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％的妊娠复杂化，并且仍然是母亲和孕妇的主要原因新生儿发病率和死亡率。在一次怀孕中经历了先兆子痫的女性很高在随后的怀孕中，先兆子痫的风险，风险的严重程度，具体取决于严重程度和指数怀孕时分娩时的妊娠年龄。先兆子痫与成人有致病性相似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）对原发性和次要预防有益心血管死亡率和其他心血管事件。生物合理性，动物数据和试验临床试验支持Pravastatin的类似作用，Pravastatin是一种具有良好安全性的亲水性他汀类药物，以防止预防先兆子痫。此外，目前来自动物研究和人类怀孕的证据暴露群体不支持pravastatin的先前致病性主张。因此，我们提出了一个多中心，双盲，安慰剂对照的随机临床试验，以确定是否预防性怀孕早期服用pravastatin治疗可减少高危女性的先兆子痫。总共 1,760名孕妇患前启示性的高风险（由于先前怀孕的先兆子痫病史在36 0/7周之前需要交付）将在100/7至166/7周之间随机分配至pravastatin 10 mg 或类似地出现安慰剂，每天就睡前直到交货。妇女及其新生儿将被遵循在整个怀孕期间和产后最多六个星期以解决主要目的：评估是否治疗 pravastatin降低了子痫前期的复发率；以及以下次要目标：（1）评估pravastatin是否改善了孕产妇和新生儿结局；（2）评估母亲和妊娠期间pravastatin的胎儿/新生儿安全性；（3）确定pravastatin是否怀孕的给药可以通过减少与先兆子痫相关的血管生成失衡抗血管生成因子的浓度可溶性FMS样酪氨酸激酶-1（SFLT-1）和可溶性内og （Seng），并增加胎盘生长因子PLGF（血管生成）。