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

Abstract

Introduction: Despite extensive multidisciplinary team (MDT) assessment, some patients have interstitial lung disease (ILD) that is considered unclassifiable (uILD), for which there are currently no approved treatments. This study will assess the efficacy and safety of the antifibrotic pirfenidone in treating uILD.

Methods and analysis: This double-blind, randomised, placebo-controlled phase II trial is enrolling adults with fibrosing ILD, including uILD that fulfils proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), that cannot be classified with moderate or high confidence to any category of ILD following MDT discussion. Study participants must have >10% fibrosis on high-resolution CT scan within the previous 12 months, forced vital capacity (FVC) ≥45% and diffusing capacity of the lung for carbon monoxide ≥30% of predicted values. Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone vs placebo will be assessed by daily measurement of FVC using a handheld spirometer over the treatment period. Other functional parameters, patient-reported outcomes, samples for biomarker analysis and safety endpoints will be collected. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without IPAF.

Ethics and dissemination: This trial is being conducted in accordance with the International Conference on Harmonisation E6 guideline for Good Clinical Practice, Declaration of Helsinki and local laws for countries in which the research is conducted.

Trial registration number: NCT03099187.

Keywords: antifibrotic; interstitial pneumonia with autoimmune features; pirfenidone; unclassifiable interstitial lung disease.

Conflict of interest statement

Competing interests: TMM has received industry-academic research funding from GlaxoSmithKline R&D and UCB, has served on a clinical trial advisory board for GlaxoSmithKline R&D, has received stock options from Apellis and has received consultancy or speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB. TJC has received unrestricted educational grants, travel assistance and speaker fees from and served on an advisory board for Boehringer Ingelheim, has received unrestricted educational grants and speaker fees from and served on an advisory board for Roche, has received unrestricted educational grants from Actelion Ltd., Bayer, BMS and Sanofi and has served on an advisory board for AstraZeneca. AF serves as a consultant and steering committee member for Boehringer Ingelheim and Roche. MK, or his institution, has received unrestricted educational grants, speaker fees and research grants from Boehringer Ingelheim and Roche and has served on advisory boards for Boehringer Ingelheim and Roche. DJL is a steering committee member for this study and has received consulting fees from and has served on advisory boards for Genentech-Roche and Veracyte, has served on advisory boards for Boehringer Ingelheim, has served on an adjudication committee for Degge Group, has received lecture fees and fees for generation of educational content from and served on a steering committee for the France Foundation and has received consulting fees from FibroGen, Global Blood Therapeutics, ImmuneWorks, Patara Pharmaceuticals, Philips Respironics and Sanofi Genzyme. DJL’s institution, Columbia University, has received funding for clinical trials in IPF from Boehringer Ingelheim, FibroGen and Global Blood Therapeutics and has received consulting fees from the Pulmonary Fibrosis Foundation. MM-M, or her institution, has received grants from AstraZeneca, Boehringer Ingelheim, BRN, Chiesi, GlaxoSmithKline, InterMune and Roche. JA is an employee of F. Hoffmann-La Roche, Ltd. K-UK is an employee and shareholder of F. Hoffmann-La Roche, Ltd. VC receives consultancy and lecture fees and support for travel to medical meetings from Actelion and Roche, receives consultancy and lecture fees, support for travel to medical meetings and fees for development of educational presentations from Boehringer Ingelheim, receives consultancy and lecture fees from Novartis and Sanofi, receives consultancy fees from Bayer, Galapagos, GlaxoSmithKline and MSD, is a member of an adjudication committee for Gilead, is a chair of the DSMB for Promedior, is a member of the DSMB for Celgene and receives grants to his institution from Boehringer Ingelheim and Roche.

Figures

Figure 1

Study design. *Washout period for study participants taking prohibited medications prior to screening; patients not taking a prohibited medication will forgo the washout period and directly enter screening. †Informed consent may be obtained either at the washout (if applicable) or screening visits and must be obtained before any trial-specific screening procedure is performed. ‡After completion of the treatment period and follow-up visit, study participants will be given the opportunity to take part in an open-label extension of pirfenidone for up to 12 months; a final follow-up visit will be performed 4 weeks after the last open-label dose of pirfenidone. ICF, informed consent form.

Figure 2

Patient case study 1—chronic fibrosing ILD in the setting of IPAF. CCP, cyclic citrullinated peptide; DLco, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution CT; IIP, interstitial pneumonia; ILD, interstitial lung disease; IPAF, interstitial pneumonia with autoimmune features; MDT, multidisciplinary team; UIP, usual interstitial pneumonia.

Figure 3

Patient case study 2—fibrotic uILD in the setting of IPAF. CTD, connective tissue disease; DLco, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution CT; ILD, interstitial lung disease; IPAF, interstitial pneumonia with autoimmune features; IPF, idiopathic pulmonary fibrosis; MDT, multidisciplinary team; uILD, unclassifiable interstitial lung disease; UIP, usual interstitial pneumonia.

Figure 4

Patient case study 3—low-confidence chronic hypersensitivity pneumonitis. DLco, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution CT; MDT, multidisciplinary team; uILD, unclassifiable interstitial lung disease.