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Biomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): a randomised, placebo-controlled study

2019; Elsevier BV; Volume: 7; Issue: 9 Linguagem: Inglês

10.1016/s2213-2600(19)30255-3

2213-2619

Toby M. Maher, Susanne Stowasser, Yasuhiko Nishioka, Eric S. White, Vincent Cottin, Imre Noth, Moisés Selman, Klaus Röhr, Andreas Michael, Carina Ittrich, Claudia Diefenbach, Gisli Jenkins, Tamera J. Corte, Ian Glaspole, Mark Holmes, Lauren Troy, Elizabeth Veitch, Benjamin Bondue, Caroline Dahlqvist, Renaud Louis, Jan P. van Meerbeeck, Wim Wuyts, Radka Bittenglová, Vı́tězslav Kolek, Norbert Pauk, Pavel Reiterer, Martina Šterclová, Maritta Kilpeläinen, Riitta Mäkitaro, Marjukka Myllärniemi, Minna Purokivi, Terhi Rantala, Vincent Cottin, Françis Couturaud, Dominique Israëł-Biet, S. Jouneau, Romain Kessler, François Lebargy, S. Marchand‐Adam, Tom Bollmann, Andreas Günther, Peter Hammerl, J Kirschner, Anne‐Marie Kirsten, Michael Kreuter, Claus Neurohr, Antje Prasse, Nicolas Schönfeld, Rainer Wiewrodt, Attila Somfay, Balazs Medgyasszay, Eszter Csánky, György Losonczy, Hiroki Hayashi, Sakae Homma, Yoshikazu Inoue, Shinyu Izumi, Hideya Kitamura, Yasuhiko Nishioka, Osamu Nishiyama, Takashi Ogura, Masaki Okamoto, Takefumi Saito, Hiroyuki Taniguchi, Yoshiaki Zaizen, Marzena Filipowska, Agnieszka Jarzemska, Władysław Pierzchała, Wojciech Piotrowski, Krzysztof Sładek, Ewa Trawińska, Young Whan Kim, Jong Sun Park, Jin Woo Song, Myriam Aburto, Diego Castillo, José María Echave-Sustaeta, Christian Garcia Fadul, Susana Herrera, Jorge Moisés, María Molina‐Molina, Amália Moreno, Asunción Nieto, María Jesús Rodríguez‐Nieto, José Antonio Rodríguez-Portal, Belén Safont, Jacobo Sellarés, Claudia Valenzuela, Huzaifa Adamali, Nazia Chaudhuri, Michael Gibbons, Rachel K. Hoyles, Toby M. Maher, Helen Parfrey, Francis Averill, Steven Chambers, Neil Ettinger, G. Giessel, Lisa Jones, Mitchell Kaye, David Oelberg, Jan Westerman, Donald F. Zoz,

Occupational exposure and asthma

Background A hallmark of idiopathic pulmonary fibrosis is the excess accumulation of extracellular matrix in the lungs. Degradation of extracellular matrix generates free-circulating protein fragments called neoepitopes. The aim of the INMARK trial was to investigate changes in neoepitopes as predictors of disease progression in patients with idiopathic pulmonary fibrosis and the effect of nintedanib on these biomarkers. Methods In this randomised, double-blind, placebo-controlled trial, patients with a diagnosis of idiopathic pulmonary fibrosis within the past 3 years and forced vital capacity (FVC) of 80% predicted or higher were eligible to participate. Patients were recruited from hospitals, private practices, clinical research units, and academic medical centres. Patients were randomly assigned (1:2) with the use of a pseudo-random number generator to receive oral nintedanib 150 mg twice a day or placebo for 12 weeks in a double-blind fashion, followed by open-label nintedanib for 40 weeks. The primary endpoint was the rate of change in C-reactive protein (CRP) degraded by matrix metalloproteinases 1 and 8 (CRPM) from baseline to week 12 in the intention-to-treat population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02788474, and with the European Clinical Trials Database, number 2015–003148–38. Findings Between June 27, 2016, and May 15, 2017, 347 patients were randomly assigned to the nintedanib group (n=116) or to the placebo group (n=231). One patient from the placebo group was not treated owing to a randomisation error. At baseline, mean FVC was 97·5% (SD 13·5) predicted. In the double-blind period, 116 patients received nintedanib and 230 patients received placebo. The rate of change in CRPM from baseline to week 12 was −2·57 × 10−3 ng/mL/month in the nintedanib group and −1·90 × 10−3 ng/mL/month in the placebo group (between-group difference −0·66 × 10−3 ng/mL/month [95% CI −6·21 × 10−3 to 4·88 × 10−3]; p=0·8146). The adjusted rate of change in FVC over 12 weeks was 5·9 mL in the nintedanib group and −70·2 mL in the placebo group (difference 76·1 mL/12 weeks [31·7 to 120·4]). In patients who received placebo for 12 weeks followed by open-label nintedanib, rising concentrations of CRPM over 12 weeks were associated with disease progression (absolute decline in FVC ≥10% predicted or death) over 52 weeks. In the double-blind period, serious adverse events were reported in eight (7%) patients given nintedanib and 18 (8%) patients given placebo. Grade 3 diarrhoea was reported in two (2%) patients in the nintedanib group and two (1%) patients in the placebo group. No patients had grade 4 diarrhoea. Interpretation In patients with idiopathic pulmonary fibrosis and preserved lung function, treatment with nintedanib versus placebo for 12 weeks did not affect the rate of change in CRPM but was associated with a reduced rate of decline in FVC. These results suggest that change in CRPM is not a marker of response to nintedanib in patients with idiopathic pulmonary fibrosis. Funding Boehringer Ingelheim.