Esomeprazole in Treatment of Early Onset Preeclampsia (ESOPE Trial)

Use of Esomeprazole in Treatment of Early Onset Preeclampsia:a Double Blind Randomized, Placebo-controlled Trial

Pre-eclampsia is one of the most serious complications of pregnancy affecting 3-8 % of pregnancies worldwide. It is a multi-system disorder involving maternal vessels (causing hypertension and endothelial dysfunction), the kidneys, the liver, the lungs, the hematological system, the cardiovascular system and the feto-placental unit. In its most severe form, it affects the brain, causing seizures (eclampsia), cerebro-vascular events and even death.

Study Overview

• Status: Completed
• Conditions: Preeclampsia
• Intervention / Treatment: Drug: Esomeprazole 40 mg Oral Tablet; Drug: Placebo Oral Tablet

Detailed Description

The key aspects in the pathophysiology of pre-eclampsia are placental oxidative stress (and hypoxia), placental release of the anti-angiogenic factors Soluble Fms Like Tyrosine Kinase -1 and soluble endoglin and maternal endothelial dysfunction. A drug that can counter these pathological steps could be a strategy to treat pre-eclampsia.

If an affordable and safe treatment was available it could temporize the disease progression of pre-eclampsia thereby delaying delivery to gain gestation. This could save the lives of many infants and decrease the hospital burden caused by iatrogenic prematurity.

Currently, there are trials investigating the possible use of pravastatin to treat pre-eclampsia, and to prevent it There are no other significant trials of orally available small molecules to treat pre-eclampsia that we are aware of.

The Translational Obstetrics Group at Melbourne University has generated strong preclinical evidence suggesting esomeprazole as one of the proton pump inhibitors may have potent actions giving it significant potential as a treatment for pre-eclampsia

Proton pump inhibitors have been commonly used in pregnancy to treat gastroesophageal reflux disorders and more serious gastrointestinal complications like Helicobacter pylori-infection, peptic and duodenal ulcers and Zollinger-Ellison syndrome.

Esomeprazole counters three key steps in pre-eclampsia pathogenesis, by up-regulating heme oxygenase-1 ( strongly decreasing the release of antiangiogenic factors Soluble Fms Like Tyrosine Kinase -1 and soluble endoglin and quenching endothelial dysfunction.

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Assiut, Egypt
    • Assiut Faculty of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Gestational age between 28 + 0 weeks and 31 + 6 weeks
• Estimated fetal weight by ultrasound between 500 gm and 1800 gm (if gestation is not certain).
• Singleton pregnancy.
• The patient will be managed with expectant management.

Exclusion Criteria:

• Patient is unable or unwilling to give consent
• Established fetal compromise that necessitates delivery.

• The presence of any of the following at presentation:

  • Eclampsia.
  • Severe hypertension.
  • Cerebrovascular event as an ischaemic or haemorrhagic stroke.
  • Renal impairment.
  • Signs of left ventricular failure which include pulmonary oedema.
  • Disseminated intravascular coagulation (DIC)
  • Haemolysis, elevated liver enzymes and low platelets (HELLP syndrome)
  • Fetal distress on cardiotocography
• Contra-indications for expectant management of pre-eclampsia
• Current use of a proton pump inhibitor
• Contraindications to the use of a proton pump inhibitor
• Previous hypersensitivity reaction to a proton pump inhibitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: study group; Patients will take esomeprazole single dose of 40 mg orally once a day	Drug: Esomeprazole 40 mg Oral Tablet; once daily oral tablets; Other Names: Nexium
Placebo Comparator: control group; Patients will take an inert tablet similar in appearance, color and consistency	Drug: Placebo Oral Tablet; once daily oral tablets; Other Names: inert

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of women who develop HELLP syndrome	1 month
The change in serum level of sFlt-1 and endoglin before the start of treatment and at termination of pregnancy	2 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Prolongation of gestation measured from the time of enrollment to the time of delivery	2 weeks
The side effects of the drugs	2 weeks

Collaborators and Investigators

• Sponsor: Assiut University
• Investigators: Study Director: Ahmed Abbas, MD, Assiut University

Publications and helpful links

General Publications

• Cluver CA, Walker SP, Mol BW, Theron GB, Hall DR, Hiscock R, Hannan N, Tong S. Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol. BMJ Open. 2015 Oct 28;5(10):e008211. doi: 10.1136/bmjopen-2015-008211.
• Lagana AS, Favilli A, Triolo O, Granese R, Gerli S. Early serum markers of pre-eclampsia: are we stepping forward? J Matern Fetal Neonatal Med. 2016 Sep;29(18):3019-23. doi: 10.3109/14767058.2015.1113522. Epub 2015 Nov 23.
• Baumann MU, Bersinger NA, Mohaupt MG, Raio L, Gerber S, Surbek DV. First-trimester serum levels of soluble endoglin and soluble fms-like tyrosine kinase-1 as first-trimester markers for late-onset preeclampsia. Am J Obstet Gynecol. 2008 Sep;199(3):266.e1-6. doi: 10.1016/j.ajog.2008.06.069.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2018
• Primary Completion (Actual): July 1, 2020
• Study Completion (Actual): October 15, 2020

Study Registration Dates

• First Submitted: July 8, 2017
• First Submitted That Met QC Criteria: July 8, 2017
• First Posted (Actual): July 11, 2017

Study Record Updates

• Last Update Posted (Actual): January 7, 2021
• Last Update Submitted That Met QC Criteria: January 6, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Esomeprazole
• Other Study ID Numbers: ESOPE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No