Pravastatin to Prevent Preeclampsia (Pravastatin)

• ClinicalTrials.gov Identifier: NCT03944512
• Recruitment Status: Active, not recruiting
• First Posted: May 9, 2019
• Last Update Posted: December 20, 2022
• Sponsor: The George Washington University Biostatistics Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): The George Washington University Biostatistics Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Preeclampsia; Obstetric Labor Complications; Hypertension in Pregnancy	Drug: Pravastatin; Other: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1550 participants
• Allocation: Randomized
• 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.

• 20 mg pravastatin daily
• Identical appearing daily placebo

• 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.
• Primary Purpose: Prevention
• 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

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pravastatin; 20 mg pravastatin daily	Drug: Pravastatin; 20 mg Pravastatin taken daily
Placebo Comparator: Placebo; Identical appearing daily placebo	Other: Placebo; Identical appearing placebo pill

Outcome Measures

Primary Outcome Measures :

1. 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

   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 :

1. Proportion of participants with preterm birth < 37 weeks [ Time Frame: Delivery before 37 weeks ]
   Preterm birth before 37 weeks gestation
2. Proportion of participants with indicated preterm birth < 37 weeks [ Time Frame: Delivery before 37 weeks ]
   Indicated preterm birth less than 37 weeks
3. Proportion of participants with preterm birth < 34 weeks [ Time Frame: Delivery before 34 weeks ]
   Preterm birth before 34 weeks gestation
4. 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)
5. 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
6. 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
7. Proportion of participants with pregnancy associated hypertension [ Time Frame: 48 hours postpartum ]
   Defined as gestational hypertension or preeclampsia
8. Proportion of participants with Gestational diabetes [ Time Frame: At any time during pregnancy through delivery (up to 30 weeks) ]
   Gestational diabetes mellitus
9. 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)
10. 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
11. Gestational age at delivery [ Time Frame: Delivery ]
    Gestational age at the time of delivery
12. 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
13. 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)
14. 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
15. 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
16. Percentage of Fetal or neonatal deaths [ Time Frame: randomization through hospital discharge ]
    Death of the fetus or neonate
17. 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
18. NICU/intermediate nursery admission [ Time Frame: Birth through hospital discharge (through study completion) ]
    Admission to the neonatal intensive care unit (NICU) or intermediate nursery
19. 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
20. Proportion of neonates needing Mechanical ventilation [ Time Frame: 72 hours post birth ]
    Mechanical ventilation in the first 72 hours of life and duration
21. Proportion of neonates needing oxygen support [ Time Frame: Birth through hospital discharge (through study completion) ]
    Provision of oxygen support for the neonate and duration
22. 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
23. 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
24. 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)
25. Proportion of neonates with Intraventricular Hemorrhage [ Time Frame: Birth through hospital discharge (through study completion) ]
    Intraventricular hemorrhage (IVH) grade III-IV
26. Proportion of neonates with Periventricular leukomalacia (PVL) [ Time Frame: Diagnosed at Birth through hospital discharge (through study completion) ]
    Periventricular leukomalacia (PVL), diagnosed by neuroimaging
27. Proportion of neonates with Retinopathy of prematurity [ Time Frame: Birth through hospital discharge (through study completion) ]
    Retinopathy of prematurity (ROP) stage III or higher
28. 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.
29. 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
30. Proportion of neonates experiencing seizures [ Time Frame: Birth through hospital discharge (through study completion) ]
    Neonatal seizure activity
31. 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
32. 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)
33. 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
34. 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

35. 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
36. 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
37. 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.

38. 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

    Classification:

    ≥ 130 Very high;120-129 High;110-119 Above average; 90-109 Average; 80-89 Below average;70-79 Low; ≤ 69 Very low

39. 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.

40. 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

41. Visual acuity and strabismus at 5 years [ Time Frame: 5 years of age ]
    Visual acuity and strabismus from visual assessment at 5 years

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama - Birmingham

Birmingham, Alabama, United States, 35233

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

United States, New York

Columbia University

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

Brown University

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

Sponsors and Collaborators

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)

Investigators

• 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)

More Information

Publications:

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.

• Responsible Party: The George Washington University Biostatistics Center
• ClinicalTrials.gov Identifier: NCT03944512
• Other Study ID Numbers: HD036801-Pravastatin; 5U10HD036801-20 ( U.S. NIH Grant/Contract )
• First Posted: May 9, 2019
• 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).
• Supporting Materials: Study Protocol

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The George Washington University Biostatistics Center:

Pregnancy; Preeclampsia

Additional relevant MeSH terms:

Pre-Eclampsia; Hypertension, Pregnancy-Induced; Obstetric Labor Complications; Hypertension; Vascular Diseases; Cardiovascular Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Pravastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors