What is the DRCR (Diabetic Retinopathy Clinical Research) Protocol T for treating diabetic macular edema?

DRCR Protocol T: Comparative Anti-VEGF Study for Diabetic Macular Edema

DRCR Protocol T compared aflibercept, bevacizumab, and ranibizumab for treating center-involved diabetic macular edema, demonstrating that all three agents improve vision, but aflibercept provides superior visual outcomes in eyes with baseline visual acuity of 20/50 or worse at 1 year. 1

Study Design and Population

Protocol T was a randomized, single-masked (year 1 only), multicenter clinical trial that enrolled 660 participants across 89 U.S. sites. 2

• Mean patient age was 61 ± 10 years, 47% women, 65% Caucasian 2
• 90% had type 2 diabetes with average duration of 17 ± 11 years 2
• Half had baseline ETDRS visual acuity of 20/32 to 20/40, and half had 20/50 to 20/320 2
• All patients had center-involving diabetic macular edema 1

Key Findings: Visual Acuity Outcomes

Year 1 Results

For eyes with baseline visual acuity of 20/50 or worse, aflibercept demonstrated significantly superior visual improvement compared to both ranibizumab (p = 0.003) and bevacizumab (p < 0.001). 2

• For eyes with better baseline visual acuity (20/32 to 20/40), there was no significant difference among the three drugs (p = 0.69) 2, 3
• All three drugs resulted in improvement in visual acuity with similar safety profiles 1

Year 2 Results

At 2 years, aflibercept remained superior to bevacizumab (p = 0.02) but was no longer statistically superior to ranibizumab (p = 0.18) among eyes with worse baseline visual acuity. 1, 2

• No clinically meaningful difference in visual acuity improvement (gain or loss of ≥10 or ≥15 letters) was observed among any agents at year 2 (p > 0.74) 2
• Post-hoc area-under-the-curve analysis over 2 years showed aflibercept vision outcomes remained superior to both bevacizumab and ranibizumab among eyes with baseline visual acuity of 20/50 or worse 3

Anatomical Outcomes

Bevacizumab was less effective than aflibercept and ranibizumab in decreasing central subfield thickness at both years 1 and 2 (p < 0.001). 2

• 12-week central subfield thickness response was not strongly associated with 2-year visual outcomes 4
• Eyes with suboptimal anatomical response at 12 weeks could still achieve meaningful vision improvement by 2 years 4

Treatment Burden and Injection Frequency

Patients in all three treatment groups received similar numbers of injections: 9-10 injections in year 1 and 5-6 injections in year 2. 2

• Treatment followed a protocol of monthly injections until success (macular edema resolves or vision reaches 20/20 or better) or until additional treatment was judged unlikely to be beneficial 1
• Once injections were withheld, treatment could be resumed if macular edema recurred or worsened 1

Early Response and Long-Term Outcomes

A suboptimal response at 12 weeks (less than 5-letter gain) did not preclude meaningful vision improvement at 2 years. 4

• Among eyes with less than 5-letter gain at 12 weeks, 42% (aflibercept), 31% (bevacizumab), and 47% (ranibizumab) gained 10 or more letters by 2 years 4
• Median 2-year visual acuity in these initially poor responders was 20/32,20/32, and 20/25 for aflibercept, bevacizumab, and ranibizumab groups, respectively 4
• This finding indicates that switching therapies based solely on 12-week response may not be necessary 4

Safety Profile

All three anti-VEGF agents demonstrated comparable ocular and systemic safety profiles. 2, 3

• Intravitreal administration has relatively few side effects overall 2
• Caution is warranted for patients with recent history or high risk of myocardial infarction or stroke 2
• Endophthalmitis remains a rare but potentially devastating complication of intravitreal injections 1

Cost-Effectiveness Considerations

Bevacizumab is substantially more cost-effective than aflibercept and ranibizumab, despite slightly inferior anatomical and visual outcomes in some subgroups. 2

• The cost of aflibercept or ranibizumab would need to decrease by 80-90% to be cost-effective relative to bevacizumab 2
• This creates clinical challenges when safety and efficacy data are at odds with cost-effectiveness results 2, 3

Clinical Application Algorithm

For eyes with baseline visual acuity of 20/32 to 20/40: Any of the three anti-VEGF agents (aflibercept, bevacizumab, or ranibizumab) can be used, as outcomes are equivalent 2, 3

For eyes with baseline visual acuity of 20/50 or worse: Aflibercept should be the preferred initial agent based on superior visual outcomes at 1 year and sustained benefit over 2 years 1, 2, 3

For cost-constrained settings: Bevacizumab remains a reasonable option given its substantial cost advantage and ability to achieve good visual outcomes in many patients, though with slightly inferior results in eyes with worse baseline vision 2

Common Pitfalls to Avoid

• Do not prematurely switch therapies based on 12-week response alone, as many eyes with suboptimal early response achieve excellent 2-year outcomes 4
• Do not assume that anatomical improvement (central subfield thickness reduction) predicts visual outcomes, as the correlation is weak 4
• Do not discontinue treatment too early, as Protocol T demonstrated that continued treatment over 2 years was necessary to maintain visual gains 1, 2
• Do not ignore cost considerations entirely, particularly in resource-limited settings where bevacizumab's cost-effectiveness may outweigh its slightly inferior efficacy in some subgroups 2