Macular Atrophy in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial Comparing Ranibizumab and Aflibercept (RIVAL Study)
NCT02130024 | RIVAL Study | Gillies MC et al. (2020)
Gillies MC, Hunyor AP, Arnold JJ, et al. Macular Atrophy in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial Comparing Ranibizumab and Aflibercept (RIVAL Study). Ophthalmology, 2020; 127:198-210.
Locations
24 sites across Australia
Study Period
April 2014 – November 2017
Study Design
Phase 4, randomized, partially masked, multicenter comparative study
Study Population
Experimental Group
Control Group
Follow-up Time: 24 months
Outcomes
Durability
Number of Injections The average number of injections per year using a negative binomial regression model applied to the 24-month study period:
• Ranibizumab: 9.6 (95% CI : 9.2 to10.0)
• Aflibercept: 9.5 (95% CI : 9.1 to 9.9)
• Injection rate ratio for ranibizumab to aflibercept : 1.01 (95%CI, 0.95 to 1.08; P= 0.75) Maximum Interval Patients with a maximum interval of 12 weeks:
• Ranibizumab: 32%
• Aflibercept: 31% Patients with a maximum interval of 8 weeks:
• Ranibizumab: 20%
• Aflibercept: 19% Patients with a maximum interval of 6 weeks:
• Ranibizumab: 20%
• Aflibercept: 23% Patients returned to monthly injections at least once:
• Ranibizumab: 64%
• Aflibercept: 59%
Vision
Best-Corrected Visual Acuity (BCVA) The mean change in BCVA (ETDRS letters) at 12 months using a mixed model (adjusting for baseline BCVA) :
• Ranibizumab: +7.2 (95% CI : 5.3 to 9.0)
• Aflibercept: +4.8 (95% CI : 3.0 to 6.7)
• The treatment difference: +2.3 letters (95% CI: -0.3 to 4.9; p = 0.08) The mean change in BCVA (ETDRS letters) at 24 months using a mixed model (adjusting for baseline BCVA) :
• Ranibizumab: +6.6 (95% CI 4.7–8.5)
• Aflibercept: +4.6 (95% CI 2.7–6.6)
• The treatment difference: +2.0 letters (95% CI -0.7 to 4.6; p = 0.15) Vision Maintaining A gain of 15 letters or more from baseline in BCVA at Month 12 → Month 24:
• Ranibizumab: 22% (28/127) → 25% (29/117)
• Aflibercept: 21% (25/121) →19% (20/108)
• OR (Month 12): 1.05 (95% CI 0.53–2.08); p = 0.89
• OR (Month 24): 1.61 (95% CI 0.77–3.35); p = 0.21 A loss of 15 letters or fewer from baseline in BCVA at Month 12 → Month 24:
• Ranibizumab: 97% (123/127) → 94% (110/117)
• Aflibercept: 95% (115/121) →94% (102/108)
• OR (Month 12): 1.63 (95% CI 0.45–5.93); p = 0.46
• OR (Month 24): 0.94 (95% CI 0.30–2.90); p = 0.91
Other
Efficacy: Progression Outcomes Macular Atrophy (MA) The mean change in the square root area of MA at 24 months by mixed-model analysis (Primary Outcome) :
• Ranibizumab: +0.36 mm (95% CI 0.27 to 0.45)
• Aflibercept: +0.28 mm (95% CI 0.19 to 0.37)
• Difference: +0.08 mm (95% CI -0.05 to 0.21); p = 0.24 The mean change in the square root area of MA at 12 months (Primary Outcome) :
• Ranibizumab: +0.16 mm (95% CI 0.07to 0.25)
• Aflibercept: +0.14 mm (95% CI 0.05 to 0.23)
• Treatment difference: +0.02 mm (95% CI to 0.11 to 0.15); p = 0.77 The proportion of patients with MA from baseline→ Month 12 → Month 24:
• Ranibizumab: 7% (10/141) → 24% (31/127) → 37% (43/117)
• Aflibercept: 6% (8/137) → 26% (31/121) → 32% (35/108)
• Odds ratio [OR]: 1.19 (95% CI 0.67–2.09); p = 0.55 Plasma Vascular Endothelial Growth Factor (VEGF) Levels The least-square means change of concentration of plasma VEGF using a random-effects mixed model at Week 5:
• Ranibizumab: +0.30 pg/ml (95% CI: -3.8 to 4.4 pg/ml)
• Aflibercept: -26.9 pg/ml (95% CI: -31 to -23 pg/ml) The least-square means change of concentration of plasma VEGF using a random-effects mixed model at Week 9:
• Ranibizumab: +1.6 pg/ml (95% CI: -2.5 to 5.8 pg/ml)
• Aflibercept: -27.3 pg/ml (95% CI: -31 to -23 pg/ml)
Immunognicity
Not reported.
Pharmokinetics
Not reported.
Anatomic
Central Subfield Foveal Thickness (CSFT) The mean change in CSFT (µm) at 12 months using a mixed model (adjusting for baseline CSFT) :
• Ranibizumab: -153 µm (95% CI: -167 to -140 µm)
• Aflibercept: -163 µm (95% CI: -177 to -150 µm)
• The treatment difference: 10.1 µm (95% CI: -8.8 to 29 µm; P =0.29) The mean change in CSFT (µm) at 24 months using a mixed model (adjusting for baseline CSFT) :
• Ranibizumab: -161 µm (95% CI: -174 to -147 µm)
• Aflibercept: -173 µm (95% CI: -186 to -159 µm)
• The treatment difference: 11.9 µm (95% CI: -7.4 to 31 µm; P = 0.23) Retinal Fluid The proportion of patients without intraretinal fluid or subretinal fluid from baseline → Month 2→ Month 12 → Month 24:
• Ranibizumab: 4% → 57%→ 56% → 57%
• Aflibercept: 4% → 61% → 64% → 61%
Safety
AEs Patients experienced at least 1 AE during the study:
• Ranibizumab: 88.7%
• Aflibercept: 93.5% Ocular AEs Patients with ocular AEs (total):
• Ranibizumab: 101 (71.6%)
• Aflibercept: 115 (82.7%)
• Common ocular AEs: Eye pain, Vitreous floaters, Age-related macular degeneration, Dry eye, and Cataract operation Non-ocular AEs Patients with arterial thromboembolic events:
• Ranibizumab: 11 (8%)
• Aflibercept: 7 (5%) Serious AEs (SAEs) Patients with ocular SAEs (total):
• Ranibizumab: 2 (1.4%)
• Aflibercept: 4 (2.9%)
• Common ocular SAEs: Cataract traumatic, Retinal artery embolism, and Retinal artery occlusion Patients with non-ocular SAEs (total):
• Ranibizumab: 50 (35.5%)
• Aflibercept: 54 (38.8)
• Common non-ocular SAEs: Atrial fibrillation, Basal cell carcinoma, Pneumonia, Squamous cell carcinoma, Aphasia, and Chest pain Study discontinuation Due to AEs:
• Ranibizumab: 9 (6%)
• Aflibercept: 14 (10%) Due to SAEs:
• Ranibizumab: 7 (5%)
• Aflibercept: 14 (10%) Death
• Ranibizumab: 3 (2.1%)
• Aflibercept: 6 (4.3%)
• None was suspected by the investigator to be related to the treatment
Conclusion
No significant differences in the rate of development or growth of macular atrophy over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen. Visual acuity, retinal thickness improvement, and safety outcomes were comparable between groups.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Patients were randomized 1:1 using a dynamic allocation method in an interactive web-based response system…” “Demographics and baseline characteristics were comparable between the treatment groups…”
Missing Outcome Data
Low risk
Note: The evidence that the primary outcome data analysis was not biased by the missingness (sensitivity analysis): “A supporting analysis of the primary end point also was carried out on the per-protocol set using the same random-effects mixed model.”
Selection of the Reported Results
Low risk Note: The protocol was published in 2019.
Deviations from Intended Observations
Low risk Note: This is a double-masked study. “The 24-month analysis was performed on the full analysis set, which comprised all randomized patients with at least one post-baseline efficacy value for the primary end point.” (mITT)
Measurement of the Outcome
Low risk Note: The assessors were masked to the intervention “Macular atrophy was diagnosed by a multimodal approach using color fundus photography, fluorescein angiography, autofluorescence, and spectral-domain OCT.” “
Overall
Low risk
Categories: Wet AMD