Pravastatin to Prevent Preeclampsia

Preeclampsia Clinical Trial

— Pravastatin  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03944512
• Other study ID #: HD036801-Pravastatin
• Secondary ID: 5U10HD036801-20
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 17, 2019
• Est. completion date: June 2031

Study information

• Verified date: September 2023
• Source: The George Washington University Biostatistics Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1550
• Est. completion date: June 2031
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypertension in Pregnancy
• Hypertension, Pregnancy-Induced
• Obstetric Labor Complications
• Pre-Eclampsia
• Preeclampsia

Intervention

Drug:
• Pravastatin
20 mg Pravastatin taken daily

Other:
• Placebo
Identical appearing placebo pill

Locations

Country	Name	City	State
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Case Western Reserve-Metro Health	Cleveland	Ohio
United States	Ohio State University Hospital	Columbus	Ohio
United States	University of Texas Medical Branch	Galveston	Texas
United States	University of Texas - Houston	Houston	Texas
United States	Columbia University	New York	New York
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Magee Women's Hospital of UPMC	Pittsburgh	Pennsylvania
United States	Brown University	Providence	Rhode Island
United States	University of Utah Medical Center	Salt Lake City	Utah

Sponsors (3)

Lead Sponsor	Collaborator
The George Washington University Biostatistics Center	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Proportion of participants with preterm birth < 37 weeks	Preterm birth before 37 weeks gestation	Delivery before 37 weeks
Secondary	Proportion of participants with indicated preterm birth < 37 weeks	Indicated preterm birth less than 37 weeks	Delivery before 37 weeks
Secondary	Proportion of participants with preterm birth < 34 weeks	Preterm birth before 34 weeks gestation	Delivery before 34 weeks
Secondary	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
Secondary	Proportion of participants with Postpartum Preeclampsia	Preeclampsia that occurs 48 hours or more after birth	48 hours postpartum through 6 weeks post partum
Secondary	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
Secondary	Proportion of participants with pregnancy associated hypertension	Defined as gestational hypertension or preeclampsia	48 hours postpartum
Secondary	Proportion of participants with Gestational diabetes	Gestational diabetes mellitus	At any time during pregnancy through delivery (up to 30 weeks)
Secondary	Rate of Adherence to study medication	Adherence to the medication regimen for the study (daily pill)	Randomization to delivery (up to 30 weeks)
Secondary	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
Secondary	Gestational age at delivery	Gestational age at the time of delivery	Delivery
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of Fetal or neonatal deaths	Death of the fetus or neonate	randomization through hospital discharge
Secondary	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
Secondary	NICU/intermediate nursery admission	Admission to the neonatal intensive care unit (NICU) or intermediate nursery	Birth through hospital discharge (through study completion)
Secondary	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)
Secondary	Proportion of neonates needing Mechanical ventilation	Mechanical ventilation in the first 72 hours of life and duration	72 hours post birth
Secondary	Proportion of neonates needing oxygen support	Provision of oxygen support for the neonate and duration	Birth through hospital discharge (through study completion)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	Proportion of neonates with Intraventricular Hemorrhage	Intraventricular hemorrhage (IVH) grade III-IV	Birth through hospital discharge (through study completion)
Secondary	Proportion of neonates with Periventricular leukomalacia (PVL)	Periventricular leukomalacia (PVL), diagnosed by neuroimaging	Diagnosed at Birth through hospital discharge (through study completion)
Secondary	Proportion of neonates with Retinopathy of prematurity	Retinopathy of prematurity (ROP) stage III or higher	Birth through hospital discharge (through study completion)
Secondary	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
Secondary	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)
Secondary	Proportion of neonates experiencing seizures	Neonatal seizure activity	Birth through hospital discharge (through study completion)
Secondary	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)
Secondary	Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE)	Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE)	Delivery through 6 weeks of age
Secondary	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
Secondary	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
Secondary	Gross Motor Function at 24 months	Level from the Gross Motor Function Classification System at 24 months of age	24 months of age
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Visual acuity and strabismus at 5 years	Visual acuity and strabismus from visual assessment at 5 years	5 years of age