1/2 A randomized controlled trial of pravastatin to prevent preeclampsia in high-risk women

1/2 普伐他汀预防高危女性先兆子痫的随机对照试验

• 批准号: 10705607
• 负责人: Maged Costantine
• 金额: --
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705607
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; 37 weeks gestation; Address; Adult; Adverse event; Angiogenesis Inhibitors; 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; 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; Hypertension; Inflammation; Injury; 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; Risk Reduction; 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; hypertensive; improved; indexing; inhibitor; 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

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 360/7 weeks) will be randomized between 100/7 and 166/7 weeks to pravastatin 10 mg or similar-appearing placebo, daily at bedtime until delivery. Women and their neonates will be followed throughout pregnancy and up to 6 weeks post partum 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).

摘要 先兆子痫合并约3%至5%的妊娠，仍然是母体和 新生儿发病率和死亡率。在一次妊娠中经历过先兆子痫的妇女处于高峰期 在后续妊娠中发生先兆子痫的风险，风险的大小取决于严重程度和 妊娠指标中分娩时的孕周。先兆子痫与成人的病原学相似 心血管疾病以及许多危险因素。内皮功能障碍和炎症 对两者的启动和发展都是至关重要的。应用多种补充剂预防子痫前期 而药物治疗的效果也有限。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)在一级和二级预防中有益 心血管死亡率和其他心血管事件。生物学可信度、动物数据和临床试验 普伐他汀是一种亲水性他汀类药物，具有良好的安全性，试验支持普伐他汀在预防 预防子痫前期。此外，目前来自动物研究和人类怀孕的证据 暴露队列不支持普伐他汀先前的致畸声明。因此，我们提出一项 多中心、双盲、安慰剂对照的随机临床试验，以确定预防 孕期早期给予普伐他汀治疗可减少高危妇女的先兆子痫。总计 1,760名先兆子痫高危孕妇(由于先前怀孕时有先兆子痫病史 要求在360/7周前分娩)将在100/7周和166/7周之间随机给予普伐他汀10 mg或 外观相似的安慰剂，每天睡前服用，直到分娩。妇女和她们的新生儿将被跟踪 在整个怀孕期间和产后6周内解决主要目标：评估治疗 使用普伐他汀可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了孕产妇和新生儿的结局；(2)评估了产妇和新生儿 妊娠期间普伐他汀对胎儿/新生儿的安全性；以及(3)确定普伐他汀是否 孕期给药通过减少先兆子痫相关的血管生成失衡 抗血管生成因子可溶性FMS样酪氨酸激酶-1(sFlt-1)和可溶性Enoglin的浓度 (Seng)，增加胎盘生长因子PlGF(血管生成)的表达。