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Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

ABSTRACT: Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403?mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1?year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1?year, pirfenidone reduced the proportion of patients with a ?10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1?year resulted in clinically meaningful reductions in disease progression in patients with IPF.

SUBMITTER: Noble PW

PROVIDER: S-EPMC4697914 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

Noble Paul W PW Albera Carlo C Bradford Williamson Z WZ Costabel Ulrich U du Bois Roland M RM Fagan Elizabeth A EA Fishman Robert S RS Glaspole Ian I Glassberg Marilyn K MK Lancaster Lisa L Lederer David J DJ Leff Jonathan A JA Nathan Steven D SD Pereira Carlos A CA Swigris Jeffrey J JJ Valeyre Dominique D King Talmadge E TE

The European respiratory journal 20151202 1

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on t ...[more]

PMID: 26647432

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Project description:IntroductionThis study assessed baseline cardiovascular (CV) risk factors, concomitant CV medication use, risk of major adverse cardiac events-plus (MACE-plus), and bleeding adverse events (AEs) in patients with idiopathic pulmonary fibrosis (IPF) in three randomized, placebo-controlled phase III trials of pirfenidone.MethodsPatients in the pirfenidone phase III trials were included. Patients with unstable or deteriorating cardiac disease within 6 months before enrollment were ineligible. Medical history at baseline and concomitant CV medication use during treatment were reported. A retrospective, blinded review of AE preferred terms was conducted to identify MACE-plus and bleeding events. Subgroup analyses examined the impact of concomitant CV medication use on how pirfenidone treatment affected clinical outcomes.ResultsIn total, 1247 patients were included [n = 623 pirfenidone (2403 mg/day) and n = 624 placebo]. The median age was 68 years, 74% were male, and 65% were current/former smokers. Commonly reported CV risk factors included hypertension (52%), obesity (44%), hypercholesterolemia (23%), and hyperlipidemia (23%). Pre-existing cardiac disorders included coronary artery disease (16%), myocardial infarction (5%), and atrial fibrillation (5%). Lipid-modifying agents (60%), antithrombotic agents (54%), and renin-angiotensin inhibitors (39%) were commonly used concomitant CV medications. The incidences of MACE-plus and bleeding events were similar between the pirfenidone and placebo groups (1.8% and 2.9% for MACE-plus events and 3.7% and 4.3% for bleeding events, respectively). Except for patients receiving heparin, pirfenidone had a beneficial effect compared with placebo on efficacy outcomes regardless of concomitant CV medications.ConclusionsCV risk factors and comorbidities and use of concomitant CV medications are common in patients with IPF. Pirfenidone did not appear to increase the risk of CV or bleeding events. Use of several concomitant CV medications, including warfarin, did not appear to adversely impact pirfenidone's beneficial effect on efficacy outcomes.Trial registrationNCT00287716, NCT00287729, and NCT01366209.FundingF. Hoffmann-La Roche Ltd. and Genentech, Inc.

Project description:INTRODUCTION:Components of the hedgehog signaling pathway are upregulated in patients with idiopathic pulmonary fibrosis (IPF). Vismodegib, a small-molecule inhibitor of hedgehog signaling, when used in combination with currently available antifibrotic therapy, may be more efficacious than antifibrotics alone. The objective of this study was to evaluate the safety and tolerability of vismodegib plus pirfenidone in patients with IPF. METHODS:Twenty-one patients were enrolled in a phase 1b open-label trial to receive vismodegib 150 mg plus pirfenidone 2403 mg/day once daily. Key endpoints were safety, tolerability, and pharmacokinetics. Exploratory endpoints included change from baseline to week 24 in % predicted forced vital capacity (FVC) and University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) scores, as well as pharmacodynamic changes in hedgehog biomarker C-X-C motif chemokine ligand 14 (CXCL14). RESULTS:All patients reported at least one treatment-emergent adverse event (AE), most frequently muscle spasms (76.2%). Serious AEs were reported in 14.3% of patients; one event of dehydration was considered related to vismodegib. One patient died due to IPF progression, unrelated to either treatment. More patients discontinued vismodegib than pirfenidone (42.9% vs. 33.3%, respectively). Changes from baseline to week 24 in % predicted FVC and UCSD-SOBQ scores were within known endpoint variability. In contrast to findings in basal cell carcinoma, vismodegib had no effect on circulating CXCL14 levels. CONCLUSION:The safety profile was generally consistent with the known profiles of both drugs, with no new safety signals observed in this small cohort. There was no pharmacodynamic effect on CXCL14 levels. Future development of vismodegib for IPF may be limited due to tolerability issues. TRIAL REGISTRATION:ClinicalTrials.gov NCT02648048. Plain language summary available for this article. FUNDING:F. Hoffmann-La Roche Ltd. and Genentech, Inc.

Project description:IntroductionNintedanib slows disease progression in patients with idiopathic pulmonary fibrosis (IPF) by reducing the rate of decline in forced vital capacity, with an adverse event profile that is manageable for most patients. We used data from six clinical trials to characterise the safety and tolerability profile of nintedanib and to investigate its effects on survival.MethodsData from patients treated with ≥1 dose of nintedanib 150 mg two times per day or placebo in the 52-week TOMORROW trial and/or its open-label extension; the two 52-week INPULSIS trials and/or their open-label extension, INPULSIS-ON; and a Phase IIIb trial with a placebo-controlled period of ≥6 months followed by open-label nintedanib were pooled. All adverse events, irrespective of causality, were included in descriptive analyses. Parametric survival distributions were fit to pooled Kaplan-Meier survival data from the trials and extrapolated to estimate long-term survival.ResultsThere were 1126 patients in the pooled nintedanib group and 565 patients in the pooled placebo group. The mean duration of nintedanib treatment was 28 months. No new safety signals were observed. Incidence rates of bleeding, liver enzyme elevations and cardiovascular events were consistent with those observed in the INPULSIS trials. Diarrhoea was reported at a lower event rate in the pooled nintedanib group than in nintedanib-treated patients in the INPULSIS trials (76.5 vs 112.6 events per 100 patient exposure-years) and infrequently led to permanent treatment discontinuation (3.6 events per 100 patient exposure-years). Based on the Weibull distribution, mean (95% CI) survival was estimated as 11.6 (9.6, 14.1) years in nintedanib-treated patients and 3.7 (2.5, 5.4) years in placebo-treated patients.ConclusionsBased on pooled data from six clinical trials, the adverse event profile of nintedanib was manageable for most patients. Exploratory analyses based on extrapolation of survival data suggest that nintedanib extends life expectancy in patients with IPF.

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Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

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Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

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