Publication by Taniguchi H, et al (Eur Resp J. 2010;35:821-829.)

Commentary by Glenn D. Rosen, MD, of Stanford University School of Medicine

Article Summary

Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Resp J. 2010;35:821-829.

Pirfenidone is a small molecule with anti-inflammatory, anti-fibrotic, and anti-oxidant activity which has been examined in Phase I and Phase II trials as a novel therapeutic agent for patients with idiopathic pulmonary fibrosis (IPF).

Taniguchi and colleagues report the results of a Phase III randomized placebo-controlled trial of high- and low-dose pirfenidone for the treatment of patients with IPF.

Study Design:

  • 275 patients randomized 2:1:2 to receive placebo, low-dose pirfenidone (1200 mg/day), or high-dose pirfenidone (1800 mg/day)
  • Primary endpoint
    • Original: change in lowest SpO2 during the 6-minute steady state exercise test (6MET, 6-minute walk test) over 52 weeks
    • New: change in vital capacity (VC) from baseline to week 52
  • Secondary endpoints
    • Progression-free survival (PFS, decline in VC ≥ 10% and/or death)
    • Change in the lowest SpO2 during 6MET
  • Last observation carried forward (LOCF) used to impute missing data, supported by a mixed model approach
  • No patient-reported outcome such as quality of life, cough, or dyspnea

The adjusted mean changes in VC based on the ANCOVA were -0.09 L and -0.16 L in the high-dose and placebo groups, respectively (P = 0.0416). A log-rank comparison revealed a longer PFS time in the high-dose group than the placebo group (P = 0.0280). No statistically significant difference was observed in mean changes of the lowest SpO2. Also, no difference in other endpoints such as DLCO, total lung capacity (TLC), or biomarkers was detected. Discontinuation rates were 37% in the high-dose pirfenidone group and 29.8% in the placebo group. Acute exacerbations occurred in 5% of the patients; there were no discontinuations due to death.

Expert Opinion:
This study follows a Phase II study by the same group, which was terminated early due to a large number of acute exacerbations in the placebo group but none in the pirfenidone group. This Phase III study suggests that high-dose pirfenidone slows the rate of VC decline compared to placebo at 52 weeks. This benefit, albeit of modest significance, was reproduced in the recently completed CAPACITY 2 pirfenidone trial. However, the parallel CAPACITY 1 trial did not detect a significant difference in FVC at 72 weeks. Also, PFS was significantly improved with pirfenidone in CAPACITY 2, but not in CAPACITY 1.

The majority of patients in the Taniguchi study who progressed had a decline of VC ≥ 10%. The beneficial effects of pirfenidone on PFS in this study and the pooled CAPACITY PFS data suggest that pirfenidone may delay disease worsening in a subset of IPF patients.

The key areas of concern for this trial are:

  • Change in primary endpoint from lowest SpO2 during 6MET to change in VC. Though this was done by the DSMB prior to unblinding, the initial entry criteria were based on the original primary endpoint
  • Use of LOCF for missing data, even validated with the mixed model approach, much missing data, and a discontinuation rate of 37% for the high-dose group and 30% for the placebo group may overestimate the drug effect on VC
  • Lack of patient-reported outcomes
  • No benefit of pirfenidone on any other endpoints such as DLCO, TLC, biomarkers, or 6MET

In summary, Taniguchi and colleagues show that IPF patients treated with pirfenidone versus placebo show a smaller VC decline and a delay in disease progression, but the conclusions are tainted by a change in primary endpoint, a large number of discontinuations, the LOCF method for missing data, and a lack of corroboration by significant effects on secondary endpoints.

Article Link:

Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Resp J. 2010;35:821-829.