Comprehensive evaluation of the safety and utility of pravastatin in prevention of preeclampsia in high-risk pregnant women

普伐他汀预防高危孕妇子痫前期的安全性和有效性综合评价

• 批准号: 9119186
• 负责人: Maged Costantine
• 金额: $ 24.15万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9119186
• 关键词: Admission activity; Adverse event; Affect; Angiogenesis Inhibitors; Birth Weight; Cardiovascular Diseases; Categories; Clinical; Clinical Trials; Data; Development; Dose; Double-Blind Method; Drug Kinetics; Enzymes; Evaluation; Exhibits; Experimental Animal Model; Exposure to; FDA approved; Fetal Death; Fetal Growth Retardation; Fetus; Genes; Gestational Age; Goals; Grant; High Risk Woman; High-Risk Pregnancy; In Vitro; Investigation; Label; Maternal Exposure; Maternal-Fetal Medicine Units Network; Modality; Morbidity - disease rate; National Institute of Child Health and Human Development; Nurseries; Oral; Outcome; PGF gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Phase III Clinical Trials; Phenotype; Pilot Projects; Placebo Control; Placebos; Population; Postpartum Period; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant Women; Premature Birth; Prevention; Prophylactic treatment; Protocols documentation; Randomized; Randomized Clinical Trials; Recurrence; Research Personnel; Risk; Safety; Site; Therapeutic; Woman; adverse pregnancy outcome; clinical practice; cohort; congenital anomaly; effective therapy; fetal; high risk; in vivo; innovation; maternal morbidity; mortality; neonatal death; neonate; pilot trial; pregnant; prevent; prospective; sulfotransferase; uptake

ABSTRACT—Clinical Project Preeclampsia (PE) affects 3% to 8% of pregnant women and remains a major cause of morbidity and mortality. With no effective therapy for PE, the only approach to prevent maternal morbidity is delivery. Due to the similarities between PE and cardiovascular disease, we and others have demonstrated the ability of pravastatin (PRA) to reverse several pathophysiologic pathways and phenotypic features of PE. The labeling of PRA as category X is predominantly due to the absence of an indication for its use in pregnancy, as data from experimental animal models and cohorts of pregnant women exposed to PRA early in pregnancy did not support the teratogenicity claims of a category X medication. Recently, as a site in the NICHD-OPRU network and after obtaining an IND from the FDA, we completed a pilot, double-blinded, randomized clinical trial (RCT) of pregnant women at high risk of PE, randomized to 10 mg PRA or placebo. The study revealed favorable maternal-fetal safety and pharmacokinetic (PK) profiles of PRA in this population. The completed pilot trial utilized the lowest dose of PRA (10 mg) allowed in the IND, and our proposed investigation in this application will evaluate PRA at a higher dose (20 mg) already approved by the FDA IND. Our hypothesis is that pravastatin, when given to pregnant women at high risk of PE, exhibits favorable maternal-fetal safety, pharmacodynamics (PD), and PK Profiles. We are proposing a double-blind, placebo- controlled RCT of 100–120 pregnant women at high risk for PE to investigate the following specific aims: (1) determine the maternal-fetal safety profile of PRA during pregnancy, (2) determine whether early prophylactic treatment with PRA in high-risk women reverses the angiogenic imbalance associated with PE, (3) determine the PK of PRA and the formation of its metabolites during pregnancy (compared to the postpartum period), and (4) determine the effects of SNPs in genes encoding uptake and efflux transporters and sulfotransferase enzymes on maternal exposure to PRA. The data obtained on safety, PK parameters, and PD will be compared between the different doses to determine which dose results in the most significant PD effect and the most favorable safety profile. This determination will provide the framework required for the implementation of a larger clinical trial to determine PRA’s ability to prevent PE.

摘要-临床项目 先兆子痫（PE）影响3%至8%的孕妇，仍然是发病的主要原因， mortality.由于没有有效的治疗PE的方法，唯一的方法，以防止孕产妇发病率是交付。由于 PE和心血管疾病之间的相似性，我们和其他人已经证明了 普伐他汀（PRA）逆转PE的几种病理生理途径和表型特征。标签 PRA作为X类的主要原因是缺乏妊娠期使用的适应症，因为数据 从实验动物模型和妊娠早期暴露于PRA的孕妇队列中， 支持X类药物的致畸性声明。最近，作为NICHD-OPRU网络中的一个站点， 在从FDA获得IND后，我们完成了一项试点、双盲、随机临床试验（RCT） PE高危孕妇，随机分配至10 mg PRA或安慰剂组。研究显示， PRA在该人群中的母胎安全性和药代动力学（PK）特征。已完成的试点试验 使用IND中允许的最低剂量PRA（10 mg），以及我们在本申请中拟定的研究 将以FDA IND批准的更高剂量（20 mg）评价PRA。 我们的假设是，当给予PE高危孕妇普伐他汀时， 母胎安全性、药效学（PD）和PK特征。我们提出了一个双盲安慰剂- 100-120例PE高危孕妇的对照RCT，旨在研究以下具体目的：（1） 确定PRA在妊娠期间的母儿安全性;（2）确定是否早期预防性使用PRA。 在高危女性中用PRA治疗逆转了与PE相关的血管生成失衡，（3）确定 妊娠期间PRA的PK及其代谢产物的形成（与产后期相比），以及 (4)确定编码摄取和外排转运蛋白和磺基转移酶的基因中SNP的影响 酶对母体暴露于PRA的影响。 将比较不同剂量之间获得的安全性、PK参数和PD数据， 确定哪种剂量产生最显著的PD效应和最有利的安全性特征。这 确定将提供实施更大规模临床试验所需的框架，以确定 PRA预防PE的能力。