Three month FVC change: a potential trial endpoint for IPF based on individual participant data meta-analysis

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 Individual participant data (IPD) from placebo arms of interventional trials were sought to determine whether short-term changes in forced vital capacity (FVC), gas transfer for carbon monoxide (DLCO) and six-minute walk distance (6MWD) could act as surrogate endpoints to accelerate early-phase trials in IPF. Methods Electronic databases were searched on 1st December 2020, and IPD were sought and meta-analysed. The primary outcome was overall mortality according to baseline and/or three-month change in either FVC, DLCO or 6MWD, with a secondary outcome of disease progression at 12 months, adjusted for age, sex, smoking status and baseline physiology. Measurements and main results IPD was available for 10/23 eligible studies totalling 1819 participants. Baseline and three-month change in all physiological variables were independently associated with disease outcomes. A 2.5% relative decline in FVC over three months was associated with mortality (adjusted hazard ratio 1.14, 95%CI 1.06;1.24, I2 = 59.9%) and disease progression (adjusted odds ratio 1.29; 95%CI 1.18;1.40, I2=67%). Optimal thresholds for three-month change in FVC for distinguishing disease outcomes were identified. Conclusions IPD meta-analysis of trial placebo arms demonstrated three-month change in physiological variables, particularly FVC, were associated with mortality and disease progression among individuals with untreated IPF. FVC change over three months may hold potential as a surrogate endpoint in IPF interventional adaptive trials.