Indonesia Pravastatin to Prevent Preeclampsia Study

Study Overview
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Brief Summary
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BACKGROUND Preeclampsia is a major cause of maternal and neonatal morbidity worldwide. There is currently no cure for preeclampsia, the only definitive treatment is termination of pregnancy by induction of labour or caesarean section. Statin has been proposed to represent a new approach to improve disease outcome/prevent preeclampsia based on its multilayered activity toward pregnancy protection, including: protection of vascular endothelial cells survival, induce expression of heme oxygenase 1 (HO-1), inhibiting the release of soluble FMS-like tirosine kinase-1 (sFlt-1) and soluble endoglin (sEng), two main culprits in the pathophysiology of preeclampsia. OBJECTIVE The aim of this study is to observe the effect of pravastatin administration in patients with high risk of preeclampsia in order to reduce maternal and neonatal mortality and morbidity. METHODS This is a prospective randomized controlled clinical trial. The research will be held in 5 maternal fetal medicine centers in Indonesia (multicenter study). The recruitment will be done by permuted block random sampling methods, with sample size around 280 patients divides into two group. Patients with high risk of preeclampsia will be randomized either to get pravastatin 2 x 20 mg per oral and aspirin 1 x 80 mg (treatment group) or low dose aspirin only (control group). The patient will be followed regularly until delivery to obtain detailed maternal and neonatal outcome. OUTCOME Primary Outcomes: Maternal preeclampsia, severe preeclampsia, gestational hypertension, indicated preterm delivery less than 37 weeks, indicated preterm delivery less than 34 weeks, maternal complications, length of hospital stay, and any serious adverse event. Secondary Outcomes: Composite fetal/neonatal mortality and morbidity (stillbirth, neonatal death, respiratory distress syndrome, intracerebral hemorrhage, neonatal sepsis, intra uterine growth restriction [Small for Gestational Age (SGA) < 5th centile], and necrotizing enterocolitis), birthweight, birthweight percentile, level of care (well baby, intermediate, NICU), NICU length of stay, ventilator usage, and length of perinatal hospital stay. KEYWORDS: pravastatin, preeclampsia, neonatal mortality, neonatal morbidity

Official Title
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Pravastatin to Prevent Preeclampsia and Reduce Maternal-Neonatal Mortality and Morbidity in High Risk Preeclampsia Patients

Conditions
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Pre-Eclampsia

Intervention / Treatment
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* Drug: Pravastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational Age 10 wk - 19 wk 6 day History of previous preeclampsia requiring birth < 37 weeks (risk 30%), or Patients with a combination of at least 2 major risk factors plus an abnormal uterine artery Doppler at 11-20 weeks gestation (risk preeclampsia 30%): Major clinical risk factors (Obesity, strong family history of preeclampsia [mother or sister], maternal age > 40 years old, chronic hypertension, Policystic Ovarian Syndrome (PCOS), Chronic kidney disease, diabetes mellitus, multiple pregnancies, first pregnancy, pregnancy interval more than 10 years, new partner/husband, Reproductive technologies (IVF pregnancy), heritable thrombophilias, Booking Blood pressure >130/80 mmHg, family history of early onset cardiovascular disease, lower socioeconomic status) Abnormal uterine artery Doppler defined as (Second trimester screening: average resistance index > 0.58 and/or or early-diastolic diastolic notch. First trimester screening: Pulsatility index > 95th centile or PI > 1.5) or: First trimester screening (11+0 to 14+1 weeks): Combination of maternal risk factors, elevated MAP, and increased Uterine artery pulsatility index (UTPI). Second trimester screening (19+0 to 24+6 weeks): Combination of maternal risk factors, elevated MAP, and increased Uterine artery pulsatility index (UTPI). Combination of elevated mean arterial pressure (MAP > 90 mmHg) in the second trimester with abnormal uterine artery Doppler Combination elevated booking blood pressure (> 130/85 mmHg) with abnormal uterine artery Doppler Live fetus, no detectable fetal anomaly Exclusion Criteria: Condition where the pregnancies should be terminated within 48 hours, on the basis of any indication (patients consume pravastatin less than 2 days). Contraindication to the statin use: Hypersensitivity to pravastatin Active liver disease Pre pregnant renal insufficiency/kidney failure (history of hemodialysis) Current use of statin Participation in any other controlled trial of investigational medical products in pregnancy

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Multicenter Randomized Non Blinded Trial comparing low dose aspirin versus low dose aspirin and pravastatin in patients with high risk developing preeclampsia
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pravastatin Treatment Group<br>In this arm, the participant will be given aspirin 80 mg daily per oral and the study drugs, Pravastatin 2 x 20 mg per oral daily. | Drug: Pravastatin<br>* The participant will be given pravastatin 2 x 20 mg per oral daily<br>* Other names: Pravastatin Sodium;|
| No Intervention: Control Group<br>In this arm, the participant will be given aspirin 80 mg daily per oral and the study drugs, Pravastatin 2 x 20 mg per oral daily. In this arm, the participant will be given aspirin 80 mg daily per oral, as it already a standard protocol for the high risk preeclampsia group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preeclampsia | Including preeclampsia, preeclampsia with severe features, and gestational hypertension. | From date of randomization until date of delivery | 
| Preterm delivery | Including indicated preterm delivery < 34 weeks and < 37 weeks | 20 - 34 weeks, and 34 - 37 weeks | 
| Maternal complication | Any maternal complication caused by preeclampsia: eclampsia, seizure, HELLP syndrome, acute pulmonary edema, acute kidney injury, Cardivascular accident, liver failure, sepsis, and pneumonia | From date of randomization until date of delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perinatal outcome | Gestational age at birth (days), birthweight (gram), birthweight percentile (INTERGROWTH), Apgar Score | At delivery | 
| Composite neonatal morbidity and mortality | stillbirths, neonatal death, respiratory distress syndrome, intracerebral hemorrhage, neonatal sepsis, necrotizing enterocolitis, length NICU admission, and length of stay | At delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preeclampsia, Pravastatin, Maternal morbidity, Neonatal mortality, Neonatal morbidity