• Bruno Crestani, John T Huggins, Mitchell Kaye, Ulrich Costabel, Ian Glaspole, Takashi Ogura, Jin Woo Song, Wibke Stansen, Manuel Quaresma, Susanne Stowasser, and Michael Kreuter.
• Assistance Publique-Hôpitaux de Paris, Service de Pneumologie A, Hôpital Bichat, DHU FIRE, Paris, France; INSERM, Unité 1152, Paris, France; Université Paris Diderot, Paris, France. Electronic address: bruno.crestani@bch.aphp.fr.
• Lancet Respir Med. 2019 Jan 1; 7 (1): 60-68.

BackgroundThe efficacy and safety of nintedanib, an intracellular tyrosine kinase inhibitor, in patients with idiopathic pulmonary fibrosis were assessed in two phase 3, placebo-controlled INPULSIS trials. Patients who completed the 52-week treatment period in an INPULSIS trial could receive open-label nintedanib in the extension trial, INPULSIS-ON. We aimed to assess the long-term efficacy and safety of nintedanib in INPULSIS-ON.MethodsPatients who completed the 52-week treatment period of INPULSIS, and the follow-up visit 4 weeks later, were eligible for INPULSIS-ON. The off-treatment period between INPULSIS and INPULSIS-ON could be 4-12 weeks. Patients receiving nintedanib 150 mg twice daily or placebo at the end of an INPULSIS trial received nintedanib 150 mg twice daily in INPULSIS-ON. Patients receiving nintedanib 100 mg twice daily or placebo at the end of an INPULSIS trial could receive nintedanib 100 mg twice daily or 150 mg twice daily in INPULSIS-ON. Spirometric tests were done at baseline, at weeks 2, 4, 6, 12, 24, 36, 48, and then every 16 weeks. The primary outcome of INPULSIS-ON was to characterise the long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis, and this was analysed in patients who received at least one dose of nintedanib in INPULSIS-ON. This study is registered with ClinicalTrials.gov, number NCT01619085, and with EudraCT, number 2011-002766-21.FindingsThe first patient was enrolled into INPULSIS-ON in July 2, 2012. Of 807 patients who completed the INPULSIS trials, 734 (91%) were treated in INPULSIS-ON. 430 (59%) patients had received nintedanib in INPULSIS and continued nintedanib in INPULSIS-ON, and 304 (41%) had received placebo in INPULSIS and initiated nintedanib in INPULSIS-ON. Median exposure time for patients treated with nintedanib in both the INPULSIS and INPULSIS-ON trials was 44·7 months (range 11·9-68·3). The safety profile of nintedanib in INPULSIS-ON was consistent with that observed in INPULSIS. Diarrhoea was the most frequent adverse event in INPULSIS-ON (60·1 events per 100 patient exposure-years in patients who continued nintedanib, 71·2 events per 100 patient exposure-years in patients who initiated nintedanib). 20 (5%) of 430 patients who continued nintedanib and 31 (10%) of 304 patients who initiated nintedanib permanently discontinued nintedanib because of diarrhoea. The adverse event that most frequently led to permanent discontinuation of nintedanib was progression of idiopathic pulmonary fibrosis (51 [12%] patients continuing nintedanib and 43 [14%] patients initiating nintedanib). The event rate of bleeding was 8·4 events per 100 patient exposure-years in patients who continued nintedanib and 6·7 events per 100 patient exposure-years in patients who initiated nintedanib. The event rate of major adverse cardiovascular events was 3·6 events per 100 patient exposure-years in patients who continued nintedanib and 2·4 events per 100 patient exposure-years in patients who initiated nintedanib. The event rate of myocardial infarction using the broad scope (ie, all possible cases) was 1·3 events per 100 patient exposure-years in patients who continued nintedanib and 0·7 events per 100 patient exposure-years in patients who initiated nintedanib.InterpretationThese findings suggest that nintedanib has a manageable safety and tolerability profile over long-term use, with no new safety signals. Patients with idiopathic pulmonary fibrosis could use nintedanib over the long-term to slow disease progression.FundingBoehringer Ingelheim.Copyright © 2019 Elsevier Ltd. All rights reserved.

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