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

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.