ISRCTN - ISRCTN51279843: Efficacy of metformin in pregnant obese women: a randomised controlled trial

Plain English Summary

Background and study aims
The purpose of the study is to see if giving a tablet called metformin to pregnant women who have a raised body mass index (BMI) improves the mother's and baby's health. We know that having a raised BMI in pregnancy may cause the baby to grow too much in the womb. It may also cause other pregnancy complications. We also know that babies born to mothers who are overweight in pregnancy are slightly more likely to develop conditions such as diabetes or become overweight themselves in later life. We know that pregnant women with a higher BMI tend to have higher blood sugar. We believe this extra sugar may contribute to the complications associated with a higher BMI in pregnancy. We want to see if giving metformin to women who have a raised BMI in pregnancy improves the mothers and baby's health. Women with a raised BMI are 'insulin resistant', i.e. the body does not respond effectively to the insulin they make. This results in higher blood sugar levels. Metformin helps to improve insulin resistance and therefore prevent higher blood sugar levels. Therefore, it might improve pregnancy outcomes.

Who can participate?
Pregnant women aged between 16 and 40 who have a BMI of 30 kg/m2 or more can participate. They must be enrolled in the study before 16 weeks of pregnancy. They must have a singleton pregnancy (i.e. not twins or triplets) and be otherwise healthy.

What does the study involve?
If you chose to enroll in the study you will have an initial visit to the hospital before 16 weeks of pregnancy to complete a consent form and have some blood tests taken to ensure you are eligible to continue. This includes a test called a glucose tolerance test to make sure you do not have diabetes. Some body measurements will also be taken. You will be issued with a supply of tablets, which will be assigned to you by a process called randomisation. The tablets will either be the active treatment metformin, or an identical looking dummy tablet (placebo). Neither the study team nor you will know which group you are in. This is called 'double-blind'. You will be provided with instructions on how to take the tablets and a diary to record how many tablets you are taking. You will be asked to take the tablets every day until your baby is born. A member of the research team will complete a telephone questionnaire when you are 20 weeks pregnant to see how you are getting on. You will have two further visits to the hospital for repeat blood tests and measurements at 28 and 36 weeks of pregnancy. When you have your baby some measurements will be taken of the baby's weight and size. There will be a final visit to the hospital to take body measurement of you and your baby when your baby is three months old. The pregnancy outcomes of women taking metformin will be compared with those taking the placebo.

What are the possible benefits and risks of participating?
We cannot promise there will any direct benefit to you from taking part but the information we obtain may help improve the future treatment of women who are pregnant with a raised BMI. The possible side effects of metformin treatment are nausea, vomiting, abdominal pain, diarrhoea and reduced appetite. Most people do not experience any side effects. Side effects are less likely if you start with a small dose and build it up gradually, which we will ask you to do.

Where is the study run from?
The study is run from the University of Edinburgh. There are 17 centres across the UK taking part including the Royal Infirmary, Edinburgh, Liverpool Women's Hospital and the University Hospital, Coventry.

When is the study starting and how long is it expected to run for?
February 2011 to April 2015

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Prof. Jane Norman
jane.norman@ed.ac.uk

Trial website

http://www.crh.ed.ac.uk/empowar/

Contact information

Type

Scientific

Primary contact

Prof Jane Norman

ORCID ID

Contact details

University of Edinburgh
Centre for Reproductive Biology
The Queens Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 (0)131 242 2694
jane.norman@ed.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

EME 08/246/09

Study information

Scientific title

A multicentre randomised placebo controlled clinical trial of metformin versus placebo in pregnant women to reduce the risk of obesity and metabolic syndrome in their babies

Acronym

EMPOWaR

Study hypothesis

Our study hypothesis is that metformin, administered to obese women during pregnancy, reduces the future life risk of obesity and metabolic syndrome in their babies. We will use high birthweight centile as a surrogate marker for future life events as its validity has been shown in large epidemiological studies.

Link to EME project website: http://www.eme.ac.uk/projectfiles/0824609info.pdf
Link to protocol: http://www.eme.ac.uk/projectfiles/0824609protocol.pdf

Ethics approval

Scotland A Research Ethics Committee, 24/02/2010, ref: 10/MRE00/12

Study design

Multicentre randomised placebo-controlled clinical trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Patient information can be found at: http://www.crh.ed.ac.uk/empowar/files/2011/12/EMPOWaR-PIL-current.pdf

Condition

Obesity, pregnancy

Intervention

Active arm:
Oral metformin tablets given three times daily to a maximum of 500 - 2500 mg daily. Total duration of treatment is from 12 weeks of gestation until delivery (maximum 30 weeks). Total duration of follow up in this study: one year after starting therapy.

Placebo arm:
Oral placebo tablets given three times daily. Total duration of treatment is from 12 weeks of gestation until delivery (maximum 30 weeks). Total duration of follow up in this study: one year after starting therapy.

Intervention type

Drug

Phase

Phase III

Drug names

Metformin

Primary outcome measure

Current primary outcome measures as of 05/11/2014:
Gestational age and sex adjusted birth weight centiles of the baby, measured at delivery of the baby

Previous primary outcome measures:
1. Gestational age and sex adjusted birthweight centiles of the baby, measured at delivery of the baby
2. Correlation between maternal insulin resistance (IR) at 36 weeks gestation
3. Adverse pregnancy outcomes, measured cumulatively as pregnancy progresses until after delivery

Secondary outcome measures

Current secondary outcome measures as of 05/11/2014:
1. Correlation between maternal insulin resistance (IR) at 36 weeks gestation and adverse pregnancy outcomes, measured cumulatively as pregnancy progresses until after delivery
2. More detailed measurements of neonatal body composition at birth including ponderal index, skinfold thickness and neonatal fat mass measured using air displacement plethysmography, measured within two weeks of birth
3. Biological mechanisms of metformin action including:
3.1. Change in whole body IR (longitudinal studies at 28 and 36 weeks) and hepatic and skeletal insulin sensitivity (36 weeks)
3.2. Maternal and neonatal inflammatory and lipid and fatty acid indices including C-reactive protein (CRP), interleukin-6 (IL-6), leptin, full lipid profile, non-esterified fatty acids, polyunsaturated fatty acids and plasminogen activator inhibitor 1 (PAI1)/plasminogen activator inhibitor 2 (PAI2) ratio, measured at 36 weeks of pregnancy
3.3. Placental glucocorticoid receptor expression, measured in the placenta after delivery of the baby
3.4. Maternal brachial arterial endothelial dependent flow mediated dilatation (FMD), measured at 36 weeks of pregnancy
3.5. In vitro measurements of maternal myometrial contractility, measured after delivery
4. Changes in maternal anthropometry from the beginning to the end of pregnancy
5. Adverse pregnancy outcomes as a composite measured cumulatively until the end of pregnancy; incidence of low birthweight centile measured at delivery
6. Gas chromatography mass spectrometry measurements of metformin in maternal plasma to determine compliance in samples obtained at 36 weeks of gestation

Previous secondary outcome measures:
1. More detailed measurements of neonatal body composition at birth including ponderal index, skinfold thickness and neonatal fat mass measured using air displacement plethysmography, measured within two weeks of birth
2. Biological mechanisms of metformin action including:
2.1. Change in whole body IR (longitudinal studies at 28 and 36 weeks) and hepatic and skeletal insulin sensitivity (36 weeks)
2.2. Maternal and neonatal inflammatory and lipid and fatty acid indices including C-reactive protein (CRP), interleukin-6 (IL-6), leptin, full lipid profile, non-esterified fatty acids, polyunsaturated fatty acids and plasminogen activator inhibitor 1 (PAI1)/plasminogen activator inhibitor 2 (PAI2) ratio, measured at 36 weeks of pregnancy
2.3. Placental glucocorticoid receptor expression, measured in the placenta after delivery of the baby
2.4. Maternal brachial arterial endothelial dependent flow mediated dilatation (FMD), measured at 36 weeks of pregnancy
2.5. In vitro measurements of maternal myometrial contractility, measured after delivery
3. Changes in maternal anthropometry from the beginning to the end of pregnancy
4. Adverse pregnancy outcomes as a composite measured cumulatively until the end of pregnancy; incidence of low birthweight centile measured at delivery
5. Gas chromatography mass spectrometry measurements of metformin in maternal plasma to determine compliance in samples obtained at 36 weeks of gestation

Overall trial start date

01/02/2011

Overall trial end date

30/04/2015

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Caucasian obese (body mass index [BMI] greater than or equal to 30 kg/m^2) pregnant women between 12-0 and 16+0 weeks gestation
2. Women aged greater than 16 years
3. Signed informed consent form

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

400

Participant exclusion criteria

1. Non Caucasian women
2. Women with a BMI less than or equal to 29 kg/m^2
3. Gestation greater than than 16 weeks
4. Women with pre-existing diabetes
5. Women with gestational diabetes in a previous pregnancy
6. Women with systemic disease requiring regular medication
7. Gestational diabetes in index pregnancy (diagnosed with 75 g oral glucose tolerance test [OGTT] prior to randomisation)
8. Previous delivery of a baby less than 3rd centile or previous pregnancy with pre-eclampsia prompting delivery before 32 weeks gestation
9. A known hypersensitivity to metformin hydrochloride or to any of the excipients
10. Known abnormalities of the liver (tested prior to randomisation)
11. Renal failure or renal dysfunction
12. Acute conditions with the potential to alter renal function such as:
12.1. Dehydration sufficient to require intravenous infusion
12.2. Severe infection
12.3. Shock
12.4. Intravascular administration of iodinated contrast agents
12.5. Acute or chronic diseases which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock or hepatic insufficiency, acute alcohol intoxication or alcoholism
13. Lactation
14. Multiple pregnancy

Recruitment start date

01/02/2011

Recruitment end date

30/04/2015

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University of Edinburgh
Edinburgh
EH16 4TJ
United Kingdom

Sponsor information

Organisation

University of Edinburgh and NHS Lothian (UK)

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: EME 08/246/09)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data