HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration 2020
• NCT02307682 (HAWK) • NCT02434328 (HARRIER) | HAWK and HARRIER Trials | Dugel PU et al. (2020)
Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology, 2020; 127(1):72-84.
Locations
408 sites across North America, Europe, Asia, Australia, and South America
Study Period
• HAWK: December 2014 to May 2016 • HARRIER: June 2015 to April 2016
Study Design
Phase 3, multicenter, randomized, double-masked, active-controlled trial
Study Population
Experimental Group
Control Group
Follow-up Time: 48 weeks
Outcomes
Durability
Dosing Maintenance For brolucizumab-treated eyes, maintaining q12w dosing after loading through Week 48 (Kaplan-Meier estimate for 95% CI):
• HAWK : 1. Brolucizumab 3 mg: 49.4% (95% CI: 43.9% to 54.6%) 2. Brolucizumab 6 mg: 55.6% (95% CI: 50.2% to 60.8%)
• HARRIER: 1. Brolucizumab 6 mg: 51.0% (95% CI: 45.7% to 56.1%)
Vision
Best-Corrected Visual Acuity (BCVA) BCVA change from baseline to Week 48 (primary outcome):
• HAWK: 1. Brolucizumab 3 mg: +6.1 (SE 0.69); Aflibercept: +6.8 (SE 0.71); least squares (LS) mean difference: -0.6 letters (95% CI: -2.5 to 1.3); p < 0.001 2. Brolucizumab 6 mg: +6.6 (SE 0.71); Aflibercept: +6.8 (SE 0.71); LS mean difference: -0.2 letters (95% CI -2.1 to 1.8); p < 0.001
• HARRIER: Brolucizumab 6 mg: +6.9 (SE 0.61); Aflibercept: +7.6 (SE 0.61); LS mean difference: -0.7 letters (95% CI: -2.4 to 1.0); p < 0.001 The average change in BCVA from baseline over Weeks 36-48:
• HAWK: 1. Brolucizumab 3 mg: +6.2 (SE 0.67); Aflibercept: +6.7 (SE 0.68); LS mean difference: -0.5 letters (95% CI: -2.4 to 1.3); p < 0.001 2. Brolucizumab 6 mg: +6.7 (SE 0.68); Aflibercept: +6.7 (SE 0.68); LS mean difference: 0 letters (95% CI: -1.9 to 1.9); p < 0.001
• HARRIER: Brolucizumab 6 mg: +6.5 (SE 0.58); Aflibercept: +7.7 (SE 0.58); LS mean difference: -1.2 letters (95% CI: -2.8 to 0.5); p < 0.001 Vision Maintaining Proportion of patients gaining ≥15 ETDRS letters at Week 48 :
• HAWK : 1. Brolucizumab 3 mg: 25.2% 2. Brolucizumab 6 mg: 33.6% 3. Aflibercept: 25.4%
• HARRIER: 1. Brolucizumab 6 mg: 29.3% 2. Aflibercept: 29.9% Proportion of patients loss ≥15 ETDRS letters at Week 48 :
• HAWK : 1. Brolucizumab 3 mg: 5.9% 2. Brolucizumab 6 mg: 6.4% 3. Aflibercept: 5.5%
• HARRIER: 1. Brolucizumab 6 mg: 3.8% 2. Aflibercept: 4.8%
Other
Efficacy: Progression Outcomes Disease Activities The disease activity in brolucizumab 6 mg-treated eyes versus aflibercept during the period up to Week 16:
• HAWK: 24.0% vs. 34.5% (95% CI for treatment difference: -17.1% to -3.5%; P = 0.001)
• HARRIER: 22.7% vs. 32.2% (95% CI for treatment difference: -15.8% to -3.1%; P = 0.002)
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CST) LS mean change in CST at Week 48:
• HAWK: Brolucizumab 6 mg: -172.8 µm; Aflibercept: -143.7 µm; Difference: -29.1 µm (95% CI -47.6 to -10.4); p = 0.001
• HARRIER: Brolucizumab 6 mg: -193.8 µm; Aflibercept: -143.9 µm; Difference: -49.9 µm (95% CI -68.9 to -30.9); p < 0.001 LS mean change in CST at Week 16:
• HAWK: Brolucizumab 6 mg: -161.4 µm; Aflibercept: -133.6 µm; Difference for treatment: -27.8 µm (95% CI: -45.1 to -10.5); P < 0.001
• HARRIER: Brolucizumab 6 mg: -174.4 µm; Aflibercept: -134.2 µm; Difference: -49.9 µm (95% CI: - 58.9 to -21.6); p < 0.001 Retinal Fluid Patients with intraretinal fluid (IRF) and/or subretinal fluid (SRF) at Week 16:
• HAWK: 1. Brolucizumab 3 mg: 41.8%; Aflibercept: 52.0%; difference: -8.2% (95% CI: -17.3% to -2.5%); p = 0.003 2. Brolucizumab 6 mg: 33.9%; Aflibercept: 52.2%; difference: -18.3% (95% CI: -25.3% to -10.9%); p <0.001
• HARRIER: Brolucizumab 6 mg: 29.4%; Aflibercept: 45.1%; difference: -15.7% (95% CI: -22.9% to -9.0%;); p <0.001 Patients with intraretinal fluid (IRF) and/or subretinal fluid (SRF) at Week 48:
• HAWK: 3. Brolucizumab 3 mg: 34.1%; Aflibercept: 44.7%; difference: -10.6% (95% CI: -17.4% to -3.3%); p = 0.002 4. Brolucizumab 6 mg: 31.2%; Aflibercept: 44.6%; difference: -13.4% (95% CI: -20.7% to -6.1%;); p <0.001
• HARRIER: Brolucizumab 6 mg: 25.8%; Aflibercept: 43.9%; difference: -18.1% (95% CI: -24.9% to -11.8%); p <0.001 Patients with intraretinal sub- retinal pigment epithelium (RPE) fluid at Week 48:
• HAWK: Brolucizumab 6 mg: 13.5%; Aflibercept: 21.6%; difference: -8.1% (95% CI: -13.6% to -2.7%); p = 0.004
• HARRIER: Brolucizumab 6 mg: 12.9%; Aflibercept: 22.0%; difference: -9.1% (95% CI: -13.8% to -3.9%); p <0.001
Safety
Ocular AEs Patients with ≥1 ocular AE:
• HAWK : 1. Brolucizumab 3 mg: 175 (48.9%) 2. Brolucizumab 6 mg: 179 (49.7%) 3. Aflibercept: 170 (47.2%)
• HARRIER: 1. Brolucizumab 6 mg: 122 (33.0%) 2. Aflibercept: 119 (32.2%) Most common ocular AEs (study eye):
• Conjunctival hemorrhage, Visual acuity reduced, Vitreous floaters, Eye pain, Dry eye, Retinal hemorrhage, Retinal pigment epithelial tear, and Vitreous detachment. Non-ocular AEs Patients with ≥1 non-ocular AE:
• HAWK : 1. Brolucizumab 3 mg: 242 (67.6%) 2. Brolucizumab 6 mg: 232 (64.4%) 3. Aflibercept: 258 (71.7%)
• HARRIER: 1. Brolucizumab 6 mg: 219 (59.2%) 2. Aflibercept: 211 (57.2%) Patients with ≥ 1 nonocular arterial thromboembolic event:
• HAWK : 1. Brolucizumab 3 mg: 11 (3.1%) 2. Brolucizumab 6 mg: 6 (1.7%) 3. Aflibercept: 10 (2.8%)
• HARRIER: 1. Brolucizumab 6 mg: 6 (1.6%) 2. Aflibercept: 8 (2.2%) Serious ocular AEs Patients with ≥1 serious ocular AE:
• HAWK : 1. Brolucizumab 3 mg: 5 (1.4%) 2. Brolucizumab 6 mg: 11 (3.1%) 3. Aflibercept: 3 (0.8%)
• HARRIER: 1. Brolucizumab 6 mg: 9 (2.4%) 2. Aflibercept: 4 (1.1%)
• Most common serious ocular AE (study eye) 1. Uveitis, Retinal detachment, Retinal pigment epithelial tear, Visual acuity reduced, Macular hole, and Cataract. Patients with ≥ 1 nonocular arterial thromboembolic event:
• HAWK : 1. Brolucizumab 3 mg: 47 (13.1%) 2. Brolucizumab 6 mg: 47 (13.1%) 3. Aflibercept: 68 (18.9%)
• HARRIER: 1. Brolucizumab 6 mg: 35 (9.5%) 2. Aflibercept: 43 (11.7%) Death
• HAWK : 1. Brolucizumab 3 mg: 4 (1.1%) 2. Brolucizumab 6 mg: 4 (1.1%) 3. Aflibercept: 6 (1.7%)
• HARRIER: 1. Brolucizumab 6 mg: 3 (0.8%) 2. Aflibercept: 4 (1.1%)
Conclusion
Brolucizumab was non-inferior to aflibercept in visual function at Week 48 and demonstrated superior anatomic outcomes with greater CST reduction. More than 50% of brolucizumab-treated eyes were maintained on q12w dosing. Safety outcomes were comparable, but ocular AEs were slightly higher in brolucizumab-treated eyes.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “A member of the Statistical Programming group who was not part of the study team generated the randomized allocation for the study treatment assignment based on a randomization plan that provided study-specific criteria for randomization.” (Even) there is no information on comparing the baseline characteristics of the groups.
Missing Outcome Data
Low risk
Note: The evidence that the primary outcome analysis was not biased by missingness (sensitivity analysis): “Supportive analyses of the primary endpoint were conducted using the per-protocol set with…”
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. The full analysis set was used to perform the primary outcome analysis (mITT).
Measurement of the Outcome
Some concerns Note: The investigators were masked. However, this is a large international multiple-site study; there may be diversity in the BCVA assessment among the different sites.
Overall
Some concerns
Categories: Wet AMD