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Abstract
Introduction Temporary dose modifications, such as reductions or interruptions, may allow patients to better manage adverse events (AEs) associated with pirfenidone use and continue treatment for idiopathic pulmonary fibrosis (IPF). However, the impact of such dosing adjustments on efficacy and safety is uncertain.
Methods Patients randomised to receive treatment with pirfenidone 2403 mg/day or placebo in the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY (Study 004 (NCT00287716)) and Study 006 (NCT00287729))) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND (Study 016 (NCT01366209)) trials were included in the analysis (n=1247). Descriptive statistics and a linear mixed-effects model (slope analysis) for annual rate of decline in forced vital capacity (FVC) by dose intensity were performed. Treatment-emergent AEs (TEAEs) were summarised and grouped by dose intensity or body size.
Results Dose reductions and interruptions occurred in 76.9% (95% CI 73.4% to 80.1%) and 46.5% (95% CI 42.6% to 50.6%) of patients receiving pirfenidone vs 72.0% (95% CI 68.3% to 75.4%) and 31.1% (95% CI 27.5% to 34.9%) of patients receiving placebo, respectively. Dose interruptions tended to occur during the first 6 months of treatment, whereas dose reductions exhibited more variability. Less FVC decline from baseline was observed in patients receiving pirfenidone versus placebo at >90% dose intensity (p<0.001) or ≤90% dose intensity (p=0.0191), showing treatment benefit in both subgroups of dose intensity. No meaningful relationship between weight and TEAEs was observed.
Conclusion Dose interruptions, which may be required to manage TEAEs, mostly occurred during the first 6 months of treatment. Despite dose reductions and interruptions, most patients with IPF maintained relatively high dose intensity on pirfenidone, without compromising its treatment effect compared with placebo.
Trial registration numbers NCT00287729, NCT00287716, NCT01366209.
- interstitial fibrosis
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Footnotes
Contributors SDN, LHL, CA, MKG, JJS, FG, K-UK, SLL, UP and PWN contributed to the conception and design of the original studies, as well as acquisition and interpretation of the data. The manuscript was critically reviewed and approved by all authors.
Funding This manuscript was sponsored by F. Hoffmann-La Roche, Ltd., and Genentech, Inc.
Competing interests SDN was a member of the ASCEND study steering committee. He has been a consultant for Genentech/Roche, served on speakers’ bureaus for Genentech/Roche and Boehringer Ingelheim and has received research funding from Genentech/Roche and Boehringer Ingelheim. LHL was a member of the ASCEND study steering committee; she has served as a consultant and on scientific advisory boards for Boehringer Ingelheim, InterMune, Genentech and Veracyte. LHL has participated as a clinical trial investigator for Boehringer Ingelheim, Genentech, Stromedix, Gilead, Afferent, FibroGen, Bayer, Celgene and Veracyte. CA was a member of the CAPACITY study steering committee; he has served on a scientific advisory board for InterMune. CA has served as a consultant, steering committee member and speaker for Roche, FibroGen and Boehringer Ingelheim. MKG was a member of the ASCEND study steering committee. JJS was a member of the ASCEND study steering committee; he has served on a scientific advisory board and received research funding from InterMune. JJS served as a consultant to Boehringer Ingelheim and Roche, and has received honoraria from Genentech. UP is an employee of Clinipace Worldwide. PWN was a member of the ASCEND study steering committee and the CAPACITY study steering committee; he has served as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, InterMune, Moerae Matrix, Roche and Takeda. FG and K-UK are employees of F. Hoffmann-La Roche, Ltd., and K-UK is a shareholder. SLL is an employee of Genentech.
Patient consent Obtained.
Ethics approval This study was conducted in full conformance with the Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. Approval was obtained from all ethics committees/independent review boards at each study site.
Provenance and peer review Not commissioned; internally peer reviewed.
Data sharing statement Qualified researchers may request access to individual patient-level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche’s criteria for eligible studies are available at https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.