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Clinical Trials of Pirfenidone
The efficacy of pirfenidone in IPF has been evaluated in four phase 3 RCTs. The first phase 3 RCT was performed in 275 patients in Japan. This trial followed an earlier, small Japanese RCT that demonstrated a decreased risk for acute exacerbation and slower decline in vital capacity. The study demonstrated a significant improvement in the primary endpoint of decline in vital capacity at 52 weeks, as well as the secondary endpoint of progression-free survival (PFS) (defined as death or decrease in vital capacity ≥10%). The Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) trials – two concurrent multicenter RCTs – were completed and published next. Study 004 randomized 435 patients in a 2 : 1 : 2 fashion to high-dose pirfenidone (2403 mg/day), low-dose pirfenidone (1197 mg/day), and placebo arms. Pirfenidone reduced the rate of decline in forced vital capacity (FVC) at 72 weeks in this study (-12.4% placebo versus -8.0% in high-dose; P = 0.001). Study 006 randomized 344 patients to either high-dose pirfenidone (2403 mg daily) or placebo. This study failed to demonstrate a reduction in the primary endpoint of change in FVC.
On the basis of the phase 3 trials mentioned above, pirfenidone was approved for the treatment of IPF in Japan, Europe, India, and Canada. Due to the discordant results of the CAPACITY trials, the US FDA requested a further confirmatory trial. The subsequent Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) results provided confirmation of the beneficial effects of pirfenidone in IPF. The study randomized 555 patients to either 2403 mg/day of pirfenidone or placebo. Pirfenidone resulted in a relative risk reduction of 47.9% in the proportion of patients with a decline in FVC of at least 10% predicted. Pirfenidone also reduced the decline in 6-min walk test (6MWT) distance (P = 0.04) and improved PFS (P < 0.001). A pooled analysis of the CAPACITY and ASCEND trials demonstrated a reduction in death from any cause (P = 0.01) and from IPF (P = 0.006) at 52 weeks. Table 1 summarizes the available RCTs on the use of pirfenidone in IPF.
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