Pravastatin for Prevention of Preeclampsia

Study Overview
=================
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.

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

Conditions
-----------------
Preeclampsia

Intervention / Treatment
-----------------
* Drug: Pravastatin
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pravastatin Group<br>Pregnant women at high-risk for preeclampsia who are taking pravastatin during their pregnancy. | Drug: Pravastatin<br>* 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.<br>* Other names: Brand name: Pravachol®;|
| Placebo Comparator: Control Group<br>Pregnant women who are at high-risk for developing preeclampsia who are taking a placebo during their pregnancy. | Drug: Placebo<br>* Women will be instructed to take a placebo pill daily beginning the day of randomization and ending the day of delivery.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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. | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
statin, preeclampsia, pravastatin, Pravachol®, high-risk pregnancy, safety, fetal morbidity and mortality, maternal morbidity and mortality, neonatal mortality, premature delivery, preemie