Research in context
Evidence before this study
We searched PubMed from database inception to May 31, 2019, for reports published in any language using the search terms (“uILD” OR “unclassifiable interstitial lung disease” OR “unclassifiable ILD” OR (“unclassifiable” AND (“interstitial lung disease” OR “ILD”))), which yielded 57 articles. After excluding publications that were not in English or not related to unclassifiable interstitial lung disease (ILD), 48 articles remained. To focus on the treatment of unclassifiable ILD, we then excluded case studies and articles on prevalence or incidence, diagnosis, disease classification, natural history, or prognosis, which left 11 articles. To focus on pharmacological treatments, we excluded two articles investigating lung transplant as a treatment for unclassifiable ILD. Of the remaining articles, seven were review articles or opinion pieces, one was a retrospective review of medical records that included only three patients with unclassifiable ILD, and one was a study design manuscript. Thus, our search identified no randomised controlled trials investigating a pharmacological treatment in patients with unclassifiable ILD.
Added value of this study
To our knowledge, this is the first randomised controlled trial to exclusively enrol patients with unclassifiable ILD, a type of ILD for which no approved pharmacological treatments exist. Pirfenidone is an antifibrotic shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF), a form of ILD that has mechanistic and clinical similarities with progressive fibrotic unclassifiable ILD. This study investigated the efficacy and safety of pirfenidone compared with placebo over 24 weeks of treatment in patients with progressive fibrotic unclassifiable ILD. As a result of unanticipated technical and analytical issues with home spirometry, it was not possible to apply the planned statistical model to the primary endpoint data. However, analysis of key secondary and exploratory endpoints measured at site visits, including forced vital capacity, carbon monoxide diffusing capacity, and 6-min walk distance, suggested that, compared with placebo, 24 weeks of treatment with pirfenidone is effective in patients with progressive fibrosing unclassifiable ILD. The safety and tolerability profile of pirfenidone was comparable with that observed in the phase 3 trials in IPF, and no new safety signals were identified.
Implications of all the available evidence
At present, no direct evidence to guide the treatment of patients with unclassifiable ILD exists and no approved pharmacological treatments are available; therefore, the results of this study are important for patients with progressive fibrosing unclassifiable ILD and clinicians involved in their treatment. This study found that pirfenidone was associated with benefits in lung function and exercise capacity compared with placebo after 24 weeks of treatment, thus supporting future studies investigating the benefits of pirfenidone in this patient population over a longer time period. Furthermore, the technical and analytical issues encountered with home spirometry in this study also have important implications for the design of future clinical trials. Thus, further analyses are needed before daily home spirometry can be used as a primary outcome measure in future clinical trials.