Dose modification and dose intensity during treatment with pirfenidone: analysis of pooled data from three multinational phase III trials

Steven D Nathan; Lisa H Lancaster; Carlo Albera; Marilyn K Glassberg; Jeffrey J Swigris; Frank Gilberg; Klaus-Uwe Kirchgaessler; Susan L Limb; Ute Petzinger; Paul W Noble

doi:10.1136/bmjresp-2018-000323

Dose modification and dose intensity during treatment with pirfenidone: analysis of pooled data from three multinational phase III trials

BMJ Open Respir Res. 2018 Aug 2;5(1):e000323. doi: 10.1136/bmjresp-2018-000323. eCollection 2018.

Authors

Affiliations

¹ Inova Fairfax Hospital, Falls Church, Virginia, USA.
² Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ University of Turin, Orbassano, Turin, Italy.
⁴ Miller School of Medicine, University of Miami, Miami, Florida, USA.
⁵ Interstitial Lung Disease Program, National Jewish Health, Denver, Colorado, USA.
⁶ F. Hoffmann-La Roche Ltd., Basel, Switzerland.
⁷ Genentech, South San Francisco, California, USA.
⁸ Accovion, Eschborn, Hessen, Germany.
⁹ Cedars-Sinai Medical Center, Los Angeles, California, USA.

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.

Keywords: interstitial fibrosis.

Associated data

ClinicalTrials.gov/NCT01366209
ClinicalTrials.gov/NCT00287729
ClinicalTrials.gov/NCT00287716