Ranibizumab and Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration: Two-Year Results
NCT00593450 | CATT Trial | Martin DF et al. (2020)
Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration: Two-Year Results. Ophthalmology, 2020; 127(4 Suppl):S135-S145.
Locations
59 clinical centers in the United States
Study Period
Not reported
Study Design
Phase III, multicenter, randomized, double-masked, parallel-group noninferiority trial
Study Population
Experimental Group
Control Group
Follow-up Time: 2 years
Outcomes
Durability
Number of Injections The mean number of injections at 24 months:
• Ranibizumab PRN: 12.6±6.6
• Bevacizumab PRN: 14.1±7.0
• Difference: p=0.01
Vision
Best-Corrected Visual Acuity (BCVA) The mean change in BCVA (ETDRS letters) at 24 months (primary outcome):
• Ranibizumab Monthly: +8.8 letters
• Bevacizumab Monthly: +7.8 letters
• Ranibizumab PRN: +6.7 letters
• Bevacizumab PRN: +5.0 letters
• Difference (Ranibizumab vs. Bevacizumab): -1.4 letters (95% CI: -3.7 to 0.8, p=0.21)
• Difference (PRN vs. Monthly): -2.4 letters (95% CI: -4.8 to -0.1, p=0.046) Vision Maintaining The proportion of patients gaining ≥15 ETDRS letters:
• Ranibizumab Monthly: 32.8%
• Bevacizumab Monthly: 31.8%
• Ranibizumab PRN: 30.7%
• Bevacizumab PRN: 28.3% The proportion of patients gaining 5-14 ETDRS letters:
• Ranibizumab Monthly: 36.6%
• Bevacizumab Monthly: 27.9%
• Ranibizumab PRN: 29.5%
• Bevacizumab PRN: 31.5% The proportion of patients change ≤4 ETDRS letters:
• Ranibizumab Monthly: 16.4%
• Bevacizumab Monthly: 24.0%
• Ranibizumab PRN: 23.5%
• Bevacizumab PRN: 19.5% The proportion of patients losing 5-14 ETDRS letters:
• Ranibizumab Monthly: 7.5%
• Bevacizumab Monthly: 8.5%
• Ranibizumab PRN: 9.1%
• Bevacizumab PRN: 9.2% The proportion of patients losing ≥15 ETDRS letters:
• Ranibizumab Monthly: 6.7%
• Bevacizumab Monthly: 7.8%
• Ranibizumab PRN: 7.2%
• Bevacizumab PRN: 11.6% The proportions with 20/20 or better visual acuity and with 20/200 or worse visual acuity were also similar among the treatment groups
Other
Economic Outcome Drug Cost The estimated 2-year drug cost per patient varied from $705 in the bevacizumab-as needed group to $44 800 in the ranibizumab-monthly group.
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Retinal Thickness The mean retinal thickness was 29µm less in patients treated monthly than in patients treated with an as-needed regimen (regimen, P=0.005) Retinal Fluid The proportion of patients without fluid on OCT ranged from 13.9% in the bevacizumab as-needed group to 45.5% in the ranibizumab-monthly group (drug, P = 0.0003; regimen, P <0.0001) Retinal Circulation Fluorescein dye leakage was absent in a higher percentage of patients treated monthly than in patients treated as needed (regimen, P =0.002) Lesion
• The mean change in lesion area from baseline ranged from -0.4 mm2 for the ranibizumab-monthly group to 3.0 mm2 for the bevacizumab-as-needed group (drug, P = 0.006; regimen, P = 0.0003).
• Most of the increase in mean lesion area occurred during year 2 Geographic Atrophy (GA) The proportion of study eyes with GA at 2 years among eyes without apparent GA at enrollment, ranging from 25.8% in the ranibizumab-monthly group to 12.9% in the bevacizumab-as-needed group, was greater among patients treated monthly (P =0.007)
Safety
Non-ocular AEs Patients with cardiac disorders:
• Ranibizumab: 47 (7.8%)
• Bevacizumab: 62 (10.6%)
• P=0.11 Patients with infections:
• Ranibizumab: 41 (6.8%)
• Bevacizumab: 54 (9.2%)
• P=0.14 Patients with nervous system disorders:
• Ranibizumab: 34 (5.7%)
• Bevacizumab: 36 (6.1%)
• P=0.81 Patients with injury and procedural complications:
• Ranibizumab: 23 (3.8%)
• Bevacizumab: 35 (6.0%)
• P=0.11 Patients with neoplasms benign and malignant:
• Ranibizumab: 27 (4.5%)
• Bevacizumab: 22 (3.8%)
• P=0.56 Patients with gastrointestinal disorders:
• Ranibizumab: 11 (1.8%)
• Bevacizumab: 28 (4.8%)
• P=0.005 Patients with any other system organ class:
• Ranibizumab: 81 (13.5%)
• Bevacizumab: 104 (17.8%)
• P=0.046 Ocular AEs (study eye) Patients with endophthalmitis:
• Ranibizumab: 4 (0.7%)
• Bevacizumab: 7 (1.2%)
• P=0.38 Patients with pseudo-endophthalmitis:
• Ranibizumab: 1 (0.2%)
• Bevacizumab: 1 (0.2%)
• P=1.00 Serious AEs (SAEs) Patients with one or more serious events:
• Ranibizumab: 190 (31.7%)
• Bevacizumab: 234 (39.9%)
• P=0.004 Patients with arteriothrombotic events:
• Ranibizumab: 28 (4.7%)
• Bevacizumab: 29 (5.0%)
• P=0.89 Patients with venous thrombotic events:
• Ranibizumab: 3 (0.5%)
• Bevacizumab: 10 (1.7%)
• P=0.054 Patients with hypertension:
• Ranibizumab: 3 (0.5%)
• Bevacizumab: 4 (0.7%)
• P=0.72 Death
• Ranibizumab: 32 (5.3%)
• Bevacizumab PRN: 36 (6.1%)
• P=0.62
Conclusion
Ranibizumab and bevacizumab had similar effects on BCVA over 2 years. Monthly dosing provided greater BCVA gains compared to PRN dosing, but PRN required fewer injections. Bevacizumab was associated with a higher rate of systemic SAEs.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Image graders, visual acuity examiners, and the medical monitor were unaware of drug and dosing regimen. Ophthalmologists were unaware of drug assignment. Clinic coordinators were aware of both drug and regimen. Patients were not informed of their drug assignment.” No information on the method of randomization. “At enrollment, there were no substantial imbalances in demographic or ocular characteristics among the 6 treatment groups…”
Missing Outcome Data
Low risk
Note: the evidence that the primary outcome analysis was not biased by the missingness (sensitivity analysis): “Adjustment for covariates and 3 alternative approaches for handling missing data (multiple imputation using propensity scoring or regression modeling and last observation carrying forward) for the 2-year visual acuity were performed as sensitivity analyses.”
Selection of the Reported Results
Low risk Note: Protocol is publicly available
Deviations from Intended Observations
Low risk Note: this is a double-masked study. “Analyses followed the intention-to-treat principle.”
Measurement of the Outcome
Some concerns Note: “Image graders, visual acuity examiners, and the medical monitor were unaware of the drug and dosing regimen.” This is a multiple-site study. There may be diversity in the BCVA among the different sites.
Overall
Some concerns
Categories: Wet AMD