ASCEND

NEJM 2014

the coarse crackle

ASCEND was a 52-week, randomized, double-blind, placebo-controlled phase 3 trial testing pirfenidone 801mg three times per day in patients with idiopathic pulmonary fibrosis. Pirfenidone significantly slowed disease progression by Pirfenidone significantly slowed disease progression by reducing the proportion of patients with a ≥10 percentage-point absolute decline in percent-predicted FVC or death (16.5% vs 31.8%), increased the proportion with no FVC decline (22.7% vs 9.7%), attenuated mean FVC loss (−235 ml vs −428 ml), reduced decline in 6-minute walk distance, and improved progression-free survival (HR 0.57)., increased the proportion with no FVC decline (22.7% vs 9.7%), and attenuated mean FVC loss (−235 ml vs −428 ml).

fine crackles

  • Pirfenidone (2403 mg/day) roughly halved the annual rate of FVC decline and improved progression-free survival in IPF, with supportive signals for reduced 1-year mortality in pooled analyses. The enrolled patients had moderate disease (i.e., a range of 50 to 90% of predicted FVC and 30 to 90% of predicted carbon monoxide diffusing capacity).

  • All-cause mortality showed fewer deaths in the pirfenidone group than in the placebo group, although the difference was not significant. Eleven patients (4.0%) in the pirfenidone group died during the study, as compared with 20 patients (7.2%) in the placebo group (hazard ratio, 0.55; 95% CI, 0.26 to 1.15; P=0.10).

  • Common, manageable adverse effects of pirfenidone are gastrointestinal upset and photosensitivity-type rash; monitor liver enzymes periodically and advise dosing with food and sun protection. In practice, photosensitivity probably occurs in about 1 in 10 patients, particularly in the first 6 months of therapy.

  • Background

    In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.

    Methods

    In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.

    Results

    In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.

    Conclusions

    Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.)