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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

  • Joshua J. SolomonEmail author
  • Sonye K. Danoff
  • Hilary J. Goldberg
  • Felix Woodhead
  • Martin Kolb
  • Daniel C. Chambers
  • Donna DiFranco
  • Cathy Spino
  • Shana Haynes-Harp
  • Shelley Hurwitz
  • Elizabeth B. Peters
  • Paul F. Dellaripa
  • Ivan O. Rosas
  • on behalf of the Trail Network
Study Protocol

Abstract

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.

Keywords

Pirfenidone Rheumatoid Pulmonary Fibrosis Interstitial Arthritis 

Notes

Acknowledgements

Participants

We would like to thank the participants of this study.

Trial Funding

The trial and article processing charges are funded by Genentech, a member of the Roche Group. The trial sponsor has no role in study design; collection, management, analysis, and interpretation of data.

Trial Registration

The trial is registered with Clinicaltrials.gov, identifier NCT02808871.

Authorship

All named authors meet the International Committee of Medical Journal. Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

JJS, SKD, HJG, CS, SH, PFD and IOS contributed to the conception and design of the study and developed the study protocol, JJS, FW, MK and DCC are responsible for the recruitment of subjects, DD, SHH and EBP are responsible for the management of the trial and DD, CS and SH are responsible for collection and analysis of the data. All authors contributed to modification of the original protocol and all authors read and approved the final manuscript.

Disclosures

JJS receives research support for unrelated studies from Pfizer and Boehringer Ingelheim. MK reports grants from Roche-Genentech, Roche, Boehringer Ingelheim, GSK, Gilead, Actelion, Respivert, Alkermes, Pharmaxis, and Prometic. MK reports personal fees from Roche, Boehringer Ingelheim, GS, Gilead, Genoa, Prometic, Indalo and Third Pole. DCC receives honorarium and grants for research from Roche. PFD receives research support for unrelated studies from Genentech and Bristol-Myers Squibb. SKD, HJG, FW, DD, CS, SHH, SH, EBP and IOR report no conflict of interest.

Compliance with Ethics Guidelines and dissemination

This trial is designed in accordance with the Standard Protocol Items for Clinical Trials (SPIRIT) 2013 statement and will be carried out in compliance with the ethical principles of the Declaration of Helsinki. All documents are initially approved by the institutional review board (IRB) at the sponsor site (BWH) and then by the individual IRBs or competent authorities at the individual sites. Written informed consent will be obtained from all participants before any study-related procedures are implemented. When available, the results will be published in an international peer-reviewed journal.

Supplementary material

12325_2019_1086_MOESM1_ESM.pdf (128 kb)
Supplementary material 1 (PDF 128 kb)

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Copyright information

© Springer Healthcare Ltd., part of Springer Nature 2019

Authors and Affiliations

  • Joshua J. Solomon
    • 1
    Email author
  • Sonye K. Danoff
    • 2
  • Hilary J. Goldberg
    • 3
  • Felix Woodhead
    • 4
  • Martin Kolb
    • 5
  • Daniel C. Chambers
    • 6
  • Donna DiFranco
    • 7
  • Cathy Spino
    • 7
  • Shana Haynes-Harp
    • 3
  • Shelley Hurwitz
    • 3
  • Elizabeth B. Peters
    • 3
  • Paul F. Dellaripa
    • 3
  • Ivan O. Rosas
    • 3
  • on behalf of the Trail Network
  1. 1.National Jewish HealthDenverUSA
  2. 2.Johns HopkinsBaltimoreUSA
  3. 3.Brigham and Women’s HospitalBostonUSA
  4. 4.University of LeicesterLeicesterUK
  5. 5.McMaster UniversityHamiltonCanada
  6. 6.University of QueenslandBrisbaneAustralia
  7. 7.School of Public HealthUniversity of MichiganAnn ArborUSA

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