Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

Athol U. Wells*, Kevin R. Flaherty, Kevin K. Brown, Yoshikazu Inoue, Anand Devaraj, Luca Richeldi, Teng Moua, Bruno Crestani, Wim A. Wuyts, Susanne Stowasser, Manuel Quaresma, Rainer Georg Goeldner, Rozsa Schlenker-Herceg, Martin Kolb, S. Abe, M. Aburto, O. Acosta, C. Andrews, D. Antin-Ozerkis, G. ArceM. Arias, S. Avdeev, A. Barczyk, R. Bascom, E. Bazdyrev, P. Beirne, E. Belloli, M. A. Bergna, E. Bergot, N. Bhatt, S. Blaas, B. Bondue, F. Bonella, E. Britt, K. Buch, J. Burk, H. Cai, A. Cantin, D. M. Castillo Villegas, A. Cazaux, S. Cerri, S. Chaaban, N. Chaudhuri, V. Cottin, B. Crestani, G. Criner, C. Dahlqvist, S. Danoff, J. Dematte D'Amico, D. Dilling, P. Elias, N. Ettinger, J. Falk, E. R. Fernández Pérez, A. Gamez-Dubuis, G. Giessel, A. Gifford, M. Glassberg, C. Glazer, J. Golden, L. Gómez Carrera, J. Guiot, R. Hallowell, H. Hayashi, J. Hetzel, N. Hirani, L. Homik, B. Hope-Gill, D. Hotchkin, K. Ichikado, M. Ilkovich, Y. Inoue, S. Izumi, E. Jassem, L. Jones, S. Jouneau, R. Kaner, J. Kang, T. Kawamura, R. Kessler, Y. Kim, K. Kishi, H. Kitamura, Y. Kondoh, C. Kono, D. Koschel, M. Kreuter, T. Kulkarni, J. Kus, F. Lebargy, A. León Jiménez, Q. Luo, Y. Mageto, T. M. Maher, S. Makino, S. Marchand-Adam, C. Marquette, R. Martinez, M. Martínez, R. Maturana Rozas, Y. Miyazaki, S. Moiseev, M. Molina-Molina, L. Morrison, L. Morrow, T. Moua, A. Nambiar, Y. Nishioka, H. Nunes, M. Okamoto, J. Oldham, M. Otaola, M. Padilla, J. S. Park, N. Patel, A. Pesci, W. Piotrowski, L. Pitts, H. Poonyagariyagorn, A. Prasse, S. Quadrelli, W. Randerath, R. Refini, M. Reynaud-Gaubert, F. Riviere, J. A. Rodríguez Portal, I. Rosas, M. Rossman, Z. Safdar, T. Saito, N. Sakamoto, M. Salinas Fénero, J. Sauleda, S. Schmidt, M. B. Scholand, M. Schwartz, S. Shapera, O. Shlobin, B. Sigal, A. Silva Orellana, D. Skowasch, J. W. Song, S. Stieglitz, H. Stone, M. Strek, T. Suda, H. Sugiura, H. Takahashi, H. Takaya, T. Takeuchi, K. Thavarajah, L. Tolle, S. Tomassetti, K. Tomii, C. Valenzuela, C. Vancheri, F. Varone, S. Veeraraghavan, A. Villar, S. Weigt, L. Wemeau, W. Wuyts, Z. Xu, V. Yakusevich, Y. Yamada, H. Yamauchi, D. Ziora

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

357 Scopus citations

Abstract

Background: The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. Methods: The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Findings: Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI −8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [−31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. Interpretation: The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Funding: Boehringer Ingelheim.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalThe Lancet Respiratory Medicine
Volume8
Issue number5
DOIs
StatePublished - May 1 2020

Funding

The INBUILD trial was funded by Boehringer Ingelheim. The authors thank the patients and investigators who participated in this trial. Writing assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng and Wendy Morris of FleishmanHillard Fishburn, London, UK, during the development of this manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of development and provided their approval on the final version. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The INBUILD trial was funded by Boehringer Ingelheim. The authors thank the patients and investigators who participated in this trial. Writing assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng and Wendy Morris of FleishmanHillard Fishburn, London, UK, during the development of this manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of development and provided their approval on the final version. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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