Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON
Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON
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DOI：
10.1016/s2213-2600(18)30339-4
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发表时间：
2019-01-01
影响因子：
76.2
通讯作者：
Kreuter, Michael
中科院分区：
文献类型：
--
作者：
Crestani, Bruno;Huggins, John T.;Kreuter, Michael
背景 尼达尼布（一种细胞内酪氨酸激酶抑制剂）在特发性肺纤维化患者中的疗效和安全性在两项 3 期安慰剂对照 INPULSIS 试验中进行了评估。在 INPULSIS 试验中完成 52 周治疗期的患者可以在扩展试验 INPULSIS-ON 中接受开放标签尼达尼布治疗。我们的目的是评估尼达尼布在 INPULSIS-ON 中的长期疗效和安全性。方法 完成 INPULSIS 52 周治疗期以及 4 周后随访的患者符合 INPULSIS-ON 的条件。 INPULSIS 和 INPULSIS-ON 之间的停药期可能为 4-12 周。在 INPULSIS 试验结束时接受尼达尼布 150 mg 每天两次或安慰剂的患者在 INPULSIS-ON 试验中接受尼达尼布 150 mg 每天两次。在 INPULSIS 试验结束时接受尼达尼布 100 mg 每天两次或安慰剂的患者可以在 INPULSIS-ON 试验中接受尼达尼布 100 mg 每天两次或 150 mg 每天两次。在基线、第 2、4、6、12、24、36、48 周进行肺活量测试，然后每 16 周进行一次。 INPULSIS-ON 的主要结局是表征特发性肺纤维化患者中尼达尼布的长期安全性和耐受性，并在 INPULSIS-ON 中接受至少一剂尼达尼布的患者中进行了分析。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01619085，并在 EudraCT 注册，编号为 2011-002766-21。 结果 第一位患者于 2012 年 7 月 2 日入组 INPULSIS-ON。在完成 INPULSIS 试验的 807 名患者中，734 名 (91%) 接受了 INPULSIS-ON 治疗。 430 名 (59%) 患者在 INPULSIS 中接受了尼达尼布，并在 INPULSIS-ON 中继续接受尼达尼布，304 名 (41%) 患者在 INPULSIS 中接受了安慰剂，并在 INPULSIS-ON 中开始了尼达尼布。 INPULSIS 和 INPULSIS-ON 试验中接受尼达尼布治疗的患者的中位暴露时间均为 44.7 个月（范围 11.9-68.3）。 INPULSIS-ON 中尼达尼布的安全性与 INPULSIS 中观察到的一致。腹泻是 INPULSIS-ON 中最常见的不良事件（继续尼达尼布治疗的患者每 100 患者暴露年有 60.1 起事件，开始尼达尼布治疗的患者每 100 患者暴露年有 71.2 起事件）。继续使用尼达尼布的 430 名患者中有 20 名 (5%) 以及开始使用尼达尼布的 304 名患者中有 31 名 (10%) 因腹泻永久停用尼达尼布。最常导致永久停用尼达尼布的不良事件是特发性肺纤维化的进展（51 名[12%] 患者继续使用尼达尼布，43 名[14%] 患者开始尼达尼布）。继续使用尼达尼布的患者中，出血事件发生率为每 100 患者暴露年 8.4 起，而开始尼达尼布治疗的患者中，出血事件率为每 100 患者暴露年 6.7 起。在继续使用尼达尼布的患者中，主要不良心血管事件的发生率为每 100 患者暴露年 3.6 起事件，在开始尼达尼布治疗的患者中，每 100 患者暴露年发生 2.4 起事件。使用广泛范围（即所有可能病例）的心肌梗死事件发生率在继续使用尼达尼布的患者中为每 100 患者暴露年 1.3 次事件，在开始尼达尼布治疗的患者中每 100 患者暴露年发生 0.7 次事件。 解释 这些结果表明，尼达尼布在长期使用过程中具有可控的安全性和耐受性，没有新的安全信号。特发性肺纤维化患者可以长期使用尼达尼布来减缓疾病进展。版权所有 (c) 2018 Elsevier Ltd. 保留所有权利。
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.