Bimonthly, treat-and-extend, and pro re nata ranibizumab in naïve neovascular age-related macular degeneration patients: 12-month outcomes of a randomized study
EudraCT 2012-003431-37 | In-Eye Study | López Gálvez MI et al. (2020)
López Gálvez MI, Arias Barquet L, Figueroa MS, García-Layana A, Ruiz Moreno JM. Bimonthly, treat-and-extend, and pro re nata ranibizumab in naïve neovascular age-related macular degeneration patients: 12-month outcomes of a randomized study. Acta Ophthalmologica, 2020; 98:e820–e829.
Locations
31 ophthalmology centers across Spain
Study Period
October 2013 – October 2016
Study Design
Phase IV, randomized, multicenter, parallel-group comparative trial
Study Population
Experimental Group
Control Group
Follow-up Time: 12 months
Outcomes
Durability
Number of Injections The mean (95%CI) number of injections at 12 months:
• Bimonthly: 7.6 (7.5–7.7) (compared to PRN: p=0.159)
• T&E: 9.3 (8.9–9.7) (compared to PRN: p<0.001)
• PRN: 7.4 (6.7–8.0) Number of Total Visits The mean (95% CI) number of total visits at 12 months:
• Bimonthly: 8.6 (8.5–8.7) (compared to PRN and T&E: p<0.001)
• T&E: 10.4 (10.0–10.8) (compared to PRN: p<0.001)
• PRN: 13.6 (13.4–13.7) Time Course The time–course in mean (SD) to achieve the mean difference in BCVA at month 12 versus visit 4:
• Bimonthly: 5.9 (4.1)
• T&E: 6.0 (4.1)
• PRN: 6.3 (3.4).
• Difference: p=0.729
Vision
Best-Corrected Visual Acuity (BCVA) Mean change in BCVA (ETDRS letters) at 12 months (primary outcome):
• Bimonthly: +7.0 (95% CI: 4.0 to 10.0)
• T&E: +6.7 (95% CI: 3.7 to 9.6)
• PRN: +7.3 (95% CI: 4.3 to 10.3) LS mean difference between T&E and PRN (95% CI): -1.74 (-5.86 to 2.37) LS mean difference between bimonthly and PRN (95% CI): 0.25 (-3.81 to 4.32) Vision Maintaining After 12 months of treatment, there were no significant differences between bimonthly, T&E, and PRN in the following: The proportion of patients achieving a BCVA ≥73 ETRDS letters (20/40 Snellen):
• Bimonthly: 46.1%
• T&E: 33.8%
• PRN: 42.1%
• Difference: p=0.279 The proportion of patients gaining ≥5 ETDRS letters:
• Bimonthly: 59.3%
• T&E: 59.1%
• PRN: 59.2%
• Difference: p=0.999 The proportion of patients gaining ≥10 ETDRS letters:
• Bimonthly: 42.9%
• T&E: 47.9%
• PRN: 46.1%
• Difference: p=0.807 The proportion of patients gaining ≥15 ETDRS letters:
• Bimonthly: 24.2%
• T&E: 23.9%
• PRN: 31.6%
• Difference: p=0.473 The proportion of patients gaining ≥30 ETDRS letters:
• Bimonthly: 5.5%
• T&E: 1.4%
• PRN: 3.9%
• Difference: p=0.436 The proportion of patients losing <5 ETDRS letters:
• Bimonthly: 12.1%
• T&E: 15.5%
• PRN: 10.5%
• Difference: p=0.666 The proportion of patients losing <10 ETDRS letters:
• Bimonthly: 6.6%
• T&E: 9.8%
• PRN: 5.3%
• Difference: p=0.567 The proportionof patients losing <15 ETDRS letters:
• Bimonthly: 5.5%
• T&E: 8.4%
• PRN: 3.9%.
• Difference: p=0.506
Other
Efficacy: Progression Outcome Atrophy The presence of atrophy at 12 months was unrelated to the presence or absence of PED at baseline (32.9% versus 35.3%, p = 0.682) Quality of Life (QoL) Vision-related QoL The overall mean (SD) score of the NEI VFL-25 from Baseline → Month 12:
• Bimonthly: 73.1 (20.5) → 76.7 (17.9)
• T&E: 76.1 (16.2) → 77.5 (17.9)
• PRN: 73.9 (18.4) → 76.6 (18.9)
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CSFT) The mean change (95% CI) in CST at 12 months:
• Bimonthly: -110.7 (-130.5 to -90.9) µm
• T&E: -132.4 (-160.2 to -104.7) µm
• PRN: -119.6 (-144.3 to -94.9) µm The LS mean difference between T&E and PRN (95% CI): -2.17 (-25.68 to 21.33) LS mean difference between bimonthly and PRN (95% CI): 9.44 (-12.36 to 31.26) Central Subfield Volume (CSV) The mean of CSV from Baseline → Month 12:
• Bimonthly: 9.8 → 8.6 µm
• T&E: 9.8 → 8.5 µm
• PRN: 9.9→ 8.5 µm The LS mean difference between T&E and PRN (95% CI): -2.17 (-25.68 to 21.33) The LS mean difference between bimonthly and PRN (95% CI): 9.44 (-12.36 to 31.26)
Safety
Ocular AEs Patients with ocular AEs:
• Bimonthly: 47.5%
• T&E: 34.7%
• PRN: 48.1% Patients with ocular AEs related to the study medications:
• Bimonthly: 10.9%
• T&E: 7.1%
• PRN: 11.5% The most common ocular AEs are allergic keratitis, Blepharitis, Cataract, Conjunctival hemorrhage, and Conjunctival hyperemia/conjunctivitis. Non-ocular AEs
• Systemic AEs included pneumonia, acute myocardial infarction, congestive heart failure, benign and malignant neoplasms, thrombocytopenia, meningitis, and pulmonary edema
• Only one case of congestive heart failure and hemorrhage was related to the study medication by the investigator. Death
• Five patients died
• Causes of death were cardiorespiratory failure in 2, acute pulmonary edema in 1, septic shock in 1, and myocardial infarction in 1.
Conclusion
The study confirmed that bimonthly and T&E ranibizumab regimens were non-inferior to PRN dosing in treatment-naïve nAMD patients. Bimonthly dosing required fewer visits, while T&E had the highest injection frequency. No major safety concerns were noted.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Patients were randomized by using a validated system by trial form support (TFS), the contract research organization (CRO)…” “Overall, patient demographics and baseline ocular characteristics were similar in the three study groups.”
Missing Outcome Data
Low risk
Note: the evidence that the primary outcome was not biased by the missingness (sensitivity analysis): “The primary efficacy variable (BCVA) and changes of CSFT and CSV were analysed in the intention to treat (ITT) and PP data sets.”
Selection of the Reported Results
Low risk Note: registration with the protocol
Deviations from Intended Observations
Some concerns Note: This is an open-label study. There is no evidence that the deviations arose due to the study context. “The primary efficacy variable (BCVA) and changes of CSFT and CSV were analysed in the intention to treat (ITT) and PP data sets.”
Measurement of the Outcome
Some concerns Note: This is an open-label study. There may ne diversity in BCVA assessment between different research sites. However, BCVA assessment should not be influenced by acknowledge of the intervention.
Overall
Some concerns
Categories: Wet AMD