Pravastatin to Prevent Preeclampsia

Phase 3

Terminated

• Conditions: Preeclampsia; Obstetric Labor Complications; Hypertension in Pregnancy
• Interventions: Drug: Pravastatin; Other: Placebo

• Registration Number: NCT03944512
• Lead Sponsor: The George Washington University Biostatistics Center

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 Timeline

• Study First Submitted: 2019-05-07
• Study First Submitted QC: 2019-05-08
• Study First Posted: 2019-05-09
• Study Start: 2019-07-17
• Primary Completion: 2021-06-06
• Study Completion: 2024-06-20
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-08
• Last Update Posted: 2024-07-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 50

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pravastatin	Pravastatin	20 mg pravastatin daily
Placebo	Placebo	Identical appearing daily placebo

Primary Outcome Measures

Name	Time	Method
Proportion of participants with composite of preeclampsia, fetal loss and maternal death	48 hours postpartum	Proportion of participants demonstrating a composite of preeclampsia, fetall; 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

Secondary Outcome Measures

Name	Time	Method
Proportion of participants with indicated preterm birth < 37 weeks	Delivery before 37 weeks	Indicated preterm birth less than 37 weeks
Proportion of participants with preterm birth < 34 weeks	Delivery before 34 weeks	Preterm birth before 34 weeks gestation
Proportion of participants with preterm birth < 37 weeks	Delivery before 37 weeks	Preterm birth before 37 weeks gestation
Proportion of participants with preeclampsia with severe features	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	48 hours postpartum through 6 weeks post partum	Preeclampsia that occurs 48 hours or more after birth
Proportion of participants with Gestational hypertension	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	48 hours postpartum	Defined as gestational hypertension or preeclampsia
Proportion of participants with Gestational diabetes	At any time during pregnancy through delivery (up to 30 weeks)	Gestational diabetes mellitus
Rate of Adherence to study medication	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)	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	Delivery	Gestational age at the time of delivery
Length of maternal hospital stay	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	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	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	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	randomization through hospital discharge	Death of the fetus or neonate
Birth weight	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	Birth through hospital discharge (through study completion)	Admission to the neonatal intensive care unit (NICU) or intermediate nursery
NICU/intermediate nursery length of stay	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 with Respiratory Distress Syndrome	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	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	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	Birth through hospital discharge (through study completion)	Intraventricular hemorrhage (IVH) grade III-IV
Proportion of neonates needing Mechanical ventilation	72 hours post birth	Mechanical ventilation in the first 72 hours of life and duration
Proportion of neonates needing oxygen support	Birth through hospital discharge (through study completion)	Provision of oxygen support for the neonate and duration
Proportion of neonates with Periventricular leukomalacia (PVL)	Diagnosed at Birth through hospital discharge (through study completion)	Periventricular leukomalacia (PVL), diagnosed by neuroimaging
Proportion of neonates with Retinopathy of prematurity	Birth through hospital discharge (through study completion)	Retinopathy of prematurity (ROP) stage III or higher
Proportion of neonates experiencing sepsis	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	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	Birth through hospital discharge (through study completion)	Neonatal seizure activity
Proportion of neonates with a Congenital anomaly / birth defect	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)	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	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	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	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	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	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)	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	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	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	5 years of age	Visual acuity and strabismus from visual assessment at 5 years

Trial Locations

Locations (12)

Magee Women's Hospital of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Texas Medical Branch; 🇺🇸 Galveston, Texas, United States

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Case Western Reserve-Metro Health; 🇺🇸 Cleveland, Ohio, United States

University of Alabama - Birmingham; 🇺🇸 Birmingham, Alabama, United States

University of Texas - Houston; 🇺🇸 Houston, Texas, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Ohio State University Hospital; 🇺🇸 Columbus, Ohio, United States

University of North Carolina - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Columbia University; 🇺🇸 New York, New York, United States

Brown University; 🇺🇸 Providence, Rhode Island, United States

University of Utah Medical Center; 🇺🇸 Salt Lake City, Utah, United States