Expansion of DRCR network opens new research opportunities
Since its inception in 2002, the Diabetic Retinopathy Clinical Research Network has initiated more than 30 clinical studies for the management and evaluation of diabetic retinopathy. In 2018, the network expanded its scope to include research of other retinal disorders, and in 2019, officially changed its name from DRCR.net to the DRCR Retina Network. The network has since opened its research doors to all retinal pathologies, an exciting prospect for network representatives, ophthalmic researchers and clinicians.
Funded primarily by the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, the network has been instrumental in furthering understanding and guiding treatment of diabetic retinopathy and diabetic macular edema, according to OSN Retina/Vitreous Board Member Judy E. Kim, MD, executive committee member, protocol chair and a former vice chair for the network.
“The recent name change reflects the belief and the desire of our network and NEI that we should take advantage of demonstrated successes of the network and its infrastructure to address best treatment and management and gain knowledge about all retinal diseases,” Kim said.
The network will continue to place its principal emphasis on clinical trials, but epidemiologic outcomes and other research may be supported as well, she said.
For several years, the network considered the feasibility of expanding its scope to other retinal diseases beyond DR, Adam Glassman, MS, director and principal investigator for the DRCR Retina Network Coordinating Center, said.
Clinical investigators frequently requested the network to expand to other retinal pathologies, he said.
“The public good from the federal funding provided to DRCR Retina Network can now be extended to the non-diabetic population by leveraging the infrastructure, experience and success of the network to address common and rare retinal diseases, including age-related macular degeneration, other retinal vascular diseases and other chorioretinal diseases such as central serous chorioretinopathy,” Glassman said.
Many of the same therapeutic interventions that have been studied by the network have clinical importance for other retinal diseases. The familiarity of network investigators with these therapeutics may enable more efficient efficacy and safety assessments when evaluating these treatments for other diseases, Glassman said.
The network’s impact on diabetic eye diseases and the ophthalmic community as a whole has been immense, Healio/OSN Board Member Rishi P. Singh, MD, said.
“But they’ve decided to switch gears, not because they’ve answered all questions around diabetic retinopathy, but because they’ve realized there are other retinal conditions that merit their focused attention as well,” Singh said.
The expansion is an important one, Glenn C. Yiu, MD, of UC Davis Health, said, as it will allow the network to leverage its large infrastructure of DRCR coordinating centers, reading centers and network of clinical sites across North America to conduct large-scale multicenter studies.
The network currently has more than 130 participating sites with more than 430 physicians throughout the United States and Canada.
“Importantly, because the DRCR is publicly funded, results are rapidly disclosed and data sets are open source, which also allows interesting post hoc analyses to be pursued. I think the next decade of the DRCR network will be even more exciting than the last two decades of its history,” Yiu said.
Protocol findings are significant
The findings of the published network protocols have greatly affected the way ophthalmologists treat patients, Singh said. Protocol I, an investigation of intravitreal Lucentis (ranibizumab, Genentech) for patients with DME with prompt vs. deferred laser treatment and its 5-year randomized trial results, has been a treasure trove of great data from which many research questions can be asked.
The results of Protocol I found patients treated with ranibizumab had superior outcomes to those who received focal laser and steroids for DME, and 5-year data showed sustained improvements despite fewer injections in the last 2 years.
A most recent subanalysis of the results showed a stratification of 1-year vision gains as determined by the first 3 months of treatment, Singh said. If patients did not experience expected visual gains in the first 3 months of treatment, clinicians realized they would gain less vision over the course of the treatment than patients who had a robust improvement over the first 3 months, he said. These results help better counsel patients on their potential for gain and to consider using alternative therapies when response is not seen.
Due to its complexity and variability, there is no one-size-fits-all approach for treating DR and DME, Kim said. Therefore, she believes it is important to learn, practice and be guided by evidence-based medicine whenever possible while trying to meet a patient’s medical, social and emotional needs.
“The findings from the DRCR Retina Network clinical trials have been enormously helpful in guiding treatment decisions,” she said.
Anti-VEGF agents as a first-line therapy
The findings of Protocol S, Kim said, have led her to recommend anti-VEGF agents as a first-line therapy for eyes with proliferative diabetic retinopathy (PDR) with DME, as both PDR and DME can be managed with anti-VEGF agents.
The phase 3 prospective multicenter randomized clinical trial evaluated prompt panretinal photocoagulation (PRP) vs. intravitreal ranibizumab with deferred PRP to treat PDR. The data showed ranibizumab is noninferior to PRP with regard to visual acuity outcomes at 2 years.
At 2 years, visual acuity improved by 2.8 letters from baseline in the ranibizumab group compared with an improvement of 0.2 letters from baseline in the PRP group, with a mean difference of 2.2 letters between treatment groups (P < .001).
For eyes without DME, Kim said a discussion regarding the pros and cons of PRP vs. anti-VEGF therapy is necessary to determine the best option for patients.
“Often, we start with intravitreal anti-VEGF injections since this treatment group had less DME development, less visual field loss and less need for vitrectomy compared to PRP in Protocol S. However, while some patients will continue on the anti-VEGF therapy, we frequently end up adding PRP, which differs from Protocol S, since most patients desire to reduce the burden of prolonged anti-VEGF therapy for PDR by having the benefit of the durability of PRP,” she said. “Also, when compliance for follow-up is an issue, I do not hesitate to recommend PRP. After all, PRP is better than no treatment.”
Protocol T has given surgeons a great starting point to treat DME with any of three current anti-VEGF therapies, Yiu said. Protocol T compared the effectiveness of intravitreal Eylea (aflibercept, Regeneron), Avastin (bevacizumab, Genentech) and ranibizumab for the treatment of DME at 2 years.
While all three offered similar improvements in vision for patients with 20/32 to 20/24 or better vision at the start of the study, aflibercept offered greater gains for patients with 20/50 or worse vision at the start of the study compared with patients who received bevacizumab at 1 and 2 years. In the same subgroup of patients, aflibercept offered greater gains compared with patients treated with ranibizumab at 1 year, but a difference could not be detected after 2 years.
“Protocol T reassured me that all three current anti-VEGFs are reasonable starting points for diabetic macular edema,” Yiu said.
Interpretations of data can differ
The results of Protocol V, which evaluated anti-VEGF injections to treat center-involved DME in patients with good vision, have been useful in clinical practice but have also led to several interpretations, Charles C. Wykoff, MD, PhD, of Retina Consultants of Houston, said.
Before Protocol V, there was a concept that earlier treatment typically led to better visual gains, Wykoff said.
“We saw a signal for that in RIDE and RISE, the phase 3 trials of ranibizumab. We saw a signal for this with VISTA and VIVID, the phase 3 trials with aflibercept. In other words, for patients who did not receive anti-VEGF dosing at the beginning of the trials, there appeared to be a long-term deficit in the ability of those eyes to achieve maximal visual gains,” he said.
The protocol was a multicenter trial that included 702 participants with central-involved DME and visual acuity of 20/25 or better. Patients were randomly assigned to initial management with aflibercept, laser photocoagulation or observation. Injections were administered in the aflibercept cohort 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 observation and laser groups were monitored at weeks 8 and 16 and then at 16-week intervals. Patients received aflibercept if a decrease of two or more lines of vision at any visit or one line at two consecutive visits was reported.
At 2 years, the rate of visual acuity loss of five or more letters did not differ significantly between any of the groups, and the average visual acuity was 20/20.
This is an important trial that challenges the simplistic assumption that any central-involved DME should be treated as early as possible, Wykoff said.
“The structure of this trial was not a direct comparison of observation vs. intervention. Rather, it was a comparison of different management approaches,” Wykoff said.
In Wykoff’s opinion, the results show that all three treatment paradigms led to similar rates of visual acuity loss by year 2, allowing clinicians to make individualized treatment approaches dependent on patient characteristics and patient preferences.
New protocols may affect practice
Several in-progress protocols in the network may affect practice. Singh said he is eager to see initial data from Protocol AE, a pilot study evaluating photobiomodulation therapy for DME.
While the protocol finished its enrollment in February, the COVID-19 pandemic has hampered progress. According to Kim, who is the study chair for Protocol AE, modifications to the protocol have been made to maintain the integrity of the study and still be able to detect potential safety and efficacy signals in the patient cohort.
“A study such as this allows us to explore totally different treatment options for patients with DME and may have important scientific, medical and public health implications,” Kim said.
The in-progress pilot study is designed to assess the effects of photobiomodulation on central subfield thickness compared with sham treatment eyes with central-involved DME and good vision. The primary efficacy outcome will be the mean change in central subfield thickness from baseline to 4 months.
The clinical trial was intended to have two phases, with the primary outcome evaluated at the end of phase 1 at 4 months, and at the 4-month visit, the participants would switch to an alternate treatment. This would provide participants in the sham group with the opportunity to receive active treatment and allow researchers to explore the post-switch effects within the treatment group. However, because of changes made as a result of the SARS-CoV-2 pandemic, the original treatment group will not receive the sham treatment after 4 months, thus limiting the opportunity to explore post-switch effects, according to Glassman.
Photobiomodulation has been shown to improve wound healing, decrease apoptosis and decrease oxidative stress in certain situations, Singh said.
“Can you apply this application to see if photobiomodulation may be helpful with DME? These are things we talk about all the time that are out there, but we don’t know if there’s any validation behind these therapies,” he said.
“The results of Protocol AA may also impact what imaging we use clinically to predict DR worsening over time,” Wykoff said.
The prospective, observational longitudinal study is designed to assess whether evaluation of the retinal far periphery on ultra-widefield images improves the ability to assess DR and predict rates of DR worsening over time compared with evaluation of the area within the seven-standard ETDRS fields.
“Does additional imaging outside of the standard seven fields impact our ability to prognosticate? Does it impact our ability to determine which eyes are at higher risk of progression of their diabetic retinopathy beyond what we learned from the Diabetic Retinopathy Severity Scale scores, which was defined by the ETDRS trials of the 1980s? This trial is likely going to have a meaningful impact on how we categorize stages of DR,” Wykoff said.
In 2019, Wykoff and colleagues published a study in JAMA Ophthalmology comparing ETDRS seven-field imaging with ultrawide-field imaging to determine severity of DR. The cross-sectional study included 737 gradable eyes on both ETDRS seven-field imaging and ultrawide-field images masked to contain the same seven fields after adjudication. The modified ETDRS seven-field images were obtained using the DRCR Retinal Network acquisition protocol, and the ultrawide-field images were captured with an Optos 200Tx system (Optos).
The researchers found 48.4% of ETDRS photos and masked ultrawide-field images were in exact agreement for DR severity, and 88% were within one-step of agreement. The ability to detect DR severity in an individual eye was considered similar in 50.9%, better for ETDRS seven-field imaging in 19% and better for ultrawide-field images in 26.7%.
Wykoff said the study also looked at the proportion of eyes with predominantly peripheral lesions, and a meaningful proportion of eyes, between 12% and 54%, had predominantly peripheral lesions on ultrawide-field imaging.
“Predominantly peripheral lesions have become important in the field because they may represent a higher risk of diabetic retinopathy progression,” Wykoff said.
Four years of follow-up data for Protocol AA are currently being analyzed, and the findings of the study will be reported later this year, Kim said.
Prevention of diabetic retinopathy
The findings of Protocol W, one of the few in-progress protocols that looks at prevention, should be of interest, Yiu said. The protocol will evaluate intravitreous anti-VEGF treatment for prevention of vision-threatening DR in eyes at high risk.
The phase 3 multicenter randomized clinical trial will evaluate a minimum of 386 eyes assigned to receive anti-VEGF or sham injections. Injections will be given at baseline, 1 month and 2 months in all participants. Injections will then be given at each 4-month visit until 2 years. After the 2-year visit, re-treatment with injections will be based on DR levels as assessed by an investigator.
Researchers will evaluate if there is a clinically important difference in the development of proliferative DR or DME between the groups at 2 years. They will also evaluate whether an increased chance of prevention of PDR or DME with anti-VEGF injections at 2 years leads to long-term beneficial visual outcomes at 4 years.
“The existing data for using anti-VEGF for preventing wet AMD, such as the PRO-CON study for aflibercept or the PREVENT study for ranibizumab, have not been convincing. However, the chronic waxing and waning nature of DR and DME is different from choroidal neovascularization development and may be more amenable to regular dosing for prevention,” Yiu said.
Kim said the study will reach its primary outcomes this year.
The results of Protocol AC should be particularly interesting as a potential cost savings for anti-VEGF treatment for DME if visual recovery is not delayed for patients treated first with bevacizumab, Singh said.
The protocol will evaluate patients with central-involved DME treated with either 2 mg intravitreous aflibercept or 1.25 mg intravitreous bevacizumab and deferred intravitreous 2 mg aflibercept if the eyes meet the switch criteria at certain timepoints.
“The interesting thing is it could be a cost savings for patients because you’d start on bevacizumab and go to aflibercept if the criteria isn’t met, but it could also be a detriment because we could see delayed visual recovery in those patients as well,” he said.
Final enrollment for Protocol AC has been completed, and the study is currently in its follow-up stage, Kim said.
Kim said her experience working with the network has improved her education in clinical trials and helped her grow as a trialist.
“The success of a clinical trial takes a village,” she said. “It is dependent not only on the investigators identifying and enrolling the subjects, but also on ensuring the safety and compliance of the subjects, following the study protocol, gathering of accurate data and appropriate analyses of the findings, and efforts of its clinical research coordinators, photographers and other staff members involved in the entire clinical trial process.”
“One of the things I value greatly about DRCR Retina Network is the openness of the network in getting the investigators involved in various stages of the trial, including protocol ideas, feasibility determination, protocol design, writing committees and presentations at national and international meetings. I encourage any young investigators who are interested in clinical trials to get involved with the network. In addition, we welcome study ideas related to all retinal conditions,” Kim said.
- A comparative effectiveness study of intravitreal aflibercept, bevacizumab and ranibizumab for diabetic macular edema. public.jaeb.org/drcrnet/stdy/206. Accessed April 9, 2020.
- A pilot study evaluating photobiomodulation therapy for diabetic macular edema. public.jaeb.org/drcrnet/stdy/523. Accessed April 9, 2020.
- Aiello LP, et al. JAMA Ophthalmol. 2019;doi:10.1001/jamaophthalmol.2018.4982.
- Baker CW, et al. JAMA. 2019;doi:10.1001/jama.2019.5790.
- Cimberle M. Protocol V trial results favor observation strategy for DME with good vision. www.healio.com/ophthalmology/retina-vitreous/news/online/%7B4d7fbf22-b5ee-4b9e-8a56-0d4993410145%7D/protocol-v-trial-results-favor-observation-strategy-for-dme-with-good-vision. Published April 30, 2019. Accessed April 7, 2020
- DRCR.Net aflibercept vs. bevacizumab + deferred aflibercept for the treatment of CI-DME (DRCR AC). clinicaltrials.gov/ct2/show/NCT03321513. Accessed April 6, 2020.
- Elman MJ, et al. Ophthalmology. 2010;doi:10.1016/j.ophtha.2010.02.031.
- Intravitreous anti-VEGF treatment for prevention of vision threatening diabetic retinopathy in eyes at high risk. public.jaeb.org/drcrnet/stdy/340. Accessed April 8, 2020.
- Intravitreous anti-VEGF vs. prompt vitrectomy for vitreous hemorrhage from proliferative diabetic retinopathy. public.jaeb.org/drcrnet/stdy/505. Accessed April 8, 2020.
- Kahl KL. DRCR.net Protocol S: Lucentis noninferior to panretinal photocoagulation for visual acuity. www.healio.com/ophthalmology/retina-vitreous/news/online/%7B1166d4b2-782d-4ef5-bdd7-9cb9f640eae1%7D/drcrnet-protocol-s-lucentis-noninferior-to-panretinal-photocoagulation-for-visual-acuity. Published Nov. 13, 2015. Accessed April 6, 2020.
- Kim JE. What is new with DRCR Retina Network. Presented at: Hawaiian Eye 2020; Jan. 18-24, 2020; Koloa, Hawaii.
- Peripheral diabetic retinopathy (DR) lesions on ultrawide-field fundus images and risk of DR worsening over time. public.jaeb.org/drcrnet/stdy/239. Accessed April 6, 2020.
- Singh RP. Applying DRCR protocols to clinical practice. Presented at: Hawaiian Eye 2020; Jan. 18-24, 2020; Koloa, Hawaii.
- Wells JA, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2016.02.022.
- For more information:
- Adam Glassman, MS, can be reached at Jaeb Center for Health Research, 15310 Amberly Drive, #350, Tampa, FL 33647; email: email@example.com.
- Judy E. Kim, MD, can be reached at Medical College of Wisconsin, 925 N. 87th St., Milwaukee, WI 53226; email: firstname.lastname@example.org.
- Rishi P. Singh, MD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: email@example.com.
- Charles C. Wykoff, MD, can be reached at Retina Consultants of Houston, 6560 Fannin St., Suite 750, Houston, TX 77030; email: firstname.lastname@example.org.
- Glenn C. Yiu, MD, PhD, can be reached at University of California, Davis Health, 4860 Y St., Suite 2400, Sacramento, CA 95817; email: email@example.com.
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