Indonesia Pravastatin to Prevent Preeclampsia Study

Pre-Eclampsia Clinical Trial

— INOVASIA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03648970
• Other study ID #: IND012018
• Status: Recruiting
• Phase: Phase 2
• Start date: March 1, 2018
• Est. completion date: December 1, 2020

Study information

• Verified date: August 2018
• Source: Universitas Airlangga
• Contact: Muhammad Ilham Aldika Akbar, MD, OBGYN
• Phone: +6281703270900
• Email: dokter_aldi[@]yahoo.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 280
• Est. completion date: December 1, 2020
• Est. primary completion date: March 1, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 15 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Eclampsia
• Pre-Eclampsia

Intervention

Drug:
• Pravastatin
The participant will be given pravastatin 2 x 20 mg per oral daily

Locations

Country	Name	City	State
Indonesia	Hasan Sadikin General Hospital	Bandung	West Java
Indonesia	Sanglah General Hospital	Denpasar	Bali
Indonesia	Dr. Wahidin Sudirohusodo General Hospital	Makasar	South Sulawesi
Indonesia	Adam Malik General Hospital	Medan	North Sumatra
Indonesia	Dr. Soetomo Hospital	Surabaya	East Java
Indonesia	Ramelan Naval Hospital	Surabaya	East Java
Indonesia	Dr. Moewardi Hospital	Surakarta	Central Java

Sponsors (1)

Lead Sponsor	Collaborator
Universitas Airlangga

Country where clinical trial is conducted

Indonesia, 

References & Publications (21)

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. — View Citation

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. Review. — View Citation

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

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. Epub 2007 Mar 26. — View Citation

Dekker G, Sibai B. Primary, secondary, and tertiary prevention of pre-eclampsia. Lancet. 2001 Jan 20;357(9251):209-15. Review. — View Citation

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. Review. — View Citation

Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. Review. — View Citation

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. — View Citation

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

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. Review. — View Citation

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

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. — View Citation

Ofori B, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol. 2007 Oct;64(4):496-509. Epub 2007 May 15. — View Citation

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

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. — View Citation

Teelucksingh S, El-Youssef J, Sohan K, Ramsewak S. Prolonged inadvertent pravastatin use in pregnancy. Reprod Toxicol. 2004 Mar-Apr;18(2):299-300. — View Citation

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. — View Citation

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

WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. Geneva: World Health Organization; 2011. — View Citation

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. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The side effect of Pravastatin	Including adverse reactions, Serious Adverse Event (SAE), and Suspected Unexpected Serious Adverse Reaction (SUSAR)	Up to 6 month after birth
Primary	Preeclampsia	Including preeclampsia, preeclampsia with severe features, and gestational hypertension.	From date of randomization until date of delivery
Primary	Preterm delivery	Including indicated preterm delivery < 34 weeks and < 37 weeks	20 - 34 weeks, and 34 - 37 weeks
Primary	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	Perinatal outcome	Gestational age at birth (days), birthweight (gram), birthweight percentile (INTERGROWTH), Apgar Score	At delivery
Secondary	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