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TRPC6 inhibitor (BI 764198) to reduce risk and severity of ARDS due to COVID-19: a phase II randomised controlled trial
Thorax ( IF 10 ) Pub Date : 2023-08-01 , DOI: 10.1136/thorax-2022-219668
Lorraine B Ware 1, 2 , Nima Soleymanlou 3 , Danny Francis McAuley 4 , Vicente Estrada 5 , George A Diaz 6 , Peter Lacamera 7 , Renee Kaste 3 , Wansuk Choi 3 , Abhya Gupta 8 , Tobias Welte 9
Affiliation  

Background Despite the availability of COVID-19 vaccinations, there remains a need to investigate treatments to reduce the risk or severity of potentially fatal complications of COVID-19, such as acute respiratory distress syndrome (ARDS). This study evaluated the efficacy and safety of the transient receptor potential channel C6 (TRPC6) inhibitor, BI 764198, in reducing the risk and/or severity of ARDS in patients hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen support (oxygen by mask or nasal prongs, oxygen by non-invasive ventilation or high-flow nasal oxygen). Methods Multicentre, double-blind, randomised phase II trial comparing once-daily oral BI 764198 (n=65) with placebo (n=64) for 28 days (+2-month follow-up). Primary endpoint: proportion of patients alive and free of mechanical ventilation at day 29. Secondary endpoints: proportion of patients alive and discharged without oxygen (day 29); occurrence of either in-hospital mortality, intensive care unit admission or mechanical ventilation (day 29); time to first response (clinical improvement/recovery); ventilator-free days (day 29); and mortality (days 15, 29, 60 and 90). Results No difference was observed for the primary endpoint: BI 764198 (83.1%) versus placebo (87.5%) (estimated risk difference –5.39%; 95% CI –16.08 to 5.30; p=0.323). For secondary endpoints, a longer time to first response (rate ratio 0.67; 95% CI 0.46 to 0.99; p=0.045) and longer hospitalisation (+3.41 days; 95% CI 0.49 to 6.34; p=0.023) for BI 764198 versus placebo was observed; no other significant differences were observed. On-treatment adverse events were similar between trial arms and more fatal events were reported for BI 764198 (n=7) versus placebo (n=2). Treatment was stopped early based on an interim observation of a lack of efficacy and an imbalance of fatal events (Data Monitoring Committee recommendation). Conclusions TRPC6 inhibition was not effective in reducing the risk and/or severity of ARDS in patients with COVID-19 requiring non-invasive, supplemental oxygen support. Trial registration number [NCT04604184][1]. Data are available upon reasonable request. To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Researchers should use the link to request access to study data and visit for further information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04604184&atom=%2Fthoraxjnl%2F78%2F8%2F816.atom

中文翻译:

TRPC6 抑制剂 (BI 764198) 可降低 COVID-19 所致 ARDS 的风险和严重程度:一项 II 期随机对照试验

背景 尽管可以接种 COVID-19 疫苗,但仍然需要研究治疗方法,以降低 COVID-19 潜在致命并发症(例如急性呼吸窘迫综合征 (ARDS))的风险或严重程度。本研究评估了瞬时受体电位通道 C6 (TRPC6) 抑制剂 BI 764198 在降低因 COVID-19 住院且需要非侵入性补充氧支持(氧气)患者 ARDS 风险和/或严重程度方面的有效性和安全性。通过面罩或鼻塞、通过无创通气或高流量鼻氧给氧)。方法 多中心、双盲、随机 II 期试验比较每日一次口服 BI 764198 (n=65) 与安慰剂 (n=64) 28 天(+2 个月随访)。主要终点:第 29 天存活且无需机械通气的患者比例。次要终点:存活且出院时无需吸氧的患者比例(第 29 天);发生院内死亡、入住重症监护病房或机械通气(第 29 天);首次反应时间(临床改善/恢复);无呼吸机天数(第 29 天);和死亡率(第 15、29、60 和 90 天)。结果 主要终点:BI 764198 (83.1%) 与安慰剂 (87.5%) 相比,未观察到差异(估计风险差异 –5.39%;95% CI –16.08 至 5.30;p=0.323)。对于次要终点,与安慰剂相比,BI 764198 的首次缓解时间更长(比率 0.67;95% CI 0.46 至 0.99;p=0.045),住院时间更长(+3.41 天;95% CI 0.49 至 6.34;p=0.023)被观测到; 没有观察到其他显着差异。试验组之间的治疗中不良事件相似,与安慰剂 (n=2) 相比,BI 764198 (n=7) 报告的致命事件更多。根据对缺乏疗效和致命事件不平衡的临时观察,治疗提前停止(数据监测委员会建议)。结论 TRPC6 抑制不能有效降低需要无创补充氧支持的 COVID-19 患者发生 ARDS 的风险和/或严重程度。试用注册号[NCT04604184][1]。数据可根据合理要求提供。为了确保对临床研究结果的独立解释,并使作者能够履行 ICMJE 标准下的角色和义务,勃林格殷格翰授予所有外部作者访问相关临床研究数据的权限。根据勃林格殷格翰关于临床研究数据透明度和发布的政策,科学和医学研究人员可以在同行评审期刊上发表原始手稿、监管活动完成且满足其他标准后请求访问临床研究数据。研究人员应该使用请求访问研究数据并访问的链接了解更多信息。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04604184&atom=%2Fthoraxjnl%2F78%2F8%2F816.atom
更新日期:2023-07-13
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