DRCR.net Helps Push Diabetes Research Forward

The Network is on the job, advancing new protocols in treating diabetes-induced retinal disorders.

By Scott M. Friedman, MD and Adam R. Glassman, MS

Eye disease from diabetes, left untreated, is the leading cause of vision loss and blindness in working-age adults in the United States. Recent advances in the management of diabetic eye disease have increased the potential treatment options for ophthalmologists, but management of the disease remains complex.

The National Institutes of Health-sponsored Diabetic Retinopathy Clinical Research Network, or DRCR.net, began in 2002 with a mission to facilitate the conduct of multicenter clinical research of diabetic retinopathy, diabetic macular edema and associated conditions. The DRCR.net supports the identification, design and implementation of multicenter clinical research initiatives focused on diabetes-induced retinal disorders.

The Network maintains an infrastructure for the conduct of multiple concurrent and consecutive studies, which allows rapid development and initiation of new protocols. To date, DRCR.net investigators from more than 140 clinical sites throughout the United States have enrolled over 6,000 study participants in approximately 20 clinical studies, resulting in 35 published manuscripts. Information on protocols conducted since the Network's inception and links to published manuscripts are located at www.drcr.net.

Currently, the Network has six active protocols — two in follow-up and four recruiting. In line with the commitment to conduct multiple concurrent and consecutive studies, DRCR.net is now developing several new protocols. Here, we will report on the ongoing and future studies from DRCR.net and discuss their clinical importance.

DRCR.net Current Protocols

■ Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for DME. The primary results of this trial, published in June 2010, represented the first breakthrough in the treatment of diabetic macular edema since 1985 when the NIH-sponsored Early Treatment Diabetic Retinopathy Study demonstrated the benefits of focal/grid laser photocoagulation in the treatment of diabetic macular edema (Figure 1).¹

This protocol found that intravitreal ranibizumab with deferred (>24 weeks) or prompt focal/grid laser is superior to focal/grid laser alone for the treatment of DME involving the center of the macula through at least two years of follow-up. Subjects enrolled in this protocol gained substantial vision and significantly fewer eyes lost significant vision. Intravitreal ranibizumab injections as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. Further follow-up in this trial is ongoing through five years to determine even longer-term safety and efficacy of ranibizumab for DME.

The results of this trial already highlight a need for the ophthalmologist to identify DME involving the center of the macula before significant vision loss has occurred, since only about 50% of patients treated in this way will gain substantial vision (compared with approximately 30% of patients treated with focal/grid laser), while less than 5% of patients treated with ranibizumab will lose substantial vision (compared with approximately 15% treated with focal/grid laser). Thus, diagnosis before substantial vision loss has occurred can result in preservation of vision for over 90% of people with diabetes and edema involving the center of the macula. This study also showed that although frequent ranibizumab injections were required in the first year (eight to nine injections), only two to three were required on average in the second year to maintain the beneficial effects.

■ An Observational Study in Individuals with Diabetic Retinopathy Without Center-Involved DME Undergoing Cataract Surgery. Approximately 25% of patients with type 2 diabetes 30 years of age and older will undergo cataract surgery during a 10-year period.² Known risk factors for these patients include poorer visual acuity outcomes, progression of diabetic retinopathy and increased levels of macular edema.³ The purpose of this protocol was to evaluate the incidence of progression of center-involved macular edema 16 weeks after cataract surgery, in eyes with diabetic retinopathy and without definite center-involved DME. Results will be available over the next several months.

This study will help to define the incidence of clinically significant diabetic macular edema after cataract surgery.

Figure 1. Ranibizumab plus deferred or prompt laser is superior to laser alone in treating DME involving the center of the macula through at least two years of follow-up.

Recruiting DRCR.net Protocols

■ An Evaluation of Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy. This protocol has been recruiting subjects since June of 2010, with expected completion of enrollment in October 2011. The prevalence of diabetic retinopathy in patients older than 40 years of age exceeds 40%, with 5%-10% developing vision-threatening complications, including proliferative diabetic retinopathy (PDR), severe non-proliferative diabetic retinopathy or macular edema.⁴

PDR can lead to vitreous hemorrhage; this affects vision and can preclude performing panretinal photocoagulation (PRP) treatment for PDR. Vitreous samples from patients with PDR have elevated VEGF concentrations,⁵ and inhibition of VEGF was shown to reduce VEGF and diabetes-induced permeability in animal models.⁶ Therefore, investigators have hypothesized that anti-VEGF could be used in cases of vitreous hemorrhage due to PDR in which the vitreous hemorrhage precludes the ability to apply PRP. The inability to apply PRP for treatment of vitreous hemorrhage may lead to vitrectomy with subsequent risk of complications, as well as increased costs from surgery.

The purpose of this prospective, multicenter randomized clinical trial is to determine if intravitreal injections of ranibizumab decrease the proportion of eyes requiring vitrectomy compared with saline injections in eyes presenting with vitreous hemorrhage from proliferative diabetic retinopathy. Results of this trial could lead to a decreased need for vitrectomy with concomitant increased cost and risks from surgery.

■ Effect of Diabetes Education During Retinal Ophthalmology Visits on Diabetes Control. Ocular complications from diabetes remain the most common cause of blindness among adults in the United States 20 to 74 years of age.⁷ A recent survey reported that loss of vision is the most feared of all diabetic complications.⁸ Therefore, investigators have hypothesized that providing diabetes education at an ophthalmology office may create more of an impact on patients' understanding of the importance of diabetes management than that received at a primary care or diabetologist/endocrinologist office.

The purpose of this study is to determine whether diabetes education in the ophthalmology office can improve subsequent HbA1c levels as compared with current standard care in an ophthalmology office. The standardized educational materials, created with the aptitude of the general diabetic population in mind, provide a synopsis of the participant's current HbA1c levels, blood pressure and retinopathy levels at each visit along with their corresponding prognosis.

This DRCR.net study should determine if education on diabetes control at the point of care within the ophthalmologist's office could impact the HbA1c level, and emphasizes the potential interaction between the retinal specialist and the person coordinating the patient's diabetes management.

■ Phase 2 Evaluation of Topical NSAIDs in Eyes with Non-Central Involved DME. The Early Diabetic Retinopathy Study (ETDRS) showed that in eyes with DME,⁹ the presence or absence of thickening involving the center of the macula was an important consideration in predicting both short- and long-term visual acuity outcomes. Approximately 25% of non-central involved cases of DME extend into the center of the macula within one year.

While the current treatment for center-threatening DME is focal/grid laser photocoagulation, there have been numerous reports of adverse side effects from laser with resultant decreased vision. Thus, if a relatively safe and economical treatment could be identified that reduced the progression of non-central involved edema to central-involved edema, that treatment could have a major public health impact.

Because topical NSAIDs are in current widespread clinical use and appear to be well tolerated and safe when administered chronically, they might be a potentially attractive alternative treatment for DME in patients who would like to delay or avoid laser or intravitreal injections with potential side effects. The purpose of this study is to assess the effects of topical NSAIDs on macular retinal volume compared with placebo in eyes with non-central DME.

Classic presentation of DME in fundus and OCT imaging.

■ Comparison of Time-domain OCT and Spectral-domain OCT Retinal Thickness Measurement in DME. Until recently, all OCT measurements in the literature used time-domain technology. However, because of substantially faster scan speeds, higher resolution, and precise ability to overlay retinal images from the same eye acquired at different times, spectral-domain OCT (SD-OCT) machines likely will replace time-domain OCT (TD-OCT) over the next five to 10 years. This provides a strong rationale for definitively assessing how SD-OCT can be used in protocols. The primary objective of this protocol is to compare thickness measurements between Zeiss's time-domain Stratus OCT and selected SD-OCT machines, estimating a conversion factor between TD-OCT and SD-OCT.

In addition, the DRCR Network will assess and compare the reproducibility of the selected SD-OCT machines using their respective software analysis algorithms. This study should be of value as more ophthalmologists move to spectral-domain machines for the evaluation and treatment of DME.

Additional information on current DRCR.net protocols is located at www.drcr.net.

Future DRCR.net Protocols

Intravitreal Bevacizumab Compared with Intravitreal Ranibizumab for DME. This protocol is expected to begin recruitment in January 2012. Bevacizumab is currently in widespread clinical use for treatment of DME. Although it was not formulated specifically for use within the eye, it was first reported as being used off-label as an intravitreal injection to treat DME in 2006.¹⁰ Since then, and despite the lack of FDA approval, physicians have used this drug widely in the clinical treatment of DME.

Furthermore, bevacizumab is derived from the same monoclonal antibody as ranibizumab. Scientific evidence also suggests that bevacizumab may have short-term efficacy in treating DME and potentially similar effects to ranibizumab on intraocular pathology in general.

Time-domain OCT image (left) and spectral-domain OCT image (right) from the same eye with center-involved DME.

Cost differences between the two drugs create a compelling socioeconomic rationale for comparing efficacy results: a single dose of 0.5 mg ranibizumab costs approximately $2,000, while a comparable dose of 1.25 mg bevacizumab costs approximately $50. The current recommended treatment regimen requires monthly dosing, and for effective treatment of DME, patients generally need multiple injections over the long term. The purpose of this protocol will be to determine if intravitreal bevacizumab is non-inferior with regard to efficacy and safety compared with ranibizumab when given to treat center-involved DME in eyes with visual acuity of 20/32 to 20/320.

■ Prompt Panretinal Photocoagulation vs. Intra-vitreal Ranibizumab with Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy. The current standard treatment for PDR is PRP, but this treatment is inherently destructive and has several potential adverse effects on peripheral vision. Thus, therapeutic alternatives that might delay or obviate the need for PRP are desirable. Studies have demonstrated that retinal neovascularization from PDR is highly responsive to anti-VEGF therapy.¹¹ The purpose of this study will be to determine if visual acuity outcomes at two years in eyes with PDR that receive anti-VEGF therapy with deferred PRP are non-inferior to those in eyes that receive standard prompt PRP therapy. This study would potentially decrease the need for PRP and subsequent associated adverse side effects.

Keep in Touch

The advances made by the DRCR.net have changed the course of treatment for diabetic retinopathy around the world. It is important for the ophthalmologist to be aware of the publications coming from the DRCR Network — some have a major impact on the standard care of a very common cause of vision loss, while other publications refine our understanding of the disease, its prognosis, or suggest potential new avenues of treatment. Ophthalmologists should review the growing information made available by the DRCR Network, involving a collaboration of almost 1,000 retina specialists from 40 states, with 35 publications.

DRCR.net would like to hear from ophthalmologists as well. The Network continues to solicit ideas for new protocols. Anyone can propose one to the organization by completing a protocol idea form located at www.drcr.net. Further, any retina specialist can contact the Network to consider participating at a clinical site as the Network prepares to start its second decade of progress to fulfill its mission of reducing the magnitude of vision loss from diabetes. OM

References

1. The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-77 e35.
2. Klein BE, Klein R, Moss SE. Incidence of cataract surgery in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Am J Ophthalmol. 1995; 119(3):295-300.
3. Chew EY, Benson WE, Remaley NA, et al. Results after lens extraction in patients with diabetic retinopathy: early treatment diabetic retinopathy study report number 25. Arch Ophthalmol. 1999;117(12):1600-1606.
4. Javitt JC, Aiello LP. Cost-effectiveness of detecting and treating diabetic retinopathy. Ann Intern Med. 1996;124(1 Pt 2):164-169.
5. Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002;133(1):70-77.
6. Schwesinger C, Yee C, Rohan RM, et al. Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. Am J Pathol. 2001;158(3):1161-1172.
7. Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed 10-13-09.
8. U.S. Adults With Diabetes Fear Blindness or Vision Loss More Than Premature Death. 10/15/2009; http://www.redorbit.com/news/health/757152/us_adults_with_diabetes_fear_blindness_or_vision_loss_more/index.html.
9. Ferris III F. Personal communication: Rational for CI DME as a surrogate outcome for VA (ETDRS); Sept 15, 2009.
10. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006;26(9):999-1005.
11. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006;113(10):1695 e1-15.

	Scott Friedman, MD, has practiced ophthalmology specializing in retina and vitreous in central Florida for over 20 years. He is active in the Diabetic Retinopathy Clinical Research network and is currently serving as a vice-Chair. He can be reached at smfriedman83@hotmail.com.
	Adam Glassman is the Director and Principal Investigator of the NIH-funded Diabetic Retinopathy Clinical Research Network Coordinating Center, at the Jaeb Center for Health Research in Tampa. He can be reached at aglassman@jaeb.org.