DRCR.net makes impact on diabetic retinopathy treatment

The Diabetic Retinopathy Clinical Research Network is making real-world impacts on the way physicians treat and manage diabetes-related eye conditions.

The DRCR.net completes and funds multicenter clinical research for the diagnosis and treatment of diabetic retinopathy, diabetic macular edema and associated conditions. The network receives funding for its research from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, according to the organization’s website.

The network has accepted and published protocols from its members since its inception in 2003. It has published 19 protocols and has six current protocols that are enrolling patients or are in the follow-up portion.

The protocols, which have included more than 9,500 participants, have provided ophthalmologists with new data and theories to treat diabetic retinopathy and diabetic macular edema and improve treatment for their patients.

Image: Wykoff CC

Most valuable protocols

The research network has provided invaluable information and knowledge for ophthalmologists to improve their clinical practices and real-world treatment, Charles C. Wykoff, MD, PhD, of Retina Consultants of Houston and Blanton Eye Institute, said.

Wykoff is on multiple writing committees and protocol development committees with the DRCR.net.

“The DRCR Network is an impressive organization that has completed several valuable trials studying various aspects of diabetic retinopathy. We’ve learned a lot from many of the trials, and there are some fascinating trials that are ongoing. We’ll continue to learn more this year and through future years. The trials that we have learned the most from over the past few years include Protocols I, T and S,” Wykoff said.

Protocol S

Protocol S was the first randomized, controlled trial to compare anti-VEGF treatments with laser therapy for the treatment of proliferative diabetic retinopathy (PDR), Wykoff said.

The protocol compared prompt panretinal photocoagulation (PRP) therapy to Lucentis (ranibizumab, Genentech) and deferred PRP for the treatment of proliferative diabetic retinopathy. The randomized, multicenter clinical trial included 394 eyes of 305 patients examined across 55 sites.

“It’s a fascinating concept because PRP has a permanent effect. Some eyes do need more than one PRP laser session, but when you put laser shots in, it’s irreversible. In comparison, intravitreal injection of an anti-VEGF pharmaceutical has a transient effect on intraocular VEGF signaling. The initial idea that one would treat a blinding disease with a potentially non-permanent treatment in a population where non-compliance can be a concern is in itself a fascinating concept,” Wykoff said.

Patients in the anti-VEGF group experienced no worse visual acuity compared with the PRP group after 2 years of treatment. Additionally, the anti-VEGF group experienced superior vision in the area under the curve analysis when compared with the PRP group at the end of 2 years.

The protocol concluded that anti-VEGF therapy had limited safety concerns for at least 2 years and is an effective treatment alternative to PRP.

Protocol S impact

The results of Protocol S had an impact on the way physicians manage patients with proliferative diabetic retinopathy, Wykoff said.

“The 2-year results of Protocol S have led me to consider combination therapy more frequently in clinical practice. In the absence of pre-retinal traction, I’ll often start my PDR patients with anti-VEGF therapy, which has an immediate impact. Once the neovascular disease is under control, in many cases I also apply a limited anterior PRP because of the permanent protective effect. I avoid applying laser near the macula and try to remain at and anterior to the equator. If the disease appears quiescent at this point, I then either stop anti-VEGF therapy or taper down the treatments every 2 or 3 months. I look forward to longer-term follow-up from Protocol S,” Wykoff said.

The data from Protocol S demonstrated that a VEGF blockade with ranibizumab was non-inferior to PRP for the treatment of PDR, Diana V. Do, MD, of Stanford University School of Medicine, said.

The data culled from both Protocol S and Protocol T have been useful for ophthalmologists and have made an impact on the way patients are treated for DME and PDR, she said.

“I have applied this [data from Protocol S] to my clinical practice by incorporating the more frequent use of intravitreal VEGF blockers in my management of PDR. I still use PRP laser, but I find it most effective to use a combination of both VEGF inhibition and laser to treat eyes with high-risk PDR,” Do said.

Longer-term data are currently being studied, and 5-year outcomes for Protocol S are being evaluated by the network.

Protocol B

Before Protocol S was published, Protocol B greatly affected clinical practice by showing focal/grid photocoagulation therapy was a more effective treatment for DME than preservative-free intravitreal triamcinolone, OSN Retina/Vitreous Board Member Michael S. Ip, MD, said.

Protocol B showed that, over 2 years, focal/grid photocoagulation therapy was more effective and had fewer side effects compared with 1-mg or 4-mg doses of preservative-free intravitreal triamcinolone for the treatment of DME.

“We didn’t know if the triamcinolone was better than or worse than the focal laser or whether it would lead to a lot of complications. It’s shown clearly over the long term that the laser treatment was more effective than the use of a corticosteroid. If you remember, at the time we didn’t have anti-VEGF — we just had laser and corticosteroid. For me, it showed me that the use of corticosteroid as an initial treatment was fraught with problems. In the long term, the laser was better, and there were some complications that were inherent with the use of corticosteroids,” he said.

Protocol T

Protocol T has had a great impact on practices and has helped clarify which patients should be treated for DME with three similar drugs, Rishi P. Singh, MD, of Cole Eye Institute, said.

Protocol T compared the 2-year results of Eylea (aflibercept, Regeneron), Avastin (bevacizumab, Genentech) and ranibizumab for the treatment of DME. Patients in the protocol received injections every 4 weeks during the first year and every 4 weeks to 16 weeks during year 2 of the treatment course. Patients received doses of 2 mg of aflibercept, 1.25 mg of bevacizumab or 0.3 mg of ranibizumab.

All three drugs were found to improve vision similarly for patients with 20/40 or better vision at the start of the study.

However, in patients with vision of 20/50 or worse at the start of the study, aflibercept offered greater gains than those who received bevacizumab at 1 year. In this same subgroup of patients with 20/50 or worse vision, aflibercept offered superior vision gains over ranibizumab at 1 year, but a difference could not be found at the 2-year follow-up.

“The study really was impactful because of the fact that we have to justify to health care organizations and insurance companies to explain to them as to why we might choose a certain drug for a certain patient. According to them, they think all these anti-VEGFs are the same. The reality is, they might be the same in certain disease states, but in diabetic macular edema, for example, it doesn’t seem to be the same and it seems to be quite different. In fact, the branded drugs seem to be superior to the non-branded drugs especially in cases of vision worse than 20/50 and when the retinal thickness exceeds 400 µm on presentation. So Protocol T has provided a concrete data set to show them the benefits and differences,” Singh said.

Do also said Protocol T has been greatly influential in her clinical practice. The study has helped her become more effective in recommending which agent is best for the treatment of DME in her patients.

“This study also revealed that in the prespecified subgroup analysis of eyes with worse vision at baseline, aflibercept performed better than bevacizumab. This data has given me more confidence in recommending either of the three VEGF blockers for the treatment of DME in my patients. Bevacizumab is clearly the most cost-effective agent. However, there is an advantage to using aflibercept in eyes with worse vision, and it influences me to choose this agent in particular subgroups of patients I encounter,” she said.

Protocol I

Protocol I was a landmark study published by the network, SriniVas R. Sadda, MD, of Doheny Eye Institute, said. The protocol helped ophthalmologists understand the importance of anti-VEGF therapy and how to best use the therapy in a clinical and practical sense.

Protocol I examined the use of intravitreal ranibizumab with prompt or deferred focal/grid laser treatment over the course of 2 years vs. just focal/grid laser therapy for the treatment of DME.

The protocol found ranibizumab with deferred focal/grid laser at 24 weeks or later was superior to focal/grid laser therapy alone involving the center of the macula at 1-year follow-up for best corrected visual acuity.

Additionally, prompt focal/grid laser treatment and intravitreal ranibizumab did not have superior vision outcomes compared with deferred focal/grid laser treatment and ranibizumab. The network found it may even be worse for long-term vision outcomes in eyes with DME involving the fovea and with vision impairment.

“Protocol I told us that diabetic macular edema is quite different than wet macular degeneration, where there seems to be many patients who continue to need fairly aggressive treatment for an extended period. There seems to be a diminishing need for treatment in patients with diabetic macular edema,” Sadda said.

The protocol has helped ophthalmologists counsel patients as to what they can expect in the long term from their treatment, he said.

On the horizon

The network is currently working on several ongoing, promising protocols that could have a tremendous impact on the way ophthalmologists treat and diagnose patients with diabetic retinopathy and DME, Wykoff said.

“Another valuable study is Protocol AA, which is evaluating how wide-field retinal imaging may impact our ability to prognosticate and predict how patients with diabetic retinopathy will do. While many retina specialists now use wide-field imaging regularly, we need more data to inform how best to apply findings from such imaging to clinical practice,” he said.

The primary objective of the ongoing Protocol AA is to assess whether using wide-field imaging to evaluate the retinal far periphery can better detect diabetic retinopathy or predict diabetic retinopathy worsening compared with the evaluation of only the seven standard ETDRS fields.

For the past five decades, ophthalmologists have assessed the severity of diabetic retinopathy by concentrating on a largely central portion of the retina. If Protocol AA demonstrates or confirms the hypothesis that the periphery of the retina is more important for this purpose, it will change how ophthalmologists go about staging and monitoring diabetic retinopathy, Sadda said.

“I think it will be a dramatic alteration in thinking about this disease by looking at wide-field imaging and specifically looking at the extent of diabetic lesions such as hemorrhages and microaneurysms outside of the central seven standard fields, which only cover approximately 70° of the retina. But looking beyond that 70° in the retinal periphery, there is pilot data from other studies that say those peripheral lesions may be the most predictive of who is going to progress. This may identify a group of patients who are at high risk for proliferative disease. Protocol AA will validate that,” he said.

Protocol U

Protocol U should also provide valuable information and have a tremendous clinical impact for patients being treated with both steroids and anti-VEGF therapy for persistent central-involved DME, Singh said.

The protocol will assess the short-term effects of a corticosteroid and anti-VEGF combination therapy on OCT retinal thickness and visual acuity. The results from this combination therapy will be compared with continued anti-VEGF therapy alone for the treatment of persistent DME.

The phase 2 study will evaluate the efficacy outcomes of both treatment groups at 24 weeks, with the mean change in visual acuity letter score adjusted for baseline as the primary outcome.

“Protocol U will look at people who have been treated both with anti-VEGF and steroids together. That will be impactful. It’s how we treat people normally in our routine clinical practice. We evaluate them, and we give them anti-VEGF for a while and then eventually give them a steroid as well. This will be very helpful,” Singh said.

Protocol V

Protocol V will help guide ophthalmologists in treatment selection for patients with central-involved DME who present with good vision, Ip said.

The randomized, multicenter clinical trial will include patients who have visual acuity of 20/25 or better in at least one eye, central-involved DME and minimal prior treatment for DME.

The patients will be randomized to prompt anti-VEGF, prompt laser and deferred anti-VEGF, or observation and deferred anti-VEGF.

“When a patient now presents with relatively good visual acuity and retinal thickening, I really don’t know which way to proceed. They have good vision, so theoretically they can just be observed, but is the observation of that patient harming them in some way now that we have anti-VEGF? But with the good vision, you almost hesitate to want to use an anti-VEGF if the patient has relatively good vision. We also have laser photocoagulation to fall back on. We have many choices. You can observe the patient, give them immediate anti-VEGF, or you can treat them with focal laser and photocoagulation. It’s an interesting clinical dilemma,” Ip said.

More data needed

Even with the tremendous amount of data being published by the network and its ongoing studies, there are still unanswered questions that need to be investigated, Do said. For example, when should ophthalmologists consider adding intravitreal steroids, such as a dexamethasone or fluocinolone implant, for patients who have a suboptimal response to VEGF inhibitors?

“Moreover, what should be the definition of a suboptimal responder? We know that inflammation plays a role in diabetic retinopathy, and I believe it’s important and clinically relevant to investigate how to incorporate treating this inflammatory component while also simultaneously using VEGF inhibitors to manage the excessive vascular permeability that is seen in DME. I’m excited about future pharmacologic innovations that can target and treat this inflammation,” Do said. – by Robert Linnehan

• References:
• Diabetic Retinopathy Clinical Research Network. https://public.jaeb.org/drcrnet/view/Presentations.
• Elman MJ, et al. Ophthalmology. 2010;doi:10.1016/j.ophtha.2010.02.031.

• For more information:
• Diana V. Do, MD, can be reached at Byers Eye Institute, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303; email: dianado@stanford.edu.
• Michael S. Ip, MD, can be reached at David Geffen School of Medicine, University of California – Los Angeles, P.O. Box 862258, Los Angeles, CA 90086; email: mip@doheny.org.
• SriniVas R. Sadda, MD, can be reached at Doheny Eye Institute, 1355 San Pablo St. #211, Los Angeles, CA 90033; email: ssadda@doheny.org.
• Rishi P. Singh, MD, can be reached at Cole Eye Institute, 9500 Euclid Ave., Cleveland, OH 44106; email: drrishisingh@gmail.com.
• Charles C. Wykoff, MD, PhD, can be reached at Retina Consultants of Houston, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin St., Suite 750, Houston, TX 77030; email: ccwmd@houstonretina.com.

Disclosures: Do reports she is a consultant for Bayer, Genentech, Clearside and Santen and receives research funding from Genentech, Regeneron and Santen. Ip reports he is a consultant for Boehringer Ingelheim, Omeros, Quark and ThromboGenics. Sadda reports he is on the advisory board/consultant for Genentech, Allergan, Novartis, Regeneron and Optos. Singh reports he is a consultant for Shire, Genentech, Regeneron and Alcon. Wykoff reports he is on multiple writing committees and development committees with the DRCR.net and is a consultant for Alimera, Allergan, Bayer, Clearside, Genentech and Regeneron.

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