Phase 2 Study of the Safety and Efficacy of Brimonidine Drug Delivery System (Brimo DDS) Generation 1 in Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration
NCT00658619 | Not reported | Kuppermann BD et al. (2021)
Kuppermann, B. D., Patel, S. S., Boyer, D. S., Augustin, A. J., Freeman, W. R., Kerr, K. J., Guo, Q., Schneider, S., López, F. J. Phase 2 Study of the Safety and Efficacy of Brimonidine Drug Delivery System (Brimo DDS) Generation 1 in Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration. Retina, 2021; 41(1):144–155.
Locations
25 sites in 7 countries
Study Period
Not reported
Study Design
Phase 2, randomized, multicenter, double-masked, sham-controlled trial
Study Population
Experimental Group
Control Group
Follow-up Time: 24 months
Outcomes
Durability
Not reported
Vision
BCVA Change
No consistent improvement or worsening over time; no meaningful differences between groups.
Other
Efficacy: Progression Outcomes
Geographic Atrophy (GA)
The mean change in GA lesion area from baseline at Month 12 in study eye:
• Brimo DDS 132 mg = 1.78 (SEM 0.20) mm² (study eye) and 1.92 mm2 (fellow eye)
• Brimo DDS 264 mg = 1.59 (SEM 0.22) mm² and 1.47 mm2 (fellow eye)
• Sham = 2.19 mm² and 1.88 (SEM 0.46) mm2 (fellow eye)
• The mean change in GA lesion area from baseline was statistically significant (P ≤ 0.002) at all follow-up visit
Reduction in GA growth rate compared to sham:
• Brimo DDS 132 mg = 19%
• Brimo DDS 264 mg = 28%
• Statistically significant differences at Month 3 (p ≤ 0.032), but not at Month 12
At Month 3, the growth in GA lesion area was significantly smaller in the Brimo DDS 132-mg group (P = 0.032) and the Brimo DDS 264-mg group (P = 0.028) compared with the sham group
The subsequent time points through Month 24, the mean values for growth in GA lesion area were consistently lower in both Brimo DDS groups than in the sham group, but the differences were not statistically significant.
Factors related to GA Growth
The baseline GA lesion area and the change from baseline in GA lesion area at Month 12:
• Brimo DDS 132 mg: The Spearman correlation coefficient=0.279 (P = 0.089)
• Brimo DDS 264 mg: The Spearman correlation coefficient=0.161 (P = 0.395)
• Sham: The Spearman correlation coefficient= 0.699 (P < 0.001)
In patients with baseline GA area ≥6 mm², the mean GA lesion growth at Month 12 was reduced by:
• 32% (Brimo DDS 132 mg)
• 36% (Brimo DDS 264 mg)
• Compared to sham (p ≤ 0.040).
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Not reported
Safety
AEs
Patients with any AE:
• Brimo DDS 132 mg: 44 (91.7%)
• Brimo DDS 264 mg: 35 (87.5%)
• Sham: 20 (87.0%)
Patients with ocular AEs:
• Brimo DDS 132 mg=37 (77.1%)
• Brimo DDS 264 mg: 31 (77.5%)
• Sham: 12 (52.2%)
Patients with nonocular AEs:
• Brimo DDS 132 mg=29 (60.4%)
• Brimo DDS 264 mg: 28 (70.0%)
• Sham: 18 (78.3%)
Ocular AEs
Conjunctival hemorrhage:
• Brimo DDS 132 mg: 22 (45.8%)
• Brimo DDS 264 mg: 11 (27.5%)
• Sham: 2 (8.7%)
Conjunctival hyperemia:
• Brimo DDS 132 mg: 8 (16.7%)
• Brimo DDS 264 mg: 3 (7.5%)
• Sham: 3 (13.0%)
Retinal hemorrhage:
• Brimo DDS 132 mg: 6 (12.5%)
• Brimo DDS 264 mg: 4 (10.0%)
• Sham: 2 (8.7%)
Cataract:
• Brimo DDS 132 mg: 3 (6.3%)
• Brimo DDS 264 mg: 3 (7.5%)
• Sham: 2 (8.7%)
Punctate keratitis:
• Brimo DDS 132 mg: 1 (2.1%)
• Brimo DDS 264 mg: 6 (15.0%)
• Sham: 1 (4.3%)
Visual acuity reduced:
• Brimo DDS 132 mg: 3 (6.3%)
• Brimo DDS 264 mg: 3 (7.5%)
• Sham: 1 (4.3%)
Vitreous detachment:
• Brimo DDS 132 mg: 3 (6.3%)
• Brimo DDS 264 mg: 2 (5.0%)
• Sham: 2 (8.7%)
Eye pain:
• Brimo DDS 132 mg: 0
• Brimo DDS 264 mg: 5 (12.5%)
• Sham: 1 (4.3%)
Vitreous floaters:
• Brimo DDS 132 mg: 2 (4.2%)
• Brimo DDS 264 mg: 4 (10.0%)
• Sham: 0
Choroidal neovascularization:
• Brimo DDS 132 mg: 3 (6.3%)
• Brimo DDS 264 mg: 1 (2.5%)
• Sham: 0
Macular degeneration:
• Brimo DDS 132 mg: 1 (2.1%)
• Brimo DDS 264 mg: 3 (7.5%)
• Sham: 0
Vitreous hemorrhage:
• Brimo DDS 132 mg: 2 (4.2%)
• Brimo DDS 264 mg: 2 (5.0%)
• Sham: 0
Corneal edema:
• Brimo DDS 132 mg: 0
• Brimo DDS 264 mg: 2 (5.0%)
• Sham: 1 (4.3%)
Posterior capsule opacification:
• Brimo DDS 132 mg: 0
• Brimo DDS 264 mg: 3 (7.5%)
• Sham: 0
Blepharitis:
• Brimo DDS 132 mg: 2 (4.2%)
• Brimo DDS 264 mg: 0
• Sham: 0
Conjunctival edema:
• Brimo DDS 132 mg: 0
• Brimo DDS 264 mg: 2 (5.0%)
• Sham: 0
Eyelids pruritus:
• Brimo DDS 132 mg: 0
• Brimo DDS 264 mg: 2 (5.0%)
• Sham: 0
Non-ocular AEs
No significant differences across treatment groups; most common non-ocular AE was systemic cardiovascular events.
Serious AEs
The only serious adverse event considered by the investigator to be potentially related to treatment was a severe decrease in visual acuity (from 20/50 to 20/250) in the study eye of a patient in the Brimo DDS 264-mg group.
Death
None were considered to be related to the study treatment:
• Brimo DDS 132 mg: 4
• Brimo DDS 264 mg: 4
• Sham: 1
Treatment-emergent AEs (TEAEs)
Patients with any TEAE:
• Brimo DDS 132 mg: 19 (39.6%)
• Brimo DDS 264 mg: 11 (27.5%)
• Sham: 2 (8.7%)
Patients with ocular TEAEs:
• Brimo DDS 132 mg: 19 (39.6%)
• Brimo DDS 264 mg: 11 (27.5%)
• Sham: 2 (8.7%)
Patients with nonocular TEAEs:
• Brimo DDS 132 mg: 0
• Brimo DDS 264 mg: 0
• Sham: 0
Conclusion
Brimo DDS was well tolerated and showed a trend toward reducing GA progression, particularly in larger baseline lesions. Although statistical significance was not reached at Month 12, the results support further investigation in Phase 3 trials.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Some concerns
Note: There is no information on the method of the allocation concealment. However, “Baseline demographic and study eye characteristics were similar across treatment groups (Table 1).”
Missing Outcome Data
Low risk
Note: The evidence that the result was not biased by missing outcome data: “A sensitivity analysis was conducted using the square root transformation strategy14 to evaluate growth of GA lesion area in study eyes”
Selection of the Reported Results
Low risk Note: Registration with the protocol.
Deviations from Intended Observations
Low risk Note: This is a double-masked study. ITT principle was applied for the primary outcome analysis.
Measurement of the Outcome
Low risk Note: This is a double-masked study. The primary efficacy measure was the change in the GA lesion area, based on stereoscopic fundus photography, as measured from digital images by the central reading center (Doheny Image Reading Center, Los Angeles, CA).
Overall
Some concerns
Categories: Dry AMD Geographic Atrophy