Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON

被引:185
作者
Crestani, Bruno [1 ,2 ,3 ]
Huggins, John T. [4 ]
Kaye, Mitchell [5 ]
Costabel, Ulrich [6 ]
Glaspole, Ian [7 ,8 ]
Ogura, Takashi [9 ]
Song, Jin Woo [10 ]
Stansen, Wibke [11 ]
Quaresma, Manuel [11 ]
Stowasser, Susanne [11 ]
Kreuter, Michael [12 ,13 ]
机构
[1] Hop Bichat Claude Bernard, AP HP, DHU FIRE, Serv Pneumol A, Paris, France
[2] INSERM, Unite 1152, Paris, France
[3] Univ Paris Diderot, Paris, France
[4] Med Univ South Carolina, Charleston, SC 29425 USA
[5] Minnesota Lung Ctr, Minneapolis, MN USA
[6] Univ Duisburg Essen, Univ Hosp, Ruhrlandklin, Essen, Germany
[7] Monash Univ, Alfred Hlth, Dept Allergy Immunol & Resp Med, Melbourne, Vic, Australia
[8] Monash Univ, Dept Med, Melbourne, Vic, Australia
[9] Kanagawa Cardiovasc & Resp Ctr, Dept Resp Med, Yokohama, Kanagawa, Japan
[10] Univ Ulsan, Coll Med, ASAN Med Ctr, Dept Pulm & Crit Care Med, Seoul, South Korea
[11] Boehringer Ingelheim Int GmbH, Ingelheim, Germany
[12] Heidelberg Univ, Thoraxklin, Ctr Interstitial & Rare Lung Dis Pneumol, Heidelberg, Germany
[13] German Ctr Lung Res, Hannover, Germany
关键词
FORCED VITAL CAPACITY; CLINICAL-PRACTICE; EFFICACY; SURVIVAL; TRIALS;
D O I
10.1016/S2213-2600(18)30339-4
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Background The 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. Methods Patients 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. Findings The 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. Interpretation These 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. Copyright (c) 2018 Elsevier Ltd. All rights reserved.
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页码:60 / 68
页数:9
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