)
 Week 26, % (n) 54.8 (40)* 64.4 (47)* 35.1 (26)
General health
 Week 8, % (n) 21.9 (16) 17.8 (13) 17.6 (13)
 Week 26, % (n) 26.0 (19) 17.8 (13) 21.6 (16)
General vision
 Week 8, % (n) 49.3 (36)* 54.8 (40)* 25.7 (19)
 Week 26, % (n) 49.3 (36)* 46.6 (34)* 28.4 (21)
Driving
 Week 8, % (n) 19.2 (14) 20.5 (15) 16.2 (12)
 Week 26, % (n) 27.4 (20) 21.9 (16) 20.3 (15)
Peripheral vision
 Week 8, % (n) 37.0 (27)* 41.1 (30)* 21.6 (16)
 Week 26, % (n) 35.6 (26) 46.6 (34)* 27.0 (20)
Color vision
 Week 8, % (n) 28.8 (21)* 19.2 (14)* 8.1 (6)
 Week 26, % (n) 26.0 (19)* 15.1 (11) 8.1 (6)
Ocular pain
 Week 8, % (n) 50.7 (37)* 47.9 (35)* 25.7 (19)
 Week 26, % (n) 58.9 (43)* 43.8 (32) 31.1 (23)
VS role difficulties
 Week 8, % (n) 52.1 (38)* 49.3 (36) 35.1 (26)
 Week 26, % (n) 58.9 (43)* 49.3 (36)* 28.4 (21)
VS dependency
 Week 8, % (n) 42.5 (31)* 34.2 (25) 21.6 (16)
 Week 26, % (n) 43.8 (32)* 41.1 (30)* 18.9 (14)
VS social functioning
 Week 8, % (n) 43.8 (32)* 32.9 (24)* 14.9 (11)
 Week 26, % (n) 45.2 (33)* 31.5 (23)* 14.9 (11)
VS mental health
 Week 8, % (n) 56.2 (41)* 60.3 (44)* 37.8 (28)
 Week 26, % (n) 67.1 (49)* 61.6 (45)* 44.6 (33)
Overall composite score
 Week 8, % (n) 54.8 (40)* 60.3 (44)* 27.0 (20)
 Week 26, % (n) 57.5 (42)* 60.3 (44)* 32.4 (24)
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