April 30, 2019
2 min read

Protocol V trial results favor observation strategy for DME with good vision

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The DRCR.net Protocol V clinical trial concludes that patients with center-involved diabetic macular edema and good vision can confidently be managed by observation, scheduling anti-VEGF injections only if vision deteriorates.

Protocol V addressed the unanswered question of whether anti-VEGF injections are the best strategy in the common clinical scenario of center-involved DME with good vision. Physicians often treat these eyes based on the good results obtained in clinical trials in which anti-VEGF treatment was evaluated in eyes with reduced visual acuity. Could patients with good vision be spared a costly and burdensome treatment at least until the signs of vision deterioration appear?

To answer this question, a multicenter trial was conducted at 91 clinical sites in the United States and Canada. Between November 2013 and September 2016, 702 participants with center-involved DME and visual acuity of 20/25 or better were randomly assigned to initial management with Eylea (aflibercept, Regeneron) (n = 226), laser photocoagulation (n = 240) or observation (n = 236). In the aflibercept group, injections were administered as needed up to every 4 weeks. In the laser photocoagulation group, patients were treated at baseline with re-treatment at 13 weeks if indicated. In the observation group, no treatment was given at baseline. Patients in the laser and observation groups were monitored closely at weeks 8 and 16 and then at 16-week intervals. They were switched to aflibercept if a decrease of two or more lines at any visit or one line at two consecutive visits was reported.

At 2 years, the rates of visual acuity loss of five or more letters did not differ significantly between groups, and the average visual acuity was 20/20, as it was at baseline, with all three management strategies. Three-quarters of the eyes in the laser group and two-thirds of the eyes in the observation group did not receive anti-VEGF injections over the 2 years of follow-up.

“Each aflibercept injection has an average Medicare cost of $1,850, and all intravitreal injections carry a small risk of endophthalmitis (< 0.1%). Thus, reducing anti-VEGF treatment in these eyes while maintaining good vision has clinical and economic advantages for patients and public health,” the authors wrote.

Close monitoring rather than proactive treatment is bound to positively affect life quality, an aspect that Protocol V did not address, Tunde Peto, MD, PhD, and Usha Chakravarthy, MD, FRCOphth, PhD, wrote in a commentary published in JAMA Ophthalmology.

“It is important to understand the effect of the visit schedules, which differed between groups, and the challenge of frequent visits and injections in the prompt aflibercept therapy group, given that those with diabetes already haves systemic comorbidities that often contribute to a burden of hospital visits,” they wrote.

“Future technology may do a better job of identifying who might benefit from early treatment, before diabetic macular edema affects vision,” Adam R. Glassman, MS, one of the study authors, said in a press release from the National Eye Institute. “But for now, close monitoring of diabetic macular edema in patients with good vision is an appropriate initial strategy as long as they are closely followed and subsequently treated if vision worsens.”

As Peto and Chakravarthy said in their commentary, Protocol V gives physicians the confidence to manage patients with DME and good vision with a vigilant observation approach.

“Such a management strategy would avoid potentially unnecessary introduction of anti-VEGF therapies at a stage of disease that may be amenable to alternative, noninvasive strategies, such as good systemic control,” they wrote. – by Michela Cimberle



Peto T, et al. JAMA Ophthalmol. 2019;doi:10.1001/jamaophthalmol.2019.1876.


Disclosures: Baker reports receipt of grants for clinical research from Regeneron, Genentech, Allergan and Novartis. Please see the study for all authors’ relevant financial disclosures.

Regeneron provided aflibercept for the study and funds to the DRCR Retina Network to defray the study’s clinical site costs.