Clinical trials in idiopathic pulmonary fibrosis: a framework for moving forward

In the current issue of the European Respiratory Journal, Raghu et al. [1] report the results of the Macitentan USe in Idiopathic Pulmonary Fibrosis Clinical (MUSIC) trial, a randomised placebo-controlled phase 2 clinical trial of macitentan, an oral endothelin antagonist, for biopsy-proven idiopathic pulmonary fibrosis (IPF). With its multicentre enrolment, appropriate allocation concealment, low withdrawal rate and intention-to-treat analysis, this clinical trial exemplifies the state-of-the-art in clinical trial design and conduct in the field of IPF. The authors should indeed be congratulated for accomplishing the difficult task of enrolling and successfully completing a clinical trial in IPF.

The MUSIC trial investigators found that macitentan was not effective for the treatment of IPF, with no meaningful differences in forced vital capacity (FVC), the study's primary end-point, or diffusing capacity of the lung for carbon monoxide at 1 year between allocation arms. The authors also detected a nonsignificant 56% relative increase in the rate of a combined end-point of lung function decline or acute respiratory decompensation of IPF among those allocated to macitentan compared to placebo, a finding driven by an acute respiratory decompensation in seven out of 119 participants in the macitentan arm compared to one out of 59 participants in the placebo arm.

The negative results of the MUSIC trial come as little surprise in light of previous reports that two other endothelin antagonist, ambrisentan [2] and bosentan [3–5], are similarly ineffective for IPF. A series of negative trials in IPF combined with the observation that the most promising therapies do not appear to improve lung function, reduce dyspnoea or prolong life [6, 7] has led to disappointment and frustration throughout the IPF community. Without a cure on the horizon, we should critically re-examine the assumptions underlying …