Combining Pirfenidone With Mycophenolate Mofetil for Systemic Sclerosis-Related Interstitial Lung Disease (Scleroderma Lung Study III): An Investigator-Initiated, Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

Overview

abstract

OBJECTIVE: Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis-related interstitial lung disease (SSc-ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. METHODS: A randomized (1:1), double-blind, placebo (PLA)-controlled phase 2 trial was conducted in SSc-ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC-%). Linear mixed-effects models assessed treatment differences in a modified intention-to-treat population. RESULTS: Only fifty-one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC-% improved from baseline to 18 months by 2.24 ± 1.35 (least-squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference -0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC-% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant (P = 0.33). For secondary outcomes, only the change over 18 months in the Patient-Reported Outcomes Measurement Information System 29-item physical function score, favoring MMF+PFD, reached statistical significance (P = 0.04). Although other related patient-reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high-resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). CONCLUSION: In this underpowered study, there was no statistically significant treatment difference in overall change in FVC-% between groups. MMF+PFD was not as well tolerated as MMF+PLA.