RCT Metformin for Reduction of Gestational Diabetes Mellitus Effects

Phase 3

Completed

Conditions: Gestational Diabetes

Interventions: Other: Placebo
Drug: Metformin Hydrochloride

Registration Number: NCT02980276

Lead Sponsor: National University of Ireland, Galway, Ireland

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 535

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Placebo	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.
Treatment	Metformin Hydrochloride	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).

Primary Outcome Measures

Name	Time	Method
Primary Composite Outcome	Enrolment through delivery, an average of 16 weeks.	The primary efficacy outcome was achieved if any participant experienced: * Insulin initiation * Fasting glucose value \>5.1 mmol/l at 32weeks or 38 weeks gestation.
Insulation of Insulin	Enrolment through delivery, an average of 16 weeks.	Initiation of insulin treatment at any time up to delivery.

Secondary Outcome Measures

Name	Time	Method
Insulin Dose Required	Enrolment through delivery, an average of 16 weeks.	Insulin dose required in any participant requiring insulin.
Time to Insulin Initiation	Time to Insulin Initiation, from date of randomization until the date of delivery, an average of 16 weeks..	Time to Insulin Initiation, from date of randomization until the date of delivery.
Postpartum Impaired Fasting Glucose	12 weeks post-partum	Impaired fasting glucose at 12 weeks postpartum
Insulin Initiated	Enrolment through delivery, an average of 16 weeks.	Whether or not insulin was initiated at any time during the study.
Fasting Hyperglycemia	Measured at 32 and 38 weeks' gestation.	Number of women with fasting hyperglycemia at 32wks or at 38wks gestation.
Gestational Weight Gain	Enrolment through delivery, an average of 16 weeks.	Change in weight (kg) from randomization until last visit before delivery
Postpartum Impaired Glucose Tolerance	12 weeks postpartum
Postpartum Metabolic Syndrome	12 weeks postpartum
Gestational Age at Delivery	At delivery, an average of 16 weeks after enrolment
Mode of Delivery - Cesarian Delivery	At delivery, an average of 16 weeks after enrolment	Delivered by Cesarian section.
Mode of Delivery - Emergency Cesarian Section	At delivery, an average of 16 weeks after randomization.	Among those having cesarian section, count of emergency procedures.
Mode of Delivery - Induced	At time of labor, an average of 16 weeks after enrolment.	Labor induced.
Maternal Morbidity - Pregnancy-induced Hypertension	From enrolment through 6 weeks postpartum, an average of 22 weeks.
Maternal Morbidity - Pre-eclampsia	Enrolment through 6 weeks postpartum, an average of 22 weeks.	Pre-eclampsia diagnosed during study participation
Maternal Morbidity - Antepartum Hemorrhage	From enrolment through delivery, an average of 16 weeks.	Any vaginal bleeding prior to delivery
Maternal Morbidity - Postpartum Hemorrhage	From delivery through 6 weeks postpartum.
Birthweight	At birth
Neonatal Head Circumference	At birth
Neonatal Height	At birth	Height in cm (crown-heel length)
Neonatal Abdominal Circumference	At birth
Neonatal Ponderal Index	At birth	Ponderal index is calculated as 100 x weight(grams)/(crown-heel length).
Birth Weight >4000g	At birth
Birth Weight >90th Percentile	At birth
Birth Weight <2500g	At birth
Birth Weight <10th Percentile	At birth
Neonatal Morbidity - Need for NICU Care	From birth until 6 weeks of life.
Neonatal Morbidity - Preterm Birth	At birth	Delivery at gestational age \<37 weeks.
Neonatal Morbidity - Respiratory Distress Syndrome Requiring Respiratory Support	From birth until 6 weeks of life.
Neonatal Morbidity - Jaundice Requiring Phototherapy	From birth until 6 weeks of life.
Neonatal Morbidity - Major Congenital Anomalies	From birth until 6 weeks of life.
Neonatal Morbidity - Apgar Score <7 at 5 Minutes	At 5 minutes after birth	The Apgar score comprises five components: 1) color, 2) heart rate, 3) reflexes, 4) muscle tone, and 5) respiration, each of which is given a score of 0, 1, or 2. (for example see: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2015/10/the-apgar-score#:\~:text=The%20Apgar%20score%20comprises%20five,0%2C%201%2C%20or%202)
Neonatal Morbidity - Neonatal Hypoglycemia	First hour of life.	serum glucose \<2.6mmol/l on at least one occasion \<60 minutes after delivery