Abstract
BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52.
RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group.
CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2518-2528 |
| Number of pages | 11 |
| Journal | The New England journal of medicine |
| Volume | 380 |
| Issue number | 26 |
| DOIs | |
| State | Published - Jun 27 2019 |
Bibliographical note
Funding Information:Dr. Distler reports receiving grant support and lecture fees from Actellion, fees for project scoring from AbbVie, consulting fees from Acceleron Pharma, Anamar, Amgen, Blade Therapeutics, CSL Behring, ChemomAb, Ergonex, Glenmark Pharma, GSK, Inventiva, Italfarmaco, iQvia, Medac, Medscape, Lilly, Sanofi, Target BioScience, and UCB, grant support, consulting fees, and lecture fees from Bayer and Boehringer Ingelheim, fees for an interview from Catenion, lecture fees from iQone, Men-arini, Mepha, and Novartis, grant support and consulting fees from Mitsubishi, lecture fees and consulting fees from MSD and Roche, and lecture fees, consulting fees, and travel support from Pfizer, and holding patent US8247389 on the treatment of systemic sclerosis, assigned to the University of Zurich; Dr. Highland, receiving grant support and lecture fees from and serving on an advisory committee for Actelion Pharmaceuticals, receiving lecture fees from Bayer Healthcare, receiving grant support, lecture fees, and consulting fees from and serving on a steering committee for Boehringer Ingelheim, serving as a site principal investigator for Genentech, Eiger Pharmaceuticals, and Reata Pharmaceuticals, and receiving grant support and lecture fees from United Therapeutics; Dr. Gahlemann, being employed by Boehringer Ingelheim; Dr. Azuma, receiving lecture fees and consulting fees from Boehringer Ingelheim, lecture fees from Shionogi, and consulting fees from Taiho Pharmaceuticals and Asahikasei Pharma; Dr. Fischer, receiving consulting fees, fees for serving on a steering committee, and fees for serving as principal investigator from Genentech-Roche and consulting fees from Pfizer and Genentech; Dr. Mayes, receiving advisory board fees from Galapagos NV Pharma, Astellas, and Mitsubishi-Tanabe, lecture fees from Medtelligence, fees for serving as a reviewer for a grant program from Actellion Pharma, and grant support from Bayer, Reata, Sanofi, Corbus, and Eicos/Sciences; Dr. Raghu, receiving consulting fees from Bellerophan, Biogen, and Genentech-Roche, serving as a consultant for BMS, Fibro-gen, Gilead, Nitto, and Promedior, receiving consulting fees and travel support from Revistan, Sanofi, and Veracyte, and receiving consulting fees from and serving as chair of a data and safety monitoring board for Avalyn; Drs. Sauter, Girard, Alves, Clerisme-Beaty, Stowasser, and Tetzlaff, being employed by Boehringer Ingelheim; Dr. Kuwana, receiving fees for serving on a steering committee, consulting fees, and fees for serving on a speakers bureau from Chugai, grant support and fees for serving on a speakers bureau from Actellion, and consulting fees from Reata, Bayer, Corbus, and CSL Behring; and Dr. Maher, receiving grant support, consulting fees, and fees for serving on data and safety monitoring committees from GlaxoSmithKline, grant support and consulting fees from UCB, consulting fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Galapagos, Indalo, Pliant, ProMetic, Samumed, and Galecto, and consulting fees and lecture fees from Boehringer Ingelheim and Roche. No other potential conflict of interest relevant to this article was reported.
Funding Information:
We thank the patients who participated in this trial; Veronika Kohlbrenner of Boehringer Ingelheim Pharmaceuticals for her advice on the interpretation of safety data; Elizabeth Ng and Wendy Morris of FleishmanHillard Fishburn, London, for medical writing assistance (supported financially by Boehringer Ingel-heim) during the preparation of an earlier version of the manuscript; the following representatives of scleroderma patient organizations for their advice regarding aspects of the design and implementation of this clinical trial: Edith Brown (Scleroderma and Raynaud’s U.K.), Ilaria Galetti (Federation of European Scleroderma Associations [FESCA] and Gruppo Italiano per la Lotta alla Sclerodermia, Italy), Alex Gonzalez (Scleroderma Research Foundation, United States), Alexandra Paula Portales Guiraud (Asociación Española de Esclerodermia, Spain), Ann Tyrrell Kennedy (FESCA), Catarina Leite (Associação Portuguesa de Doentes com Esclerodermia, Portugal), Michael Oeschger (Sklerodermie Selbsthilfe e.V., Germany), Robert J. Riggs (Scleroderma Foundation, United States), Annelise Rønnow (FESCA and Sklerodermiforeningen, Denmark), Maureen Sauvé (Scleroderma Canada), and Joep Welling (FESCA); and the members of the Data Monitoring Committee (James R. Seibold [chair], Ulrich Costabel, Robert Makuch, and Timothy Shapiro) and the Adjudication Committee (Lorcan McGarvey [chair], Murat İnanç, Alan B Miller, Scott Kasner, and Bradley Knight). We acknowledge general support to Dr. Maher from the National Institute for Health Research (NIHR Clinician Scientist Fellowship) and the British Lung Foundation (British Lung Foundation Chair in Respiratory Research). See also section M of the Supplementary Appendix.
Publisher Copyright:
Copyright © 2019 Massachusetts Medical Society.
Keywords
- Administration, Oral
- Adult
- Diarrhea/chemically induced
- Disease Progression
- Double-Blind Method
- Enzyme Inhibitors/adverse effects
- Female
- Humans
- Indoles/adverse effects
- Lung Diseases, Interstitial/drug therapy
- Male
- Middle Aged
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Scleroderma, Systemic/complications
- Vital Capacity
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Randomized Controlled Trial
- Multicenter Study
- Journal Article
