Although the planned statistical model could not be applied to primary end point data, key secondary end point analysis in a study published in The Lancet: Respiratory Medicine suggested that patients with progressive fibrosing unclassifiable interstitial lung disease (ILD) could benefit from treatment with pirfenidone.
This phase 2, multicenter, randomized, double-blind, placebo-controlled trial at 70 centers throughout Europe, Canada, and Australia (ClinicalTrials.gov Identifier: NCT03099187) was designed to assess the safety and efficacy of pirfenidone in patients between 18 and 85 years old with progressive fibrosing unclassifiable ILD (N=253). Eligible patients had a high-resolution computed tomography (CT) from the previous 12 months, >10% fibrosis on high-resolution CT, percent predicted carbon monoxide diffusing capacity (DLco) of ≥30%, and a percent predicted forced vital capacity (FVC) of ≥45%. Participants were randomly assigned (1:1) to placebo or 2403 mg oral pirfenidone daily, stratified by use of concomitant mycophenolate mofetil and absence or presence of interstitial pneumonia with autoimmune features. Baseline characteristics were similar between groups.
The primary study end point was mean predicted FVC change from baseline over 24 weeks, measured by daily home spirometry. Secondary study end points (all compared with baseline) were FVC change measured by site spirometry, change in percent predicted DLco, proportion of patients with >5% or >10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in 6-minute walk distance (6MWD), change in cough visual analogue scale, change in Leicester Cough Questionnaire score, and changes in total and subscores of the St George’s Respiratory Questionnaire (SGRQ), progression-free survival, and the proportion of patients experiencing nonelective hospitalization (respiratory and all-cause) and acute exacerbations. Safety was assessed in all participants receiving ≥1 dose of the study drug.
Among the total 253 participants, 127 were randomly assigned to pirfenidone and 126 to placebo, with 2 placebo group participants not receiving treatment due to errors in randomization. The application of the prespecified statistical model for analysis of the primary end point was made impossible by 2 issues. First, the home spirometry readings were affected by technical reliability issues (obtained values were physiologically implausible), and it was not suitable to apply a linear regression model with a small number of spirometry readings collected over a short time period.
At 24 weeks, mean predicted FVC change from baseline was -17.9 mL (range, -5799 to 16,411) in the pirfenidone group and 116.6 mL (range, -7256 to 33,794) in the placebo group and the median predicted FVC change from baseline measured by daily home spirometry was -87.7 mL (Q1 to Q3, -338.1 to 148.6) in the pirfenidone group and -157.1 mL (Q1 to Q3, -370.9 to 70.1) in the placebo group.
Statistical assumptions were met when applied to secondary study end points. Among participants with 1 baseline and ≥2 post-baseline measurements of FVC (118 pirfenidone participants and 119 placebo participants) at week 24, mean FVC decline was lower in the pirfenidone participants compared with the placebo participants (-17.8 mL vs -113.0 mL; between-group difference, 95.3 mL [95% CI, 35.9-154.6], P =.002). Fewer pirfenidone participants had > 5% absolute decline in percent predicted FVC compared with placebo participants (pirfenidone: 47 of 127, [37%] vs placebo: 74 of 126 [59%]; odds ratio [OR], 0.42; 95% CI, 0.25-0.69; P =.001), and fewer pirfenidone participants compared with placebo participants had a more than 10% absolute decline in percent predicted FVC (18 of 127 [14%] vs 34 of 126 [27%]; OR, 0.44; 95% CI, 0.23-0.84; P =.011).
The week 24 mean DLco change from baseline was -0.7% (SD, 7.1) for pirfenidone participants and -2.5% (SD, 8.8) for placebo participants, and the mean 6MWD change from baseline was -2.0 meters (SD, 68.1) for pirfenidone participants and -26.7 meters (SD, 79.3) for placebo participants. Similar between-group changes from baseline to week 24 were seen in the cough visual analogue scale and the Leicester Cough Questionnaire, UCSD-SOBQ, and SGRQ scores.
Because of the small number of events, no meaningful results were obtained from the analysis of hospital admissions, acute exacerbations, and time to death from respiratory causes, and no differences were identified between the groups in progression-free survival. In the pirfenidone group, 120 of 127 (94%) experienced treatment-emergent adverse events and 18 of 127 (14%) experienced serious treatment-emergent adverse events compared with 101 of 124 (81%) treatment-emergent adverse events and 20 of 124 (16%) serious treatment-emergent adverse events in the placebo group.
Study limitations included differing treatment effects on a case-by-case basis, potential misdiagnoses, and limited treatment duration.
Disclosure: This clinical trial was supported by F Hoffmann-La Roche. Several study authors declare affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Maher TM, Corte TJ, Fischer A, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial [published online September 29, 2019]. Lancet Respir Med. doi:10.1016/S2213-2600(19)30341-8