Safety and Efficacy of Different Doses and Regimens of Faricimab vs. Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial
NCT02484690 | AVENUE Trial | Sahni J et al. (2020)
Sahni J, Dugel PU, Patel SS, et al. Safety and Efficacy of Different Doses and Regimens of Faricimab vs. Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial. JAMA Ophthalmol, 2020; 138(9):955-963.
Locations
58 sites in the United States
Study Period
August 2015 – September 2017
Study Design
Phase 2, randomized, double-masked, active-controlled, parallel-group trial
Study Population
Experimental Group
Control Group
Follow-up Time: 36 weeks
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA) For Group 1 (Arm A, B, C, and D), the adjusted mean change in BCVA (ETDRS letters) to week 36 (primary outcome):
• Arm A: Reference
• Arm B vs. Arm A: 1.6 (80%CI:-1.6 to 4.7) (p=0.52)
• Arm C vs. Arm A: -1.6 (80% CI,: -4.9 to 1.7) (p=0.53)
• Arm D vs. Arm A: -1.5 (80%CI: -4.6t to 1.6) (p=0.53)
• The difference in ETDRS letters between any of the faricimab arms and the 0.5-mg ranibizumab arm was at least 0.24 for all comparisons Vision Maintaining For Group 1 (Arm A, B, C, and D), the proportion of patients gaining ≥15 ETDRS letters:
• Arm A: 31.3%
• Arm B: 37.5%
• Arm C: 27.0%
• Arm D: 22.7%
• The difference between arm A and any of the B, C, or D, P>0.05 For Group 1 (Arm A, B, C, and D), the proportion of patients with BCVA is 20/40 or better:
• Arm A: 50.0%
• Arm B: 50.0%
• Arm C: 40.5%
• Arm D: 43.2%
• The difference between arm A qnd any of the B, C, or D, P>0.05 For Group 1 (Arm A, B, C, and D), the proportion of patients with BCVA 20/200 or worse:
• Arm A: 7.8%
• Arm B: 7.5%
• Arm C: 19.2%
• Arm D: 9.1% The difference between arm A and any of the B, C, or D, P>0.05
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CST) The mean (80% CI) reduction in CST (µm) at Week 12:
• Arm A: –173 (–185, –160)
• Arm B: –151 (–166, –137)
• Arm C: –164 (–180, –149)
• Arm D: –165 (–179, –151)
• Arm E: –152 (–165, –140) For Group 1 (Arm A, B, C, and D) at week 36:
• All faricimab groups had visual and anatomical improvements (CST, CNV area, and leakage) similar to the monthly ranibizumab group at week 36
• A large and rapid reduction in CST was noted as early as week 4 and was maintained until week 36.
Safety
Ocular AEs Patients with any ocular AEs:
• Arm A: 41.8%
• Arm B: 45.7%
• Arm C: 53.8%
• Arm D: 58.7%
• Arm E: 43.8% Patients with intraocular inflammation:
• Arm A: 4.5%
• Arm B: 6.5%
• Arm C: 0%
• Arm D: 0%
• Arm E: 3.1% Patients with endophthalmitis:
• Arm A: 0%
• Arm B: 2.2%
• Arm C: 0%
• Arm D: 0%
• Arm E: 1.6% Other common ocular AE: Vitreous hemorrhage Non-ocular AEs Patients with any non-ocular AEs:
• Arm A: 55.2%
• Arm B: 80.4%
• Arm C: 59.0%
• Arm D: 65.2%
• Arm E: 67.2% APTC events: Nonfatal myocardial infarction; Nonfatal stroke; Vascular or cardiac death or death of unknown cause Serious AEs (SAEs) Patients with any ocular SAEs:
• Arm A: 0%
• Arm B: 6.5%
• Arm C: 0%
• Arm D: 0%
• Arm E: 3.1% Patients with any non-ocular SAEs:
• Arm A: 13.4%
• Arm B: 15.2%
• Arm C: 17.9%
• Arm D: 8.7%
• Arm E: 9.4% Death One in Arm E due to Vascular or cardiac death.
Conclusion
Faricimab was not superior to monthly ranibizumab but showed comparable BCVA and anatomical improvements, supporting further phase 3 evaluation as an alternative to monthly anti-VEGF therapy.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Some concerns
Note: No information on the randomization and concealment method. However, the baseline is balanced between the two groups.
Missing Outcome Data
High risk
Note: The total missingness is 10.6% (1-244/273), and no correction for the missing bias was performed. In addition, the reasons for withdrawing or discontinuing from the study were not balanced among the five groups.
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. Sixty-three participants reported at least one major protocol deviation. However, ITT (Figure 1) was performed even though this was not announced in the paper. In addition, the paper announced that "Protocol deviations were not considered to meaningfully change the safety and efficacy findings."
Measurement of the Outcome
Some concerns Note: This is a double-masked study. As a multiple-site study, the measurement may be different from site to site.
Overall
High risk
Categories: Wet AMD