Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials

Abstract

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.

FIGURE 1

FVC outcomes. a) Proportion of patients with forced vital capacity (FVC) % predicted decline ≥10% or death. Rank ANCOVA (pirfenidone 2403 mg·day⁻¹ versus placebo). b) Cumulative distribution of change from baseline to month 12 in FVC % pred in the pooled population (n=1247). c) Mean change from baseline in FVC in the pooled population. Assessed at weeks 12, 24, 36 and 48 in CAPACITY [1] and weeks 13, 26, 39 and 52 in ASCEND [2].

FIGURE 2

Subgroup analysis of change in forced vital capacity (FVC) % predicted at 1 year in the pooled population. D_LCO: diffusing capacity of the lung for carbon monoxide; 6MWD: 6-min walk distance; FEV₁: forced expiratory volume in 1 s. p>0.05 for all tests for interaction between treatment and subgroup except time since diagnosis (nominal p=0.034; not corrected for multiple comparisons).

FIGURE 3

Secondary outcomes. a) Proportion of patients with a decline in 6-min walk distance ≥50 m or death. Rank ANCOVA (pirfenidone 2403 mg·day⁻¹ versus placebo). b) Progression-free survival at 1 year. Time to death or disease progression (confirmed ≥10% decline in forced vital capacity % predicted or ≥50 m decline in 6-min walk distance). c) Proportion of patients with an increase in UCSD SOBQ score ≥20 points or death. Rank ANCOVA (pirfenidone 2403 mg·day⁻¹ versus placebo). HR: hazard ratio; UCSD SOBQ: University of California San Diego Shortness of Breath Questionnaire (scale 0–120; higher scores indicate worse dyspnoea). ^#: Cox proportional hazards model; ^¶: log-rank test.

FIGURE 4

Summary of clinical efficacy outcomes at 1 year in the pooled population (n=1247). FVC: forced vital capacity; 6MWD: 6-min walk distance; UCSD SOBQ: University of California San Diego Shortness of Breath Questionnaire; IPF: idiopathic pulmonary fibrosis.

FIGURE 5

Summary of clinical efficacy outcomes at 1 year across studies. FVC: forced vital capacity; 6MWD: 6-min walk distance; UCSD SOBQ: University of California San Diego Shortness of Breath Questionnaire; TE: treatment-emergent; IPF: idiopathic pulmonary fibrosis; STE: standardised treatment effect. p>0.05 for all tests for interaction between treatment and study. ^#: decline in FVC % predicted ≥10% or death; ^¶: decline in 6MWD ≥50 m or death; ⁺: increase in UCSD SOBQ score ≥20 points or death; ^§: estimated as the difference in the rank mean change from baseline between groups divided by the estimate of the common standard deviation from each study.

FIGURE 6

a) Kaplan–Meier distribution of time to confirmed ≥10% decline in forced vital capacity (FVC) % predicted or death in the pooled population. b) Kaplan–Meier distribution of progression-free survival in the pooled population. Time to first occurrence of death or disease progression (confirmed >10% decline in FVC % pred or confirmed >50 m decrement in 6MWD). c) Kaplan–Meier distribution of time to confirmed ≥50 m decline in 6MWD or death in the pooled population. d) Kaplan–Meier distribution of time to worsening dyspnoea or death in the pooled population. Defined as a confirmed ≥20-point increase in UCSD SOBQ score or death. HR: hazard ratio; UCSD SOBQ: University of California San Diego Shortness of Breath Questionnaire (scale 0–120; higher scores indicate worse dyspnoea). ^#: Cox proportional hazards model; ^¶: log-rank test. ⁺: reported as the number of patients at risk on the last day of each 12-week study period in each study (excludes five patients from the pirfenidone group and six patients from the placebo group who had no post-randomisation follow-up assessment).