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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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)

Conditions
-----------------
Gestational Diabetes

Intervention / Treatment
-----------------
* Drug: Metformin Hydrochloride
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to provide written informed consent Participants aged 18-50 Pregnancy gestation up to 28 weeks (+ 6 days) confirmed by positive pregnancy test Singleton pregnancy as determined by scan 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 Resident in the locality and intending to deliver within the trial site Exclusion Criteria: Participants who have an established diagnosis of diabetes (Type 1, Type 2, Monogenic or secondary) Participants with a fasting glucose > 7mmol/l or a 2h value > 11.1 mmol/l Multiple pregnancies (twins, triplets etc.) as determined by scan Known intolerance to metformin 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 Major congenital malformations or an abnormally deemed unsuitable for metformin by the site PI or attending consultant 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) Known gestational hypertension or pre-eclampsia or ruptured membranes Participants who have a history of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements Participants with significant gastrointestinal problems such as severe vomiting, Crohn's disease or colitis which will inadvertently affect absorption of the study drug Participants with congestive heart failure or history of congestive heart failure Participants with serious mental illness which would affect adherence to study medication or compliance with study protocol in the opinion of the investigator Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment<br>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<br>* 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.<br>|
| Placebo Comparator: Control<br>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<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Gestational Diabetes, Diabetes, Pregnancy