2/2: A Randomized Controlled Trial of Pravastatin for the Prevention of Preeclampsia in High Risk Women

2/2：普伐他汀预防高危女性先兆子痫的随机对照试验

基本信息

批准号：
10022162
负责人：
Rebecca Gersnoviez Clifton
金额：
$ 217.54万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-23 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022162
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A 37 weeks gestation Address Adult Adverse event Angiogenic Factor Animals Authorization documentation Basic Science Biological Birth Weight Budgets Cardiovascular Diseases Cardiovascular system Cessation of life Characteristics Clinical Trials Complication Data Coordinating Center Development Direct Costs Disease Dose Double-Blind Method Drug Kinetics Effectiveness Endoglin Endothelium Evaluation Event Exposure to Fetal Death Fetal safety Fetus Funding Gestational Age Grant Growth Half-Life Hepatic High Risk Woman Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Inflammation Injury Lead Letters Life Maternal-Fetal Medicine Units Network Maternal-fetal medicine Mission Morbidity - disease rate Mothers Multicenter Studies National Heart, Lung, and Blood Institute National Institute of Child Health and Human Development Neonatal Neonatal Mortality Obstetric Fetal Pharmacology Organ failure Oxidative Stress Oxidoreductase PGF gene Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phase Pilot Projects Placebos Postpartum Period Pravastatin Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Pregnancy Rate Pregnant Women Premature Birth Prevention Primary Prevention Property Prophylactic treatment Randomized Randomized Controlled Trials Recording of previous events Recurrence Renal clearance function Research Risk Risk Factors Role Route Safety Secondary Prevention Seizures Seminal Series Serious Adverse Event Severities Teratogens Vascular Endothelial Growth Factor Receptor-1 Woman animal data cardiovascular disorder prevention cardiovascular disorder risk clinical center cohort design effective therapy endothelial dysfunction experience fetal high risk hydrophilicity improved indexing inhibitor/antagonist maternal morbidity maternal outcome mortality neonatal morbidity neonatal outcome neonate pilot trial preclinical study prevent randomized placebo controlled trial randomized placebo-controlled clinical trial randomized trial success

项目摘要

ABSTRACT Preeclampsia complicates approximately 3% to 5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. Women who have experienced preeclampsia in one pregnancy are at high risk for preeclampsia in subsequent pregnancies with the magnitude of the risk depending on the severity and gestational age at delivery in the index pregnancy. Preeclampsia shares pathogenic similarities with adult cardiovascular diseases as well as many risk factors. Endothelial dysfunction and inflammation are fundamental for the initiation and progression of both. Prevention of preeclampsia using various supplements and medications have had limited success. In contrast, there is strong evidence that 3-hydroxy-3- methylglutaryl-coenzyme A reductase inhibitors (statins) are beneficial in primary and secondary prevention of cardiovascular mortality and other cardiovascular events. Biological plausibility, animal data, and pilot clinical trials support a similar role for pravastatin, a hydrophilic statin with a favorable safety profile, in preventing preeclampsia prevention. In addition, the current evidence from animal studies and human pregnancy exposure cohorts do not support previous teratogenicity claims of pravastatin. Therefore we propose a multicenter, double blind, placebo-controlled randomized clinical trial to determine whether prophylactic treatment with pravastatin administered early in pregnancy reduces preeclampsia in high-risk women. A total of 1,760 pregnant women at high risk for preeclampsia (due to history of preeclampsia in a prior pregnancy that required delivery before 36 0/7 weeks) will be randomized between 100/7 and 166/7 weeks to pravastatin 10 mg or similarly appearing placebo, daily at bedtime until delivery. Women and their neonates will be followed throughout pregnancy and up to six weeks postpartum to address the primary aim: evaluate whether treatment with pravastatin reduces the recurrence rate of preeclampsia; as well as the following secondary aims: (1) evaluate whether pravastatin improves maternal and neonatal outcomes; (2) assess the maternal and fetal/neonatal safety profile of pravastatin during pregnancy; and (3) determine whether pravastatin administration in pregnancy reverses the angiogenic imbalance associated with preeclampsia by reducing the concentrations of the anti-angiogenic factors soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and increasing that of placental growth factor PlGF (angiogenic).

抽象的先兆子痫使大约 3% 至 5% 的妊娠变得复杂，并且仍然是孕产妇和孕妇的主要原因。新生儿发病率和死亡率。在一次妊娠中经历过先兆子痫的女性患病率较高随后怀孕时发生先兆子痫的风险，风险的大小取决于严重程度和妊娠指数中分娩时的胎龄。先兆子痫与成人具有致病相似性心血管疾病以及许多危险因素。内皮功能障碍和炎症是两者的启动和发展的基础。使用各种补充剂预防先兆子痫药物治疗的成功有限。相反，有强有力的证据表明 3-羟基-3- 甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）有利于一级和二级预防心血管死亡率和其他心血管事件。生物学合理性、动物数据和试点临床试验支持普伐他汀（一种具有良好安全性的亲水性他汀类药物）在预防先兆子痫的预防。此外，目前来自动物研究和人类怀孕的证据暴露队列不支持先前关于普伐他汀致畸性的说法。因此我们提出一个多中心、双盲、安慰剂对照随机临床试验，以确定是否可以预防性治疗怀孕早期给予普伐他汀治疗可减少高危女性的先兆子痫。总共有 1,760 名孕妇有先兆子痫的高风险（由于之前怀孕时有先兆子痫病史）需要在 36 0/7 周之前分娩）将在 100/7 至 166/7 周之间随机分配至普伐他汀 10 mg 或类似的安慰剂，每天睡前服用，直至分娩。妇女及其新生儿将受到跟踪在整个怀孕期间和产后六周内，以实现主要目标：评估治疗是否有效与普伐他汀一起降低先兆子痫的复发率；以及以下次要目标：(1) 评估普伐他汀是否改善孕产妇和新生儿结局； (2) 评估产妇和妊娠期间普伐他汀的胎儿/新生儿安全性概况； (3)确定普伐他汀是否妊娠期给药可通过减少与先兆子痫相关的血管生成失衡来逆转抗血管生成因子可溶性 Fms 样酪氨酸激酶 1 (sFlt-1) 和可溶性内皮糖蛋白的浓度 (sEng)，并增加胎盘生长因子 PlGF（血管生成）。