Metformin in Obese Non-diabetic Pregnant Women

NCT ID: NCT01273584

Last Updated: 2016-01-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 450 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2015-09-30

Brief Summary

Obesity is on the rise in all developed countries. Of particular concern is that more young people including children are being recognised as being overweight or obese. We know from a recent large national enquiry into all maternal and child deaths in the UK, known as CEMACH, that obesity is a major risk both for the mother and her child. When all deaths in women during pregnancy are analysed, obesity comes out as the most common risk factor. Babies of obese mothers are more than 3 times as likely to need admission to the Neonatal Intensive Care Unit.

Traditionally, obesity is treated by lifestyle measures encouraging healthy eating and increasing physical activity. Unfortunately these measures are often insufficient to produce significant improvements in weight. If obese women gain little or even no weight during pregnancy, the outcome of the pregnancy is known to be improved. This was shown in a very large study of more than 120, 000 obese women.

The drug metformin has been used for years in the treatment of diabetes and more recently for polycystic ovary syndrome (PCOS). Studies in pregnant PCOS women and women with diabetes in pregnancy have shown it to be safe and effective. Fortunately it is relatively cheap and taken as a tablet with meals.

Metformin has the great advantage of not causing weight gain and often leads to a small amount of weight loss. It works by improving the body's sensitivity to insulin which is important as resistance to insulin is common in obesity.

We have a lot of experience using metformin to treat women with diabetes in pregnancy where it is greatly beneficial. We now wish to examine its potential for obese women who do not have diabetes. We are hoping to show that it will benefit these women by causing less weight gain, less high blood pressure, and less diabetes. We anticipate babies will also have better birth weights, will be easier to deliver naturally, will not need to go to special care baby units and will be healthier.

Detailed Description

Obesity in Pregnancy has been identified by the Confidential Enquiry into Maternal and Child Health [CEMACH] report (2007) as a major health risk to mother and baby:

• 35% of women who died were obese
• 30% of the mothers who had a stillbirth or a neonatal death were obese

Obesity increases the risk of miscarriages, GDM, pregnancy-induced hypertension/PET, Caesarean sections, deep venous thrombosis, puerperal sepsis and LGA babies. There is a 5-fold increase in costs of antenatal care. Results from various studies have concluded that limited or no weight gain during pregnancy in obese women results in more favourable pregnancy outcomes. By improving insulin sensitivity and enhancing GLP-1 release, metformin is associated with weight reduction by approximately 5.8% with no serious adverse events.

The aim of this study is to test the hypothesis that management of obese non-diabetic pregnant women with standardised life-style intervention (diet and physical activity) plus metformin will lead to improved maternal and perinatal outcomes compared with life-style intervention alone.

The study will also seek to determine whether metformin will improve body fat distribution as measured by bioimpedance during pregnancy with particular emphasis on metabolic active visceral fat.

Genetic studies will investigate whether patients with polymorphisms of the candidate fat gene, FTO gene, differ in their response to metformin and whether this is associated with favourable pregnancy outcomes.

This is a randomised, multicentre, double blind, placebo-controlled trial.Assuming power 90%, significance level 5% and 2-sided testing, we will recruit 425 subjects per arm of the trial.This will allow the detection of a difference in mean centile (z-score) of 0.21 standard deviations.

All women will undergo oral glucose tolerance testing at booking and at 28 wks; those found to have GDM at 28 weeks will commence home glucose monitoring and will receive metformin if glucose values are outside target range.

The primary outcome will be the birth weight centile (z score). Secondary outcomes include maternal and neonatal outcomes, body composition scores, patient satisfaction and infant development at 2 years. The relation between FTO gene variants and pregnancy outcomes will be examined. Parametric and non-parametric tests will be used as appropriate.

This is a multicentre trial to be undertaken in 7 centres in the UK over a period of 3 years in order to reach the required sample size. Mr Hassan Shehata, Clinical lead and Consultant Obstetrician and Gynecologist is the Chief Investigator of the trial and the trial will be centrally coordinated by Dr Jyoti Balani at Epsom and St Helier University Hospital. In the first phase of the research, we would be recruiting a total of 546 pregnant women into the trial. 200 women would be recruited at Epsom and St Helier Hospital, 200 women at kings college Hospital under the supervision of Professor Kypros Nicolaides and 146 at Royal Surrey County Hospital under the supervision of Dr Lesley Roberts.

Given the low cost of metformin and the potentially high impact on health for both mother and baby, we anticipate the study will show metformin to be highly cost-effective. We anticipate improved patient satisfaction scores in those taking metformin as they gain less weight and develop fewer complications. Improvements in the metabolic milieu during interuterine growth is expected to improve long term outcome for the infants of mothers treated with metformin.

Benefits to patients will be immediate from the time the project's findings are presented. Implementation into clinical practice is expected to greatly benefit the NHS.

Conditions

Pregnancy Complications; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Metformin

Tablet Metformin 500 mg, starting dose of 1 tablet twice a day with meals, gradually titrated upwards by 1 tablet every week to a maximum dose of 2 tablets three times a day.

Tablets started at recruitment and continued till the delivery of the baby

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Maximum dosage 500 mg 2 tablets 3 times a day (with each meal) start with 1 tablet twice a day and gradually titrate upwards to maximum dose

Placebo

Tablet Placebo 500 mg, starting dose of 1 tablet twice a day with meals, gradually titrated upwards by 1 tablet every week to a maximum dose of 2 tablets three times a day.

Tablets started at recruitment and continued till the delivery of the baby

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo maximum dosage 2 tablets 3 times a day ( with meals) start with 1 tablet twice a day and gradually titrate upwards to maximum dose

Interventions

Metformin

Maximum dosage 500 mg 2 tablets 3 times a day (with each meal) start with 1 tablet twice a day and gradually titrate upwards to maximum dose

Intervention Type: DRUG

Placebo

Placebo maximum dosage 2 tablets 3 times a day ( with meals) start with 1 tablet twice a day and gradually titrate upwards to maximum dose

Intervention Type: DRUG

Other Intervention Names

Glucophage; Dummy tablet

Eligibility Criteria

Inclusion Criteria

• Obese pregnant women with BMI>35
• Informed written consent

Exclusion Criteria

• Diabetes at booking
• Presence of contra-indication to metformin(renal, liver, heart failure)
• moving out of study area for pregnancy management
• Participants who suffer with hyperemesis
• Participants who are 18 years and below
• Participants with significantly raised creatinine
• Participants with high alcohol intake

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Fetal Medicine Foundation

OTHER

Sponsor Role: collaborator

King's College Hospital NHS Trust

OTHER

Sponsor Role: collaborator

Epsom and St Helier University Hospitals NHS Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mr Hassan Shehata, MD MRCOG

Role: PRINCIPAL_INVESTIGATOR

Epsom and St Helier University Hospitals NHS Trust

Dr Steve Hyer, MD, FRCP

Role: STUDY_DIRECTOR

Epsom and St Helier University Hospitals NHS Trust

Prof Kypros Nicolaides, PhD, MRCOG

Role: PRINCIPAL_INVESTIGATOR

King's College London

Dr Jyoti Balani, MD

Role: PRINCIPAL_INVESTIGATOR

Epsom and St Helier University Hospitals NHS Trust

Dr Ranjit Akolekar

Role: PRINCIPAL_INVESTIGATOR

Medway Hospital NHS Trust

Locations

Medway Hospital NHS Trust

Gillingham, Kent, United Kingdom

Epsom and St Helier University Hospitals NHS Trust

Carshalton, Surrey, United Kingdom

Kings College, London

London, , United Kingdom

Countries

United Kingdom

References

Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study. Diabet Med. 2009 Aug;26(8):798-802. doi: 10.1111/j.1464-5491.2009.02780.x.

Reference Type: BACKGROUND

PMID: 19709150 (View on PubMed)

Glueck CJ, Goldenberg N, Wang P, Loftspring M, Sherman A. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod. 2004 Mar;19(3):510-21. doi: 10.1093/humrep/deh109. Epub 2004 Jan 29.

Reference Type: BACKGROUND

PMID: 14998944 (View on PubMed)

Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193.

Reference Type: BACKGROUND

PMID: 18463376 (View on PubMed)

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 May 11;316(5826):889-94. doi: 10.1126/science.1141634. Epub 2007 Apr 12.

Reference Type: BACKGROUND

PMID: 17434869 (View on PubMed)

Galtier-Dereure F, Boegner C, Bringer J. Obesity and pregnancy: complications and cost. Am J Clin Nutr. 2000 May;71(5 Suppl):1242S-8S. doi: 10.1093/ajcn/71.5.1242s.

Reference Type: BACKGROUND

PMID: 10799397 (View on PubMed)

Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med. 2016 Feb 4;374(5):434-43. doi: 10.1056/NEJMoa1509819.

Reference Type: DERIVED

PMID: 26840133 (View on PubMed)

Other Identifiers

2008-005892-83

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

WCH/2008/001

Identifier Type: -

Identifier Source: org_study_id