Improving the Feasibility of Glaucoma Clinical Trials Using Trend-Based Visual Field Progression End Points

Purpose: There have been concerns that short-term clinical trials for evaluating new treatments in glaucoma would require prohibitively large sample sizes when using visual field end points, given that glaucoma often is a slowly progressing disease. This study sought to determine the required sample size for such trials using event-based analyses and whether it can be reduced using trend-based analyses. Design: Longitudinal, observational study. Participants: Three hundred twenty-one eyes of 240 glaucoma participants followed up under routine clinical care using 24-2 visual field testing for an average of 10 years. Methods: Sample size requirements were derived using computer simulations that reconstructed real-world visual fields by combining estimates of pointwise variability according to different threshold levels and rates of change obtained from the clinical glaucoma cohort. A clinical trial lasting 2 years with testing every 3 months was simulated, assuming that the new treatment halted visual field change in various percentages of participants (or “responders”). Treatment efficacy was evaluated by: (1) difference in incidence of pointwise event-based progression (similar to the commercially available Guided Progression Analysis; Carl Zeiss Meditec, Dublin, CA) and (2) difference in rate of visual field mean deviation (MD) change between groups using linear mixed models (LMMs). Main Outcome Measures: Sample size to detect a statistically significance difference between groups. Results: Between-group trend-based analyses using LMMs reduced sample size requirements by 85% to 90% across the range of new treatment effects when compared with the conventional pointwise event-based analysis. For example, to detect the effect of a new treatment that halted progression in 30% of the participants under routine clinical care (equal to a 30% reduction in average rate of MD change) with 90% power, 1924 participants would be required per group using event-based analysis, but only 277 participants would be required per group if LMMs were used. Conclusions: The feasibility of future glaucoma clinical trials can be improved substantially by evaluating differences in the rate of visual field change between groups.