Metformin and Esomeprazole in Preterm Pre-eclampsia

May 27, 2025 updated by: Kendall Bielak, MD, Christiana Care Health Services

Use of Combination Metformin and Esomeprazole in Preterm Pre-eclampsia: a Randomized Controlled Trial

The purpose of this study is to better understand diagnosis and treatment of preterm preeclampsia. Currently, there are limited laboratory tests that can be used to diagnosis preeclampsia. Additionally, there are few treatments for this condition. This clinical trial will explore treatment options, Metformin and Esomeprazole, as well as serum markers that could improve the diagnosis and treatment of preterm preeclampsia.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

BACKGROUND:

The pathophysiology of preeclampsia

To achieve normal vascular function during pregnancy, the placental vascular endothelium secretes vasoactive substances and growth factors, most notably vascular endothelial growth factor (VEGF), sFlt-1, placental growth factor (PlGF) and soluble endoglin (sEng). These substrates interact with maternal natural killer cells to promote remodeling of the uterine spiral arteries in order to create a uteroplacental interface. Circulating vasoconstrictors, such as Thromboxane A2, and vasodilators play an important role in regulating the vascular endothelium in response to the developing uteroplacental interface.

In patients with preeclampsia, however, trophoblast cells demonstrate insufficient invasion of the spiral arteries, leading to poor remodeling, narrow vessel diameter and high vascular resistance. The endothelial dysfunction occurs in two phases. In the first phase, defective placental trophoblastic invasion of the uterine spiral arteries occurs at 14-18 weeks of gestation. This dysfunctional invasion leads to poor uteroplacental blood flow and the release of antiangiogenic factors and vasoconstrictive substances in the second phase.

In Defense of Metformin, Esomeprazole

Lower sFlt1 levels were detected in placental villous explants from patients diagnosed with preterm preeclampsia and treated with metformin. Metformin downgraded endothelial cell secretion by 53% and placental cell secretion by 63%. Similarly, in a meta-analysis of patients on metformin for gestational diabetes (GDM), Kalafat and Sukur concluded that the use of metformin was associated with a reduced risk of preeclampsia (relative risk (RR): 0.56; 95% confidence interval (CI): 0.37-0.85; n = 1260 women)

A recent randomized controlled trial by Cluver et al included 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomized to extended release metformin and 90 to placebo. Investigators found that extended release metformin (3g daily) can prolong gestation in women with preterm pre-eclampsia

In vitro studies show proton pump inhibitors decrease soluble fems like tyrosine kinase -1 (sFlt-1) and soluble endoglin and improve markers of endothelial dysfunction. Esomeprazole reduces blood pressure in a preeclampsia transgenic mouse model that overexpresses sFlt-1.

Combination metformin and esomeprazole has shown promise in the treatment of preeclampsia as both agents reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. Kaitu'u-Lino et al found that combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells.

Safety of Metformin, Esomeprazole

Metformin is a biguanide that inhibits hepatic gluconeogenesis and glucose absorption and stimulates glucose uptake in peripheral tissues.

In one large trial, 751 women with GDM were randomly assigned to receive insulin therapy or metformin. Both groups experienced similar rates of a composite outcome of perinatal morbidity, consisting of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, prematurity, and low Apgar scores. Additionally, five randomized clinical trials showed the safety of metformin as well as its efficiency in dealing with GDM compared with insulin. A meta-analysis by Gui et al. demonstrated that metformin was superior to insulin in reducing the incidence of preeclampsia.

Proton pump inhibitors (PPI) such as esomeprazole have long-term safety data in the treatment of gastric reflux in pregnancy. The Motherisk Program conducted a meta-analysis on use of PPIs in 593 pregnancies and showed no increase in risk of malformations. Furthermore, in a large cohort study from the Swedish Medical Birth Registry on 955 infants whose mothers used PPIs during pregnancy showed no difference in birth weights, rates of congenital malformations, perinatal death, or low Apgar scores.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Delaware
      • Newark, Delaware, United States, 19718
        • ChristianaCare Health System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Women 18 years or older
  • Women diagnosed with preeclampsia or preeclampsia with severe features or superimposed preeclampsia with chronic hypertension
  • Candidates for expectant management and had no clinical indication for immediate delivery

Exclusion Criteria:

  • Delivery within 48hr is highly likely
  • Maternal or fetal compromise that necessitated immediate delivery
  • Diabetes or gestational diabetes currently on metformin therapy
  • Reflux disease or other conditions currently on esomeprazole
  • Contraindications to metformin, esomeprazole
  • Baseline creatinine >124 μmol/L
  • Hypersensitivity to metformin or esomeprazole
  • Current use of metformin or esomeprazole
  • Metabolic acidosis
  • Use of drugs that might interact with metformin (glyburide, furosemide, or cationic drugs)
  • Multiple gestations

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin and Esomeprazole
Patients diagnosed with preterm preeclampsia receive expectant management with additional metformin/esomeprazole.
Drug: Metformin

Oral Metformin schedule:

Day 1: 500 milligrams in morning Day 2: 500 milligrams two times a day Day 3: 1000 milligrams in morning, 500 milligrams in evening Day 4 onwards: 1000 milligrams two times a day based on individual tolerance

Oral Esomeprazole schedule:

40 milligrams Oral Esomeprazole daily until delivery which can be tapered down to 20 milligrams daily based on individual tolerance.

Drug: Esomeprazole
40 milligrams Oral Esomeprazole daily until delivery which can be tapered down to 20 milligrams daily based on individual tolerance.
No Intervention: No Intervention
Patients diagnosed with preterm preeclampsia receive expectant management only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean plasma difference in sFlt-1
Time Frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
sFlt-1 from serum samples
Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean plasma difference in vascular endothelial growth factor (VEGF)
Time Frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
VEGF from serum samples
Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Mean plasma difference in placental growth factor (PIGF)
Time Frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
PIGF from serum samples
Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Mean plasma difference in soluble endoglin (sEng)
Time Frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
sENG from serum samples
Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
sFlt-1:PIGF ratio
Time Frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
sFLT-1:PIGF from serum samples
Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Prolongation of gestation
Time Frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Difference in time of expectant management between experimental and control group.
Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Christiana Care Health Services

Investigators

  • Study Director: Derek Bowden, MA,CIP,CHRC, ChristianaCare Institutional Review Board

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 11, 2021

Primary Completion (Actual)

May 8, 2025

Study Completion (Actual)

May 8, 2025

Study Registration Dates

First Submitted

March 30, 2024

First Submitted That Met QC Criteria

April 8, 2024

First Posted (Actual)

April 11, 2024

Study Record Updates

Last Update Posted (Actual)

May 31, 2025

Last Update Submitted That Met QC Criteria

May 27, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 41138
  • 605095 (Other Identifier: DDD)

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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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