Three-Month FVC Change: A Trial Endpoint for Idiopathic Pulmonary Fibrosis Based on Individual Participant Data Meta-analysis.

ABSTRACT

Rationale Novel therapies for idiopathic pulmonary fibrosis (IPF) are in development, but there remains uncertainty about the optimal trial endpoint. An earlier endpoint would enable assessment of a greater number of therapies in adaptive trial designs. Objectives: To determine whether short-term changes in FVC, DlCO, and six-minute-walk distance could act as surrogate endpoints to accelerate early-phase trials in IPF. Methods: Individual participant data (IPD) from IPF clinical trials were included in a two-step random-effects meta-analysis to determine whether baseline or 3-month changes in FVC, DlCO, and 6-minute-walk distance were associated with mortality or disease progression in placebo arms. Three-month and 12-month FVC decline endpoints were compared with treatment arm data from antifibrotic studies by meta-regression. Measurements and Main Results: IPD were available from 12 placebo cohorts totaling 1,819 participants, with baseline and 3-month changes in all physiological variables independently associated with poorer outcomes. Treatment data were available from six cohorts with 1,684 participants. For each 2.5% relative decline in FVC over 3 months, there was an associated 15% (adjusted hazard ratio, 1.15; 95% confidence interval [CI], 1.06-1.24; I2 = 59.4%) and 20% (adjusted hazard ratio, 1.20; 95% CI, 1.12-1.28; I2 = 18.0%) increased risk for mortality in untreated and treated individuals, respectively. An FVC change treatment effect was observed between treatment and placebo arms at 3 months (difference in FVC change of 42.9 ml; 95% CI, 24.0-61.8 ml; P < 0.001). Conclusions: IPD meta-analysis demonstrated that 3-month changes in physiological variables, particularly FVC, were associated with mortality among individuals with IPF. FVC change over 3 months may hold potential as a surrogate endpoint in IPF adaptive trials.