Intravitreal Aflibercept Injection vs Sham as Prophylaxis Against Conversion to Exudative Age-Related Macular Degeneration in High-risk Eyes: A Randomized Clinical Trial
NCT02462889 | Not reported | Heier JS et al. (2021)
Heier, J. S., Brown, D. M., Shah, S. P., Saroj, N., Dang, S., Waheed, N. K., Wykoff, C. C., Prenner, J. L., Boyer, D. S. Intravitreal Aflibercept Injection vs Sham as Prophylaxis Against Conversion to Exudative Age-Related Macular Degeneration in High-risk Eyes: A Randomized Clinical Trial. JAMA Ophthalmol, 2021; 139(5):542-547.
Locations
4 sites in the United States
Study Period
June 23, 2015 – March 13, 2019
Study Design
Prospective, single-masked, randomized, sham-controlled clinical trial
Study Population
Experimental Group
Control Group
Follow-up Time: 24 Months
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA)
The Mean change in BCVA remained relatively stable over time:
• IAI: -2.8 letters (95% CI, 0.70 to 6.64)
• Sham: 0.2 letters (95% CI, -4.39 to 2.52)
• χ2 analysis for difference: p = 0.10
Other
Efficacy: Progression Outcomes
Exudative AMD (eAMD)
The proportion of patients with conversion to eAMD at 24 months:
• IAI = 6/63 (9.5%)
• Sham = 7/64 (10.9%)
• χ2 analysis for difference: p = 0.98
The conversion rate in the fellow eye:
• Patients with fellow-eye eAMD for >2 years: IAI = 6.3%, Sham = 6.3%
• Patients with fellow-eye eAMD for ≤2 years: IAI = 12.9%, Sham = 15.6%
Geographic Atrophy (GA)
Mean growth in GA over time:
• IAI: 0.34 mm² (95% CI, -0.07 to 0.36)
• Sham: 0.43 mm² (95% CI, 0.11 to 0.96)
• χ2 analysis for difference: p = 0.67
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Non-exudative choroidal neovascularization (CNV)
The number of study eyes with the presence of non-exudative CNV:
• Detected in 6.3% (IAI) and 9.4% (Sham) at baseline
• Increased to 17.5% (IAI) and 20.3% (Sham) before conversion to eAMD
Safety
Ocular-related AEs (Study Eye)
1 patient in IAI group lost 31 letters due to GA progression into the fovea
Non-ocular AEs
Nonfatal cerebrovascular accidents:
• IAI = 1
• Sham = 1
Death
Pneumonia deaths:
• IAI = 1
• Sham = 1
Natural cause deaths:
• Sham = 1
Fatal cardiovascular accident:
• Sham = 3
Conclusion
Quarterly intravitreal aflibercept injections did not reduce the risk of conversion to exudative AMD compared with sham injections at 24 months. Future studies should explore alternative dosing strategies or different therapeutic targets for prophylaxis.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Some concerns
Note: According to the attached protocol “Subjects will be randomized in a 1:1 ratio to treatment and observations groups by simple random assignment.” No information on the method of allocation concealment.
“Groups were balanced with respect to demographic and baseline characteristics.”
Missing Outcome Data
High risk
Note: Total missingness is 16/128=12.5%, which is more than the sample anticipant (8%). In addition, there is no evidence that the result was not biased by missing outcome data.
There were differences between intervention groups in the proportions of missing outcome data (5/64 vs. 11/64) and the missingness in the outcome could be influenced by its true value.
Selection of the Reported Results
Low risk
Deviations from Intended Observations
Low risk Note: “Patients, visual acuity examiners, and the reading center were masked to study treatment assignment…” “Primary statistical analyses were performed based on intention to treat.”
Measurement of the Outcome
Low risk Note: “Patients, visual acuity examiners, and the reading center were masked to study treatment assignment…” “The primary outcome measure of the study was the proportion of patients with conversion to eAMD at 24 months as confirmed by the independent, masked reading center.”
Overall
High risk
Categories: Dry AMD Geographic Atrophy