A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration
NCT03345082 | ONYX Trial | Jackson et al. (2023)_A Randomization
Jackson TL, Slakter J, Buyse M, et al. A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration. Ophthalmology, 2023; 130:588-597.
Locations
109 sites across Europe, Israel, and the United States
Study Period
December 1, 2017 – November 30, 2018
Study Design
Phase 2b, dose-ranging, randomized, double-masked, sham-controlled trial
Study Population
Experimental Group
Control Group
Follow-up Time: 24 weeks
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA)
BCVA change at Week 24 (Primary Outcome):
• 2.0 mg OPT-302: +14.2 letters (SD 11.61)
• Sham: +10.8 letters (SD 11.52)
• p-value: 0.01
BCVA change at Week 24 (0.5 mg group):
• 0.5 mg OPT-302: +9.44 letters (SD 11.32); p-value: 0.83.
Vision Maintaining
Proportion of patients gaining ≥15 letters:
• 2.0 mg OPT-302: 45.0%
• Sham: 40.5%
• 0.5 mg OPT-302: 33.0%
Proportion of patients gaining ≥10 letters:
• 2.0 mg OPT-302: 70.0%
• Sham: 57.8%
• 0.5 mg OPT-302: 55.4%
Proportion of patients gaining ≥5 letters:
• 2.0 mg OPT-302: 85.0%
• Sham: 75.9%
• 0.5 mg OPT-302: 71.4%
Proportion of patients losing ≥15 letters:
• 2.0 mg OPT-302: 0.8%
• Sham: 3.4%
• 0.5 mg OPT-302: 5.4%.
Other
Quality of Life (QoL)
The National Eye Institute 25-item Visual Function Questionnaire (VFQ-25) composite score
The mean of VFQ-25 composite score at Week 24:
• 2.0 mg OPT-302: 4.2± 8.88
• Sham: 3.10±10.82
• 0.5 mg OPT-302: 2.2 ±10.44
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CST)
CST reduction at Week 24:
• 2.0 mg OPT-302: -146.7 µm
• Sham: -133.8 µm
• 0.5 mg OPT-302: -147.8 µm.
Retinal Fluid
Subretinal fluid presence at Week 24:
• 2.0 mg OPT-302: 18.5%
• Sham: 29.3%
• 0.5 mg OPT-302: 23.2%.
Intraretinal Cysts
Intraretinal cysts presence at Week 24:
• 2.0 mg OPT-302: 16.8%
• Sham: 21.6%
• 0.5 mg OPT-302: 19.6%.
Choroidal Neovascularization (CNV)
Change in Choroidal Neovascularization (CNV) Area at Week 24:
• 2.0 mg OPT-302: -4.96 mm²
• Sham: -3.60 mm²
• 0.5 mg OPT-302: -4.45 mm²
Safety
Ocular AEs
Study eye AEs were similar across the 3 groups.
Most common ocular AEs: Eye pain, conjunctival hemorrhage, vitreous floaters, eye irritation.
Ocular AEs considered related to the injection procedure:
• 2.0 mg OPT-302: 29.8%
• Sham: 24.8%
• 0.5 mg OPT-302: 28.3%.
Ocular Serious AEs (study eye) There were 2 ocular serious AEs, endophthalmitis and vitritis, which were both in the 0.5mg OPT-302 group and considered potentially related to ranibizumab or 0.5 mg OPT-302
Discontinuation of the study
Two participants (0.5%) had study eye AEs leading to the discontinuation of the study product
Death
Two participants died, both in the sham group. Neither death was considered related to the study product.
Conclusion
The 2.0 mg OPT-302 + ranibizumab combination provided statistically superior BCVA gain over ranibizumab alone at 24 weeks, with a favorable safety profile. The 0.5 mg OPT-302 dose did not show a significant difference from sham.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Randomization was via an online interactive system (IXRS, Almac Clinical Technologies)”
“Baseline characteristics and attrition were well balanced across groups…”
Missing Outcome Data
Low risk
Note: the evidence that the first outcome data analysis was not biased by the missingness: “A mixed-effects model for repeated measures was used, which considered the presence of missing data and yielded valid estimates under the assumption of data missing at random.”
Selection of the Reported Results
Low risk Note: registration with protocol
Deviations from Intended Observations
Low risk Note: “Study participants, assessing clinicians, reading center graders (the Digital Angiography Reading Center, New York, NY), and other outcome assessors were masked.” “The primary analysis was the comparison of mean change in ETDRS BCVA between baseline and week 24 for each of the OPT-302 0.5 mg and 2.0 mg treatment groups, compared with sham, in the modified intent-to-treat (mITT) population.”
Measurement of the Outcome
Some concerns Note: “Study participants, assessing clinicians, reading center graders (the Digital Angiography Reading Center, New York, NY), and other outcome assessors were masked.” However, as a multiple-site study, the assessment of BCVA may exist diversity.
Overall
Some concerns
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