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.
Medical University of South Carolina, Charleston, SC, USA.
Lancet Respir Med. 2019 Jan;7(1):60-68. doi: 10.1016/S2213-2600(18)30339-4. Epub 2018 Sep 14.
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.
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.
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.
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.
Boehringer Ingelheim.
在两项随机、安慰剂对照的 INPULSIS 试验中评估了细胞内酪氨酸激酶抑制剂尼达尼布治疗特发性肺纤维化患者的疗效和安全性。在 INPULSIS 试验中完成 52 周治疗期的患者可在扩展试验 INPULSIS-ON 中接受开放标签尼达尼布治疗。我们旨在评估尼达尼布在 INPULSIS-ON 中的长期疗效和安全性。
在 INPULSIS 试验中完成 52 周治疗期及随后 4 周随访的患者有资格参加 INPULSIS-ON。INPULSIS 和 INPULSIS-ON 之间的停药期可为 4-12 周。在 INPULSIS 试验结束时接受尼达尼布 150mg 每日两次或安慰剂治疗的患者在 INPULSIS-ON 中接受尼达尼布 150mg 每日两次治疗。在 INPULSIS 试验结束时接受尼达尼布 100mg 每日两次或安慰剂治疗的患者在 INPULSIS-ON 中可接受尼达尼布 100mg 每日两次或 150mg 每日两次治疗。在基线、第 2、4、6、12、24、36、48 周以及之后每 16 周进行肺量计测试。INPULSIS-ON 的主要终点是描述特发性肺纤维化患者尼达尼布的长期安全性和耐受性，这在 INPULSIS-ON 中至少接受一剂尼达尼布治疗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。
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，有 734 名（91%）接受了 INPULSIS-ON 治疗。430 名（59%）患者在 INPULSIS 中接受了尼达尼布治疗，并在 INPULSIS-ON 中继续使用尼达尼布治疗，304 名（41%）患者在 INPULSIS 中接受了安慰剂治疗，并在 INPULSIS-ON 中开始使用尼达尼布治疗。接受尼达尼布治疗的患者在 INPULSIS 和 INPULSIS-ON 试验中的中位暴露时间为 44.7 个月（范围为 11.9-68.3）。尼达尼布在 INPULSIS-ON 中的安全性与 INPULSIS 中的安全性一致。腹泻是 INPULSIS-ON 中最常见的不良事件（在继续使用尼达尼布的患者中，每 100 名患者暴露年发生 60.1 次事件，在开始使用尼达尼布的患者中每 100 名患者暴露年发生 71.2 次事件）。在继续使用尼达尼布的 430 名患者中，有 20 名（5%）和在开始使用尼达尼布的 304 名患者中，有 31 名（10%）因腹泻而永久停用尼达尼布。导致尼达尼布永久停药的最常见不良事件是特发性肺纤维化进展（继续使用尼达尼布的 51 名患者[12%]和开始使用尼达尼布的 43 名患者[14%]）。继续使用尼达尼布的患者出血事件发生率为每 100 名患者暴露年 8.4 次，开始使用尼达尼布的患者出血事件发生率为每 100 名患者暴露年 6.7 次。继续使用尼达尼布的患者主要不良心血管事件发生率为每 100 名患者暴露年 3.6 次，开始使用尼达尼布的患者主要不良心血管事件发生率为每 100 名患者暴露年 2.4 次。继续使用尼达尼布的患者心肌梗死的发生率（使用广义范围，即所有可能的病例）为每 100 名患者暴露年 1.3 次，开始使用尼达尼布的患者心肌梗死的发生率为每 100 名患者暴露年 0.7 次。
这些发现表明，尼达尼布在长期使用过程中具有可管理的安全性和耐受性，没有新的安全性信号。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。
勃林格殷格翰。
