• Oliver Distler, Kristin B Highland, Martina Gahlemann, Arata Azuma, Aryeh Fischer, Maureen D Mayes, Ganesh Raghu, Wiebke Sauter, Mannaig Girard, Margarida Alves, Emmanuelle Clerisme-Beaty, Susanne Stowasser, Kay Tetzlaff, Masataka Kuwana, Toby M Maher, and SENSCIS Trial Investigators.
• From the Department of Rheumatology, University Hospital Zurich, Zurich (O.D.), and Boehringer Ingelheim (Schweiz), Basel (M. Gahlemann) - both in Switzerland; the Respiratory Institute, Cleveland Clinic, Cleveland (K.B.H.); the Departments of Pulmonary Medicine and Oncology (A.A.) and Allergy and Rheumatology (M.K.), Nippon Medical School Graduate School of Medicine, Tokyo; University of Colorado School of Medicine, Aurora (A.F.); the Division of Rheumatology and Clinical Immunogenetics, University of Texas McGovern Medical School, Houston (M.D.M.); University of Washington, Seattle (G.R.); Boehringer Ingelheim Pharma, Biberach an der Riss (W.S.), Boehringer Ingelheim International, Ingelheim am Rhein (M.A., E.C.-B., S.S., K.T.), and the Department of Sports Medicine, University of Tübingen, Tübingen (K.T.) - all in Germany; Boehringer Ingelheim France, Reims, France (M. Girard); and the National Heart and Lung Institute, Imperial College London, and the National Institute for Health Research Clinical Research Facility, Royal Brompton Hospital, London (T.M.M.).
• N. Engl. J. Med. 2019 Jun 27; 380 (26): 2518-2528.

BackgroundInterstitial 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.MethodsWe 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.ResultsA 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.ConclusionsAmong 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.).Copyright © 2019 Massachusetts Medical Society.

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