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
基本信息
- 批准号:9119186
- 负责人:
- 金额:$ 24.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Admission activityAdverse eventAffectAngiogenesis InhibitorsBirth WeightCardiovascular DiseasesCategoriesClinicalClinical TrialsDataDevelopmentDoseDouble-Blind MethodDrug KineticsEnzymesEvaluationExhibitsExperimental Animal ModelExposure toFDA approvedFetal DeathFetal Growth RetardationFetusGenesGestational AgeGoalsGrantHigh Risk WomanHigh-Risk PregnancyIn VitroInvestigationLabelMaternal ExposureMaternal-Fetal Medicine Units NetworkModalityMorbidity - disease rateNational Institute of Child Health and Human DevelopmentNurseriesOralOutcomePGF genePathway interactionsPatientsPatternPharmaceutical PreparationsPharmacodynamicsPhase III Clinical TrialsPhenotypePilot ProjectsPlacebo ControlPlacebosPopulationPostpartum PeriodPravastatinPre-EclampsiaPregnancyPregnancy ComplicationsPregnant WomenPremature BirthPreventionProphylactic treatmentProtocols documentationRandomizedRandomized Clinical TrialsRecurrenceResearch PersonnelRiskSafetySiteTherapeuticWomanadverse pregnancy outcomeclinical practicecohortcongenital anomalyeffective therapyfetalhigh riskin vivoinnovationmaternal morbiditymortalityneonatal deathneonatepilot trialpregnantpreventprospectivesulfotransferaseuptake
项目摘要
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
子痫前期(PE)影响3%至8%的孕妇,仍然是发病率和
死亡率。在没有有效的PE治疗的情况下,预防产妇发病率的唯一方法就是分娩。由于
PE和心血管疾病的相似之处,我们和其他人已经证明了
普伐他汀(PRA)逆转PE的几个病理生理途径和表型特征。贴上标签
将PRA列为X类的主要原因是没有关于其在怀孕中的使用的迹象,作为数据
来自实验动物模型和妊娠早期暴露于PRA的孕妇的队列没有
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)。
对于PE高危孕妇,随机给予10毫克PRA或安慰剂。这项研究显示出有利于
PRA在该人群中的母婴安全性和药代动力学(PK)谱。已完成的试点试验
使用了IND中允许的最低剂量的PRA(10毫克),以及我们在此应用中建议的研究
将以FDA Ind已经批准的较高剂量(20毫克)评估PRA。
我们的假设是,当普伐他汀用于PE高危孕妇时,表现出良好的疗效
母婴安全性、药效学(PD)和PK配置文件。我们提出了一种双盲安慰剂-
对照研究100-120例PE高危孕妇随机对照试验
确定孕期PRA的母儿安全状况;(2)确定是否早期预防
高危女性的PRA治疗逆转了与PE相关的血管生成失衡,(3)确定
孕期PRA的PK及其代谢产物的形成(与产后相比),以及
(4)确定SNPs在编码摄取和外排转运蛋白和磺基转移酶基因中的作用
酵素对母亲暴露于PRA的影响。
安全性、PK参数和PD的数据将在不同剂量之间进行比较
确定哪种剂量可产生最显著的局部放电效应和最有利的安全性。这
确定将为实施更大的临床试验提供所需的框架,以确定
PRA预防PE的能力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Maged Costantine', 18)}}的其他基金
Developing Extracellular Vesicle Based MPRINT Translational Resource Platform for Monitoring Therapeutics Response During Pregnancy
开发基于细胞外囊泡的 MPRINT 转化资源平台,用于监测妊娠期间的治疗反应
- 批准号:
10747545 - 财政年份:2023
- 资助金额:
$ 24.15万 - 项目类别:
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:
10087196 - 财政年份:2019
- 资助金额:
$ 24.15万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 24.15万 - 项目类别:
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:
10162643 - 财政年份:2019
- 资助金额:
$ 24.15万 - 项目类别:
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:
10455106 - 财政年份:2019
- 资助金额:
$ 24.15万 - 项目类别:
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