Clinical trial NCT03944512: Pravastatin to Prevent Preeclampsia
Official title: A Randomized Controlled Trial of Pravastatin to Prevent Preeclampsia in High Risk Women
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Preeclampsia
Obstetric Labor Complications
Hypertension in Pregnancy
Keywords: Pregnancy
Preeclampsia
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2019-05-09
Enrollment: 50
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of participants with composite of preeclampsia, fetal loss and maternal death
timeFrame: 48 hours postpartum
Secondary outcomes:
measure: Proportion of participants with preterm birth < 37 weeks
timeFrame: Delivery before 37 weeks
measure: Proportion of participants with indicated preterm birth < 37 weeks
timeFrame: Delivery before 37 weeks
measure: Proportion of participants with preterm birth < 34 weeks
timeFrame: Delivery before 34 weeks
measure: Proportion of participants with preeclampsia with severe features
timeFrame: 48 hours postpartum
measure: Proportion of participants with Postpartum Preeclampsia
timeFrame: 48 hours postpartum through 6 weeks post partum
measure: Proportion of participants with Gestational hypertension
timeFrame: 48 hours postpartum
measure: Proportion of participants with pregnancy associated hypertension
timeFrame: 48 hours postpartum
measure: Proportion of participants with Gestational diabetes
timeFrame: At any time during pregnancy through delivery (up to 30 weeks)
measure: Rate of Adherence to study medication
timeFrame: Randomization to delivery (up to 30 weeks)
measure: Rate of Adverse Events of Special Interest (AESI)
timeFrame: Randomization through 48 hours postpartum
measure: Gestational age at delivery
timeFrame: Delivery
measure: Length of maternal hospital stay
timeFrame: Randomization through discharge from the hospital (through study completion)
measure: Concentrations of angiogenic factors
timeFrame: Between 12-16 weeks, 23-28 weeks, and 33-37 weeks gestation
measure: Concentrations of cholesterol and triglycerides
timeFrame: Between 12-16 weeks, 23-28 weeks, and 33-37 weeks gestation
measure: Proportion of participants with Severe maternal morbidity composite
timeFrame: Randomization through 6 weeks postpartum
measure: Percentage of Fetal or neonatal deaths
timeFrame: randomization through hospital discharge
measure: Birth weight
timeFrame: Birth
measure: NICU/intermediate nursery admission
timeFrame: Birth through hospital discharge (through study completion)
measure: NICU/intermediate nursery length of stay
timeFrame: NICU or intermediate nursery admission to NICU or intermediate nursery discharge (through study completion)
measure: Proportion of neonates needing Mechanical ventilation
timeFrame: 72 hours post birth
measure: Proportion of neonates needing oxygen support
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates with Respiratory Distress Syndrome
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates with Bronchopulmonary Dysplasia
timeFrame: 28 days of life and 36 weeks corrected gestational age
measure: Proportion of neonates with Necrotizing Enterocolitis
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates with Intraventricular Hemorrhage
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates with Periventricular leukomalacia (PVL)
timeFrame: Diagnosed at Birth through hospital discharge (through study completion)
measure: Proportion of neonates with Retinopathy of prematurity
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates experiencing sepsis
timeFrame: within 72 hours of birth and greater than 72 hours after birth
measure: Proportion of neonates with Composite Neonatal Outcome
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates experiencing seizures
timeFrame: Birth through hospital discharge (through study completion)
measure: Proportion of neonates with a Congenital anomaly / birth defect
timeFrame: Post randomization through hospital discharge (through study completion)
measure: Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE)
timeFrame: Delivery through 6 weeks of age
measure: BMI for age at 24 corrected months and 5 years
timeFrame: 24 months of age and 5 years of age
measure: Cognitive, Motor and Language Scale Scores From the Bayley Certified Scales of Infant Development III Edition
timeFrame: 24 months of age
measure: Gross Motor Function at 24 months
timeFrame: 24 months of age
measure: Proportion of children with Hearing loss or vision problems at 24 months of age
timeFrame: 24 months of age
measure: Child Behavior Checklist Total Problems Score and Syndrome Scale at 24 months and 5 years
timeFrame: 24 months and 5 years of age
measure: Cognitive and Achievement Levels From the Differential Ability Scales (DAS II)
timeFrame: 5 years of age
measure: Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score at 5 years
timeFrame: 5 years of age
measure: Vineland Adaptive Behavior Scales - Adaptive Behavior Composite Score at 5 years
timeFrame: 5 years of age
measure: Visual acuity and strabismus at 5 years
timeFrame: 5 years of age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve-Metro Health
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Women's Hospital of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: Ohio State University
name: Maged Costantine, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Monica Longo, MD, PHD
role: STUDY_DIRECTOR
affiliation: The George Washington University Biostatistics Center
name: Rebecca Clifton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Victoria Pemberton, RNC, MS, CCRC
role: STUDY_DIRECTOR
References:
citation: 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.