Pravastatin to Prevent Preeclampsia (Pravastatin)
|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: NCT03944512|
Recruitment Status : Active, not recruiting
First Posted : May 9, 2019
Last Update Posted : December 20, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Preeclampsia Obstetric Labor Complications Hypertension in Pregnancy||Drug: Pravastatin Other: Placebo||Phase 3|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||1550 participants|
|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.
|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.|
|Official Title:||A Randomized Controlled Trial of Pravastatin to Prevent Preeclampsia in High Risk Women|
|Actual Study Start Date :||July 17, 2019|
|Estimated Primary Completion Date :||June 2026|
|Estimated Study Completion Date :||June 2031|
20 mg pravastatin daily
20 mg Pravastatin taken daily
Placebo Comparator: Placebo
Identical appearing daily placebo
Identical appearing placebo pill
- Proportion of participants with composite of preeclampsia, fetal loss and maternal death [ Time Frame: 48 hours postpartum ]
Proportion of participants demonstrating a composite of preeclampsia, fetall
- 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
- 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.
- HELLP a) Hemolysis AND b)Thrombocytopenia AND c) AST/ALT ≥ 70 IU/L
- Atypical HELLP an occurrence of 2 of the 3: a) Hemolysis, b)Thrombocytopenia, OR c) AST/ALT ≥ 70 IU/L
- Competing outcomes: maternal death before delivery or fetal loss < 20wks, 0 days
- Proportion of participants with preterm birth < 37 weeks [ Time Frame: Delivery before 37 weeks ]Preterm birth before 37 weeks gestation
- Proportion of participants with indicated preterm birth < 37 weeks [ Time Frame: Delivery before 37 weeks ]Indicated preterm birth less than 37 weeks
- Proportion of participants with preterm birth < 34 weeks [ Time Frame: Delivery before 34 weeks ]Preterm birth before 34 weeks gestation
- Proportion 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)
- Proportion of participants with Postpartum Preeclampsia [ Time Frame: 48 hours postpartum through 6 weeks post partum ]Preeclampsia that occurs 48 hours or more after birth
- Proportion 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
- Proportion of participants with pregnancy associated hypertension [ Time Frame: 48 hours postpartum ]Defined as gestational hypertension or preeclampsia
- Proportion 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, 23-28 weeks, and 33-37 weeks gestation ]Concentrations of angiogenic factors (sFlt-1, sEng, and PlGF)
- Concentrations of cholesterol and triglycerides [ Time Frame: Between 12-16 weeks, 23-28 weeks, and 33-37 weeks gestation ]Concentrations of cholesterol (total, low density lipoprotein, high density lipoprotein) and triglycerides
- Proportion 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
- Percentage 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
- Proportion of neonates needing Mechanical ventilation [ Time Frame: 72 hours post birth ]Mechanical ventilation in the first 72 hours of life and duration
- Proportion of neonates needing oxygen support [ Time Frame: Birth through hospital discharge (through study completion) ]Provision of oxygen support for the neonate and duration
- Proportion 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
- Proportion 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
- Proportion 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)
- Proportion of neonates with Intraventricular Hemorrhage [ Time Frame: Birth through hospital discharge (through study completion) ]Intraventricular hemorrhage (IVH) grade III-IV
- Proportion of neonates with Periventricular leukomalacia (PVL) [ Time Frame: Diagnosed at Birth through hospital discharge (through study completion) ]Periventricular leukomalacia (PVL), diagnosed by neuroimaging
- Proportion of neonates with Retinopathy of prematurity [ Time Frame: Birth through hospital discharge (through study completion) ]Retinopathy of prematurity (ROP) stage III or higher
- Proportion 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.
- Proportion 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
- Proportion of neonates experiencing seizures [ Time Frame: Birth through hospital discharge (through study completion) ]Neonatal seizure activity
- Proportion 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
- Proportion 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
≥ 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||16 Years and older (Child, Adult, Older Adult)|
|Sexes Eligible for Study:||Female|
|Accepts Healthy Volunteers:||No|
- 16 years or older at time of consent with ability to give informed consent
- 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.
- Gestational age at randomization between 12 weeks 0 days and 16 weeks 6 days based on clinical information and evaluation of the earliest ultrasound.
- 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.
- Normal serum transaminase (AST/ALT) concentrations documented in the last 6 months.
- Monoamniotic gestation because of the risk of fetal demise
- Known chromosomal, genetic or major malformations
- 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.
Contraindications for statin therapy:
- Hypersensitivity to pravastatin or any component of the product
- Active liver disease: acute hepatitis or chronic active hepatitis
- Statin use in current pregnancy
Patients with any of the following medical conditions:
- Uncontrolled hypothyroidism with a TSH level above 10 mIU/L, because of increased risk of myopathy
- HIV positive, because of increased risk of myopathy with use of protease inhibitors
- Chronic renal disease with baseline serum creatinine ≥1.5 mg/dL, because of association with adverse pregnancy outcomes
- 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.
- Participating in another intervention study that influences the primary outcome in this study
- Plan to deliver in a non-network site
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03944512
|United States, Alabama|
|University of Alabama - Birmingham|
|Birmingham, Alabama, United States, 35233|
|United States, Illinois|
|Chicago, Illinois, United States, 60611|
|United States, New York|
|New York, New York, United States, 10032|
|United States, North Carolina|
|University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599|
|United States, Ohio|
|Case Western Reserve-Metro Health|
|Cleveland, Ohio, United States, 44109|
|Ohio State University Hospital|
|Columbus, Ohio, United States, 43210|
|United States, Pennsylvania|
|Hospital of the University of Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19104|
|Magee Women's Hospital of UPMC|
|Pittsburgh, Pennsylvania, United States, 15213|
|United States, Rhode Island|
|Providence, Rhode Island, United States, 02905|
|United States, Texas|
|University of Texas Medical Branch|
|Galveston, Texas, United States, 77555|
|University of Texas - Houston|
|Houston, Texas, United States, 77030|
|United States, Utah|
|University of Utah Medical Center|
|Salt Lake City, Utah, United States, 84132|
|Principal Investigator:||Maged Costantine, MD||Ohio State University|
|Study Director:||Monica Longo, MD, PHD||Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|
|Principal Investigator:||Rebecca Clifton, PhD||The George Washington University Biostatistics Center|
|Study Director:||Victoria Pemberton, RNC, MS, CCRC||National Heart, Lung, and Blood Institute (NHLBI)|
|Responsible Party:||The George Washington University Biostatistics Center|
|Other Study ID Numbers:||
5U10HD036801-20 ( U.S. NIH Grant/Contract )
|First Posted:||May 9, 2019 Key Record Dates|
|Last Update Posted:||December 20, 2022|
|Last Verified:||December 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|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).|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
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