Metformin to Prevent Preterm Birth in Twin Pregnancy

NCT05412056 | Unknown Phase 2

• 1 other identifier: UW 20-315
• Study Type: interventional
• Target: 790
• Locations: 0 countries
• Sites: N/A

Brief Summary

Preterm birth (PTB) is a major challenge to perinatal health. It accounts for 75% of perinatal deaths and more than 50% of long-term neurological disabilities. Neonates born preterm are also at risk of significant comorbidities, for example respiratory distress syndrome, chronic lung disease, retinopathy of prematurity, necrotizing enterocolitis, intraventricular haemorrhage and sepsis in the short term, as well as cerebral palsy, motor and sensory impairment, learning difficulties, and increased risk of chronic disease in long run. Twin pregnancy is associated with a higher risk of PTB when compared to singleton pregnancy. The National Vital Statistics reveals the PTB rate is 8.2% and 60.3% in singleton and twin pregnancy respectively in 2018. The mechanism of PTB in twin pregnancy is not completely understood and may be different from that of singleton pregnancy. At present, there are no good strategies to prevent PTB in twin pregnancy. In singleton pregnancy, metformin has been used for the treatment of gestational diabetes in pregnant women with obesity/ overweight or polycystic ovarian syndrome (PCOS). The rate of PTB of pregnant women with PCOS is significantly lower after using metformin. A decreasing trend of PTB is also noted after metformin use in obese pregnant women without PCOS. There is no study to investigate the effect of metformin in twin pregnancy. Premature uterine and amnion stretching in twin pregnancy can trigger preterm labour by increased prostaglandin synthesis and interleukin-1, activation of activator protein-1, expression of connexin-43 and stimulation of stretch dependent focal adhesion signaling. Inflammation is another risk factor for PTB. Metformin is an anti-inflammatory agent which can suppress inflammatory cytokines production and downregulate AMP-activated protein kinase medicated connexin-43 and nuclear factor κB activation. Anti-inflammatory actions of metformin can also reduce production of nitric oxide, prostaglandin E2 and pro-inflammatory cytokines through inhibition of NFκB activation in macrophages. Another possible mechanism to prevent PTB is the inhibition of mammalian target of rapamycin complex 1,which has a role in the timing of birth, by AMP-activated protein kinase. Therefore, metformin can be potentially used to prevent PTB in twin pregnancy. However, its effect in twin pregnancy has not been studied. The objective of the study is to determine if the use of metformin in twin pregnancy can prevent PTB.

Conditions

Preterm Birth; Premature Obstetric Labor; Twin; Complicating Pregnancy; Pregnancy Complications; Pregnancy Preterm; Metformin; Drug Effect

Outcome Measures

Primary Outcomes (1)

• Preterm birth

  Number of participants with preterm birth

  before 34+0 gestational weeks

Secondary Outcomes (2)

• Preterm birth

  before 32+0 weeks

• Preterm birth

  before 28+0 weeks

Study Arms (2)

Metformin

ACTIVE COMPARATOR

Metformin will be prescribed before 20 weeks to 33+6 weeks, started at a daily dose of 500mg in the first week, and the daily dose is increased by 500mg per week to a maximum of 2000mg in week 4 (1000mg twice per day). Women will be asked to take the maximum tolerated dose if they experience side effects from the medication.

Drug: Metformin

Placebo

PLACEBO COMPARATOR

Placebo will be prescribed before 20 weeks to 33+6 weeks, started at a daily dose of 1 tablet in the first week, and the daily dose is increased by 1 tablet per week to a maximum of 4 tablets in week 4 (2 tablets twice per day). Women will be asked to take the maximum tolerated dose if they experience side effects from the medication.

Drug: Placebo oral tablet

Interventions

Metformin DRUG

as in arm/group description

Metformin

Placebo oral tablet DRUG

as in arm/group description

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All women age ≥ 18 years old
• Viable twin pregnancy with dichorionic diamnioticity or monochorionic diamnioticity
• Gestational age less than 20 completed weeks

You may not qualify if:

• High order multiple pregnancy such as triplets or higher order multiple pregnancy with fetal reduction to twin pregnancy
• Monochorionic monoamniotic twin pregnancy
• Twin pregnancy with silent miscarriage of one twin
• Excessive vaginal bleeding
• Presence of congenital anomaly
• Rupture of membranes
• Congenital uterine anomaly
• Unwillingness or inability to comply with study procedures
• Known paternal or maternal abnormal karyotype
• Known renal, liver, or heart failure
• Pre-existing type 1 or 2 diabetes
• Treatment with metformin at the time of screening
• Allergic to metformin

Sponsors & Collaborators

• The University of Hong Kong: lead

MeSH Terms

Conditions

Premature Birth; Obstetric Labor, Premature; Pregnancy Complications

Interventions

Metformin

Condition Hierarchy (Ancestors)

Obstetric Labor Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Central Study Contacts

Mimi Tin-yan Seto, MRCOG

CONTACT

(852)22554647; mimiseto@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Consultant

Study Record Dates

• First Submitted: June 6, 2022
• First Posted: June 9, 2022
• Study Start: June 1, 2022
• Primary Completion: June 1, 2025
• Study Completion: June 1, 2025
• Last Updated: June 23, 2022

Record last verified: 2022-06