Metformin and Esomeprazole in Preterm Pre-eclampsia

Preeclampsia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT06359015
• Other study ID #: 41138
• Secondary ID: 605095
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: February 11, 2021
• Est. completion date: June 2025

Study information

• Verified date: April 2024
• Source: Christiana Care Health Services
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 4
• Est. completion date: June 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Eclampsia
• Pre-Eclampsia
• Preeclampsia
• Preeclampsia Severe
• Premature Birth
• Preterm

Intervention

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

Locations

Country	Name	City	State
United States	Christianacare Health System	Newark	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Christiana Care Health Services

Country where clinical trial is conducted

United States, 

References & Publications (3)

Cluver CA, Hiscock R, Decloedt EH, Hall DR, Schell S, Mol BW, Brownfoot F, Kaitu'u-Lino TJ, Walker SP, Tong S. Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial. BMJ. 2021 Sep 22;374:n2103. doi: 10.1136/bmj.n2103. — View Citation

Kaitu'u-Lino TJ, Brownfoot FC, Beard S, Cannon P, Hastie R, Nguyen TV, Binder NK, Tong S, Hannan NJ. Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction - implications for treating preeclampsia. PLoS One. 2018 Feb 21;13(2):e0188845. doi: 10.1371/journal.pone.0188845. eCollection 2018. — View Citation

Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193. Erratum In: N Engl J Med. 2008 Jul 3;359(1):106. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean plasma difference in sFlt-1	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	Mean plasma difference in vascular endothelial growth factor (VEGF)	VEGF from serum samples	Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Secondary	Mean plasma difference in placental growth factor (PIGF)	PIGF from serum samples	Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Secondary	Mean plasma difference in soluble endoglin (sEng)	sENG from serum samples	Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Secondary	sFlt-1:PIGF ratio	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
Secondary	Prolongation of gestation	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