Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Quantitative Assessment of Optic Nerve Changes in Patients With Diabetic Macular Edema Treated With Fluocinolone Acetonide Vitreous Implants

Richard K. Parrish II, MD; Carlo E. Traverso, MD; Ken Green, PhD; Ronald P. Danis, MD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate glaucomatous changes in patients with diabetic macular edema (DME) treated with intravitreal implants releasing 0.2 µg/day or 0.5 µg/day fluocinolone acetonide (FAc) (Iluvien 0.2 µg/day; Alimera Sciences, Alpharetta, GA) or sham control.

PATIENTS AND METHODS:

Fundus photographs were assessed to determine clinically significant changes in glaucomatous indicators.

RESULTS:

The mean cup-to-disc ratio (CDR) change was similar with all three treatments. Compared with sham control, a significantly greater proportion of patients treated with 0.5 µg/day but not 0.2 µg/day FAc experienced a CDR increase of greater than 0.1. There was no significant increase in the proportion of patients experiencing a CDR increase of greater than 0.2 with either dose of implant versus sham control. Other indicators of glaucomatous change did not differ significantly with treatment. Subgroup analyses showed no differences in cupping based on ocular or baseline characteristics.

CONCLUSION:

Treatment with FAc for 36 months was not associated with significant glaucomatous optic nerve head changes in patients with DME with or without increased intraocular pressure.

[Ophthalmic Surg Lasers Imaging Retina. 2016;47:418–425.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate glaucomatous changes in patients with diabetic macular edema (DME) treated with intravitreal implants releasing 0.2 µg/day or 0.5 µg/day fluocinolone acetonide (FAc) (Iluvien 0.2 µg/day; Alimera Sciences, Alpharetta, GA) or sham control.

PATIENTS AND METHODS:

Fundus photographs were assessed to determine clinically significant changes in glaucomatous indicators.

RESULTS:

The mean cup-to-disc ratio (CDR) change was similar with all three treatments. Compared with sham control, a significantly greater proportion of patients treated with 0.5 µg/day but not 0.2 µg/day FAc experienced a CDR increase of greater than 0.1. There was no significant increase in the proportion of patients experiencing a CDR increase of greater than 0.2 with either dose of implant versus sham control. Other indicators of glaucomatous change did not differ significantly with treatment. Subgroup analyses showed no differences in cupping based on ocular or baseline characteristics.

CONCLUSION:

Treatment with FAc for 36 months was not associated with significant glaucomatous optic nerve head changes in patients with DME with or without increased intraocular pressure.

[Ophthalmic Surg Lasers Imaging Retina. 2016;47:418–425.]

INTRODUCTION

The Fluocinolone Acetonide for Diabetic Macular Edema (FAME) trials demonstrated visual acuity improvements in patients with diabetic macular edema (DME) who received non-bioerodable intravitreal implant(s) delivering fluocinolone acetonide (FAc) (Iluvien 0.2 µg/day; Alimera Sciences, Alpharetta, GA) compared with sham control at 24 and 36 months.1–3 The U.S. Food and Drug Administration (FDA) approved 0.2 µg/day FAc for use in “the treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.”2 The European Medicines Agency approved 0.2 µg/day FAc for the treatment of “chronic DME considered insufficiently responsive to available therapies.”4

The 0.2-µg/day FAc implant is the only continuous, multiyear, submicrogram, daily intravitreal corticosteroid therapy for DME. As such, understanding known class-related adverse events, including elevated intraocular pressure (IOP), associated with intravitreal corticosteroid use is essential for therapeutic management.5 In the FAME trials, elevated IOP was managed with topical medication (38% of 0.2 µg/day FAc-treated patients), laser trabeculoplasty (1.3% of 0.2 µg/day FAc-treated patients), or surgery (4.8% of 0.2 µg/day FAc-treated patients).3

This report assesses glaucomatous change, analyzed by an independent fundus photograph reading center, associated with FAc implant use. Glaucomatous change was quantified by differences in the vertical cup-to-disc ratio (CDR). Optic nerve head evaluation by estimating the CDR is a routine assessment of glaucomatous change.6,7 Although CDRs can be measured either vertically or horizontally, the vertical CDR is more commonly used in clinical practice.8 Color fundus photographs taken at baseline and most follow-up visits during the study were graded in a masked fashion for quantitative assessment of optic nerve cupping, an indicator of nerve fiber loss and a primary characteristic of glaucomatous optic neuropathy.9,10 Subjective optic nerve cupping assessment in clinical practice has more variability than standardized assessment by trained assessors in a reading center environment.11–14

Patients/Materials/Methods

Study Design

Details of the FAME trials have been described elsewhere.1 Patients with a history of glaucoma, ocular hypertension (OHT), or IOP greater than 21 mm Hg, or those taking IOP-lowering medication at initial evaluation, were excluded. Fundus photographs were obtained at baseline and at months 6, 12, 18, 24, and 36. The study eye was designated at baseline, and one eye was eligible for participation.

Reading Center Methods and Assessments

Certified Early Treatment Diabetic Retinopathy Study (ETDRS) photographers obtained stereoscopic color fundus photographs using the standard seven fields stipulated by the ETDRS protocol, including the optic nerve head. The University of Wisconsin Fundus Photograph Reading Center performed optic nerve head grading. Both digital and film images were used for this evaluation, dependent upon equipment availability. Two independent graders trained in optic nerve head evaluations assessed vertical CDRs and optic nerve or disc abnormalities. In this study, CDRs were calculated to two significant figures.

Adjudication was based on a CDR difference of 0.1 between visits by either grader and a CDR difference of 0.2 between graders for the corresponding eye and visit. The fellow eye was independently graded and adjudicated. Images were graded in a masked fashion regarding date and treatment. Reproducibility based on masked image regrading yielded a modest correlation between graders when CDR was treated as a continuous variable (intraclass correlation of 0.363). However, agreement within 0.1 and 0.2 cup-to-disc units was 84.3% and 97.8%, respectively, indicating good reproducibility for the major outcome variable of change of 0.2 units or greater.

Statistical Analyses

The intent-to-treat (ITT) population included all randomized patients who received one or more study treatment and had a baseline and one or more post-baseline optic nerve head study eye assessment. Missing data were estimated using the last-observation-carried-forward method and included baseline and last observed post-baseline assessments. Unless otherwise indicated, assessments were performed in the study eye only.

Subgroup Analyses

Optic nerve head data were also analyzed within subgroups of the ITT population using the last observed value. Baseline variables included in these analyses were age, continent where the study was conducted, sex, self-identified ancestry, glycosylated hemoglobin, lens status, IOP, history of intravitreal corticosteroid use, OHT diagnosis or IOP-lowering medication use, DME duration, and vertical CDR. Patients were also evaluated based on trial outcome data, including number of study treatments; administration of IOP-lowering medication during the trial; trabeculoplasty, incisional IOP-lowering surgery, or both; and cupping progression.

Vertical Cup-to-Disc Ratio

Differences between baseline and follow-up vertical CDRs were evaluated using an analysis of covariance model with treatment group and baseline visual acuity strata (≤ 49 letters, > 49 letters) as fixed effects. Age and baseline IOP were included as covariates in the model. The difference from sham control in the number and percentage of patients with a vertical CDR change was summarized and analyzed statistically. Differences were defined as change from baseline of greater than 0.1. Pairwise comparisons between treatment groups were made using a Cochran-Mantel-Haenszel (CMH) chi-square test stratified by study eye baseline visual acuity strata and a 95% confidence interval around the difference in these percentages between groups was calculated. Vertical CDR change from baseline values within subgroups was analyzed using an analysis of variance model with treatment group and baseline visual acuity as fixed effects.

Other Glaucomatous Indicators

Optic nerve pallor, disc hemorrhage, and disc notching were graded categorically according to the following scale: “absent,” “questionable,” “definite,” “cannot grade,” or “not applicable.” Values for “cannot grade” and “not applicable” were set to missing for analytical purposes. These variables were summarized by frequency distribution and analyzed using a CMH chi-square test stratified by baseline visual acuity strata. For each variable, the number and percentage of patients with worsening were summarized. Change was defined as moving from “absent” to “questionable” or “definite” or from “questionable” to “definite.” Pairwise comparisons between treatment groups used a CMH chi-square test stratified by study eye baseline visual acuity strata and a 95% confidence interval around the difference in these percentages between groups was calculated.

Results

Baseline Demographic and Clinical Characteristics

The ITT population included 169 patients in the sham-control group, 354 in the 0.2-µg/day FAc group, and 368 in the 0.5-µg/day FAc group. The mean age was 62.4 years (range: 20.5 years to 86.6 years), the majority of patients were white (70.4%), and 59.6% were men. More than half of patients (65%) were phakic. Although the protocol stipulated exclusion of patients with a history of glaucoma, OHT, or IOP greater than 21 mm Hg, or those taking IOP-lowering medication at initial evaluation, 18 patients (2%) included in the ITT population were diagnosed as having OHT or were receiving IOP-lowering medication at baseline. Prior study eye treatment for DME, in addition to the required macular laser, included intravitreal corticosteroid (19.4%) or anti-vascular endothelial growth factor (6.3%) treatments. The median baseline IOP was 15 mm Hg, most patients had type 2 diabetes (92.1%), and the median HbA1c was 7.5%. Key demographics and baseline characteristics were similar among the treatment arms.

Vertical Cup-to-Disc Ratio

The mean vertical CDR change represents an arithmetic mean; that is, it was determined by calculating the difference between the last observation and baseline value for each patient, summing these values, and dividing by the number of observations. The mean vertical CDR change was similar between the sham-control and 0.2-µg/day FAc groups (0.005 vs. 0.016; P = .098), as well as the 0.5-µg/day FAc group (0.005 vs. 0.014; P = .117) (Table 1). Table 2 shows the frequency distribution of vertical CDR change from baseline for study and contralateral eyes. Regardless of study treatment received, 97% or more of patients did not experience a vertical CDR change of 0.1 or greater in the contralateral eye. The two 0.2 µg/day FAc treated-patients with the largest vertical CDR increase had no history of ocular steroid treatment before implant receipt.


Mean Change in Vertical Cup-to-Disc Ratio at the Last Observation (Intent-to-Treat Population)

Table 1:

Mean Change in Vertical Cup-to-Disc Ratio at the Last Observation (Intent-to-Treat Population)


Frequency Distribution of Change From Baseline in Vertical Cup-to-Disc Ratio in Study and Contralateral Eyes at Final Observation (Intent-to-Treat Population)

Table 2:

Frequency Distribution of Change From Baseline in Vertical Cup-to-Disc Ratio in Study and Contralateral Eyes at Final Observation (Intent-to-Treat Population)

A comparison of increased vertical CDR incidence using a threshold of greater than 0.1 or greater than 0.2 among patients treated with sham control, 0.2 µg/day FAc, or 0.5 µg/day FAc is shown in Table 3. The proportion of patients with increased CDR was similar between those randomized to 0.2 µg/day FAc and sham control regardless of whether the greater than 0.1 or greater than 0.2 CDR threshold was applied (P = .134 and P = .162, respectively). The proportion of patients with increased CDR was significantly greater between those randomized to 0.5 µg/day FAc and sham control when the greater than 0.1 (P = .043), but not the greater than 0.2 CDR (P = .240) threshold was applied.


Percentage of Patients With Worsening of Vertical Cup-to-Disc Ratio at Final Observation (Intent-to-Treat Population)

Table 3:

Percentage of Patients With Worsening of Vertical Cup-to-Disc Ratio at Final Observation (Intent-to-Treat Population)

Other Glaucomatous Indicators

Although no attempt was made to standardize color saturation or hue after image capture, the majority of patients did not experience progressive optic nerve pallor. At baseline and last observation, optic nerve pallor was present in one patient each in the sham-control and 0.2-µg/day FAc groups and zero patients in the 0.5-µg/day FAc group. Numerically fewer patients in the sham-control group experienced optic nerve pallor worsening than in the 0.2-µg/day FAc group (0 vs. 4 [1.2%]; P = .180) or the 0.5-µg/day FAc group (0 vs. 4 [1.2%]; P = .165).

At baseline, disc hemorrhage was present in one, two, and four patients in the sham-control, 0.2-µg/day FAc, and 0.5-µg/day FAc groups, respectively. At last observation, two patients in each FAc group had a disc hemorrhage compared with zero in the sham control group. None of the sham control-treated patients developed a disc hemorrhage, compared with four 0.2 µg/day FAc-treated (1.2%; P = .145) and one 0.5 µg/day FAc-treated patients (0.3%; P = .542).

Few patients developed a notch of the disc — no patients in the sham-control group and one patient each from the 0.2-µg/day FAc (0.3%; P = .470) and 0.5-µg/day FAc (0.3%; P = .472) groups.

Subgroup Analyses

Subgroup analyses were performed for all optic nerve assessments; however, only vertical CDR results are shown because of the limited number of patients who experienced other abnormalities. Mean vertical CDR changes according to baseline characteristics are shown in Table 4. Within each treatment group, no baseline variables were associated with a clinically significant difference between subgroups. Table 5 shows mean vertical CDR changes according to trial outcomes. Within each treatment group, no trial outcome-related subgroup was associated with a meaningful difference in mean vertical CDR change.


Mean Change in Vertical Cup-to-Disc Ratio at Final Observation by Demographic and Other Baseline Characteristics (Intent-to-Treat Population)

Table 4:

Mean Change in Vertical Cup-to-Disc Ratio at Final Observation by Demographic and Other Baseline Characteristics (Intent-to-Treat Population)


Mean Change in Vertical Cup-to-Disc Ratio at Final Observation by Trial Outcome-Related Subgroup (Intent-to-Treat Population)

Table 5:

Mean Change in Vertical Cup-to-Disc Ratio at Final Observation by Trial Outcome-Related Subgroup (Intent-to-Treat Population)

Association of Increased Vertical Cup-to-Disc Ratio and IOP

Results of the association between IOP-lowering medication use and development of clinically relevant cupping (CDR > 0.1) are presented in Table 6. Overall, 31 of these patients (3.6%) experienced a vertical CDR increase from baseline and the incidence was dose-related (sham: two [1.2%]; 0.2 µg/day FAc: 12 [3.5%]; 0.5 µg/day FAc: 17 [4.7%]) (Tables 3 and 6). Fifty percent to 67% of these patients received IOP-lowering medication during the study (sham: 1/2 [50%]; 0.2 µg/day FAc: 8/12 [67%]; 0.5 µg/day FAc: 10/17 [59%]). Among the patients who required IOP-lowering therapy, 94% to 96% did not experience a significant vertical CDR increase (sham: 24/25 [96%]; 0.2 µg/day FAc: 126/134 [94%]; 0.5 µg/day FAc: 163/173 [94.2%]). This proportion was similar in patients who did not require IOP-lowering therapy who also had no significant vertical CDR increase (sham: 140/141 [99.3%]; 0.2 µg/day FAc: 207/211 [98.1%]; 0.5 µg/day FAc: 179/186 [96.2%]). No treatment group showed significant association between medication usage and cupping. Compared with the sham-control group, neither active treatment arm had a significantly different association between medication usage and cupping.


Frequency Distribution of Patients Who Received IOP-Lowering Medication and Had a Clinically-Meaningfula Increase in Vertical Cup-to-Disc Ratio (Intent-to-Treat Population)

Table 6:

Frequency Distribution of Patients Who Received IOP-Lowering Medication and Had a Clinically-Meaningful Increase in Vertical Cup-to-Disc Ratio (Intent-to-Treat Population)

The IOP and best-corrected visual acuity (BCVA) during the course of the study period for the 0.2 µg/day FAc-treated patient with the largest vertical CDR increase (0.45) from the FAME trials were investigated. Prior to surgical intervention at month 33, this patient experienced two IOP spikes as high as 44 mm Hg and IOP was managed with medication and two laser trabeculoplasty procedures, whereas visual acuity remained at its 6-month high (58 ETDRS letters). At month 24, nerve fiber layer hemorrhage was reported coincident with increased cupping. Given the six IOP increases of greater than 35 mm Hg prior to surgery, more aggressive IOP-lowering measures may have been warranted.

Discussion

In this study, fundus photographs from FAME participants were assessed to determine whether FAc implant use was associated with a risk of glaucomatous change to the optic nerve. The mean vertical CDR changes between the FAc implant and sham-control groups were similar. The incidence of increased CDR greater than 0.1 was only significant for the 0.5-µg/day FAc compared with the sham-control group. Using the CDR greater than 0.2 threshold, seven patients (four and three in the 0.2-µg/day and 0.5-µg/day FAc groups, respectively) were considered to have clinically significant increased cupping. There was no elevated risk of increased cupping with multiple FAc treatments. Other indicators of glaucomatous change did not differ significantly with control or FAc treatment. Baseline visual field testing to assess glaucomatous change was not performed as macular edema likely affected central vision depression and per the FAME protocol exclusion criteria, these patients did not have glaucoma or OHT. There was a marginal association of IOP-lowering medication use with increased cupping, and the majority of patients receiving IOP-lowering therapy did not experience glaucomatous optic nerve damage.

In the patient case presented, BCVA improved from 30 to 58 ETDRS letters between baseline and month 6, and visual acuity benefit was maintained throughout the study. The patient's elevated IOP was treated with trabeculoplasty followed by surgery at month 33. This patient experienced nerve fiber layer hemorrhage coincident with increased cupping at month 24. Whether earlier, more aggressive IOP-lowering intervention would have resulted in less optic nerve damage is unknown.

The IOP elevation and cataract development associated with 0.2-µg/day FAc implants are recognized corticosteroid class-related adverse events.1,3,5 The present data further quantify corticosteroid-induced IOP elevation risk with 0.2-µg/day FAc implants during the 3 years after FAc implant therapy. The FDA indication for 0.2 µg/day FAc requires a course of corticosteroid therapy without a clinically significant IOP elevation prior to implant receipt.2 This stipulation is meant to mitigate the associated elevated IOP risk. The distinction between corticosteroid-induced IOP increase without subsequent glaucomatous change (OHT) and glaucomatous optic neuropathy is important. This analysis demonstrates that although IOP increases occur in patients after FAc implant reception, concomitant confirmed glaucomatous optic nerve changes associated with FAc implants were similar to those in the sham control-treated population. Further, no association was determined between IOP-lowering medication use or any other ocular or baseline characteristic and progressive optic neuropathy.

References

  1. Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626–635.e2. doi:10.1016/j.ophtha.2010.12.028 [CrossRef]
  2. Iluvien (fluocinolone acetonide intravitreal implant) [package insert]. Alpharetta, GA: Alimera Sciences; 2014.
  3. Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125–2132. doi:10.1016/j.ophtha.2012.04.030 [CrossRef]
  4. Alimera Sciences F. UK ILUVIEN Summary of Product Characteristics. https://www.medicines.org.uk/emc/medicine/27636. Updated 2013. Accessed September 25, 2013.
  5. Schwartz SG, Flynn HW Jr., Scott IU. Intravitreal corticosteroids in the management of diabetic macular edema. Curr Ophthalmol Rep. 2013;1(3). doi:10.1007/s40135-013-0015-3 [CrossRef].
  6. Ungar AK, Wollstein G, Ishikawa H, et al. Evaluating objective and subjective quantitative parameters at the initial visit to predict future glaucomatous visual field progression. Ophthalmic Surg Lasers Imaging. 2012;43(5):416–424. doi:10.3928/15428877-20120524-01 [CrossRef]
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  8. Tatham AJ, Weinreb RN, Zangwill LM, Liebmann JM, Girkin CA, Medeiros FA. The relationship between cup-to-disc ratio and estimated number of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2013;54(5):3205–3214. doi:10.1167/iovs.12-11467 [CrossRef]
  9. Hayreh SS. Pathogenesis of cupping of the optic disc. Br J Ophthalmol. 1974;58(10):863–876. doi:10.1136/bjo.58.10.863 [CrossRef]
  10. Quigley HA, Green WR. The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology. 1979;86(10):1803–1830. doi:10.1016/S0161-6420(79)35338-6 [CrossRef]
  11. Feuer WJ, Parrish RK 2nd, Schiffman JC, et al. The Ocular Hypertension Treatment Study: reproducibility of cup/disk ratio measurements over time at an optic disc reading center. Am J Ophthalmol. 2002;133(1):19–28. doi:10.1016/S0002-9394(01)01338-1 [CrossRef]
  12. Abrams LS, Scott IU, Spaeth GL, Quigley HA, Varma R. Agreement among optometrists, ophthalmologists, and residents in evaluating the optic disc for glaucoma. Ophthalmology. 1994;101(10):1662–1667. doi:10.1016/S0161-6420(94)31118-3 [CrossRef]
  13. Varma R, Spaeth GL, Steinmann WC, Katz LJ. Agreement between clinicians and an image analyzer in estimating cup-to-disc ratios. Arch Ophthalmol. 1989;107(4):526–529. doi:10.1001/archopht.1989.01070010540027 [CrossRef]
  14. Tielsch JM, Katz J, Quigley HA, Miller NR, Sommer A. Intraobserver and interobserver agreement in measurement of optic disc characteristics. Ophthalmology. 1988;95(3):350–356. doi:10.1016/S0161-6420(88)33177-5 [CrossRef]

Mean Change in Vertical Cup-to-Disc Ratio at the Last Observation (Intent-to-Treat Population)

Sham Control0.2 µg/day FAc0.5 µg/day FAc
Last Observation, N166345359

Mean (SE)0.352 (0.0089)0.356 (0.0066)0.360 (0.0066)

Mean change (SE)0.005 (0.0024)0.016 (0.0027)0.014 (0.0029)
Difference (95% CI)−0.009 (−0.019 to 0.002)−0.008 (−0.018 to 0.002)
P valuea.098.117

Frequency Distribution of Change From Baseline in Vertical Cup-to-Disc Ratio in Study and Contralateral Eyes at Final Observation (Intent-to-Treat Population)

ObservedSham Control, n (%)0.2 µg/day FAc, n (%)0.5 µg/day FAc, n (%)

Study Eye

N166345359
> 0.5 to ≤ 0.6 increase001 (0.3)
> 0.4 to ≤ 0.5 increase01 (0.3)0
> 0.3 to ≤ 0.4 increase01 (0.3)1 (0.3)
> 0.2 to ≤ 0.3 increase02 (0.6)1 (0.3)
> 0.1 to ≤ 0.2 increase2 (1.2)8 (2.3)14 (3.9)
0.0 to = 0.1 increase61 (36.7)153 (44.3)152 (42.3)
No change55 (33.1)103 (29.9)101 (28.1)
0.0 to ≤ 0.1 decrease48 (28.9)76 (22.0)88 (24.5)
> 0.1 to ≤ 0.2 decrease01 (0.3)1 (0.3)

Contralateral Eye

N161338354
> 0.5 to ≤ 0.6 increase000
> 0.4 to ≤ 0.5 increase000
> 0.3 to ≤ 0.4 increase000
> 0.2 to ≤ 0.3 increase001 (0.3)
> 0.1 to ≤ 0.2 increase1 (0.6)7 (2.1)8 (2.3)
0.0 to ≤ 0.1 increase68 (42.2)136 (40.2)146 (41.2)
No change47 (29.2)118 (34.9)113 (31.9)
0.0 to ≤ 0.1 decrease45 (28.0)77 (22.8)84 (23.7)
> 0.1 to ≤ 0.2 decrease001 (0.3)
> 0.2 to ≤ 0.3 decrease001 (0.3)

Percentage of Patients With Worsening of Vertical Cup-to-Disc Ratio at Final Observation (Intent-to-Treat Population)

Sham Control (N = 166)0.2 µg/day FAc (N = 345)0.5 µg/day FAc (N = 359)
Patients with increase of > 0.1, n (%)2 (1.2)12 (3.5)17 (4.7)
Difference (95% CI)−2.3 (−4.8 to 0.3)−3.5 (−6.3 to −0.8)
P valuea.134.043

Patients with increase of > 0.2, n (%)04 (1.2)3 (0.8)
Difference (95% CI)−1.2 (−2.3 to 0.0)−0.8 (−1.8 to 0.1)
P value.162.240

Mean Change in Vertical Cup-to-Disc Ratio at Final Observation by Demographic and Other Baseline Characteristics (Intent-to-Treat Population)

Sham Control0.2 µg/day FAc0.5 µg/day FAc

NMean ChangeNMean ChangeNMean Change

Agea
  < Median920.0031580.0151840.018b
  ≥ Median740.0081870.0171750.010

Sex
  Male1000.0051940.0152250.016b
  Female660.0061510.0171340.010

Self-Identified Ancestry
  White1170.0062470.019b2460.016
  Non-white490.003980.0081130.011

Geographic Region
  North America1140.0072420.0202470.019
  Europe15−0.004350.002370.005
  India370.003680.010750.005

HbA1cc (%)
  < Median690.0031360.0171560.014
  ≥ Median700.0061670.0141560.015

Lens Status
  Pseudophakic580.0161270.0191140.017
  Phakic1080.0002180.014b2450.013b

Baseline IOP
  < 15 mm Hg770.0071390.0111550.021b
  ≥ 15 mm Hg890.0042060.019b2040.009

Prior Ocular Corticosteroids
  No1290.0012690.013b2850.013b
  Yes340.017670.025680.019

Diagnosis of OHT or Use of IOP-Lowering Medication
  No1650.0053370.016b3510.014b
  Yes10.13380.011d80.027d

Duration of DME
  < 3 years590.0051500.0181610.015
  ≥ 3 years1060.0061940.0141960.014

Baseline Cup-to-Disc Ratioe
  < Median860.0051720.0131860.015
  ≥ Median800.0061730.0191730.014

Mean Change in Vertical Cup-to-Disc Ratio at Final Observation by Trial Outcome-Related Subgroup (Intent-to-Treat Population)

SubgroupTreatment Group

Sham Control0.2 µg/day FAc0.5 µg/day FAc

NMean ChangeNMean ChangeNMean Change

Number of Study Treatments
  1 Treatment1240.0062770.0152750.015
  > 1 Treatment420.003680.019840.013

Received IOP-Lowering Medication
  No1500.0062670.0152570.016
  Yes15−0.003780.0191020.010

Underwent Trabeculoplasty
  No1660.0053430.016b3570.014
  Yes020.02620.018

Underwent IOP-Lowering Incisional Surgerya
  No1660.0053420.016b3530.014
  Yes030.00560.018

Presence of Cupping
  No1640.0043330.0093420.006
  Yes20.121120.192170.182

Frequency Distribution of Patients Who Received IOP-Lowering Medication and Had a Clinically-Meaningfula Increase in Vertical Cup-to-Disc Ratio (Intent-to-Treat Population)

Any IOP-Lowering MedicationChange in Cup-to-Disc RatioSham Control (N = 166), n (%)0.2 µg/day FAc (N = 345), n (%)0.5 µg/day FAc (N = 359), n (%)
NoNo140 (84.3)207 (60.0)179 (49.9)
Yes1 (0.6)4 (1.2)7 (2.0)

YesNo24 (14.5)126 (36.5)163 (45.4)
Yes1 (0.6)8 (2.3)10 (2.8)

P valueb.279.067.458

P valuec.709.360
Authors

From Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami (RKP); University of Genova, Department of Neurosciences, Ophthalmology, and Genetics / University Eye Clinic / IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy (CET); Alimera Sciences, Alpharetta, GA (KG); and the University of Wisconsin, School of Medicine and Public Health; Department of Ophthalmology & Visual Sciences; Madison, WI (RPD).

Presented previously at The Association for Research in Vision and Ophthalmology annual meeting in 2014.

Writing assistance was provided by Meditech Media, funded by Alimera Sciences. The study was supported by Alimera Sciences, Alpharetta, GA. The sponsor participated in data collection, data management, data analysis, interpretation of the data, preparation of the manuscript, and review of the manuscript. Employees of Alimera Sciences (Kathleen Billman, Barry Kapik, and Francis Kane) were responsible for conducting the study, data acquisition analysis, and reporting.

Dr. Parrish received personal fees from Alimera Sciences during the conduct of the study; receives personal fees from Aerie Pharmaceuticals, Alcon Laboratories, Glaukos Corporation, InnFocus, and AqueSys; and receives grants from the National Eye Institute outside of the submitted work. Dr. Traverso was the principal investigator during the conduction of the study, with funds received only by the institution. Dr. Green is an employee of Alimera Sciences, with stock options. Dr. Danis received grants from Alimera Sciences during the conduct of the study; receives grants and personal fees from Allergan and GlaxoSmithKline; receives grants from Genentech and KangHong; and receives personal fees from Thrombogenics outside of the submitted work.

Address correspondence to Richard K. Parrish II, MD, 900 NW 17th St, Miami, FL 33136; 800-329-7000; email: rparrish@med.miami.edu.

Received: November 09, 2015
Accepted: March 21, 2016

10.3928/23258160-20160419-04

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