Clinical trial NCT03648970: Indonesia Pravastatin to Prevent Preeclampsia Study
Official title: Pravastatin to Prevent Preeclampsia and Reduce Maternal-Neonatal Mortality and Morbidity in High Risk Preeclampsia Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Pre-Eclampsia
Keywords: Preeclampsia
Pravastatin
Maternal morbidity
Neonatal mortality
Neonatal morbidity
Lead sponsor: Universitas Airlangga
Sponsor class: OTHER
First posted: 2018-08-28
Enrollment: 280
Sex: FEMALE
Minimum age (years): 15
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter Randomized Non Blinded Trial comparing low dose aspirin versus low dose aspirin and pravastatin in patients with high risk developing preeclampsia
Primary purpose: PREVENTION

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


Eligibility criteria: 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

Primary outcomes:
measure: Preeclampsia
timeFrame: From date of randomization until date of delivery
measure: Preterm delivery
timeFrame: 20 - 34 weeks, and 34 - 37 weeks
measure: Maternal complication
timeFrame: From date of randomization until date of delivery
Secondary outcomes:
measure: Perinatal outcome
timeFrame: At delivery
measure: Composite neonatal morbidity and mortality
timeFrame: At delivery
Other outcomes:
measure: The side effect of Pravastatin
timeFrame: Up to 6 month after birth
Locations:
city: Denpasar
country: Indonesia
facility: Sanglah General Hospital
state: Bali
city: Surakarta
country: Indonesia
facility: Dr. Moewardi Hospital
state: Central Java
city: Surabaya
country: Indonesia
facility: Ramelan Naval Hospital
state: East Java
city: Surabaya
country: Indonesia
facility: Dr. Soetomo Hospital
state: East Java
city: Medan
country: Indonesia
facility: Adam Malik General Hospital
state: North Sumatra
city: Makasar
country: Indonesia
facility: Dr. Wahidin Sudirohusodo General Hospital
state: South Sulawesi
city: Bandung
country: Indonesia
facility: Hasan Sadikin General Hospital
state: West Java
Study officials:
affiliation: Universitas Airlangga
name: Muhammad Ilham Aldika Akbar, MD, OBGYN
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: Brennan LJ, Morton JS, Davidge ST. Vascular dysfunction in preeclampsia. Microcirculation. 2014 Jan;21(1):4-14. doi: 10.1111/micc.12079.
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. doi: 10.1161/CIRCULATIONAHA.106.660134. Epub 2007 Mar 26.
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.
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(100):153-160. doi: 10.1016/j.jri.2013.12.120. Epub 2014 Jan 16.
citation: 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.
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.
citation: 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.
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. doi: 10.1161/01.hyp.38.3.718.
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.
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. No abstract available.
citation: 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.
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. No abstract available.
citation: 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.
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.
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.
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. doi: 10.1172/JCI17189.
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.
citation: 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.
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. doi: 10.1016/j.reprotox.2003.11.003. No abstract available.
citation: 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/