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Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial

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Summary

Background

At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD.

Methods

We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18–85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03099187, and is no longer recruiting.

Findings

Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was −87·7 mL (Q1–Q3 −338·1 to 148·6) in the pirfenidone group versus −157·1 mL (−370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was −0·7% (SD 7·1) for the pirfenidone group and −2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was −2·0 m (68·1) for the pirfenidone group and −26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%]).

Interpretation

Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD.

Funding

F Hoffmann-La Roche.

Introduction

Interstitial lung diseases (ILDs) are a large, heterogeneous group of diseases characterised by abnormalities of the pulmonary interstitium or alveoli, including fibrosis.1 Patients with ILD have difficulty with daily activities, shortness of breath, tiredness, and fatigue.2 ILDs might be associated with environmental exposures or can be secondary to another condition, such as a connective tissue disease, but in many cases, a cause is not established, and these patients are diagnosed with idiopathic interstitial pneumonias.1

Although some ILDs have a progressive fibrosing phenotype similar to idiopathic pulmonary fibrosis (IPF), which is the most common form of idiopathic interstitial pneumonia,3 the clinical course of other ILDs varies.1, 4, 5 Diagnosis of a specific ILD is important for identifying the most appropriate management strategy and informing disease prognosis.1, 4, 5 However, as recognised by American Thoracic Society/European Respiratory Society diagnostic guidelines for idiopathic interstitial pneumonia,6 despite thorough investigation by a multidisciplinary team (including pulmonologists, radiologists, and lung pathologists), a final diagnosis is not always possible,4 subsequently leading to a diagnosis of unclassifiable ILD.7

The management of patients with ILD is divided into two categories: patients with IPF and patients with all other progressive forms of fibrotic ILD. For IPF, two antifibrotic drugs are available—pirfenidone and nintedanib—which have been shown to slow disease progression.8, 9, 10 In the absence of clinical evidence guiding the treatment of other fibrosing ILDs (eg, unclassifiable ILD, hypersensitivity pneumonitis, connective tissue disease ILD), options include treatment with short-term immunosuppression followed by an evaluation of treatment response, or continued observation without pharmacotherapy.3, 5, 11

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.

Although these treatments can be used in practice, at present, no approved treatments are available for unclassifiable ILD.12 Considering the mechanistic and clinical similarities between IPF and other ILDs with a progressive fibrosing phenotype, it is reasonable to hypothesise that antifibrotics might be beneficial in patients with progressive unclassifiable ILDs characterised by fibrosis.12, 13

We aimed to assess the efficacy and safety of pirfenidone versus placebo in patients with progressive fibrosing unclassifiable ILD over 24 weeks of treatment.12

Section snippets

Study design and participants

We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 clinical centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. The methods of this study have been previously described.12

Eligible patients were aged between 18 and 85 years and had fibrosing unclassifiable ILD, defined as fibrosing ILD that could not be classified with moderate or high confidence to any category of ILD

Results

Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive pirfenidone (n=127) or placebo (n=126). Two patients in the placebo group did not receive treatment due to randomisation errors. 253 patients were included in the ITT analysis set (127 patients in the pirfenidone group and 126 patients in the placebo group; figure 1) and all randomly assigned patients who received at least one dose of study drug were included in the safety population (127 patients in the

Discussion

In this randomised, controlled trial of pirfenidone in patients with progressive fibrosing unclassifiable ILD, the planned statistical model could not be applied to the primary endpoint data. However, results for the key secondary endpoints support the conclusion that 24 weeks of treatment with pirfenidone slows disease progression when compared with placebo in patients with progressive fibrosing unclassifiable ILD. The safety and tolerability profile of pirfenidone was comparable with that in

Data sharing

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (//www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm

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