Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol

Catherine A Cluver, Susan P Walker, Ben W Mol, Gerard B Theron, David R Hall, Richard Hiscock, N Hannan, S Tong, Catherine A Cluver, Susan P Walker, Ben W Mol, Gerard B Theron, David R Hall, Richard Hiscock, N Hannan, S Tong

Abstract

Introduction: Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far greater numbers of fetal losses. There is no definitive treatment other than delivery. A drug that can quench the disease process could be useful to treat early onset pre-eclampsia, as it could allow pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have generated preclinical data to show esomeprazole, a proton pump inhibitor used for gastric reflux, has potent biological effects that makes it a worthwhile therapeutic candidate. Esomeprazole potently decreases soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin secretion from placenta and endothelial cells, and has biological actions to mitigate endothelial dysfunction and oxidative stress.

Methods and analysis: We propose undertaking a phase II, double blind, randomised controlled clinical trial to examine whether administering 40 mg esomeprazole daily may prolong gestation in women with early onset pre-eclampsia. We will recruit 120 women (gestational age of 26+0 to 31+6 weeks) who will be randomised to receive either esomeprazole or an identical placebo. The primary outcome will be the number of days from randomisation to delivery. Secondary outcomes include maternal, fetal and neonatal composite and individual outcomes. Maternal outcomes include maternal death, eclampsia, pulmonary oedema, severe renal impairment, cerebral vascular events and liver haematoma or rupture. Neonatal outcomes include neonatal death within 6 weeks after the due date, intraventricular haemorrhage, necrotising enterocolitis and bronchopulmonary dysplasia. We will examine whether esomeprazole can decrease serum sFlt-1 and soluble endoglin levels and we will record the safety of esomeprazole in these pregnancies.

Ethics and dissemination: This study has ethical approval (Protocol V.2.4, M14/09/038, Federal Wide assurance Number 00001372, IRB0005239), and is registered with NHREC (ID 3649) and the Pan African Clinical Trial Registry (PACTR201504000771349). Data will be presented at international conferences and published in peer-reviewed journals.

Keywords: PERINATOLOGY.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

References

    1. Lain KY, Roberts JM. Contemporary concepts of the pathogenesis and management of preeclampsia. JAMA 2002;287:3183–6. 10.1001/jama.287.24.3183
    1. ACOG Committee on Obstetric Practice. Practice bulletin# 33: diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002;99:159–67. 10.1016/S0029-7844(01)01747-1
    1. Dolea C, AbouZahr C. Global burden of hypertensive disorders of pregnancy in the year 2000. Evidence and information for policy (EIP). Geneva: World Health Organization, 2003.
    1. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592–4. 10.1126/science.1111726
    1. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99. 10.1016/S0140-6736(05)17987-2
    1. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol 2003;102:181–92. 10.1016/S0029-7844(03)00475-7
    1. Zhang J, Meikle S, Trumble A. Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States. Hypertens Pregnancy 2003;22:203–12. 10.1081/PRG-120021066
    1. United Nations Millenium Development Goals. (accessed Feb 2015).
    1. Levine RJ, Maynard SE, Qian C et al. . Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672–83. 10.1056/NEJMoa031884
    1. Gill SK, O'Brien L, Einarson TR et al. . The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol 2009;104:1541–5. 10.1038/ajg.2009.122
    1. Matok I, Levy A, Wiznitzer A et al. . The safety of fetal exposure to proton-pump inhibitors during pregnancy. Dig Dis Sci 2012;57:699–705. 10.1007/s10620-011-1940-3
    1. Pasternak B, Hviid A. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects. N Engl J Med 2010;363:2114–23. 10.1056/NEJMoa1002689
    1. Onda K, Hannan N, Beard S, et al.Proton Pump inhibitors for treatment of preeclampsia Abstract 6-OR. XIX Word Congress ISSHP; 26–29 Oct 2014.
    1. Magee LA, Pels A, Helewa M et al. . Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens 2014;4:105–45. 10.1016/j.preghy.2014.01.003
    1. Hall DR, Odendaal HJ, Steyn DW et al. . Expectant management of early onset, severe pre-eclampsia: maternal outcome. BJOG 2000;107:1252–7. 10.1111/j.1471-0528.2000.tb11616.x
    1. Ryan TP. Sample Size Determination and Power. Hoboken, New Jersey: John Wiley and Sons, Inc; 2013.
    1. World Health Organization. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. WHO Tech Rep Ser 1995;850:97–137.
    1. Thadhani R, Kisner T, Hagmann H et al. . Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 2011;124:940–50. 10.1161/CIRCULATIONAHA.111.034793
    1. Ramma W, Ahmed A. Therapeutic potential of statins and the induction of heme oxygenase-1 in preeclampsia. J Reprod Immunol 2014;101-102:153–60. 10.1016/j.jri.2013.12.120
    1. Costantine MM, Tamayo E, Lu F et al. . Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia. Obstet Gynecol 2010;116:114–20. 10.1097/AOG.0b013e3181e10ebd
    1. Teratology Society Public Affairs Committee. FDA classification of drugs for teratogenic risk. Teratology 1994;49:446–7. 10.1002/tera.1420490603

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel