Statin: Pravastatin for Prevention of Preeclampsia

Sponsor

The University of Texas Medical Branch, Galveston (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01717586

Collaborator

University of Pittsburgh (Other), Northwestern University (Other), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

Enrollment

Locations

Arms

124

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Preeclampsia	Drug: Pravastatin Drug: Placebo	Phase 1

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.

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).
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Aug 1, 2012

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pravastatin Group Pregnant women at high-risk for preeclampsia who are taking pravastatin during their pregnancy.	Drug: Pravastatin Comparison of different drug dosages. Women will be instructed to take a pravastatin pill everyday starting the day of randomization and ending the day of delivery. The women will be divided into three cohorts. Each cohort will receive one of the following doses of pills: 10mg or 20mg or 40mg. Other Names: pravastatin sodium Brand name: Pravachol®
Placebo Comparator: Control Group Pregnant women who are at high-risk for developing preeclampsia who are taking a placebo during their pregnancy.	Drug: Placebo Women will be instructed to take a placebo pill daily beginning the day of randomization and ending the day of delivery.

Arm

Intervention/Treatment

Active Comparator: Pravastatin Group

Pregnant women at high-risk for preeclampsia who are taking pravastatin during their pregnancy.

Drug: Pravastatin

Comparison of different drug dosages. Women will be instructed to take a pravastatin pill everyday starting the day of randomization and ending the day of delivery. The women will be divided into three cohorts. Each cohort will receive one of the following doses of pills: 10mg or 20mg or 40mg.

Other Names:

pravastatin sodium

Brand name: Pravachol®

Placebo Comparator: Control Group

Pregnant women who are at high-risk for developing preeclampsia who are taking a placebo during their pregnancy.

Drug: Placebo

Women will be instructed to take a placebo pill daily beginning the day of randomization and ending the day of delivery.

Outcome Measures

Primary Outcome Measures

Number and type of maternal adverse events [From the date of randomization until the date of delivery, assessed up to 210 days]
The presence of side effects and adverse events will be assessed at each study visit by: a symptoms checklist any other report of adverse events at select visits: laboratory testing for liver function test(LFT) and creatine kinase(CK)
Number and type of fetal/neonatal adverse events [From date of birth up to discharge or 120 days after birth.]
The presence of adverse events will be assessed by evaluating Fetal and neonatal death Birthweight (including rate of small for gestational age) Apgar scores Congenital malformations Auditory brainstem response (ABR) evoked potential Cord blood lipid profile, AST/ALT, and CK levels
Pharmacokinetic parameters of pravastatin sodium during pregnancy [Between Pre-dose (0) and 24 hours post dose]
Timed blood and urine collection performed once between 18 wks 0 days GA and 23 wks 6 days GA and once between 30 wks 0 days GA and 33 wks 6 days GA. Timed blood collection intervals: pre-dose(0)and 0.5hr, 1hr, 1.5hr, 2hr, 3hr, 4hr, 6hr, 8hr post dose. Time urine collection intervals: pre-dose (0) and 0-4hr, 4-8hr hr post dose. Evaluation parameters:Maximum observed plasma concentration (Cmax) and peak time (Tmax), Steady-state area under the plasma concentration-time curve during the 24-h dosing interval (AUC0-24h), Steady-state apparent oral clearance (CL/F), Elimination half-life (t½), Renal clearance of pravastatin

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Documented history (review of chart or delivery note) of prior severe early onset PE in a prior pregnancy and requiring delivery ≤340/7 weeks' gestation. If in the index pregnancy, the woman was induced at the upper limit of 34 0/7 weeks of pregnancy and delivered within 48 hours in the same hospitalization, that woman could be enrolled. Women with severe PE in a pregnancy remote (greater than 2 pregnancies removed) from the current pregnancy do not qualify.

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.
Willingness to participate in planned PK study visits

Exclusion Criteria:

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

Patients with contraindications for statin therapy:
Hypersensitivity to pravastatin or any component of the product
Active liver disease (acute hepatitis, chronic active hepatitis, persistently abnormal liver enzymes (2 x normal of serum transaminases)
History of myopathy or rhabdomyolysis
Patients with any of the following conditions:
HIV positive
Status post solid organ transplant
Chronic renal disease/insufficiency with baseline serum creatinine ≥1.5 mg/dL
Uterine malformations (didelphus, bicornuate, unicornate)
Cancer
Statin use in current pregnancy
Current use of medications with potential drug interactions with statins, such as cyclosporine, fibrates, gemfibrozil, niacin, erythromycin, fluconazole, itraconazole, cholestyramine, digoxin, rifampin (patients will not be excluded if the drug has been discontinued, or is prescribed for a short duration of time)
Participating in another intervention study that influences the outcomes of this study
Plans to deliver in a non-network site

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
3	University of Texas Medical Branch	Galveston	Texas	United States	77555

Sponsors and Collaborators

The University of Texas Medical Branch, Galveston
University of Pittsburgh
Northwestern University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)