Indonesia Pravastatin to Prevent Preeclampsia Study

NCT03648970 | Unknown Phase 2 DMC

• 1 other identifier: IND012018
• Study Type: interventional
• Target: 280
• Locations: 1 country
• Sites: 7

Brief Summary

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

Conditions

Pre-Eclampsia

Keywords

Preeclampsia; Pravastatin; Maternal morbidity; Neonatal mortality; Neonatal morbidity

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• Perinatal outcome

  At delivery

• Composite neonatal morbidity and mortality

  At delivery

Other Outcomes (1)

• The side effect of Pravastatin

  Up to 6 month after birth

Study Arms (2)

Pravastatin Treatment Group

EXPERIMENTAL

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

Control Group

NO INTERVENTION

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

Interventions

Pravastatin DRUG

The participant will be given pravastatin 2 x 20 mg per oral daily

Also known as: Pravastatin Sodium

Pravastatin Treatment Group

Eligibility Criteria

• Age: 15 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Universitas Airlangga: lead

Study Sites (7)

Sanglah General Hospital

Denpasar, Bali, Indonesia

NOT YET RECRUITING

Dr. Moewardi Hospital

Surakarta, Central Java, 57126, Indonesia

NOT YET RECRUITING

Ramelan Naval Hospital

Surabaya, East Java, 60244, Indonesia

NOT YET RECRUITING

Dr. Soetomo Hospital

Surabaya, East Java, 60285, Indonesia

RECRUITING

Adam Malik General Hospital

Medan, North Sumatra, Indonesia

NOT YET RECRUITING

Dr. Wahidin Sudirohusodo General Hospital

Makassar, South Sulawesi, Indonesia

NOT YET RECRUITING

Hasan Sadikin General Hospital

Bandung, West Java, Indonesia

RECRUITING

Related Publications (21)

• Ahmed A, Ramma W. Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm? Br J Pharmacol. 2015 Mar;172(6):1574-86. doi: 10.1111/bph.12977.

  PMID: 25303561 BACKGROUND

• Brennan LJ, Morton JS, Davidge ST. Vascular dysfunction in preeclampsia. Microcirculation. 2014 Jan;21(1):4-14. doi: 10.1111/micc.12079.

  PMID: 23890192 BACKGROUND

• Cudmore M, Ahmad S, Al-Ani B, Fujisawa T, Coxall H, Chudasama K, Devey LR, Wigmore SJ, Abbas A, Hewett PW, Ahmed A. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. 2007 Apr 3;115(13):1789-97. doi: 10.1161/CIRCULATIONAHA.106.660134. Epub 2007 Mar 26.

  PMID: 17389265 BACKGROUND

• 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.

  PMID: 26723196 BACKGROUND

• Ramma W, Ahmed A. Therapeutic potential of statins and the induction of heme oxygenase-1 in preeclampsia. J Reprod Immunol. 2014 Mar;101-102(100):153-160. doi: 10.1016/j.jri.2013.12.120. Epub 2014 Jan 16.

  PMID: 24503248 BACKGROUND

• Ahmed A, Cudmore MJ. Can the biology of VEGF and haem oxygenases help solve pre-eclampsia? Biochem Soc Trans. 2009 Dec;37(Pt 6):1237-42. doi: 10.1042/BST0371237.

  PMID: 19909254 BACKGROUND

• Dulak J, Deshane J, Jozkowicz A, Agarwal A. Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis. Circulation. 2008 Jan 15;117(2):231-41. doi: 10.1161/CIRCULATIONAHA.107.698316.

  PMID: 18195184 BACKGROUND

• Dekker G, Sibai B. Primary, secondary, and tertiary prevention of pre-eclampsia. Lancet. 2001 Jan 20;357(9251):209-15. doi: 10.1016/S0140-6736(00)03599-6.

  PMID: 11213110 BACKGROUND

• Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction. Hypertension. 2001 Sep;38(3 Pt 2):718-22. doi: 10.1161/01.hyp.38.3.718.

  PMID: 11566964 BACKGROUND

• Seki H. Balance of antiangiogenic and angiogenic factors in the context of the etiology of preeclampsia. Acta Obstet Gynecol Scand. 2014 Oct;93(10):959-64. doi: 10.1111/aogs.12473. Epub 2014 Sep 17.

  PMID: 25139038 BACKGROUND

• Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension. 2008 Apr;51(4):970-5. doi: 10.1161/HYPERTENSIONAHA.107.107607. Epub 2008 Feb 7. No abstract available.

  PMID: 18259009 BACKGROUND

• Ofori B, Rey E, Berard A. Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol. 2007 Oct;64(4):496-509. doi: 10.1111/j.1365-2125.2007.02905.x. Epub 2007 May 15.

  PMID: 17506782 BACKGROUND

• Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, Zeeman GG, Brown MA. The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. Pregnancy Hypertens. 2014 Apr;4(2):97-104. doi: 10.1016/j.preghy.2014.02.001. Epub 2014 Feb 15. No abstract available.

  PMID: 26104417 BACKGROUND

• Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. doi: 10.1210/edrv.18.1.0287. No abstract available.

  PMID: 9034784 BACKGROUND

• Zarek J, Koren G. The fetal safety of statins: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2014 Jun;36(6):506-509. doi: 10.1016/S1701-2163(15)30565-X.

  PMID: 24927189 BACKGROUND

• von Dadelszen P, Magee LA. Pre-eclampsia: an update. Curr Hypertens Rep. 2014 Aug;16(8):454. doi: 10.1007/s11906-014-0454-8.

  PMID: 24915961 BACKGROUND

• Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003 Mar;111(5):649-58. doi: 10.1172/JCI17189.

  PMID: 12618519 BACKGROUND

• Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Semin Nephrol. 2011 Jan;31(1):33-46. doi: 10.1016/j.semnephrol.2010.10.004.

  PMID: 21266263 BACKGROUND

• Hod T, Cerdeira AS, Karumanchi SA. Molecular Mechanisms of Preeclampsia. Cold Spring Harb Perspect Med. 2015 Aug 20;5(10):a023473. doi: 10.1101/cshperspect.a023473.

  PMID: 26292986 BACKGROUND

• Teelucksingh S, El-Youssef J, Sohan K, Ramsewak S. Prolonged inadvertent pravastatin use in pregnancy. Reprod Toxicol. 2004 Mar-Apr;18(2):299-300. doi: 10.1016/j.reprotox.2003.11.003. No abstract available.

  PMID: 15019727 BACKGROUND

• WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. Geneva: World Health Organization; 2011. Available from http://www.ncbi.nlm.nih.gov/books/NBK140561/

  PMID: 23741776 BACKGROUND

MeSH Terms

Conditions

Pre-Eclampsia

Interventions

Pravastatin

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Muhammad Ilham Aldika Akbar, MD, OBGYN

  Universitas Airlangga

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Muhammad Ilham Aldika Akbar, MD, OBGYN

CONTACT

+6281703270900; dokter_aldi@yahoo.com

Gustaaf Dekker, MD, PhD

CONTACT

+61881829306; gustaaf.dekker@adelaide.edu.au

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The diagnosis is made by resident unaware of the medication patients received
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, MFM Consultant

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

Study Record Dates

• First Submitted: August 22, 2018
• First Posted: August 28, 2018
• Study Start: March 1, 2018
• Primary Completion: March 1, 2020
• Study Completion: December 1, 2020
• Last Updated: August 28, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

ID (7)