Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND

Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

METHODS

TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871.

FINDINGS

From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths.

INTERPRETATION

Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials.

FUNDING

Genentech.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests SKD reports grants and salary support from Brigham and Women's Hospital, during the study; grants, personal fees, and non-financial support from Boehringer Ingelheim; personal fees and non-financial support from Galaplagos; personal fees from Galecto, and Lupin Pharma; grants from Bristol Meyers Squibb; salary support from the Pulmonary Fibrosis Foundation, and Royalties for Topics on systemic erythematous pneumonia- interstitial lung disease and myositis- interstitial lung disease from UpToDate, outside the submitted work. IG reports personal fees from Boehringer Ingelheim and personal fees from Ad Alta, Amplia, Accendatech, and Lassen, outside the submitted work. PFD served on an unpaid advisory committee at Boehringer Ingleheim, and reports receiving non-financial support for serving as a site-principal investigator for Bristol Myers and Genentech, outside the submitted work. RV reports grants from Bristol Myers Squibb, Pfizer, and Sun Pharma, outside the submitted work. PGC reports grants from InterMune, outside the submitted work. KRF reports grants and personal fees from Boehringer Ingelheim; personal fees from Roche/Genentech, Bellerophon, Respivant, Shionogi, DevPro, AstraZeneca, Pure Health, Horizon, Fibrogen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean, Pure Tech, Trevi Pharmaceuticals, CSL Behring, Daewong, DevPro, Dispersol, Immumet, and NeRRe Therapeutics, outside the submitted work. LT reports personal fees from Boehringer Ingelheim outside the submitted work. MBS reports grants from Boehringer Ingelheim, Veracyte, and Genentech; financial support from Genentech, United Therapeutics, Veracyte; honoraria from Boehringer Ingelheim, United Therapeutics, and Veracyte, and meeting and travel support from Genentech and the American College of Chest Physicians. NC reports personal fees from Boehringer Ingelheim, Redex, Novartis, Liminal Biosciences, Vicor Pharma, Bridge Biotherapeutics, and Roche, outside the submitted work. DAL reports grants from Boehringer Ingelheim and grants and personal fees from Calyx, outside the submitted work; DAL has a patent issued on systems and methods for automatic detection and quantification of pathology using dynamic feature classification (US10706533B2). DCC reports that Roche/Genentech provided the investigational medicinal product free of charge during the study; and that he served as principal investigator for a trial site in a Roche sponsored study outside the submitted work, in which per patient fees were paid to the site. MK reports grants from Genentech, during the study; grants from Canadian Pulmonary Fibrosis Foundation and Canadian Institute for Health Research; an allowance as chief editor from European Respiratory Journal; grants and personal fees from Boehringer Ingelheim and Roche Canada; and personal fees from Horizon, Algernon, CSL Behring, and DevPro; and served as a site principal investigator for industry sponsored clinical trials (Roche and Boehringer Ingelheim); outside the submitted work. GR served as a consultant/steering committee member for IPF and PPF studies for Roche/Genentech and served on a data safety monitoring board for an IPF study (Avalyn), outside the submitted work. HJG reports receiving support to participate as a member of the Clinical Coordinating Center and coprincipal investigator, from Genentech, during the study. FAW is currently an employee at Avalyn. IOR reports grants from Genentech/Roche, during the conduct of the study and personal fees from Genentech/Roche, Boehringer Ingelheim, and Immunomet, outside the submitted work. All other authors declare no competing interests.