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Pravastatin for Prevention of Preeclampsia (Statin)

Primary Purpose

Preeclampsia

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Pravastatin

Placebo

About this trial

This is an interventional prevention trial for Preeclampsia focused on measuring preeclampsia, pravastatin, Pravachol®, statin, high-risk pregnancy, safety, fetal morbidity and mortality, maternal morbidity and mortality, neonatal mortality, premature delivery, preemie

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept 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

Sites / Locations

Northwestern University
University of Pittsburgh
University of Texas Medical Branch

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Pravastatin Group

Control Group

Arm Description

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

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

Outcomes

Primary Outcome Measures

Number and type of maternal adverse events

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

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

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

Secondary Outcome Measures

Full Information

NCT ID

NCT01717586

First Posted

January 3, 2012

Last Updated

March 20, 2023

Sponsor

The University of Texas Medical Branch, Galveston

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT01717586

Brief Title

Pravastatin for Prevention of Preeclampsia

Acronym

Statin

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 2012 (undefined)

Primary Completion Date

December 2025 (Anticipated)

Study Completion Date

December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The University of Texas Medical Branch, Galveston

Collaborators

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

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Preeclampsia

Keywords

preeclampsia, pravastatin, Pravachol®, statin, high-risk pregnancy, safety, fetal morbidity and mortality, maternal morbidity and mortality, neonatal mortality, premature delivery, preemie

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Pravastatin Group

Arm Type

Active Comparator

Arm Description

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

Arm Title

Control Group

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Pravastatin

Other Intervention Name(s)

pravastatin sodium, Brand name: Pravachol®

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

Number and type of maternal adverse events

Description

Time Frame

From the date of randomization until the date of delivery, assessed up to 210 days

Title

Number and type of fetal/neonatal adverse events

Description

Time Frame

From date of birth up to discharge or 120 days after birth.

Title

Pharmacokinetic parameters of pravastatin sodium during pregnancy

Description

Time Frame

Between Pre-dose (0) and 24 hours post dose

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Maged Costantine, MD

Organizational Affiliation

UTexasGalveston; Ohio State

Official's Role

Principal Investigator

Facility Information:

Facility Name

Northwestern University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

University of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

Facility Name

University of Texas Medical Branch

City

Galveston

State/Province

Texas

ZIP/Postal Code

77555

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

per NICHD guidelines

Citations:

PubMed Identifier

26723196

Citation

Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, Easterling TR, Haas DM, Haneline LS, Caritis SN, Venkataramanan R, West H, D'Alton M, Hankins G; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17. doi: 10.1016/j.ajog.2015.12.038. Epub 2015 Dec 23.

Results Reference

background

PubMed Identifier

34033812

Citation

Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, Stika CS, Rytting E, Wang X, Ahmed MS; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Centers (OPRC) Network, Bethesda, MD. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol. 2021 Dec;225(6):666.e1-666.e15. doi: 10.1016/j.ajog.2021.05.018. Epub 2021 May 24.

Results Reference

background

PubMed Identifier

23344286

Citation

Costantine MM, Cleary K; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network*. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol. 2013 Feb;121(2 Pt 1):349-353. doi: 10.1097/AOG.0b013e31827d8ad5.

Results Reference

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Pravastatin for Prevention of Preeclampsia

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