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

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.

Conflict of interest statement

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.

Figures

Figure 1

Distribution of any dose reductions over time by treatment. Percentages are based on the total number of dose reductions until 12 months within the respective treatment arm. Based on actual dose, modified intention-to-treat population.

Figure 2

Kaplan-Meier analysis for time to first dose reduction in pirfenidone and placebo groups (based on actual dose).

Figure 3

Distribution of any dose interruptions over time by treatment. Percentages are based on the total number of dose interruptions until 12 months within the respective treatment arm. Based on actual dose, modified intention-to-treat population.

Figure 4

Kaplan-Meier analysis for time to first dose interruption in pirfenidone and placebo groups (based on actual dose).

Figure 5

Modelled mean (SEM) observed forced vital capacity (FVC) volume change from baseline (mL) over time by dose intensity (>90%, ≤90%), based on actual dose (modified intention-to-treat population). No imputation for missing values and deaths. Months 3, 6, 9 and 12 correspond to weeks 12, 24, 36 and 48 for CAPACITY (004 and 006) studies and weeks 13, 26, 39 and 52 for ASCEND (016), respectively. The annual rate of decline was estimated from the linear mixed-effects model comparing pirfenidone with placebo for each of the dose intensity groups (>90%, ≤90%), with change from baseline as the outcome variable. Study (CAPACITY 004 and 006 and ASCEND 016), treatment, sex, age and height were evaluated as fixed effects, and patient and assessment time were evaluated as random effects in an unstructured variance–covariance matrix.