ArticlesPirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials
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.
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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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