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Pravastatin for Prevention of Preeclampsia (Statin)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01717586
Recruitment Status : Active, not recruiting
First Posted : October 30, 2012
Last Update Posted : October 27, 2020
Sponsor:
Collaborators:
University of Pittsburgh
Northwestern University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
The University of Texas Medical Branch, Galveston

Tracking Information
First Submitted Date  ICMJE January 3, 2012
First Posted Date  ICMJE October 30, 2012
Last Update Posted Date October 27, 2020
Study Start Date  ICMJE August 2012
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2017)
  • Number and type of maternal adverse events [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
Original Primary Outcome Measures  ICMJE
 (submitted: October 26, 2012)
  • Number and type of maternal adverse events [ Time Frame: 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 [ Time Frame: 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
    • Ponderal index
    • Congenital malformations
    • Auditory brainstem response (ABR) evoked potential
    • Cord blood lipid profile, AST/ALT, and CK levels
  • Pharmacokinetic parameters of pravastatin sodium during pregnancy [ Time Frame: 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, 10hr, 12hr and 24hr post dose. Time urine collection intervals: pre-dose (0) and 0-4hr, 4-8hr, 8-12hr, 12-24 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
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pravastatin for Prevention of Preeclampsia
Official Title  ICMJE Pravastatin for the Prevention of Preeclampsia in High-Risk Women: A Phase I Pilot Study
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Preeclampsia
Intervention  ICMJE
  • 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®
  • Drug: Placebo
    Women will be instructed to take a placebo pill daily beginning the day of randomization and ending the day of delivery.
Study Arms  ICMJE
  • Active Comparator: Pravastatin Group
    Pregnant women at high-risk for preeclampsia who are taking pravastatin during their pregnancy.
    Intervention: Drug: Pravastatin
  • Placebo Comparator: Control Group
    Pregnant women who are at high-risk for developing preeclampsia who are taking a placebo during their pregnancy.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 9, 2019)
48
Original Estimated Enrollment  ICMJE
 (submitted: October 26, 2012)
40
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01717586
Other Study ID Numbers  ICMJE 12-097 OPRU/OPRC Pravastatin
U54HD047891 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: per NICHD guidelines
Responsible Party The University of Texas Medical Branch, Galveston
Study Sponsor  ICMJE The University of Texas Medical Branch, Galveston
Collaborators  ICMJE
  • University of Pittsburgh
  • Northwestern University
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
Principal Investigator: Maged Costantine, MD UTexasGalveston; Ohio State
PRS Account The University of Texas Medical Branch, Galveston
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP