Objectives

The initial objective of the PANTHER-IPF study was to evaluate the effectiveness of a drug combination of prednisone, azathioprine, and N-acetylcysteine in the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF) compared to N-acetylcysteine alone or placebo. After interim analysis presented safety concerns regarding the three drug regimen, the protocol was modified to evaluate only N-acetylcysteine effectiveness.

Background

IPF is a chronic, progressive lung disease of unknown cause that is characterized by the histopathological or radiologic patterns of usual interstitial pneumonia in a typical clinical setting. The median survival of patients with idiopathic pulmonary fibrosis after diagnosis is 2 to 5 years. To date, no pharmacologic therapies have been shown to improve survival. Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking.

Participants

Patients between the ages of 35 and 85 years who had IPF were eligible to participate in the study if they had mild-to-moderate impairment in pulmonary function, which was defined as a forced vital capacity (FVC) of 50% or more of the predicted value and a carbon monoxide diffusing capacity of 30% or more of the predicted value. A diagnosis of IPF was determined on the basis of high-resolution computed tomography (HRCT) or biopsy. All patients had received a diagnosis of IPF within 48 months before enrollment. Prior to the clinical alert, 77 patients were randomized into the combination drug therapy. A total of 264 patients were randomized (pre- and post-clinical alert) into the full acetylcysteine compared with placebo trial.

Design

Patients with mild-to-moderate impairment in pulmonary function were randomly assigned to receive a three-drug regimen (prednisone, azathioprine, and acetylcysteine), acetylcysteine alone (plus matched placebos for prednisone and azathioprine), or matched placebos for each of the active therapies. After the planned midpoint interim analysis, the data and safety monitoring board recommended discontinuation of the three-drug regimen because of an excess in the number of deaths, hospitalizations, and serious adverse events among patients in the combination-therapy group, as compared with the placebo group. After NHLBI accepted this recommendation on October 14, 2011, the three-drug regimen was discontinued and patients were recruited for only the acetylcysteine group and the placebo group. Patients were seen at the clinical centers for screening, at baseline, and at 4, 15, 30, 45, and 60 weeks. The primary outcome measure was change in FVC over 60 weeks.

Conclusions

As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death or acute exacerbation.

N Engl J Med. 2014 May 29;370(22):2093-101.
N Engl J Med. 2012 May 24;366(21):1968-77.

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