Investigating the effects of nintedanib on biomarkers of extracellular matrix turnover in patients with IPF: design of the randomised placebo-controlled INMARK®trial

Abstract

Introduction: A feature of the pathogenesis of idiopathic pulmonary fibrosis (IPF) is the excess accumulation of extracellular matrix (ECM) in the lungs. Cleavage of the ECM by metalloproteinases (MMPs) generates free-circulating protein fragments known as neoepitopes. The PROFILE study suggested that changes in ECM turnover proteins may be of value as markers of disease progression in patients with IPF. Nintedanib is an approved treatment for IPF that slows disease progression by reducing decline in forced vital capacity (FVC).

Methods and analysis: The INMARK® trial is evaluating the effect of nintedanib on the rates of change of biomarkers of ECM turnover in patients with IPF, the value of changes in these biomarkers as predictors of disease progression and whether nintedanib affects the associations between changes in these biomarkers and disease progression. Following a screening period, 347 patients with IPF and FVC ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg two times a day or placebo for 12 weeks, followed by an open-label period in which all patients will receive nintedanib for 40 weeks. The primary endpoint is the rate of change in C reactive protein degraded by MMP-1/8 from baseline to week 12.

Ethics and dissemination: This trial is being conducted in compliance with the protocol, the ethical principles detailed in the Declaration of Helsinki and in accordance with the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice. The results of the trial will be presented at national and international meetings and published in peer-reviewed journals.

Trial registration number: NCT02788474.

Keywords: interstitial fibrosis.

Conflict of interest statement

Competing interests: TMM has, via his institution, received industry-academic funding from GlaxoSmithKline and UCB as well as consultancy or speakers fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, GlaxoSmithKline, ProMetic, Roche, Sanumed and UCB as well as stock options from Apellis, outside the submitted work. YN reports grants from the Diffuse Lung Diseases Research Group from the Japanese Ministry of Health, Labour and Welfare, Core Research and Evolutional Science and Technology, Japan Science and Technology Corporation, Boehringer Ingelheim and Shionogi as well as personal fees from Boehringer Ingelheim and Shionogi, outside the submitted work. ESW reports grants from the US National Institutes of Health and Boehringer Ingelheim as well as personal fees from Boehringer Ingelheim, Kadmon Pharmaceuticals, Akcea Pharmaceuticals, outside the submitted work; he is also a Medical Advisory Board Member of the Pulmonary Fibrosis Foundation and International Conference Committee Chair-appointee of the American Thoracic Society. VC reports personal fees from Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Sanofi as well as grants from Actelion, Boehringer Ingelheim, GlaxoSmithKline, Pfizer and Roche outside the submitted work. IN reports personal fees from Boehringer Ingelheim, Genentech, ImmuneWorks, Sanofi-Aventis and Global Blood Therapeutics as well as grants from the US National Institutes of Health, outside the submitted work and has a patent pending re: TOLLIP and pharmacogenetics. MS reports personal fees from Boehringer Ingelheim, outside the submitted work. RGJ reports grants from GlaxoSmithKline, the UK Medical Research Council, Biogen, Galecto and MedImmune as well as personal fees from Boehringer Ingelheim, GlaxoSmithKline, InterMune, MedImmune, PharmAkea, Roche and Pulmatrix, outside the submitted work; he has served as a consultant for Pliant Therapeutics and MuMedii and a trustee for the charities Action for Pulmonary Fibrosis and the British Thoracic Society. SS, ZB, DW and CD are employees of Boehringer Ingelheim.

Figures

Figure 1

Design of the INMARK® trial.