Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial
NCT03038880 | STAIRWAY Trial | Khanani AM et al. (2020)
Khanani AM, Patel SS, Ferrone PJ, et al. Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial. JAMA Ophthalmology, 2020; 138(9):964-972.
Locations
25 clinical sites in the United States
Study Period
January 2017 – March 2018
Study Design
Randomized, active-controlled, parallel-group, multicenter Phase 2 trial
Study Population
Experimental Group
Control Group
Follow-up Time: 52 weeks
Outcomes
Durability
Number of Injections The mean number of injections through Week 52:
• Ranibizumab Q4W: 12.9
• Faricimab Q12W: 6.7
• Faricimab Q16W: 6.2.
Vision
Best-Corrected Visual Acuity (BCVA) The adjusted mean change in BCVA (ETDRS letters) at Week 40 (primary outcome):
• Ranibizumab Q4W: +11.4 (80% CI: 7.8 to 15.0)
• Faricimab Q12W: +9.3 (80% CI: 6.4 to 12.3); Difference vs ranibizumab: -2.1 (80% CI: -6.8 to 2.6)
• Faricimab Q16W: +12.5 (80% CI: 9.9 to 15.1); Difference vs ranibizumab: 1.1 (80% CI: -3.4 to 5.5) The adjusted mean change in BCVA (ETDRS letters) at Week 52:
• Ranibizumab Q4W: +9.6 (80% CI: 5.9 to 13.3)
• Faricimab Q12W: +10.1 (80% CI: 7.1 to 13.1); Difference vs ranibizumab: 0.5 (80% CI: -4.3 to 5.3)
• Faricimab Q16W: +11.4 (80% CI: 8.8 to 14.1); Difference vs ranibizumab: 1.8 (80% CI: -2.7 to 6.4) Vision Maintaining The proportion of patients gaining ≥15 ETDRS letters at Week 40:
• Ranibizumab Q4W: 33.3% (80% CI: 17.7% to 48.9%)
• Faricimab Q12W: 38.1% (80% CI: 24.5% to 51.7%); Difference vs ranibizumab: 1.91% (80% CI: 0.60% to 6.08%)
• Faricimab Q16W: 39.3% (80% CI: 27.5% to 51.1%); Difference vs ranibizumab: 1.86% (80% CI: 0.60% to 5.7%) The proportion of patients gaining ≥15 ETDRS letters at Week 52:
• Ranibizumab Q4W: 37.5% (80% CI: 22.0% to 53.0%)
• Faricimab Q12W: 33.3% (80% CI: 20.2% to 46.5%); Difference vs ranibizumab: -4.2% (80% CI: -24.5% to 16.2%)
• Faricimab Q16W: 46.4% (80% CI: 34.4% to 58.5%); Difference vs ranibizumab: 8.9% (80% CI: -10.7% to 28.6%) The proportion of patients not losing ≥15 ETDRS letters at Week 40:
• Ranibizumab Q4W: 100% (80% CI: 100% to 100%)
• Faricimab Q12W: 95.2% (80% CI: 89.3% to 100%); Difference vs ranibizumab: -4.76% (80% CI: -10.72% to 1.19%)
• Faricimab Q16W: 96.4% (80% CI: 91.9% to 100%); Difference vs ranibizumab: -3.57% (80% CI: -8.07% to 0.92%) The proportion of patients not losing ≥15 ETDRS letters at Week 52:
• Ranibizumab Q4W: 100% (80% CI: 100% to 100%)
• Faricimab Q12W: 100% (80% CI: 100% to 100%); Difference vs ranibizumab: 0
• Faricimab Q16W: 96.4% (80% CI: 91.9% to 100%); Difference vs ranibizumab: -3.57% (80% CI: -8.07% to 0.92%) The proportion of patients with BCVA 20/40 or better at Week 40:
• Ranibizumab Q4W: 40.0% (80% CI: 23.8% to 56.2%)
• Faricimab Q12W: 61.9% (80% CI: 48.3% to 75.5%); Difference vs ranibizumab: 21.9% (80% CI: 0.76% to 43.1%)
• Faricimab Q16W: 78.6% (80% CI: 68.6% to 88.5%); Difference vs ranibizumab: 38.6% (80% CI: 19.6% to 57.6%) The proportion of patients with BCVA 20/40 or better at Week 52:
• Ranibizumab Q4W: 37.5% (80% CI: 22.0% to 53.0%)
• Faricimab Q12W: 57.1% (80% CI: 43.3% to 71.0%); Difference vs ranibizumab: 19.6% (80% CI: -1.1% to 40.4%)
• Faricimab Q16W: 71.4% (80% CI: 60.5% to 82.4%); Difference vs ranibizumab: 33.9% (80% CI: 15.0% to 52.9%) The proportion of patients with BCVA 20/200 or worse at Week 40:
• Ranibizumab Q4W: 0
• Faricimab Q12W: 0
• Faricimab Q16W: 3.6% (80% CI: 0 to 8.1%); Difference vs ranibizumab: 3.57% (80% CI: -0.92% to 8.07%) The proportion of patients with BCVA 20/200 or worse at Week 52:
• Ranibizumab Q4W: 0
• Faricimab Q12W: 4.8% (80% CI: 0 to 10.7%); Difference vs ranibizumab: 4.8% (80% CI: -1.2% to 10.7%)
• Faricimab Q16W: 3.6% (80% CI: 0 to 8.1%); Difference vs ranibizumab: 3.6% (80% CI: -0.9% to 8.1%)
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CST) The adjusted mean change in CST (µm) from baseline to Week 40:
• Ranibizumab Q4W: -126.3 (80% CI: -145.2 to -107.4)
• Faricimab Q12W: -138.6 (80% CI: -154.0 to -123.1); Difference vs ranibizumab: -16.9 (80% CI: -42.7 to 8.8)
• Faricimab Q16W: -121.3 (80% CI: -135.1 to -107.6); Difference vs ranibizumab: 11.0 (80% CI: -14.3 to 36.3) The adjusted mean change in CST (µm) from baseline to Week 52:
• Ranibizumab Q4W: -129.9 (80% CI: -146.7 to 113.0)
• Faricimab Q12W: -138.5 (80% CI: -152.4 to -124.7); Difference vs ranibizumab: -8.6 (80% CI: -30.4 to13.1)
• Faricimab Q16W: -122.5 (80% CI: -134.8 to –110.3); Difference vs ranibizumab: 7.36 (80% CI: -13.7 to 28.6) Lesion The changes in total lesion area and total lesion leakage area were comparable between the groups.
Safety
AEs Overall, faricimab was well tolerated, and no new or unexpected safety events were observed in STAIRWAY. Patients experienced at least one AE:
• Ranibizumab Q4W: 81.3% (13/16)
• Faricimab Q12W: 75.0% (18/24)
• Faricimab Q16W: 74.2% (23/31) Ocular AEs Patients experienced at least one ocular AE:
• Ranibizumab Q4W: 50.0% (8/16)
• Faricimab Q12W: 37.5% (9/24)
• Faricimab Q16W: 35.5% (11/31) Non-ocular AEs Patients experienced at least one non-ocular AE:
• Ranibizumab Q4W: 56.3% (9/16)
• Faricimab Q12W: 58.3% (14/24)
• Faricimab Q16W: 64.5% (20/31) Serious AEs (SAEs) No ocular SAE (study eye) reported Patients experienced non-ocular SAEs:
• Ranibizumab Q4W: 0
• Faricimab Q12W: 16.7% (4/24)
• Faricimab Q16W: 9.7% (3/31) Study Discontinuation No AEs were reported that led to discontinuation of treatment. Death
• Ranibizumab Q4W: 0
• Faricimab Q12W: one due to an ischemic stroke
• Faricimab Q16W: one due to sepsis and one due to metastatic neoplasm
• None were considered related to the study treatment per the study investigator’s assessment
Conclusion
Faricimab every 12 weeks or 16 weeks maintained vision gains and anatomical improvements comparable to monthly ranibizumab, with fewer injections, supporting the potential for extended interval dosing.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Randomization was performed through an interactive voice and web response system (IxRS) and stratified for baseline BCVA (ETDRS letter score ≥55 vs ≤54).” “Baseline patient demographics and ocular characteristics in STAIRWAY were generally balanced across treatment arms…”
Missing Outcome Data
Low risk
Note: There is no evidence that the primary outcome analysis was not biased by the missingness (no adjustment for sensitivity analysis). The reasons for the missingness was supplied clearly in the paper (e.g., GCP violation, physician decision, and death), which did not depend on true value.
Selection of the Reported Results
Low risk Note: registration with protocol
Deviations from Intended Observations
Low risk Note: “STAIRWAY was a patient and outcome assessor (BCVA and central reading center)–masked trial…” “Primary, secondary, and exploratory efficacy analyses were performed for all randomized participants, except for 5 participants excluded from all analyses owing to GCP noncompliance at a single site.”_mITT “The 5 participants from this site were excluded from efficacy and safety analyses (including the safety-evaluable population) and did not demonstrate additional BCVA benefit or new safety signals compared with ranibizumab, 0.5 mg, every 4 weeks.”
Measurement of the Outcome
Some concerns Note: “STAIRWAY was a patient and outcome assessor (BCVA and central reading center)–masked trial…” This is a multiple-site study, there may be diversity for the BCVA measurement between the different study sites.
Overall
Some concerns
Categories: Wet AMD