Pravastatin for Prevention of Preeclampsia

Preeclampsia Clinical Trial

— Statin  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01717586
• Other study ID #: 12-097 OPRU/OPRC Pravastatin
• Secondary ID: U54HD047891
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: August 2012
• Est. completion date: December 2025

Study information

• Verified date: March 2023
• Source: The University of Texas Medical Branch, Galveston
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 48
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia

Intervention

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

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	University of Texas Medical Branch	Galveston	Texas
United States	University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (4)

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

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	From the date of randomization until the date of delivery, assessed up to 210 days
Primary	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	From date of birth up to discharge or 120 days after birth.
Primary	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	Between Pre-dose (0) and 24 hours post dose