A Randomized Placebo Controlled Trial of the Effectiveness of Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Mellitus Effects (EMERGE)

A Randomised Placebo Controlled Trial of the Effectiveness of Early MEtformin in Addition to Usual Care in the Reduction of Gestational Diabetes Mellitus Effects (EMERGE)

The overall objective of the EMERGE trial is to determine whether metformin + usual care, compared to placebo + usual care (introduced at the time of initial diagnosis of GDM), reduces a) the need for insulin use, or hyperglycemia (primary outcome measure); b) excessive maternal weight gain; c) maternal and neonatal morbidities and, d) cost of treatment for women with Gestational Diabetes Mellitus.

Study Overview

• Status: Completed
• Conditions: Gestational Diabetes
• Intervention / Treatment: Drug: Metformin Hydrochloride; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 535
• Phase: Phase 3

Contacts and Locations

Study Locations

• Ireland
  • Galway, Ireland
    • University Hospital Galway
  • Galway
    • Ballinasloe, Galway, Ireland
      • Portiuncula University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent
2. Participants aged 18-50
3. Pregnancy gestation up to 28 weeks (+ 6 days) confirmed by positive pregnancy test
4. Singleton pregnancy as determined by scan
5. Positive diagnosis of Gestational Diabetes Mellitus on a Oral Glucose Tolerance Test (OGTT) according to the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria if any one of the following are achieved: i) Fasting glucose >/= 5.1mmol/l and <7mmol/l, or ii) 1 hour post glucose load of >/=10mmol/l, or iii) 2 hour post glucose load of >/=8.5 mmol/l and <11.1mmo/l
6. Resident in the locality and intending to deliver within the trial site

Exclusion Criteria:

1. Participants who have an established diagnosis of diabetes (Type 1, Type 2, Monogenic or secondary)
2. Participants with a fasting glucose > 7mmol/l or a 2h value > 11.1 mmol/l
3. Multiple pregnancies (twins, triplets etc.) as determined by scan
4. Known intolerance to metformin
5. Known contraindication to the use of metformin which include: i) renal insufficiency (defined as serum creatinine of greater than 130 µmol/L or creatinine clearance <60 ml/min), ii) moderate to severe liver dysfunction (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than 3 times the upper limit of normal, iii) shock or sepsis, and iv) previous hypersensitivity to metformin
6. Major congenital malformations or an abnormally deemed unsuitable for metformin by the site PI or attending consultant
7. Known small for gestational age (Small for gestational age (SGA) refers to foetal growth less than the 10th percentile (RCOG, 2014), or if foetal growth is deemed unsatisfactory by the treating obstetrician)
8. Known gestational hypertension or pre-eclampsia or ruptured membranes
9. Participants who have a history of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements
10. Participants with significant gastrointestinal problems such as severe vomiting, Crohn's disease or colitis which will inadvertently affect absorption of the study drug
11. Participants with congestive heart failure or history of congestive heart failure
12. Participants with serious mental illness which would affect adherence to study medication or compliance with study protocol in the opinion of the investigator
13. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment; Participants randomised to the treatment arm will receive active metformin in addition to standard care. Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose targets. Tablets will be in 500mg doses and will commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg).	Drug: Metformin Hydrochloride; Women randomised to the metformin group will receive metformin 500mg once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg Metformin daily (5 tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until delivery.
Placebo Comparator: Control; Participants randomised to the placebo arm will receive placebo in addition to standard care. Placebo will be titrated according to the dosing schedule to achieve the pre-specified glucose targets. Placebo tablets will commence at 1 tablet per day and will be increased to a maximum of 5 tablets per day over 10 days as with the treatment group.	Other: Placebo; Women randomised to the placebo group will receive 1 placebo tablet once daily, with the dose titrated upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition to usual care (exercise and MNT), and taken until delivery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Initiation/Fasting Glucose	The primary efficacy outcome is a composite of: Insulin initiation (Yes/No); Fasting glucose value </=5.1 mmol/l and >5.1 mmol/l	Change from Gestational Weeks 32 and 38

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Insulin Initiation and Insulin Dose Required	Time to Insulin Initiation, from date of randomization until the date delivery, assessed up to 40 weeks	Time to Insulin Initiation, from date of randomization until the date delivery, assessed up to 40 weeks
Maternal Morbidity at Delivery	Number of women with maternal morbidity at delivery that is related to treatment (e.g. hypertensive disorders, antepartum/postpartum haemorrhage, polyhydramnios)	Delivery
Mode of Delivery	Mode of delivery (e.g. vaginal, cesarean)	Delivery
Time of Delivery	Gestational weeks at delivery	Delivery
Postpartum glucose status, insulin resistance, and metabolic syndrome	Number of women with abnormal glucose values/insulin resistance/metabolic syndrome	12 weeks post-partum
Post-partum BMI	Post-partum BMI in kg/m2 in participants between groups	12 weeks post-partum
Infant Birth Weight	Weight in kg at birth	Delivery
Neonatal height and head circumference at delivery	Height in cm Head circumference in cm	Delivery
Neonatal morbidities	Number of neonates with respiratory distress, jaundice, congenital anomalies, Apgar score, need for neonatal care unit	Delivery
Neonatal hypoglycaemia	Number of neonates with glucose <2.6mmol/l	Delivery
Neonatal hypoglycaemia	Number of neonates with glucose <2.6mmol/l	12 weeks post-partum
Treatment Acceptability	Treatment acceptability determined by Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Rowan Questionnaire	4 weeks post-partum
Quality of Life (EQ5D-5L)	Quality of Life determined by EQ5D-5L Questionnaire	Treatment week 12
Post partum waist circumference	waist circumference in cm in participants between groups	12 weeks post partum
Gestational weight gain	Change in weight (kg) from 24 weeks gestation until last visit before delivery	Change in weight from 24 weeks gestation until last visit before delivery

Other Outcome Measures

Outcome Measure	Time Frame
Cost effectiveness and budget impact of metformin treatment in addition to standard care	24 weeks gestation to 12 weeks post-partum

Collaborators and Investigators

• Sponsor: National University of Ireland, Galway, Ireland
• Collaborators: Health Research Board, Ireland; University Hospital of Limerick; University College Hospital Galway; HRB Clinical Research Facility Galway, Ireland; Portiuncula University Hospital; University Maternity Hospital Limerick; Clinical Research Support Unit, University of Limerick
• Investigators: Principal Investigator: Prof. Fidelma Dunne, National University of Ireland, Galway, Ireland

Publications and helpful links

General Publications

• Dunne F, Newman C, Devane D, Smyth A, Alvarez-Iglesias A, Gillespie P, Browne M, O'Donnell M. A randomised placebo-controlled trial of the effectiveness of early metformin in addition to usual care in the reduction of gestational diabetes mellitus effects (EMERGE): study protocol. Trials. 2022 Sep 21;23(1):795. doi: 10.1186/s13063-022-06694-y.

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2017
• Primary Completion (Actual): January 12, 2023
• Study Completion (Actual): April 13, 2023

Study Registration Dates

• First Submitted: November 9, 2016
• First Submitted That Met QC Criteria: November 29, 2016
• First Posted (Estimated): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 11, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Pregnancy; Gestational Diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Diabetes Mellitus; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: NUIG-2016-01

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