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

项目摘要 Remdesivir是第一种有初步证据证明有效治疗COVID-19的药物，最近被 从FDA获得紧急使用授权，用于记录的COVID住院患者- 19.关于在以下药物中使用，尚无记录的药代动力学（PK）和有限的安全性数据 怀孕与妊娠相关的生理变化可能对药物治疗产生巨大影响。 处置和在妊娠期间使用治疗剂引起独特的安全性问题。的目标 拟定的IV期前瞻性、开放标签、非随机研究旨在评价PK（特定目的1）和 通过同情使用计划或开放获取方案提供的Remdesivir的安全性（具体目标2） 在20名住院治疗COVID-19相关症状的孕妇中， 研究方法和利用NIH赞助的国际孕产妇 儿童青少年艾滋病临床试验（IMPAACT）网络，并与吉利德科学合作。的 研究将在美国多个经验丰富的IMPAACT附属研究中心进行，这些研究中心已被证明可获得 研究人群。计划接受COVID-19治疗的18岁以上住院孕妇 如果愿意并能够提供知情同意书，则作为临床护理一部分的Remdesivir将有资格入组， 如果一名法律认可的代表可以代表她这样做的话。主要结果指标将是 比较研究参与者（妊娠女性）与非妊娠女性的Remdesivir PK参数 成年人了主要PK终点是remdesivir及其主要代谢产物GS-441524，第1天的AUC 0 - 24 h， 末次给药后的GS-441524 AUCtau。密集和稀疏采样的瑞德西韦浓度将用于 群体PK分析，以评估协变量（如妊娠阶段和COVID严重程度）的影响- 19例疾病的Remdesivir PK参数。将定量血浆Remdesivir和GS-441524浓度 在实验室中，正在进行的由吉利德支持的在非妊娠成人中进行的瑞德西韦研究， 确保可比性。入组时和末次给药后，安全性监测将包括肝功能和肾功能 检查和全血细胞计数（如果未在24小时内获得临床护理）和病历提取 其他实验室检查结果和临床事件。实验室检查结果的病历摘要， 临床事件也将在给药后4周以及分娩和分娩后进行。拟定研究 将提供急需的妊娠特异性临床药理学数据，以确保Remdesivir可以 尽快安全有效地用于孕妇。这项研究也可以作为 该模型可以快速提供其他COVID治疗药物的妊娠PK和安全性数据， available.

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.