Elsevier

The Lancet

Volume 377, Issue 9779, 21–27 May 2011, Pages 1760-1769
The Lancet

Articles
Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials

https://doi.org/10.1016/S0140-6736(11)60405-4Get rights and content

Summary

Background

Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis.

Methods

In two concurrent trials (004 and 006), patients (aged 40–80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716.

Findings

In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was −8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and −12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at week 72 was −9·0% (SD 19·6) in the pirfenidone group and −9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, −3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups.

Interpretation

The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis.

Funding

InterMune.

Introduction

Idiopathic pulmonary fibrosis is a chronic, progressive, and fatal lung disease with no known cause or cure. It is characterised by progressive dyspnoea and irreversible loss of lung function.1 Disease progression is heterogeneous; however, the clinical course is ultimately deterioration, with an estimated median survival of 2–5 years.2, 3, 4 The uniformly poor prognosis, with paucity of treatments, provides a strong rationale for the development of novel drugs that target the underlying fibroproliferative process and attenuate decline in pulmonary function.

Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is an orally bioavailable synthetic molecule. It was shown to regulate the activity of transforming growth factor (TGF) β and tumour necrosis factor (TNF) α in vitro;5, 6, 7, 8, 9 and inhibit fibroblast proliferation and collagen synthesis and reduce cellular and histological markers of fibrosis in animal models of lung fibrosis.6, 9, 10, 11, 12

Clinical proof of concept was shown in a randomised, double-blind, placebo-controlled phase 2 study of 107 Japanese patients with idiopathic pulmonary fibrosis.13 This study was stopped early because an interim analysis showed favourable efficacy; final analysis at 9 months showed a reduced decline in the mean change in vital capacity in pirfenidone-treated patients (p=0·037).13 These findings led to three phase 3 studies with primary endpoints of change in lung function—one in Japan and two across North America and Europe. In the Japanese phase 3, randomised, double-blind, placebo-controlled study of 275 patients with idiopathic pulmonary fibrosis, pirfenidone reduced mean change in vital capacity at week 52 (absolute difference 70 mL; relative difference 44%; p=0·042), and improved progression-free survival time (p=0·028).14 These data, with the results of the phase 2 study, led to regulatory approval of pirfenidone in Japan for the treatment of idiopathic pulmonary fibrosis.

The CAPACITY (Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes) programme included two similar multinational trials (studies 004 and 006) designed to confirm the effect of pirfenidone on reduction of decline in lung function.

Section snippets

Patients

The studies were done at 110 centres in 13 countries (Australia [n=3], Belgium [n=2], Canada [n=9], France [n=5], Germany [n=6], Ireland [n=1], Italy [n=9], Mexico [n=1], Poland [n=2], Spain [n=4], Switzerland [n=1], UK [n=3], and USA [n=64]). All methods apply to both studies 004 and 006, unless otherwise noted. Eligible patients were aged 40–80 years with a diagnosis of idiopathic pulmonary fibrosis in the previous 48 months and no evidence of improvement in measures of disease severity over

Results

Between April, 2006, and November, 2008, 435 patients were enrolled in study 004, and 344 in study 006. Table 1 shows that there were no pronounced baseline imbalances between treatment groups within each study. The percentages of patients with diagnoses of idiopathic pulmonary fibrosis within 1 year, on supplemental oxygen, and enrolment at US sites were higher in study 006 than in study 004 (table 1). 713 (92%) of 779 patients met criteria for definite idiopathic pulmonary fibrosis with HRCT;

Discussion

The results of study 004 showed a pirfenidone treatment effect on the change in percentage predicted FVC at week 72. Significant treatment effect was also noted at earlier timepoints, in the repeated-measures analysis over all study timepoints, and on progression-free survival and categorical FVC change. An efficacy dose-response relation was noted. In study 006, no significant difference was noted between the pirfenidone and placebo groups on percentage predicted FVC change at week 72.

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