Abstract
Background Little is known about generalisability of randomised controlled trials (RCTs) for idiopathic pulmonary fibrosis (IPF). We evaluated eligibility criteria for phase III IPF RCTs to determine their representativeness in clinical registries, and calculated forced vital capacity (FVC) changes according to eligibility criteria.
Methods Common eligibility criteria used in >60% of IPF RCTs were identified from a literature search and applied to patients with IPF from prospective Australian and Canadian registries. Additional pre-specified criteria of 6-min walk distance (6MWD) and different measures of preceding disease progression were also evaluated. Joint longitudinal-survival modelling was used to compare FVC decline according to eligibility for individual and composite criteria.
Results Out of 990 patients with IPF, 527 (53%) met all common RCT eligibility criteria at the first clinic visit, including 343 with definite IPF and 184 with radiological probable usual interstitial pneumonia pattern without histological confirmation (i.e. provisional IPF). The percentages of eligible patients for landmark RCTs of nintedanib and pirfenidone were 19–50%. Adding 6MWD ≥150 m and different measures of preceding disease progression to the composite common criteria reduced the percentages of patients meeting eligibility to 52% (n=516) and 4–18% (n=12–61), respectively. Patients meeting the composite common criteria had less-rapid 1-year FVC decline than those who did not (−90 versus −103 mL, p=0.01). Definite IPF generally had more-rapid 1-year FVC decline compared to provisional IPF.
Conclusions Eligibility criteria of previous IPF RCTs have limited generalisability to clinical IPF populations, with FVC decline differing between eligible and ineligible populations.
Abstract
Phase III RCTs in IPF have restrictive eligibility criteria, with differing FVC decline between trial eligible and ineligible populations. Findings from IPF RCTs should be extrapolated with caution given the low external validity. https://bit.ly/3lJmCZ1
Footnotes
The other investigators in the Austin ILD Registry and CARE-PF Investigators group are: Gerard Cox (Department of Medicine, McMaster University, Hamilton, Canada), Charlene D. Fell (Department of Medicine, University of Calgary, Calgary, Canada), Andrea S. Gershon (Department of Medicine, University of Toronto, Toronto, ON, Canada), Nicole Goh (Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia), Andrew J. Halayko (Department of Internal Medicine, University of Manitoba, Winnipeg, Canada), Stacey Lok (Department of Medicine, University of Saskatchewan, Saskatoon, Canada), Julie Morisset (Département de Médecine, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada), Mohsen Sadatsafavi (Department of Medicine, University of British Columbia, Vancouver, BC, Canada), Shane Shapera (Department of Medicine, University of Toronto, Toronto, ON, Canada), Teresa To (Department of Medicine, University of Toronto, Toronto, ON, Canada), Pearce G. Wilcox (Department of Medicine, University of British Columbia, Vancouver, BC, Canada), Alyson W. Wong (Department of Medicine, University of British Columbia, Vancouver, BC, Canada).
Conflict of interest: Y.H. Khor reports fellowship support from NHMRC Investigator Grant, and support for the CARE-PF registry (with no influence on this study) from Boehringer Ingelheim, during the conduct of the study. K.A. Johannson reports personal fees, non-financial support and other from Boehringer Ingelheim, personal fees from Hoffman-La Roche Ltd, Pliant Therapeutics and Thyron, grants from University Hospital Foundation, Pulmonary Fibrosis Society of Calgary and University of Calgary Cumming School of Medicine, and personal fees and non-financial support from Three Lakes Foundation, outside the submitted work. V. Marcoux reports grants from Boehringer Ingelheim, during the conduct of the study; grants from University of British Columbia and Boehringer Ingelheim, outside the submitted work. J.H. Fisher reports grants from Boehringer Ingelheim, during the conduct of the study; grants from Canadian Pulmonary Fibrosis Foundation and University of Toronto, and personal fees from Boehringer Ingelheim and AstraZeneca, outside the submitted work. D. Assayag reports grants from Boehringer Ingelheim Canada, and lecture honoraria from Boehringer Ingelheim and Hoffman La Roche, outside the submitted work. H. Manganas reports support for the present manuscript from University of British Columbia; grants from Boehringer Ingelheim Canada, Hoffmann La Roche, Galapagos and BMS, honoraria for educational events from Boehringer Ingelheim Canada, and advisory board membership for Boehringer Ingelheim Canada, outside the submitted work. M. Kolb reports grants from Boehringer Ingelheim, Pieris and Roche, consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, Abbvie, Bellerophon, Algernon, CSL Behring, United Therapeutics and LabCorp, lecture honoraria from Roche, Novartis and Boehringer Ingelheim, payment for expert testimony from Roche, advisory board participation with United Therapeutics and LabCorp, and reports an editorial allowance from ERJ, outside the submitted work. C.J. Ryerson reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, and personal fees from Veracyte, Pliant Therapeutics, AstraZeneca and Cipla Ltd, outside the submitted work. All other authors have nothing to disclose.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00346-2023
Support statement: Y.H. Khor received fellowship support from the National Health and Medical Research Council Investigator Grant (ID: 2008255). The Canadian Registry for Pulmonary Fibrosis (CARE-PF) is funded by Boehringer Ingelheim, which had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 10, 2022.
- Accepted February 8, 2023.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org