Pravastatin to Prevent Preeclampsia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Controlled Trial of Pravastatin to Prevent Preeclampsia in High Risk Women

Conditions
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Preeclampsia, Obstetric Labor Complications, Hypertension in Pregnancy

Intervention / Treatment
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* Drug: Pravastatin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pravastatin<br>20 mg pravastatin daily | Drug: Pravastatin<br>* 20 mg Pravastatin taken daily<br>|
| Placebo Comparator: Placebo<br>Identical appearing daily placebo | Other: Placebo<br>* Identical appearing placebo pill<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with composite of preeclampsia, fetal loss and maternal death | 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 Eclampsia Competing outcomes: maternal death before delivery or fetal loss < 20wks, 0 days | 48 hours postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with preterm birth < 37 weeks | Preterm birth before 37 weeks gestation | Delivery before 37 weeks | 
| Proportion of participants with indicated preterm birth < 37 weeks | Indicated preterm birth less than 37 weeks | Delivery before 37 weeks | 
| Proportion of participants with preterm birth < 34 weeks | Preterm birth before 34 weeks gestation | Delivery before 34 weeks | 
| Proportion of participants with preeclampsia with severe features | 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) | 48 hours postpartum | 
| Proportion of participants with Postpartum Preeclampsia | Preeclampsia that occurs 48 hours or more after birth | 48 hours postpartum through 6 weeks post partum | 
| Proportion of participants with Gestational hypertension | Defined as new onset hypertension in the absence of accompanying proteinuria or other features of preeclampsia | 48 hours postpartum | 
| Proportion of participants with pregnancy associated hypertension | Defined as gestational hypertension or preeclampsia | 48 hours postpartum | 
| Proportion of participants with Gestational diabetes | Gestational diabetes mellitus | At any time during pregnancy through delivery (up to 30 weeks) | 
| Rate of Adherence to study medication | Adherence to the medication regimen for the study (daily pill) | Randomization to delivery (up to 30 weeks) | 
| Rate of Adverse Events of Special Interest (AESI) | Adverse events of Special Interest (AESI) including myalgia and muscle weakness, and serious AESI defined as maternal myositis, myopathy, rhabdomyolysis, or serious liver injury | Randomization through 48 hours postpartum | 
| Gestational age at delivery | Gestational age at the time of delivery | Delivery | 
| Length of maternal hospital stay | Length of maternal hospital stay for the delivery admission and number and length of maternal hypertension related and overall hospitalizations during the pregnancy | Randomization through discharge from the hospital (through study completion) | 
| Concentrations of angiogenic factors | Concentrations of angiogenic factors (sFlt-1, sEng, and PlGF) | Between 12-16 weeks, 23-28 weeks, and 33-37 weeks gestation | 
| Concentrations of cholesterol and triglycerides | Concentrations of cholesterol (total, low density lipoprotein, high density lipoprotein) and triglycerides | Between 12-16 weeks, 23-28 weeks, and 33-37 weeks gestation | 
| Proportion of participants with Severe maternal morbidity composite | 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 | Randomization through 6 weeks postpartum | 
| Percentage of Fetal or neonatal deaths | Death of the fetus or neonate | randomization through hospital discharge | 
| Birth weight | Birth weight and rate of small for gestational age as measured by birth weight: a) < 5th percentile and b) < 10th percentile for gestational age | Birth | 
| NICU/intermediate nursery admission | Admission to the neonatal intensive care unit (NICU) or intermediate nursery | Birth through hospital discharge (through study completion) | 
| NICU/intermediate nursery length of stay | Length of stay in the neonatal intensive care unit (NICU) and/or intermediate nursery | NICU or intermediate nursery admission to NICU or intermediate nursery discharge (through study completion) | 
| Proportion of neonates needing Mechanical ventilation | Mechanical ventilation in the first 72 hours of life and duration | 72 hours post birth | 
| Proportion of neonates needing oxygen support | Provision of oxygen support for the neonate and duration | Birth through hospital discharge (through study completion) | 
| Proportion of neonates with Respiratory Distress Syndrome | 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 | Birth through hospital discharge (through study completion) | 
| Proportion of neonates with Bronchopulmonary Dysplasia | Bronchopulmonary dysplasia (BPD), defined as oxygen requirement at 28 days of life and at 36 weeks corrected gestational age | 28 days of life and 36 weeks corrected gestational age | 
| Proportion of neonates with Necrotizing Enterocolitis | 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) | Birth through hospital discharge (through study completion) | 
| Proportion of neonates with Intraventricular Hemorrhage | Intraventricular hemorrhage (IVH) grade III-IV | Birth through hospital discharge (through study completion) | 
| Proportion of neonates with Periventricular leukomalacia (PVL) | Periventricular leukomalacia (PVL), diagnosed by neuroimaging | Diagnosed at Birth through hospital discharge (through study completion) | 
| Proportion of neonates with Retinopathy of prematurity | Retinopathy of prematurity (ROP) stage III or higher | Birth through hospital discharge (through study completion) | 
| Proportion of neonates experiencing sepsis | 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. | within 72 hours of birth and greater than 72 hours after birth | 
| Proportion of neonates with Composite Neonatal Outcome | 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 | Birth through hospital discharge (through study completion) | 
| Proportion of neonates experiencing seizures | Neonatal seizure activity | Birth through hospital discharge (through study completion) | 
| Proportion of neonates with a Congenital anomaly / birth defect | Congenital anomaly or birth defect excluding any conditions that must have been present before randomization | Post randomization through hospital discharge (through study completion) | 
| Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE) | Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE) | Delivery through 6 weeks of age | 
| BMI for age at 24 corrected months and 5 years | Body mass index for age at 24 corrected months and 5 years using Centers for Disease Control (CDC) pediatric growth charts | 24 months of age and 5 years of age | 
| Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition | 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 | 24 months of age | 
| Gross Motor Function at 24 months | Level from the Gross Motor Function Classification System at 24 months of age | 24 months of age | 
| Proportion of children with Hearing loss or vision problems at 24 months of age | Hearing loss or vision problems (severe nearsightedness or farsightedness, and eye movement problems) at 24 months of age | 24 months of age | 
| Child Behavior Checklist Total Problems Score and Syndrome Scale at 24 months and 5 years | 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. | 24 months and 5 years of age | 
| Cognitive and Achievement Levels From the Differential Ability Scales (DAS II) | 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 | 5 years of age | 
| Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score at 5 years | 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. | 5 years of age | 
| Vineland Adaptive Behavior Scales - Adaptive Behavior Composite Score at 5 years | 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 | 5 years of age | 
| Visual acuity and strabismus at 5 years | Visual acuity and strabismus from visual assessment at 5 years | 5 years of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Preeclampsia