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 Csete, Jeffrey J. Swigris, Frank Gilberg, Klaus Uwe Kirchgaessler, Susan L. Limb, Ute Petzinger, Paul W. Noble

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere000323
JournalBMJ Open Respiratory Research
Volume5
Issue number1
DOIs
StatePublished - Aug 1 2018

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Idiopathic Pulmonary Fibrosis
Placebos
Therapeutics
Vital Capacity
Safety
pirfenidone
Body Size
Outcome Assessment (Health Care)
Weights and Measures
Research

Keywords

  • interstitial fibrosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Dose modification and dose intensity during treatment with pirfenidone : Analysis of pooled data from three multinational phase III trials. / Nathan, Steven D.; Lancaster, Lisa H.; Albera, Carlo; Glassberg Csete, Marilyn K; Swigris, Jeffrey J.; Gilberg, Frank; Kirchgaessler, Klaus Uwe; Limb, Susan L.; Petzinger, Ute; Noble, Paul W.

In: BMJ Open Respiratory Research, Vol. 5, No. 1, e000323, 01.08.2018.

Research output: Contribution to journalArticle

Nathan, Steven D. ; Lancaster, Lisa H. ; Albera, Carlo ; Glassberg Csete, Marilyn K ; Swigris, Jeffrey J. ; Gilberg, Frank ; Kirchgaessler, Klaus Uwe ; Limb, Susan L. ; Petzinger, Ute ; Noble, Paul W. / Dose modification and dose intensity during treatment with pirfenidone : Analysis of pooled data from three multinational phase III trials. In: BMJ Open Respiratory Research. 2018 ; Vol. 5, No. 1.
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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.",
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T2 - Analysis of pooled data from three multinational phase III trials

AU - Nathan, Steven D.

AU - Lancaster, Lisa H.

AU - Albera, Carlo

AU - Glassberg Csete, Marilyn K

AU - Swigris, Jeffrey J.

AU - Gilberg, Frank

AU - Kirchgaessler, Klaus Uwe

AU - Limb, Susan L.

AU - Petzinger, Ute

AU - Noble, Paul W.

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N2 - 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.

AB - 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.

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