Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial
NCT02140151 | PREVENT | Chan CK et al. (2022)
Chan, C. K., Lalezary, M., Abraham, P., Elman, M., Beaulieu, W. T., Lin, S. G., Khurana, R. N., Bansal, A. S., Wieland, M. R., Palmer, J. D., Chang, L. K., Lujan, B. J., & Yiu, G. Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial. Ophthalmology Retina, 2022; 6 (6): 484-494.
Locations
4 sites in the United States
Study Period
September 17, 2014 – July 9, 2020
Study Design
Phase 2, randomized, single-masked, sham-controlled clinical trial
Study Population
Experimental Group
Control Group
Follow-up Time: 24 months
Outcomes
Durability
Injection numbers when neovascular conversion occurred
Regarding the eyes that converted:
• IVR (7 eyes)= Median of 2 (IQR, 2-4; range, 1-4)
• SHAM (7 eyes)= Median of 3 (IQR, 3-5; range, 1-8)
Vision
Best-Corrected Visual Acuity (BCVA), letters
Mean BCVA change at 12 months:
• IVR = -0.9 (SD 4.4) letters, SHAM = -0.3 (SD 7.9) letters
• Adjusted mean difference = -0.5 (95% CI, -3.2 to 2.2; P = 0.70)
Mean BCVA change at 24 months:
• IVR = -2.1 (SD 5.4) letters, SHAM = -1.4 (SD 7.7) letters
• Adjusted difference = -0.8 letters (95% CI: -3.7 to 2.2, p = 0.62)
Visual Acuity Loss
≥10 Letters from baseline to 24 months:
• IVR: 2/39 (5%)
• SHAM: 4/40 (10%)
≥5 Letters from baseline to 24 months:
• IVR: 11/39 (28%)
• SHAM 7/40 (18%)
Other
Progression:
Conversion to nAMD
Over 24 months (Primary Outcome):
• IVR = 7/54 (13%) vs. SHAM = 7/54 (13%)
• HR = 0.91 (95% CI: 0.32–2.59, p = 0.86)
Cumulative Incidence of nAMD
• At 12 months: IVR = 10% (95% CI, 1%-18%) vs. SHAM = 15% (95% CI, 4%-25%)
• At 24 months: IVR = 14% (95% CI: 4%–23%) vs. SHAM = 15% (95% CI: 4%–25%)
• A sensitivity analysis: Non-study eyes produced similar results (hazard ratio =1.12 [95% CI, 0.37-3.40]; P - 0.84)
Factors related to progression
Among the 10 factors (age, sex, BCVA, CST, macular thickness, macular volume, drusen area, drusen volume, AREDs severity level, and subretinal drusenoid deposits) evaluated, while controlling for treatment assignment, there were no significant associations with conversion to nAMD.
Possible Subclinical Neovascular Lesions
• Fourteen (13%) of 108 eyes: Definitive clinical signs of conversion to nAMD associated with intraretinal or subretinal fluid and/or subretinal hyperreflective material:
• Nine (8%) of 108 additional eyes: Small intraretinal or subretinal hyporeflective lesions (approximately≥50 microns in diameter)
• Similarly distributed: 5 in IVR vs. 4 in SHAM)
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Not reported
Safety
Withdraw
• IVR= 9 vs. SHAM=9
Ocular-related AEs (Study Eye) No serious ocular AEs were reported.
Non-ocular AEs
• IVR: 2 deaths, Sham: 1 death (none related to study drug)
• One patient in IVR developed a mild cerebral vascular accident with minimal long-term effects.
Conclusion
Quarterly ranibizumab injections did not reduce the incidence of nAMD compared with sham injections, but the study was likely underpowered. No effect on visual acuity was observed at 24 months. Other strategies are needed to prevent neovascular conversion in high-risk eyes.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “The study coordinator at the main study coordinating center (Southern California Desert Retina Consultants) used computer-generated random numbers to assign eligible participants to a treatment group. The individual study centers then enrolled the participants.” “Baseline characteristics were balanced between treatment groups for the study eyes and largely balanced for the contralateral, non-study eyes.”
Missing Outcome Data
Low risk
Note: “A sensitivity analysis that adjusted time from the initial development of nAMD to study onset in the contralateral, non-study eyes produced similar results”
Selection of the Reported Results
Low risk Note: the project was registered with the protocol.
Deviations from Intended Observations
Low risk Note: The ITT principle was applied for primary outcome analysis.
Measurement of the Outcome
Low risk Note: “Neovascular conversion of a study eye was established by clinical examination by a study investigator and confirmed by independent image assessment at the University of California Davis Reading Center (G.Y.).”
Overall
Low risk
Categories: Dry AMD