The ascend study: A randomized, double-blind, placebo controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF)

Introduction: The ASCEND Study is a Phase 3 multinational, randomized, double-blind, placebo controlled trial designed to confirm the effect of pirfenidone on disease progression in patients with IPF. Methods: Eligible patients were randomized (1:1) to oral pirfenidone 2403 mg/day or matched placebo for 52 weeks. Eligibility required a centrally-confirmed IPF diagnosis by high resolution computed tomography + surgical lung biopsy, percent predicted forced vital capacity (%FVC) ≥50% and ≤90%, and percent predicted DLCO ≥30% and ≤90%. The primary endpoint was %FVC change at week 52. Two key secondary endpoints (progression-free survival [PFS] and 6-minute walk distance [6MWD] and three additional secondary endpoints (all-cause mortality [ACM], treatment-emergent [TE] IPF-related mortality, and dyspnea) were pre-specified, with the mortality analyses to be performed on both the ASCEND population and the pooled population from ASCEND and CAPACITY (through 52 weeks). Results: 555 patients were randomized; 93.5% and 94.6% of patients in the pirfenidone and placebo groups, respectively, completed the study, died, or were transplanted. Primary analysis demonstrated that pirfenidone reduce the decline in %FVC at Week 52 compared with placebo (p<0.000001; Figure 1). Both key secondary endpoints were achieved: pirfenidone improved PFS (HR 0.57; 95% CI 0.43-0.77; p=0.0001) and reduced the decline in 6MWD (p=0.036). The dyspnea endpoint (change in UCSD SOBQ score) was not achieved (p=0.158). Both pre-specified 52-week mortality endpoints numerically favored pirfenidone in ASCEND and showed significant effect in the pooled analysis (ACM [HR 0.52; 95% CI 0.31-0.87; p=0.0107]; TE IPF-related mortality [HR 0.32; 95% CI 0.14-0.76; p=0.0061]). Treatment discontinuations due to adverse events occurred in 14.4% and 10.8% of pirfenidone and placebo patients, respectively. There were fewer serious adverse events (SAE; 19.8% vs. 24.9%) and TE deaths (2.9% vs. 5.4%) in the pirfenidone group. Aminotransferase elevations > 3 X ULN occurred in 2.9% and 0.7% of pirfenidone and placebo patients, respectively, and were reversible. Gastrointestinal and skin-related events were more common in the pirfenidone group; these were typically mild to moderate in severity and infrequently led to treatment discontinuation. Conclusions: Pirfenidone treatment for 52 weeks reduced IPF disease progression as measured by lung function, exercise capacity, and PFS. All-cause mortality and TE IPF-related mortality were significantly reduced in patients receiving pirfenidone in the pooled analysis of the ASCEND and CAPACITY studies. Pirfenidone was generally safe and well-tolerated. These findings suggest a favorable benefit-risk profile of pirfenidone in patients with IPF. (Figure Presented).