Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis

doi:10.1016/S2213-2600(16)30326-5

The Lancet Respiratory Medicine

Volume 5, Issue 1, January 2017, Pages 33-41

https://doi.org/10.1016/S2213-2600(16)30326-5 Get rights and content

Summary

Background

In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks.

Methods

We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo—Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72–120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)—for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks 52, 72, and 120. We also did meta-analyses of these data and data from two Japanese trials of pirfenidone versus placebo—Shionogi Phase 2 (SP2) and Shionogi Phase 3 (SP3; trial durations 36–52 weeks).

Findings

At week 52, the relative risk of death for all four mortality outcomes was significantly lower in the pirfenidone group than in the placebo group in the pooled population (all-cause mortality hazard ratio [HR] 0·52 [95% CI 0·31–0·87; p=0·0107]; treatment-emergent all-cause mortality 0·45 [0·24–0·83; 0·0094]; idiopathic-pulmonary-fibrosis-related mortality 0·35 [0·17–0·72; 0·0029]; treatment-emergent idiopathic-pulmonary-fibrosis-related mortality 0·32 [0·14–0·76; 0·0061]). Consistent with the pooled analysis, meta-analyses for all-cause mortality at week 52 also showed a clinically relevant and significant risk reduction in the pirfenidone group compared with the placebo group. Over 120 weeks, we noted significant differences in the pooled analysis favouring pirfenidone therapy compared with placebo for treatment-emergent all-cause mortality (p=0·0420), idiopathic-pulmonary-fibrosis-related mortality (0·0237), and treatment-emergent idiopathic-pulmonary-fibrosis-related (0·0132) mortality; similar results were shown by meta-analyses.

Interpretation

Several analytic approaches demonstrated that pirfenidone therapy is associated with a reduction in the relative risk of mortality compared with placebo over 120 weeks.

Funding

F Hoffmann-La Roche/Genentech.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, unpredictable, and often rapidly fatal fibrosing lung disease.¹ Although the clinical course varies, prognosis is poor, with an estimated median survival of 2–5 years from diagnosis.2, 3 Pirfenidone is an oral anti-fibrotic drug with anti-inflammatory properties approved in the European Union and USA for treatment of IPF. The safety and efficacy of pirfenidone in patients with IPF was shown in three phase 3, randomised, multinational, placebo-controlled clinical trials, and in two previous Japanese clinical trials—Shionogi Phase 2 (SP2) and Shionogi Phase 3 (SP3).4, 5, 6, 7

All-cause mortality is commonly thought to be the most robust endpoint in therapeutic clinical trials in IPF. However, in typical IPF trial populations, the all-cause mortality is low because inclusion criteria are skewed towards patients with a forced vital capacity (FVC) of 50–90%.⁸ One way to overcome this issue is to combine studies through pooling or meta-analysis, or both. In pooled analyses, patient-level data are used to estimate treatment effects, whereas group-level data are used in meta-analyses, which allows for assessment of heterogeneity between studies.

Characterisation of mortality related to IPF is an important supplement to analyses of all-cause mortality, because deaths due to causes other than the disease could potentially confound all-cause mortality findings. This differentiation is especially relevant in IPF, a disease of elderly people who might die from causes other than progressive fibrosis. Treatment-emergent mortality outcomes allow for characterisation of patients who die while receiving (or having recently discontinued) therapy and might better reflect the clinical scenario of continued treatment than the intention-to-treat analyses typically used in prospective clinical trials.

In a previous analysis⁶ of the combined Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016) and Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006) studies, pirfenidone was associated with a significant reduction compared with placebo in the relative risk of all-cause mortality and treatment-emergent IPF-related mortality at 52 weeks. These mortality analyses were pooled to increase statistical power and generate a more stable estimate of treatment effect. Notably, they were included in the ASCEND study design as prespecified secondary endpoints. The data were censored at week 52 to ensure consistent follow-up time across the three trials.⁶ Although all-cause mortality and treatment-emergent IPF-related mortality were the key mortality analyses, treatment-emergent all-cause mortality and IPF-related mortality analyses at 52 weeks were additional prespecified exploratory endpoints.

Research in context

Evidence before this study

We searched PubMed with the terms “mortality”, “pirfenidone”, and “idiopathic pulmonary fibrosis” for studies published before Sept 1, 2016. We did not restrict our findings by language of publication. We identified five randomised controlled trials in which the role of pirfenidone in idiopathic pulmonary fibrosis was examined—three multinational, placebo-controlled phase 3 trials and two earlier Japanese clinical trials (one phase 2 and one phase 3). Pirfenidone is an oral antifibrotic agent with anti-inflammatory properties that is approved for treatment of idiopathic pulmonary fibrosis. In a previous pooled analysis of the three multinational, placebo-controlled phase 3 trials, pirfenidone was associated with significant reductions in the relative risk of all-cause mortality and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at 52 weeks.

Added value of this study

We did this analysis to establish the impact of pirfenidone on mortality after 52 weeks. Four different outcomes (all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality) were assessed in the combined populations through to the end of study (week 120). Overall, compared with placebo, pirfenidone was associated with a reduced relative risk of death for patients for all mortality outcomes, irrespective of statistical approach.

Implications of all the available evidence

Our findings show the robustness of pooled and metadata analyses in assessing drug efficacy outcomes in the pirfenidone trials. They show a pirfenidone treatment effect on mortality that is consistent across study populations and timepoints. Further studies are strongly encouraged to analyse reductions in the risk of mortality in patients after longer-term exposure to pirfenidone in open-label extension trials, registries, and real-world practice, as these studies will undoubtedly also help to inform future clinical decision making.

We aimed to explore further the impact of pirfenidone on long-term mortality outcomes (ie, up to 120 weeks). We assessed four different outcomes (all-cause mortality, treatment-emergent all-cause mortality, IPF-related mortality, and treatment-emergent IPF-related mortality) in the combined population of the three pirfenidone phase 3 multinational trials and the two Japanese clinical trials. Data were available for up to 120 weeks while patients were on blinded therapy.

Section snippets

Study population and mortality analyses

Patients with IPF who were randomly assigned to receive either 2403 mg pirfenidone a day or placebo in the CAPACITY (CAPACITY 004 and CAPACITY 006) or ASCEND 016 trials were included in our analysis. The eligibility criteria have been described previously (appendix).4, 5, 6, 7 Patients in the Japanese SP2 and SP3 trials, who received 1800 mg pirfenidone a day or placebo (equivalent to 2403 mg per day when the average lighter weight of Japanese patients is adjusted for), were also included.

The

Results

In the three phase 3 multinational trials, 623 patients were randomly assigned to pirfenidone and 624 to placebo (table 1). In the SP2 and SP3 trials, 183 patients were randomly assigned to pirfenidone and 145 to placebo. The demographic makeup, baseline measurements of pulmonary function, and time since diagnosis of IPF were similar between the two treatment groups within each of the five trials as previously described.4, 7, 12 The number of assessable patients dropped off at 52 weeks, as a

Discussion

We demonstrated, through both pooled analyses and meta-analyses, the beneficial effect of pirfenidone on all-cause mortality, treatment-emergent IPF-related mortality, treatment-emergent all-cause mortality, and IPF-related mortality outcomes across the three individual phase 3 trials and the two Japanese trials (for the meta-analyses). Overall, pirfenidone was associated with a reduced relative risk of death compared with placebo for pooled and meta-analyses mortality outcomes over time,

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ArticlesEffect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population and mortality analyses

Results

Discussion

Lancet

Contemp Clin Trials

Chest

An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management

Am J Respir Crit Care Med

A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis

Am J Respir Crit Care Med

The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis

Am J Respir Crit Care Med

Pirfenidone in idiopathic pulmonary fibrosis

Eur Respir J

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis

N Engl J Med

Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials

Am J Respir Crit Care Med

Articles
Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis