The Design and Rationale of the Trail1 Trial: A Randomized Double-Blind Phase 2 Clinical Trial of Pirfenidone in Rheumatoid Arthritis-Associated Interstitial Lung Disease

Introduction: Rheumatoid arthritis (RA) is the most common of the connective tissue diseases (CTD), affecting up to 0.75% of the United States (U.S.) population with an increasing prevalence. Interstitial lung disease is prevalent and morbid condition in RA (RA-ILD), affecting up to 60% of patients with RA, leading to premature death in 10% and accruing an average of US$170,000 in healthcare costs per patient over a 5-year period. Although there have been significant advances in the management of this joint disease, there are no ongoing randomized clinical trials looking at pharmacologic treatments for RA-ILD, and there currently are no U.S. Food and Drug Administration-approved drugs for RA-ILD. Methods/Design: We describe the Treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRAIL1) trial, a multicenter randomized, double-blind, placebo-controlled, phase 2 study of the safety, tolerability and efficacy of pirfenidone in patients with RA-ILD. The study will enroll approximately 270 subjects across a network of sites who have RA and ILD as defined by a fibrotic abnormality involving greater than 10% of the lung parenchyma. The primary endpoint of the study is the incidence of the composite endpoint of decline in percent predicted forced vital capacity of 10 or greater or death during the 52-week study period. A number of secondary and exploratory endpoints have been chosen to evaluate the safety and efficacy in different domains. Discussion: The TRAIL1 trial is designed to evaluate the safety and efficacy of pirfenidone in RA-ILD, a disease with significant impact on patients’ quality of life and outcome. In addition to investigating the safety and efficacy of pirfenidone, this trial looks at a number of exploratory endpoints in an effort to better understand the impact of therapy on areas such as changes in quantitative high-resolution computed tomography scores and a patient’s quality of life. Biospecimens will be collected in order to investigate biomarkers that could potentially predict the subtype of disease, its behavior over time, and its response to therapy. Finally, by creating a network of institutions and clinician investigators with an interest in RA-ILD, this trial will pave the way for future studies of investigational agents in an effort to reduce or eliminate the burden of disease for those suffering from RA-ILD. Trial Funding: Genentech, a member of the Roche Group. Trial Registration: Clinicaltrials.gov, identifier NCT02808871.