Effect of Adding Dexamethasone to Continued Ranibizumab Treatment in Patients With Persistent Diabetic Macular Edema: A DRCR Network Phase 2 Randomized Clinical Trial

Abstract

Importance: Some eyes have persistent diabetic macular edema (DME) following anti-vascular endothelial growth factor (anti-VEGF) therapy for DME. Subsequently adding intravitreous corticosteroids to the treatment regimen might result in better outcomes than continued anti-VEGF therapy alone.

Objective: To compare continued intravitreous ranibizumab alone with ranibizumab plus intravitreous dexamethasone implant in eyes with persistent DME.

Design, setting, and participants: Phase 2 multicenter randomized clinical trial conducted at 40 US sites in 129 eyes from 116 adults with diabetes between February 2014 and December 2016. Eyes had persistent DME, with visual acuity of 20/32 to 20/320 after at least 3 anti-VEGF injections before a run-in phase, which included an additional 3 monthly 0.3-mg ranibizumab injections. Data analysis was according to intent to treat.

Interventions: Following the run-in phase, study eyes that had persistent DME and were otherwise eligible were randomly assigned to receive 700 μg of dexamethasone (combination group, 65 eyes) or sham treatment (ranibizumab group, 64 eyes) in addition to continued 0.3-mg ranibizumab in both treatment arms as often as every 4 weeks based on a structured re-treatment protocol.

Main outcomes and measures: The primary outcome was change in mean visual acuity letter score at 24 weeks as measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS). The principal secondary outcome was change in mean central subfield thickness as measured with the use of optical coherence tomography.

Results: Of the 116 randomized patients, median age was 65 years (interquartile range [IQR], 58-71 years); 50.9% were female and 60.3% were white. Mean (SD) improvement in visual acuity from randomization was 2.7 (9.8) letters in the combination group and 3.0 (7.1) letters in the ranibizumab group, with the adjusted treatment group difference (combination minus ranibizumab) of -0.5 letters (95% CI, -3.6 to 2.5; 2-sided P = .73). Mean (SD) change in central subfield thickness in the combination group was -110 (86) μm compared with -62 (97) μm for the ranibizumab group (adjusted difference, -52; 95% CI, -82 to -22; 2-sided P < .001). Nineteen eyes (29%) in the combination group experienced increased intraocular pressure or initiated treatment with antihypertensive eyedrops compared with 0 in the ranibizumab group (2-sided P < .001).

Conclusions and relevance: Although its use is more likely to reduce retinal thickness and increase intraocular pressure, the addition of intravitreous dexamethasone to continued ranibizumab therapy does not improve visual acuity at 24 weeks more than continued ranibizumab therapy alone among eyes with persistent DME following anti-VEGF therapy.

Trial registration: clinicaltrials.gov Identifier: NCT01945866.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Maturi reported receiving consultancy fees, research grants, payment for manuscript preparation, and travel, accommodations, and meeting expenses from Allergan, Inc; grants from Allegro Pharmaceuticals; research grants from AbbVie, Genentech, GlaxoSmithKline, Joslin Diabetes Center, Kalvista, and Santen; consultancy fees from the American Academy of Ophthalmology, Graybug Inc, Henry & Beaver LLP, and Navigant Consulting; and travel, accommodations, meeting expenses, and payment for development of educational presentations from the University of Rochester. Mr Glassman reported receiving grant support from the National Institutes of Health, nonfinancial support from Genentech, institutional grant support from Allergan, and consultancy fees from the Macula Society. He is a member of the editorial board of JAMA Ophthalmology. Ms Liu reported receiving institutional grant support from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Beck reported receiving grant support from the National Eye Institute. Dr Bhavsar reported receiving personal fees and nonfinancial support from Allergan. Dr Bressler reported receiving grant support from Bayer, Genentech (Roche), Lumenis, Novartis, Regeneron, and Samsung Bioepis. Dr Jampol reported receiving grant support from the National Eye Institute. He is a member of the editorial board of JAMA Ophthalmology. Ms Melia reported institutional grant support from the National Eye Institute. Dr Sun reported receiving consultancy fees from Allergan, Bayer, Eleven Biotherapeutics, Kowa, Merck, and Novartis; grant support from Adaptive Sensory Technology, Boston Micromachines, Genentech, Kalvista, and OptoVUE; payment for manuscript preparation from JAMA Ophthalmology; and other/nonfinancial support from the American Diabetes Association and Springer Inc. She is a member of the editorial boards of Current Diabetes Reports and JAMA Ophthalmology. No other disclosures were reported.

Figures

Figure 1.. Completion of Follow-up

Protocol-specified visits occurred at baseline (randomization) and every 4 weeks (±1 week) at 4, 8, 12, 16, 20, and 24 weeks after randomization. For the primary analysis, a visit conducted between 20 and 30 weeks was included for the 24-week visit. For other protocol-specified follow-up visits, an analysis window of plus or minus 4 weeks was defined.

Figure 2.. Mean Change in Visual Acuity and Central Subfield Thickness (CST) on Optical Coherence Tomography (OCT) Across 24 Weeks

A, Mean change in visual acuity. B, Mean change in CST on OCT. Error bars indicate 95% CIs. Outlying values were truncated to 3 SDs from the mean.