Improving the Feasibility of Glaucoma Clinical Trials With Trend-Based Analysis of Visual Field Change Between Groups as an Endpoint

Abstract

Purpose : As glaucoma is often a slowly progressive disease, there have been concerns about the feasibility of short-term clinical trials evaluating new treatments for this disease, as the required sample size could be prohibitively large. The United Kingdom Glaucoma Treatment Study has shown that differences between a new treatment and placebo can be demonstrated with relatively short follow-up. However, as the effect size between new and existing treatments are likely smaller, a correspondingly larger sample size for short-term trials would be required. This study sought to determine the required sample size for such short-term trials using visual field event-based endpoints, and whether it can be reduced using trend-based analysis.

Methods : Sample sizes were determined by running computer simulations reconstructing 24-2 visual field results over time, after extracting real-world estimates of point-wise variability according to different threshold levels and rates of change from a cohort of 321 eyes of 240 glaucoma participants followed under routine clinical care for a mean of 10 years. “Real-world” visual fields were reconstructed in a similar manner described by Russell et al (PLoS ONE, 2013). 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: a) Difference in the incidence of point-wise event-based progression (similar to the commercially available Guided Progression Analysis) and b) Difference in rate of visual field mean deviation (MD) change between groups using linear mixed models.

Results : 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 MD rate of change) with 90% power for example, 1924 participants would be required per group using event-based analysis, but only 240 participants per group if linear mixed models were used. A plot of the power to detect against the sample size in each group is shown in the Figure (grey and black respectively for the two methods).

Conclusions : Feasibility of future glaucoma clinical trials can be substantially improved by evaluating differences in the rate of visual field change between groups.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.