Randomized Phase IIb Study of Brimonidine Drug Delivery System Generation 2 for Geographic Atrophy in Age-Related Macular Degeneration
NCT02087085 | BEACON | Freeman et al. (2023)
Freeman WR, Bandello F, Souied E, et al. Randomized Phase IIb Study of Brimonidine Drug Delivery System Generation 2 for Geographic Atrophy in Age-Related Macular Degeneration. Ophthalmology Retina, 2023; 7:573-585.
Locations
41 centers across the United States, Europe, and Australia
Study Period
May 2014 – March 2018
Study Design
Randomized, double-masked, multicenter, sham-controlled Phase IIb trial
Study Population
Experimental Group
Control Group
Follow-up Time: 30 months (The study was terminated early by the study sponsor due to the slow progression rate (~1.6 mm2/year) in the enrolled population)
Outcomes
Durability
Not reported.
Vision
Retinal Sensitivity
Brimo DDS: Less loss than sham; p-value: 0.053 at Month 24.
Best-Corrected Visual Acuity (BCVA)
• Standard BCVA in the study eye decreased progressively in both treatment groups throughout the study (~2 to 3 lines of vision loss by month 30).
• Treatment with Brimo DDS did not slow the progression of vision loss
Low-luminance BCVA
• Low-luminance BCVA in the study eye decreased progressively during the study in both treatment groups (~ 2 lines of vision loss by month 30), with no effect of Brimo DDS treatment on this measure.
Other
Efficacy: Progression Outcomes
Geographic Atrophy (GA)
The GA lesion area reduced at Month 24 (Primary Outcome):
• Brimo DDS: +3.24 mm² (SE 0.13)
• Sham: +3.48 mm² (SE 0.13)
• Difference: -0.25 mm² (7% reduction); p-value= 0.150
The GA lesion area reduced at Month 30:
• Brimo DDS: +4.09 mm² (SE 0.15)
• Sham: +4.52 mm² (SE 0.15)
• Difference: -0.43 mm² (10% reduction); p-value= 0.033
The effective radius of the GA lesion change from baseline to Month 30:
• Brimo DDS: -0.034 mm (9%) vs. Sham at Month 24; p-value: 0.07.
For patients with baseline GA lesion area ≥4.5 mm², the GA lesion area reduced:
• Brimo DDS: -0.30 mm² (7%) at Month 24, -0.49 mm² (9%) at Month 30.
Immunognicity
Not reported.
Pharmokinetics
Plasma brimonidine concentrations were quantifiable but remained low throughout the study.
Anatomic
Not reported.
Safety
AEs
Patients with any AE:
• Brimo DDS: 123 (79.9%)
• Sham: 126 (80.8%)
Patients with ocular AEs:
• Brimo DDS: 96 (62.3%)
• Sham: 71 (45.5%)
Patients with nonocular AEs:
• Brimo DDS: 93 (60.4%)
• Sham: 107 (68.6%)
Treatment-Related AE (TRAEs)
Patients with ocular TRAEs:
• Brimo DDS: 67 (43.5%)
• Sham: 24 (15.4%)
Patients with nonocular TRAEs:
• Brimo DDS: 4 (2.6%)
• Sham: 2 (1.3%)
Serious AEs (SAEs)
Patients with any SAEs:
• Brimo DDS: 48 (31.2%)
• Sham: 37 (23.7%)
Patients with ocular SAEs:
• Brimo DDS: 7 (4.5%)
• Sham: 2 (1.3%)
Patients with nonocular SAEs:
• Brimo DDS: 44 (28.6%)
• Sham: 35 (22.4%)
Discontinuation due to AE
• Brimo DDS: 10 (6.5%)
• Sham: 14 (9.0%)
Death
• Brimo DDS: 5 (3.2%)
• Sham: 6 (3.8%)
Conclusion
Brimonidine DDS (Gen 2) was well tolerated, but the primary efficacy endpoint at 24 months was not met. The study showed a trend toward GA reduction at Month 30 but was terminated early due to a lower-than-expected GA progression rate in the control group.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “The randomization scheme was computer-generated and provided by the study sponsor, and an automated interactive voice response system/interactive web response system was used to manage the treatment assignments.”
“Baseline demographics and disease characteristics were well balanced between the treatment groups”
Missing Outcome Data
High risk
The study was terminated early
Selection of the Reported Results
Low risk Note: registration with the Protocol.
Deviations from Intended Observations
Low risk Note: “Patients, investigators who performed ocular assessments, study personnel involved in the collection of efficacy data, and the CRC personnel were masked to the study treatment assignment.” “Efficacy outcomes were evaluated in the modified intent-to-treat population…”
Measurement of the Outcome
Low risk Note: “Patients, investigators who performed ocular assessments, study personnel involved in the collection of efficacy data, and the CRC personnel were masked to the study treatment assignment.” “…assessed with fundus autofluorescence (FAF) at screening and confirmed by the central reading center (CRC)…”
Overall
High risk
Categories: Dry AMD Geographic Atrophy