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Trial registered on ANZCTR


Registration number
ACTRN12612001277831
Ethics application status
Approved
Date submitted
17/11/2012
Date registered
10/12/2012
Date last updated
27/03/2019
Date data sharing statement initially provided
27/03/2019
Date results information initially provided
27/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Metformin and dietary advice to improve insulin sensitivity and promote gestational restriction of weight in pregnant women who are overweight or obese: the GroW Randomised trial.
Scientific title
Metformin and dietary advice compared with dietary advice alone in overweight or obese pregnant women to restrict gestational weight gain and reduce the risk of infants being born above 4.0 kg.
Secondary ID [1] 281550 0
Nil known
Universal Trial Number (UTN)
U1111-1137-0803
Trial acronym
GRoW
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High birth weight of infants of obese pregnant women 287823 0
Condition category
Condition code
Reproductive Health and Childbirth 288171 288171 0 0
Other reproductive health and childbirth disorders
Metabolic and Endocrine 288190 288190 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Metformin and dietary and exercise advice.
Women will commence at enrollment taking one 500 mg tablet once daily increasing to two tablets twice daily (2000 mg) over the first four weeks and continue until birth.

Initially, there will be a planning session with a research dietitian, in which women will be provided with written dietary and activity information, an individual diet and physical activity plan, recipe book and example menu plans.

Over the course of pregnancy, each woman will receive 1-2 sessions with the dietitian of up to 45 minutes duration, shortly after trial entry and again at 28 weeks gestation; and telephone calls of up to 20 minutes duration from the research assistant at 24, 32 and 36 weeks gestation.

Dietary advice provided will be consistent with current Australian dietary standards, designed to limit gestational weight gain. The dietary intervention will maintain a balance of carbohydrates, fat and protein, while specifically encouraging women to reduce their intake of energy dense and non-core foods high in refined carbohydrates and saturated fats, while increasing their intake of fibre, and promoting consumption of two serves of fruit and five serves of vegetables each day.

Women will be encouraged to be active every day and will receive written information about exercise in pregnancy consistent with the Guidelines for exercise in pregnancy produce by the British royal College of Obstetricians and Gynaecologists.
Intervention code [1] 286068 0
Treatment: Drugs
Intervention code [2] 286069 0
Lifestyle
Intervention code [3] 286082 0
Prevention
Comparator / control treatment
Placebo and dietary and exercise advise.

The placebo will be identical in taste and appearance to the metformin tablets.

Women will commence at enrollment taking one placebo tablet once daily increasing to two tablets twice daily over the first four weeks and continue until birth.

Initially, there will be a planning session with a research dietitian, in which women will be provided with written dietary and activity information, an individual diet and physical activity plan, recipe book and example menu plans.

Over the course of pregnancy, each woman will receive 1-2 sessions with the dietitian of up to 45 minutes duration, shortly after trial entry and again at 28 weeks gestation; and telephone calls of up to 20 minutes duration from the research assistant at 24, 32 and 36 weeks gestation.

Dietary advice provided will be consistent with current Australian dietary standards, designed to limit gestational weight gain. The dietary intervention will maintain a balance of carbohydrates, fat and protein, while specifically encouraging women to reduce their intake of energy dense and non-core foods high in refined carbohydrates and saturated fats, while increasing their intake of fibre, and promoting consumption of two serves of fruit and five serves of vegetables each day.

Women will be encouraged to be active every day and will receive written information about exercise in pregnancy consistent with the Guidelines for exercise in pregnancy produce by the British royal College of Obstetricians and Gynaecologists.

Dietary and exercise advice will be the same as a advice given to women in the intervention group.
Control group
Active

Outcomes
Primary outcome [1] 288372 0
Reduction in risk of infant being born with birth weight above 4.0 kg
Timepoint [1] 288372 0
At birth
Secondary outcome [1] 299992 0
Please note this is not a composite and all outcomes will be reported separately, including: preterm birth (birth before 37 weeks gestation); mortality (either a stillbirth (intrauterine fetal death after trial entry and prior to birth), or infant death (death of a live born infant prior to hospital discharge, and excluding lethal congenital anomalies)); infant birth weight less than 2500 grams; infant birth weight >4500 grams; infant birth weight less than the 10th centile for gestational age and infant sex; infant birth weight greater than the 90th centile for gestational age and infant sex; hypoglycaemia requiring intravenous treatment; admission to neonatal intensive care unit, or special care baby unit; hyperbilirubinaemia requiring phototherapy; nerve palsy; fracture; birth trauma; shoulder dystocia.
Timepoint [1] 299992 0
At birth or up until primary hospital discharge.
Secondary outcome [2] 299994 0
Please note this is not a composite and all outcomes will be reported separately, including: maternal hypertension and pre-eclampsia (in accordance with recognised Australasian Society for the Study of Hypertension in Pregnancy criteria); maternal gestational diabetes; need for and length of antenatal hospital stay; antepartum haemorrhage requiring hospitalisation; preterm prelabour ruptured membranes; chorioamnionitis; need and reason for induction of labour; any antibiotic use during labour; caesarean section; postpartum haemorrhage (blood loss >600mL); perineal trauma; wound infection; endometritis; length of postnatal hospital stay; thromboembolic disease; maternal death.
Timepoint [2] 299994 0
Up until hospital discharge following birth.
Secondary outcome [3] 299995 0
Please note this is not a composite and all outcomes will be reported separately, including:

Maternal quality of life and emotional wellbeing as measured by questionnaires completed by the woman at six months postpartum relating to quality of life (as measured using the SF12 Health Survey Questionnaire), preferences for treatment, satisfaction with care, anxiety (as measured by the Short Form Spielberger State Trait Inventory) and depression (as measured by the Edinburgh Postnatal Depression Scale). Women will be asked a series of questions about their satisfaction with the intervention, using items modified from a previous childbirth questionnaire.
Timepoint [3] 299995 0
Quality of life measures assessed at trial entry, 28 and 36 weeks gestation and 4-6 months postpartum.

Satisfaction with care and the intervention assessed 4-6 months postpartum.
Secondary outcome [4] 299996 0
Please note this is not a composite and all outcomes will be reported separately, including:

Fetal growth and wellbeing at 28 and 36 weeks’ gestation assessed by ultrasound (fetal biometry, estimated weight, liquor volume, umbilical artery Doppler waveform, and adiposity)
Timepoint [4] 299996 0
Assessed at 28 and 36 weeks gestation.
Secondary outcome [5] 323587 0
This outcome is not a composite and all outcomes will be reported separately. Maternal changes in diet and physical activity as measured by questionnaires completed by the woman at trial entry, 28 and 36 weeks gestation, and 6 months after birth (Harvard Semi-quantitative Food Frequency Questionnaire, and the Short Questionnaire to Assess Health-enhancing physical activity (SQUASH)). Dietary analysis will include an assessment of diet quality using the Healthy Eating Index (HEI) and description of dietary patterns. Physical activity is reported as a metabolic equivalent task (MET) unit.
Timepoint [5] 323587 0
Trial entry, 28 and 36 weeks of gestation and 6 months postpartum.
Secondary outcome [6] 323588 0
Maternal weight gain outcomes including total gestational weight gain; gestational weight gain below/within/above IoM recommendations.

Timepoint [6] 323588 0
Up until last recorded maternal weight prior to birth.

Eligibility
Key inclusion criteria
Women with a singleton, live gestation between 10 +0 and 20 +0 weeks gestation with a BMI above or equal to 25 kg/m2 at their first antenatal visit.
Minimum age
16 Years
Maximum age
50 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women with a multiple pregnancy, type 1 or 2 diabetes diagnosed prior to pregnancy, known renal or hepatic failure.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Research staff will call a central telephone randomisation service that will verify the participants eligibility and allocate a unique study number and treatment pack number. Repeat treatment pack numbers will be allocated by phoning the randomisation service and entering the participants study id and hospital record number to ensure a treatment pack with the same treatment group allocation is allocated.
All treatment packs will be identical in appearance as will the metformin and placebo tablets.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation schedule will use balanced variable blocks and will be prepared by an investigator not involved with recruitment, clinical care or data collection for the study.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Initial analysis will examine baseline characteristics of all randomised women as an indication of comparable treatment groups. Primary and secondary outcomes will be analysed on an intention to treat basis according to treatment allocation at randomisation. Relative risks and 95% confidence intervals will be reported for outcomes.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 301 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 302 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [3] 303 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [4] 304 0
Modbury Hospital - Modbury
Recruitment postcode(s) [1] 6028 0
5006
Recruitment postcode(s) [2] 6110 0
5042 - Bedford Park
Recruitment postcode(s) [3] 6111 0
5092 - Modbury
Recruitment postcode(s) [4] 6109 0
5112 - Elizabeth Vale

Funding & Sponsors
Funding source category [1] 286335 0
Government body
Name [1] 286335 0
National Health and Medical Research Council of Australia
Address [1] 286335 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 286335 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Discipline of Obstetrics and Gynaecology
Women's and Children's Hospital
72 King William St
North Adelaide SA 5006
Country
Australia
Secondary sponsor category [1] 285125 0
None
Name [1] 285125 0
Address [1] 285125 0
Country [1] 285125 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288412 0
Women's and Children's Health Network Human Research Ethics
Ethics committee address [1] 288412 0
72 King William St
North Adelaide SA 5006
Ethics committee country [1] 288412 0
Australia
Date submitted for ethics approval [1] 288412 0
19/11/2012
Approval date [1] 288412 0
26/03/2013
Ethics approval number [1] 288412 0

Summary
Brief summary
There are a number of complications that women who are obese during pregnancy may develop and can impact on their health an don the health of their baby. There are also longer term risk for infants born including being overweight or obese in childhood and an increased risk of diabetes and heart disease in later life.

Metformin lowers blood glucose by improving insulin sensitivity and is commonly used to treat diabetes and gestational diabetes. Women who are obese are more likely to be insulin resistant and in pregnancy this increases the risk of developing gestational diabetes. Insulin resistance raises blood glucose levels and provides excess nutrients to the baby increasing the chance that they will be born large for gestational age. Metformin may modify this risk.

This study is a double blind placebo controlled trial; women will be randomly allocated to receive metformin or an identical placebo. All women in the study will receive dietary and exercise advice from a qualified dietitian throughout their pregnancy to help them adopt a healthy diet and lifestyle.
Information about the woman’s pregnancy, birth and postnatal admission and the baby’s postnatal hospital stay will be obtained from case notes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34960 0
Prof Jodie Dodd
Address 34960 0
Discipline of Obstetrics and Gynaecology
72 King William St
North Adelaide SA 5006
Country 34960 0
Australia
Phone 34960 0
+61881617619
Fax 34960 0
+61881617652
Email 34960 0
jodie.dodd@adelaide.edu.au
Contact person for public queries
Name 18207 0
Ms Ms Andrea Deussen
Address 18207 0
Discipline of Obstetrics and Gynaecology
72 King William St
North Adelaide SA 5006
Country 18207 0
Australia
Phone 18207 0
+61 8 81617657
Fax 18207 0
+61 8 81617652
Email 18207 0
andrea.deussen@adelaide.edu.au
Contact person for scientific queries
Name 9135 0
Ms Professor Jodie Dodd
Address 9135 0
Discipline of Obstetrics and Gynaecology
72 King William St
North Adelaide SA 5006
Country 9135 0
Australia
Phone 9135 0
+61 8 81617619
Fax 9135 0
+61 8 81617652
Email 9135 0
jodie.dodd@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Other publications
Have study results been made publicly available in another format?
No
Results – plain English summary
The aim of this randomised trial was, for the first time, to evaluate the effects of antenatal metformin as an adjuvant therapy to dietary and lifestyle advice among overweight and obese pregnant women on maternal and infant outcomes.

Pregnant women with BMI above 25kg/m2, at their first antenatal visit, were randomly allocated to receive either metformin to a maximum dose of 2000mg per day, or an identical appearing placebo, using a computer generated schedule. All women received an antenatal dietary and lifestyle intervention across the course of pregnancy. The primary outcome was the proportion of infants with birthweight above 4000grams. Secondary outcomes included gestational weight gain (GWG), maternal pregnancy, labour and birth, and infant outcomes.

In the largest pregnancy study to date evaluating metformin, 524 women were randomised (261 Metformin; 263 Placebo). There was no significant difference in the proportion of infants with birthweight above 4000g. While women who received metformin had lower weekly gestational weight gain and were more likely to have weight gain below the Institute of Medicine recommendations, total gestational weight gain was not statistically significantly different between the two treatment groups. The use of metformin was not associated with any evidence of impact on pregnancy and birth outcomes.

Although these findings provide some evidence that metformin as an adjuvant therapy to a dietary intervention in overweight and obese pregnant women reduces some measures of gestational weight gain, there was no evidence of an impact on pregnancy and birth outcomes. Use of metformin in this clinical setting is not advocated.