Clinical trial NCT01717586: Pravastatin for Prevention of Preeclampsia
Official title: Pravastatin for the Prevention of Preeclampsia in High-Risk Women: A Phase I Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Preeclampsia
Keywords: preeclampsia
pravastatin
Pravachol®
statin
high-risk pregnancy
safety
fetal morbidity and mortality
maternal morbidity and mortality
neonatal mortality
premature delivery
preemie
Lead sponsor: The University of Texas Medical Branch, Galveston
Sponsor class: OTHER
Collaborators: name: University of Pittsburgh
name: Northwestern University
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2012-10-30
Enrollment: 48
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

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

Primary outcomes:
measure: Number and type of maternal adverse events
timeFrame: From the date of randomization until the date of delivery, assessed up to 210 days
measure: Number and type of fetal/neonatal adverse events
timeFrame: From date of birth up to discharge or 120 days after birth.
measure: Pharmacokinetic parameters of pravastatin sodium during pregnancy
timeFrame: Between Pre-dose (0) and 24 hours post dose
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
Study officials:
affiliation: UTexasGalveston; Ohio State
name: Maged Costantine, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.