Ignite Creation Date:
2024-05-06 @ 8:21 PM
Last Modification Date:
2024-10-26 @ 3:26 PM
Study NCT ID:
NCT06359015
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-11
First Post:
2024-03-30
Brief Title:
Metformin and Esomeprazole in Preterm Pre-eclampsia
Sponsor:
Christiana Care Health Services
Organization:
Christiana Care Health Services
Study Overview
Official Title:
Use of Combination Metformin and Esomeprazole in Preterm Pre-eclampsia a Randomized Controlled Trial
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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 056 95 confidence interval CI 037-085 n 1260 women
A recent randomized controlled trial by Cluver et al included 180 women with preterm pre-eclampsia between 260 to 316 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 Kaituu-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
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 056 95 confidence interval CI 037-085 n 1260 women
A recent randomized controlled trial by Cluver et al included 180 women with preterm pre-eclampsia between 260 to 316 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 Kaituu-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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 605095 | OTHER | DDD | None |