Analyses of efficacy end points in a controlled trial of interferon-γ1b for idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a devastating disease, yet validated, reliable criteria for evaluating patient response to therapies in clinical trials are lacking. Methods: To optimize selection of end point criteria for the study of interferon (IFN)-gamma1b in patients with IPF, we retrospectively analyzed the components of the primary efficacy end point used in a large, controlled study of 330 patients for reliability, validity, and sensitivity to treatment effect. The primary end point components were death, disease progression defined as a greater than or equal to 5 mm Hg increase in resting alveolar-arterial oxygen pressure gradient (P[A-a]O-2), and disease progression defined as a greater than or equal to 10% decrease in percentage of predicted FVC. Results: We found that the P(A-a)O-2, criterion was not reliable and was not associated with mortality. In contrast, the FVC criterion was reliable and was associated with a 2.4-fold increase in the risk of death. Of the three measures, only mortality was sensitive to a treatment effect of IFN-gamma1b. Additionally, the tendency for mortality benefit was observed in nearly all patient subgroups defined by baseline physiology. The effect of IFN-gamma1b on mortality was strongest in patients with baseline percentage of predicted FVC greater than or equal to 55% (p = 0.004) or percentage of predicted diffusing capacity of the lung for carbon monoxide greater than or equal to 30% (p = 0.008). Conclusion: We conclude that mortality is the most inclusive end point for future trials of IFN-gamma1b in patients with IPF, and that a > 10% decrement in the percentage of predicted FVC represents a valid measure of disease progression.