Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment

Abstract

Background: A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial.

Methods: The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO(2)), and the lowest oxygen saturation by pulse oximetry (SpO(2)) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52.

Results: Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO(2) < 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea.

Conclusions: IPF patients having %VC ≥ 70% and SpO(2) < 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment.

Trial registration: This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (REGISTRATION NUMBER: JAPICCTI-050121).

Figure 1

Categorical changes in VC from baseline to week 52 in Subgroup A [baseline %VC ≥ 70 and the lowest SpO₂ < 90]. A) High-dose vs Placebo groups, B) Low-dose vs Placebo groups, C) pirfenidone-treated (High + Low-dose) vs placebo groups. (The changes in VC are rated as follows: improved, VC ≥ 10% increase; stable, VC < 10% change; worsened, VC ≥ 10% decline). The white, gray, and black areas indicate improvement, stability, and deterioration, respectively. The p-values of Wilcoxon rank sum test are indicated on the right.

Figure 2

Temporal changes in cough score in subpopulations. A) Full analysis set (FAS; all patients), B) Subgroup A [%VC ≥ 70 and the lowest SpO₂ < 90], and C) Subgroup B [PaO2 ≥ 70 and the lowest SpO₂ < 90]. Data are shown as mean ± SE. High-dose (solid line); low dose (dashed line); placebo (dashed line in bold). The mean changes from baseline to week 52 were compared between high (or low-dose) and placebo groups with ANCOVA.

Figure 3

Temporal changes in dyspnea score (F, H-J classification) in subpopulations. A) Full analysis set (FAS; all patients), B) Subgroup A [%VC ≥ 70 and SpO₂ during 6MET < 90], and C) Subgroup B [PaO2 ≥ 70 and SpO₂ during 6MET < 90]. Data are shown as mean ± SE. High-dose (solid line); low dose (dashed line); placebo (dashed line in bold). The mean changes from baseline to week 52 were compared between high or low-dose and placebo groups with ANCOVA.