Intravitreal Combined Aflibercept + Anti-PDGFRβ for Neovascular Age-Related Macular Degeneration: Results of the Phase 2 CAPELLA Trial
NCT02418754 | CAPELLA Trial | Heier JS et al. (2020)
Heier JS, Wykoff CC, Waheed NK, et al. Intravitreal Combined Aflibercept + Anti-PDGFRβ for Neovascular Age-Related Macular Degeneration: Results of the Phase 2 CAPELLA Trial. Ophthalmology, 2020; 127(2):211-220.
Locations
93 sites in the United States (82) and Japan (11)
Study Period
April 2015 – March 2017
Study Design
Phase 2, randomized, double-masked, multicenter comparative trial
Study Population
Experimental Group
Control Group
Follow-up Time: 52 weeks
Outcomes
Durability
Not reported.
Vision
Best-Corrected Visual Acuity (BCVA) The mean change in BCVA (ETDRS letters) at Week 12 (Primary Outcome):
• LD combo: +5.8
• HD combo: +5.8
• IAI: +7.5
• Difference (High-dose vs. IAI): p =0.21
• Difference (High-dose vs. IAI): p = 0.10 The mean change in BCVA (ETDRS letters) at Week 28:
• LD combo: +6.3
• HD combo: +6.6
• IAI: +8.3; p-values not reported. Vision Maintaining Mean BCVA gains (letters) from baseline at week 28:
• LD combo: 6.3
• HD combo: 6.6
• HD combo →IAI: 7.8
• IAI → HD combo: 8.9
• IAI: 8.3 The proportion of patients gaining ≥15 letters at Week 12:
• LD combo: 12%
• HD combo: 19%
• IAI: 22% The proportion of patients gaining ≥15 letters at Week 28:
• LD combo: 16%
• HD combo: 25%
• HD combo →IAI: 28%
• IAI → HD combo: 31%
• IAI: 27%
Other
N/A
Immunognicity
Not reported.
Pharmokinetics
Not reported.
Anatomic
Central Subfield Thickness (CST) The mean change in CST (µm) at Week 12:
• LD combo: -126.1
• HD combo: -127.1
• IAI: -126.9 The mean change in CST (µm) at Week 28:
• LD combo: -135.6
• HD combo: - 140.1
• HD combo →IAI: -150.9
• IAI → HD combo: -124.6
• IAI: -135.8 Retinal Fluid Proportion of eyes with complete resolution of retinal fluid at Week 12:
• LD combo: 35%
• HD combo: 24%
• IAI: 42%
• Numerically in favor of IAI (42% vs. 24%) Proportion of eyes with complete resolution of retinal fluid at Week 12:
• LD combo: 46%
• HD combo: 29%
• HD combo →IAI: 37%
• IAI → HD combo: 37%
• IAI: 50%
• Numerically in favor of IAI (50% vs. 29%) Subretinal Hyperreflective Material (SHRM) The proportion of eyes with complete resolution of SHRM at Week 12:
• LD combo: 19%
• HD combo: 13%
• IAI: 26%
• Numerically in favor of IAI (26% vs. 13%) The proportion of eyes with complete resolution of SHRM at Week 12:
• LD combo: 19%
• HD combo: 19%
• HD combo →IAI: 20%
• IAI → HD combo: 24%
• IAI: 32%
• Numerically in favor of IAI (32% vs. 19%)
Safety
Ocular AEs Patients with at least one ocular AE (study eye):
• LD and HD combo: 35.2%
• IAI: 47.9% Patients with conjunctival hemorrhage (most common ocular AE):
• LD and HD combo: 3.8%
• IAI: 11.7% Patients with retinal hemorrhage (most common ocular AE):
• LD and HD combo: 2.8%
• IAI: 7.5% Patients with Intraocular inflammation (most common ocular AE):
• HD combo: 7.5%
• IAI: 0 Non-ocular AEs Patients with non-ocular AEs:
• LD and HD combo: 69.4%
• IAI: 61.5% Patients with urinary tract infection (most common non-ocular AE):
• LD and HD combo: 3.7%
• IAI: 13.8% Patients with nasopharyngitis (most common non-ocular AE):
• LD and HD combo: 2.9%
• IAI: 8.5% Patients with arterial thromboembolic events:
• LD and HD combo: 0.9%
• IAI: 2.1% Serious AEs (SAEs) Patients with ocular SAEs:
• LD and HD combo: 2.1%
• IAI: 4.9% Patients with non-ocular SAEs:
• LD and HD combo: 13.6%
• IAI: 19.4% Death Ten deaths occurred in the study with an incidence:
• LD combo: 3 (2.9%)
• HD combo: 2 (1.9%)
• HD combo →IAI: 1 (1.1%)
• IAI → HD combo: 1 (1.1%)
• IAI: 3 (2.8%)
• None of the deaths were determined to be related to the study drug
Conclusion
Combination therapy with aflibercept and anti-PDGFRβ (rinucumab) did not provide additional visual or anatomical benefits over aflibercept monotherapy. The incidence of intraocular inflammation was higher in the high-dose combination group.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Some concerns
Note: There is no information on the allocation concealment or the method of randomization. However, “All demographics and baseline characteristics appeared similar among all 5 treatment groups.”
Missing Outcome Data
Low risk
Note: “In all efficacy analyses, missing values were imputed using the last observation carried forward (LOCF) approach”, which is inappropriate. According to Table 1, the missingness is similar to each group (all less than 5%), which indicates that the missingness did not depend on the true value.
Selection of the Reported Results
Low risk Note: registration with the protocol.
Deviations from Intended Observations
Low risk Note: This is a double-masked study. “Efficacy was evaluated on the full analysis set, including all randomized patients who received at least 1 study injection...” (mITT)
Measurement of the Outcome
Some concerns Note: This is a double-masked study. “The BCVA was evaluated using the 4-m Early Treatment Diabetic Retinopathy Study protocol.” However, as a multiple–site study, the BCVA measurement may have diversity between different sites.
Overall
Some concerns
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