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Pravastatin to Prevent Preeclampsia (Pravastatin)

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ClinicalTrials.gov Identifier: NCT03944512
Recruitment Status : Recruiting
First Posted : May 9, 2019
Last Update Posted : July 20, 2020
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
The George Washington University Biostatistics Center

Tracking Information
First Submitted Date  ICMJE May 7, 2019
First Posted Date  ICMJE May 9, 2019
Last Update Posted Date July 20, 2020
Actual Study Start Date  ICMJE July 17, 2019
Estimated Primary Completion Date June 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
Number of participants with composite of preeclampsia, fetal loss and maternal death [ Time Frame: Prior to 48 hours postpartum ]
  1. Baseline Normotensive: a) Severe hypertension (HTN) or b) Mild HTN w/ any of the following: i.) New-onset proteinuria or doubling in protein w/ baseline proteinuria ii.) Thrombocytopenia iii.) Progressive renal insufficiency iv). Impaired liver function v.) Pulmonary edema vi.) New-onset & persistent cerebral or visual symptoms
  2. Baseline chronic HTN: any of the following a)Severe HTN b) New onset proteinuria or doubling in protein from baseline proteinuria c)Thrombocytopenia d) Progressive renal insufficiency e) Impaired liver function f) Pulmonary edema g) New-onset & persistent cerebral or visual symptoms.
  3. HELLP a) Hemolysis AND b)Thrombocytopenia AND c) AST/ALT ≥ 70 IU/L
  4. Atypical HELLP an occurrence of 2 of the 3: a) Hemolysis, b)Thrombocytopenia, OR c) AST/ALT ≥ 70 IU/L
  5. Eclampsia
  6. Competing outcomes: maternal death before delivery or fetal loss < 20wks, 0 days
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Number of participants with preterm birth < 37 weeks [ Time Frame: Delivery before 37 weeks ]
    Preterm birth before 37 weeks gestation
  • Number of participants with indicated preterm birth < 37 weeks [ Time Frame: Delivery before 37 weeks ]
    Indicated preterm birth less than 37 weeks
  • Number of participants with preterm birth < 34 weeks [ Time Frame: Delivery before 34 weeks ]
    Preterm birth before 34 weeks gestation
  • Number of participants with preeclampsia with severe features [ Time Frame: 48 hours postpartum ]
    Preeclampsia with severe features as defined by the American College of Obstetricians and Gynecologists (ACOG) diagnostic criteria (i.e., severe hypertension, thrombocytopenia, impaired liver function, progressive renal insufficiency, pulmonary edema, new-onset and persistent cerebral or visual symptoms)
  • Number of participants with Postpartum Preeclampsia [ Time Frame: 48 hours postpartum through 6 weeks post partum ]
    Preeclampsia that occurs 48 hours or more after birth
  • Number of participants with Gestational hypertension [ Time Frame: 48 hours postpartum ]
    Defined as new onset hypertension in the absence of accompanying proteinuria or other features of preeclampsia
  • Number of participants with pregnancy associated hypertension [ Time Frame: 48 hours postpartum ]
    Defined as gestational hypertension or preeclampsia
  • Number of participants with Gestational diabetes [ Time Frame: At any time during pregnancy through delivery (up to 30 weeks) ]
    Gestational diabetes mellitus
  • Rate of Adherence to study medication [ Time Frame: Randomization to delivery (up to 30 weeks) ]
    Adherence to the medication regimen for the study (daily pill)
  • Rate of Adverse Events of Special Interest (AESI) [ Time Frame: Randomization through 48 hours postpartum ]
    Adverse events of Special Interest (AESI) including myalgia and muscle weakness, and serious AESI defined as maternal myositis, myopathy, rhabdomyolysis, or serious liver injury
  • Gestational age at delivery [ Time Frame: Delivery ]
    Gestational age at the time of delivery
  • Length of maternal hospital stay [ Time Frame: Randomization through discharge from the hospital (through study completion) ]
    Length of maternal hospital stay for the delivery admission and number and length of maternal hypertension related and overall hospitalizations during the pregnancy
  • Concentrations of angiogenic factors [ Time Frame: Between 12-16 weeks, 24-27 weeks, and 34-36 weeks gestation ]
    Concentrations of angiogenic factors (sFlt-1, sEng, and PlGF)
  • Concentrations of cholesterol and triglycerides [ Time Frame: Between 12-16 weeks, 24-27 weeks, and 34-36 weeks gestation ]
    Concentrations of cholesterol (total, low density lipoprotein, high density lipoprotein) and triglycerides
  • Number of participants with Severe maternal morbidity composite [ Time Frame: Randomization through 6 weeks postpartum ]
    A composite of severe maternal morbidity of either maternal death, eclampsia, HELLP syndrome, cerebral vascular accident, heart failure, myocardial infarction, acute respiratory distress syndrome requiring mechanical ventilation, disseminated intravascular coagulopathy, pulmonary edema, renal failure, liver rupture, or placental abruption
  • Number of Fetal or neonatal deaths [ Time Frame: randomization through hospital discharge ]
    Death of the fetus or neonate
  • Birth weight [ Time Frame: Birth ]
    Birth weight and rate of "small for gestational age" as measured by birth weight: a) < 5th percentile and b) < 10th percentile for gestational age
  • NICU/intermediate nursery admission [ Time Frame: Birth through hospital discharge (through study completion) ]
    Admission to the neonatal intensive care unit (NICU) or intermediate nursery
  • NICU/intermediate nursery length of stay [ Time Frame: NICU or intermediate nursery admission to NICU or intermediate nursery discharge (through study completion) ]
    Length of stay in the neonatal intensive care unit (NICU) and/or intermediate nursery
  • Number of neonates needing Mechanical ventilation [ Time Frame: 72 hours post birth ]
    Mechanical ventilation in the first 72 hours of life and duration
  • Number of neonates needing oxygen support [ Time Frame: Birth through hospital discharge (through study completion) ]
    Provision of oxygen support for the neonate and duration
  • Number of neonates with Respiratory Distress Syndrome [ Time Frame: Birth through hospital discharge (through study completion) ]
    Respiratory distress syndrome (RDS), defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with an oxygen requirement and confirmed by a chest x-ray
  • Number of neonates with Bronchopulmonary Dysplasia [ Time Frame: 28 days of life and 36 weeks corrected gestational age ]
    Bronchopulmonary dysplasia (BPD), defined as oxygen requirement at 28 days of life and at 36 weeks corrected gestational age
  • Number of neonates with Necrotizing Enterocolitis [ Time Frame: Birth through hospital discharge (through study completion) ]
    Necrotizing enterocolitis (NEC), defined as modified Bell Stage 2 (clinical signs and symptoms with pneumatosis intestinalis on radiographs) or Stage 3 (advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation)
  • Number of neonates with Intraventricular Hemorrhage [ Time Frame: Birth through hospital discharge (through study completion) ]
    Intraventricular hemorrhage (IVH) grade III-IV
  • Number of neonates with Periventricular leukomalacia (PVL) [ Time Frame: Diagnosed at Birth through hospital discharge (through study completion) ]
    Periventricular leukomalacia (PVL), diagnosed by neuroimaging
  • Number of neonates with Retinopathy of prematurity [ Time Frame: Birth through hospital discharge (through study completion) ]
    Retinopathy of prematurity (ROP) stage III or higher
  • Number of neonates experiencing sepsis [ Time Frame: within 72 hours of birth and greater than 72 hours after birth ]
    Neonatal sepsis (within 72 hours and > 72 hours after birth). The diagnosis of sepsis will require the presence of a clinically ill infant in whom systemic infection is suspected with a positive blood, cerebral spinal fluid (CSF), or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an unequivocal radiograph confirming infection.
  • Number of neonates with Composite Neonatal Outcome [ Time Frame: Birth through hospital discharge (through study completion) ]
    Fetal or neonatal death, RDS, Grade III-IV IVH, PVL, Stage 2 or 3 NEC, BPD, Stage III or higher ROP, or early onset sepsis
  • Number of neonates experiencing seizures [ Time Frame: Birth through hospital discharge (through study completion) ]
    Neonatal seizure activity
  • Number of neonates with a Congenital anomaly / birth defect [ Time Frame: Post randomization through hospital discharge (through study completion) ]
    Congenital anomaly or birth defect excluding any conditions that must have been present before randomization
  • Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE) [ Time Frame: Delivery through 6 weeks of age ]
    Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE)
  • BMI for age at 24 corrected months and 5 years [ Time Frame: 24 months of age and 5 years of age ]
    Body mass index for age at 24 corrected months and 5 years using Centers for Disease Control (CDC) pediatric growth charts
  • Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition [ Time Frame: 24 months of age ]
    Bayley Certified Scales of Infant Development III Edition scores for cognitive, motor and language abilities at 24 months of age. Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Results can also be expressed as percentile ranks relative to the standardization sample, with a mean and median of 50 and range from 1 to 99
  • Gross Motor Function at 24 months [ Time Frame: 24 months of age ]
    Level from the Gross Motor Function Classification System at 24 months of age
  • Number of children with Hearing loss or vision problems at 24 months of age [ Time Frame: 24 months of age ]
    Hearing loss or vision problems (severe nearsightedness or farsightedness, and eye movement problems) at 24 months of age
  • Child Behavior Checklist Total Problems Score and Syndrome Scale at 24 months and 5 years [ Time Frame: 24 months and 5 years of age ]
    Total problems score and syndrome scale (emotionally reactive, anxious/depressed, somatic complaints, withdrawn, attention problems, aggressive behavior) scores from the Child Behavior Checklist at 24 months and 5 years of age The CBCL is filled out by the caregiver. Each of the 100 questions indicates a behavior for which the caregiver scores as Not True (0), Sometimes True (1), or Often True (2). The scores for all the questions are then summed and evaluated against the normative data/T-scores. A T-score of less than 60 is considered to be in the normal range. A T-score of 60-63 is a borderline, and a T-score of more than 63 is in the clinical range. Lower scores represent better outcomes.
  • Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) [ Time Frame: 5 years of age ]
    Overall general conceptual ability score (GCA)and subscale (verbal ability, non-verbal reasoning ability, and spatial ability) scores from the Differential Ability Scales at 5 years of age Classification: ≥ 130 Very high;120-129 High;110-119 Above average; 90-109 Average; 80-89 Below average;70-79 Low; ≤ 69 Very low
  • Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score at 5 years [ Time Frame: 5 years of age ]
    Assess executive function behaviors in the school and home environments with the BRIEF, a questionnaire developed for parents and teachers of school-age children. Designed to assess the abilities of a broad range of children and adolescents, the BRIEF is useful when working with children who have learning disabilities and attention disorders, traumatic brain injuries, lead exposure, pervasive developmental disorders, depression, and other developmental, neurological, psychiatric, and medical conditions. Raw scores are converted to T-scores. Higher T-scores indicate greater impairment. For all BRIEF2 clinical scales and indexes, T-scores from 60 to 64 are considered mildly elevated, and T-scores from 65 to 69 are considered potentially clinically elevated. T-scores at or above 70 are considered clinically elevated.
  • Vineland Adaptive Behavior Scales - Adaptive Behavior Composite Score at 5 years [ Time Frame: 5 years of age ]
    Adaptive Behavior Composite score and domain (communication, daily living skills, socialization and motor skills) scores from the Vineland Adaptive Behavior Scale at 5 years of age. Higher scores indicate better functioning. Domain and ABC Standard Score Ranges High 130 to 140 Moderately High 115 to 129 Adequate 86 to 114 Moderately Low 71 to 85 Low 20 to 70
  • Visual acuity and strabismus at 5 years [ Time Frame: 5 years of age ]
    Visual acuity and strabismus from visual assessment at 5 years
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pravastatin to Prevent Preeclampsia
Official Title  ICMJE A Randomized Controlled Trial of Pravastatin to Prevent Preeclampsia in High Risk Women
Brief Summary This study is a double-blind randomized placebo-controlled trial of 1,550 high-risk women to assess whether daily treatment with pravastatin administered early in pregnancy reduces the rate of a composite outcome of preeclampsia, fetal loss and maternal death. Women with a prior history of preeclampsia with preterm delivery less than 34 weeks will be randomized to pravastatin or placebo daily until delivery. Women will have monthly study visits during pregnancy, a follow-up visit at 6 weeks postpartum and children will have follow-up visits at 2 and 5 years of age.
Detailed Description

Preeclampsia complicates approximately 3% to 5% of pregnancies and remains a major cause of maternal and neonatal morbidities and mortality. Women who experience preeclampsia in one pregnancy are at higher risk of developing preeclampsia in a subsequent pregnancy than those who have never experienced the condition. There is evidence from laboratory studies and clinical trials, as well as biological plausibility, to suggest that statins may prevent the development of preeclampsia by reversing various pathways associated with preeclampsia. Pravastatin has a favorable safety profile and pharmacokinetic properties.

The study is a randomized placebo-controlled multi-center clinical trial of 1,550 women with a prior history of preeclampsia that required delivery at less than 34 weeks, randomized to either 20mg pravastatin or an identical appearing placebo daily until delivery. Women with a singleton or twin gestation will be randomized between 12 weeks 0 days and 16 weeks 6 days will be followed monthly during pregnancy and then at 6 weeks postpartum. Children will have follow-up visits at 2 and 5 years of age to assess growth, cognition, behavior, motor skills, vision and hearing.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study is a randomized controlled multi-center clinical trial of 1,550 women with a prior history of preeclampsia that required delivery at less than or equal to 34 weeks 0 days gestation, randomized to one of two arms at participating Maternal Fetal Medicine Units Network clinical centers.

  • 20 mg pravastatin daily
  • Identical appearing daily placebo
Masking: Double (Participant, Investigator)
Masking Description:
Consenting women will be assigned to pravastatin or placebo in a 1:1 ratio according to a randomization sequence prepared and maintained centrally by the Data Coordinating Center (DCC). The two study medication arms of the study (pravastatin or placebo) are double masked; neither the patient nor the clinical staff will be aware of the treatment assignment.
Primary Purpose: Prevention
Condition  ICMJE
  • Preeclampsia
  • Obstetric Labor Complications
  • Hypertension in Pregnancy
Intervention  ICMJE
  • Drug: Pravastatin
    20 mg Pravastatin taken daily
  • Other: Placebo
    Identical appearing placebo pill
Study Arms  ICMJE
  • Experimental: Pravastatin
    20 mg pravastatin daily
    Intervention: Drug: Pravastatin
  • Placebo Comparator: Placebo
    Identical appearing daily placebo
    Intervention: Other: Placebo
Publications * 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.

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 8, 2019)
1550
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2031
Estimated Primary Completion Date June 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 16 years or older at time of consent with ability to give informed consent
  2. Single or twin gestation with cardiac activity in one or both fetuses. Higher order multifetal gestations reduced to twins, either spontaneously or therapeutically, are not eligible unless the reduction occurred by 13 weeks 6 days project gestational age.
  3. Gestational age at randomization between 12 weeks 0 days and 16 weeks 6 days based on clinical information and evaluation of the earliest ultrasound.
  4. Documented history (by chart or delivery/operative note review) of prior preeclampsia with delivery less than or equal to 34 weeks 0 days gestation in any previous pregnancy. If in the index pregnancy, the woman was induced by 34 weeks 0 days gestation and delivered within 48 hours in the same hospitalization, that woman would be eligible.
  5. Normal serum transaminase (AST/ALT) concentrations documented in the last 6 months.

Exclusion Criteria:

  1. Monoamniotic gestation because of the risk of fetal demise
  2. Known chromosomal, genetic or major malformations
  3. Fetal demise or planned termination of pregnancy. Selective reduction by 13 weeks 6 days gestation, from triplets to twins or twins to singleton is not an exclusion.
  4. Contraindications for statin therapy:

    1. Hypersensitivity to pravastatin or any component of the product
    2. Active liver disease: acute hepatitis or chronic active hepatitis
  5. Statin use in current pregnancy
  6. Patients with any of the following medical conditions:

    1. Uncontrolled hypothyroidism with a TSH level above 10 mIU/L, because of increased risk of myopathy
    2. HIV positive, because of increased risk of myopathy with use of protease inhibitors
    3. Chronic renal disease with baseline serum creatinine ≥1.5 mg/dL, because of association with adverse pregnancy outcomes
  7. Current use of concomitant medication with potential for drug interaction with statins (i.e.,, cyclosporine, fibrates, niacin, erythromycin). Patients will not be excluded if the drug is discontinued (at least one week) prior to randomization.
  8. Participating in another intervention study that influences the primary outcome in this study
  9. Plan to deliver in a non-network site
  10. Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, do not have to be excluded.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rebecca Clifton, PhD 301-881-9260 rclifton@bsc.gwu.edu
Contact: Trisha Boekhoudt 301-881-9260 trishab@bsc.gwu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03944512
Other Study ID Numbers  ICMJE HD036801-Pravastatin
5U10HD036801-20 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The dataset will be shared per NIH policy after the completion and publication of the main analyses. The limited access data set will be submitted to NICHD (Data and Specimen Hub - DASH) and NHLBI (Biologic Specimen and Data Repository Information Coordinating Center - BioLINCC).
Supporting Materials: Study Protocol
Responsible Party The George Washington University Biostatistics Center
Study Sponsor  ICMJE The George Washington University Biostatistics Center
Collaborators  ICMJE
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Study Chair: Maged Costantine, MD University of Texas
Study Director: Andrew Bremer, MD, PhD, MAS Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Rebecca Clifton, PhD The George Washington University Biostatistics Center
PRS Account The George Washington University Biostatistics Center
Verification Date July 2020

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