Pravastatin for Prevention of Preeclampsia

Condition(s) targeted: Preeclampsia

Intervention: Pravastatin (Drug); Placebo (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Official(s) and/or principal investigator(s):
Gary D. Hankins, MD, Principal Investigator, Affiliation: University of Texas
Steve Caritis, MD, Principal Investigator, Affiliation: University of Pittsburgh
Mary F. Hebert, PharmD, FCCP, Principal Investigator, Affiliation: University of Washington
David Flockhart, MD, PhD, Principal Investigator, Affiliation: Indiana University

The primary purpose of this pilot study is to determine the pharmacokinetic (PK) parameters and collect preliminary safety data for pravastatin when used as a prophylactic daily treatment in pregnant women at high risk of preeclampsia.

Official title: Pravastatin for the Prevention of Preeclampsia in High-Risk Women: A Phase I Pilot Study

Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Primary outcome:

Number and type of maternal adverse events

Number and type of fetal/neonatal adverse events

Pharmacokinetic parameters of pravastatin sodium during pregnancy

Detailed description: 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. There is strong evidence that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are beneficial in primary and secondary prevention of cardiovascular mortality and other cardiovascular events. Biological plausibility as well as animal data supports a similar role for statins in preeclampsia. Currently, there are no clinically available agents to prevent preeclampsia. However because of the below properties of statins, this class of medications could substantially contribute to preeclampsia prevention. 1. Statins pleiotropic actions on various mechanisms: reversing the angiogenic imbalance by upregulating vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), and reducing the antiangiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). 2. Statins up regulation of endothelial nitric oxide synthase, leading to improved nitric oxide production in the vasculature and to activate the heme oxygenase-1/carbon monoxide (HO-1/CO) pathway, protecting the endothelium and reducing the inflammatory and oxidative insults. The purpose of this pilot study is to evaluate the maternal-fetal safety and pharmacokinetic (PK) profiles of pravastatin when used in pregnant women at high-risk of developing preeclampsia.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Documented history (by chart review) of prior severe preeclampsia in either of the

two pregnancies preceding the current one and requiring delivery at 34 weeks or less gestation.

- 18 years or older with the ability to give informed consent

- Singleton pregnancy

- Normal serum transaminase (ALT and AST) concentrations in the last 6-months

- Gestational age (GA) between 12 weeks 0 days to 16 weeks 6 days based on clinical

information and confirmed by an ultrasound per study procedures Exclusion Criteria:

- Known chromosomal, genetic, or major fetal malformations, fetal demise, or planned

termination

- Multifetal gestation

- Patient with contraindications for statin therapy

- Hypersensitivity to pravastatin or any component of the product

- Active liver disease in the past 6 months (acute hepatitis, chronic active

hepatitis) by medical history

- Unexplained elevations (1. 5x normal) of serum transaminases persistent on

repeated laboratory testin in the 6 months before this visit

- Patients with any of the following conditions as it may predispose them to adverse

events or side effects.

- Current (past month) heavy alcohol use defined as ≥2 drinks per day

- Illicit drug use

- Amyotrophic lateral sclerosis (ALS)

- Concomitant therapy with fibrates, niacin, cyclosporine, clarithromycin or

erythromycin

- Recent (<6 months) history of liver disease or have unexplained elevated

transaminases or jaundice

- History of cholestasis of the liver in prior pregnancy

- Personal or family history of myopathy or rhabdomyolysis

- Statin use in current pregnancy or in the last month prior to pregnancy

- Patients with any of the following medical conditions as described in medical record

or patient history:

- Pregestational diabetes mellitus

- HIV positive

- Status post solid organ transplant

- Chronic renal disease/insufficiency with baseline serum creatinine ≥1. 5 mg/dL

- Epilepsy or other seizure disorder

- Uterine malformations

- Cancer

- Familial hypercholesterolemia

- Heart disease including prior myocardial infarction and prior cerebrovascular

accident

- Concurrent and chronic ( > 6 months) use of medications with potential drug

interactions with statins such as immunosuppressive drugs, gemfibrozil, niacin, erythromycin, itraconazole, cholestyramine, digoxin, rifampin (Patients will not be excluded if the drug has been discontinued)

- Inability to tolerate oral medications secondary to severe nausea and vomiting of

pregnancy

- Participating in another intervention study that influences maternal and fetal

morbidity and mortality

- Plans to deliver in a non-network site.

Indiana University School of Medicine, Indianapolis, Indiana 46202, United States

University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

University of Texas Medical Branch, Galveston, Texas 77555, United States

University of Washington, Seattle, Washington 98195, United States

Link is for OPRU home page

Starting date: August 2012
Last updated: April 30, 2015