© 2005 American Thoracic Society
The Questionable Efficacy of Pirfenidone in IPFTo the Editor:Azuma and colleagues (1) report that pirfenidone treatment improves vital capacity and prevents acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF) but fails to improve end-exercise hypoxemia in this population. Given the paucity of data from randomized, controlled trials in IPF, this investigation might have added important information regarding a promising therapy. Unfortunately, several serious design and methodologic issues limit the inferences that can be drawn from this study. First, selection of the subjects was clearly biased. Randomization occurred before identification of an eligible population. By excluding the 27 subjects who were unable to complete the six minute exercise test (6MET) at baseline, the investigators lost the benefits of randomization, including prevention of confounding (2). Second, using an unvalidated test (the 6MET) as a primary outcome limited the assessment of the intervention. More troubling from a methodologic view, however, was the differential assessment of the 6MET. Every subject had a walking speed "tailored to their comfort," ranging from 40 to 80 m/min, and was monitored for desaturation until a nadir SpO2 was reached. Clearly, the work required to reach a nadir while walking at a speed of 80 m/min is different from the work required to reach a nadir while walking at 40 m/min. Thus, even the trivial (but statistically significant) difference in lowest SpO2 attained in the subgroup analysis is questionable. Third, the early stopping of the trial was based upon adverse events in the placebo arm. Clinical trials are usually stopped for three reasons: (1) for efficacy, i.e., better outcomes in the treatment arm; (2) for futility, i.e., no demonstrable benefit in the treatment arm; or (3) for safety concerns in the treatment arm. Although the authors state that the study was stopped for safety, the study was actually stopped for "superiority" of pirfenidone based upon better outcomes (fewer acute exacerbations of IPF) in the treatment arm. The clinical significance of acute exacerbations of IPF is unclear, as neither the incidence nor the impact of acute exacerbations upon the natural history of the disease is known. Thus, stopping the trial based upon five events of uncertain significance in the placebo arm is dubious. Since the Data and Safety Monitoring Board (DSMB) was integral to this decision, full disclosure regarding membership should be reported (3). Ultimately, despite the authors' call for a "well designed phase III clinical trial," stopping the trial early due to the "superiority" of pirfenidone will make further placebo-controlled trials difficult to justify.
Johns Hopkins University, Baltimore, Maryland FOOTNOTES Conflict of Interest Statement: S.C.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.J.P. received $3,500 in 2003 and $2,500 in 2004 for serving on an Advisory Board for Intermune. REFERENCES
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