LOC-IMPAACT Leadership GroupPharmacokinetics and Safety of Remdesivir for Treatment of COVID-19 in Pregnant Women in the US

项目总结 雷米西韦是第一个有初步证据表明对新冠肺炎有疗效的药物，最近 获得FDA的紧急使用授权，用于有记录的COVID住院患者- 19.没有记录的药代动力学(PK)和有限的安全数据可用于 怀孕了。与怀孕相关的生理变化可能会对药物产生巨大影响 在怀孕期间使用治疗剂引起了独特的安全问题。该计划的目标是 拟议的第四阶段前瞻性、开放标签、非随机研究将评估PK(特定目标1)和 通过同情使用计划或开放获取协议提供的瑞希韦的安全性(具体目标2) 在20名住院孕妇中用于治疗新冠肺炎相关症状，采用了一套行之有效的 研究方法和利用NIH赞助的国际产妇的广泛基础设施 儿童青少年艾滋病临床试验(IMPAACT)网络，并与吉列德科学公司合作。这个 研究将在美国多个经验丰富的IMPAACT附属网站进行，这些网站已被证明可以访问 研究人口。住院孕妇&18岁，新冠肺炎预定接诊 作为临床护理的一部分，如果愿意并能够提供知情同意或 如果法律认可的代表可以代表她这样做。主要结果衡量标准将是 受试者(孕妇)与非孕妇瑞希韦PK参数的比较 成年人。第一天的主要PK终点是瑞美西韦及其主要代谢物GS-441524，AUC0-24，以及 末次给药后GS-441524 AUCtau。密集和稀疏采样的瑞希韦浓度将用于 人口PK分析，以评估协变量的影响，如怀孕阶段和严重程度的COVID- 19个疾病在Remdesivir PK参数上。将对雷米德韦和GS-441524的血浆浓度进行量化 在用于正在进行的吉列德支持的非妊娠成人雷米希韦研究的实验室中， 确保可比性。在进入和最后一次注射后，安全监测将包括肝和肾功能。 化验和完整的血细胞计数(如果在24小时内无法获得临床护理)和病历摘要 获取其他实验室检测结果和临床事件。实验室检测结果的病历摘要 临床事件也将在给药后4周以及分娩和分娩后进行。建议进行的研究 将提供急需的针对妊娠的临床药理学数据，以确保瑞希韦可以 尽快在孕妇身上安全有效地使用。这项研究也可以作为一种 快速为其他COVID治疗药物提供怀孕PK和安全数据的模型 可用。

PROJECT SUMMARY Remdesivir, the first drug with preliminary evidence of efficacy for treatment of COVID-19, has recently been awarded Emergency Use Authorization from the FDA for use in hospitalized patients with documented COVID- 19. There are no documented pharmacokinetic (PK) and limited safety data available regarding use in pregnancy. The physiological changes associated with pregnancy can have a dramatic impact on drug disposition, and use of therapeutic agents during pregnancy poses unique safety concerns. The aims of the proposed Phase IV prospective, open label, non-randomized study are to evaluate the PK (Specific Aim 1) and safety (Specific Aim 2) of remdesivir provided through a compassionate use program or open access protocol in 20 hospitalized pregnant women for treatment of symptoms related to COVID-19, using a well-established study approach and leveraging the extensive infrastructure of the NIH-sponsored International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network and in collaboration with Gilead Sciences. The study will be conducted at multiple experienced IMPAACT-affiliated sites in the US with proven access to the study population. Hospitalized pregnant women >18 years of age with COVID-19 scheduled to receive remdesivir as part of clinical care will be eligible for enrollment if willing and able to provide informed consent or if a legally recognized representative can do so on her behalf. The primary outcome measure will be a comparison of remdesivir PK parameters from study participants (pregnant women) with those in non-pregnant adults. The primary PK endpoints are remdesivir and its major metabolite, GS-441524, AUC0-24h at Day 1, and GS-441524 AUCtau after last dose. Intensive and sparse sampling remdesivir concentrations will be used in a population PK analysis to assess the impact of covariates such as stage of pregnancy and severity of COVID- 19 disease on remdesivir PK parameters. Plasma remdesivir and GS-441524 concentrations will be quantified in the laboratory being used for ongoing Gilead-supported studies of remdesivir in non-pregnant adults, ensuring comparability. At entry and after the last dose, safety monitoring will include liver and renal function tests and complete blood count (if not obtained within 24 hours for clinical care) and medical record abstraction for other laboratory test results and clinical events. Medical record abstraction for laboratory test results and clinical events will also be performed at 4 weeks postdosing and after labor and delivery. The proposed study will provide urgently needed pregnancy-specific clinical pharmacology data that will ensure that remdesivir can be used safely and effectively in pregnant women as rapidly as possible. This research could also serve as a model to rapidly provide pregnancy PK and safety data for other COVID- therapeutics as they become available.