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Clinical Trial Results:
Does metformin improve pregnancy outcomes [ incidence of LGA (≥90% birth weight centile) babies onset of maternal Gestational Diabetes, hypertension, PET, shoulder dystocia, admission to SCBU) in obese non-diabetic women?

Summary
EudraCT number	2008-005892-83
Trial protocol	GB
Global end of trial date	21 Aug 2015

Results information
Results version number	v1(current)
This version publication date	11 Jun 2016
First version publication date	11 Jun 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

WCH/2008/001

ISRCTN number

US NCT number

NCT01273584

WHO universal trial number (UTN)

Sponsor organisation name

Epsom and St Helier University Hospitals NHS Trust

Sponsor organisation address

St Helier Hospital, Wrythe Lane, carshalton, Surrey, Carshalton, Surrey, United Kingdom, SM5 1AA

Public contact

Jyoti Balani, Epsom and St Helier University Hospitals NHS Trust, 44 0208296 2140, jyoti.balani@esth.nhs.uk

Scientific contact

Jyoti Balani, Epsom and St Helier University Hospitals NHS Trust, 44 0208296 2140, jyoti.balani@esth.nhs.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Aug 2015

Was the trial ended prematurely?

Main objective of the trial

There is substantial evidence that obesity in pregnancy contributes to increased morbidity and mortality for both mother and baby. The purpose of the study is whether management of obese non-diabetic pregnant women with standarised lifestyle intervention (diet and physical activity) and metformin will lead to improve maternal and peri-natal outcomes compared to lifestyle intervention alone. We aim to compare peri-natal outcomes in women randomised to the two home glucose monitoring protocols: Group 1 - Standardised lifestyle intervention and placebo. Group 2 - Standardised lifestyle intervnetion and metformin.

Protection of trial subjects

The dose of Metformin?placebo given was gradually increased by 1 tablet every week so that the gastric side effects were minimum.

Background therapy

Low glycaemic index carbohydrate diet and regular excercise was recommended to all patients

Evidence for comparator

It was a placebo controlled trial and placebo which matched Metformin were manufactured

Actual start date of recruitment

12 Oct 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 450

Worldwide total number of subjects

450

EEA total number of subjects

450

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

450

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

October 2010 to June 2015 at 3 NHS Hospitals in the UK Epsom and St Helier Hospitals Kings College Hospital, Medway Maritime Hospital

Screening details

1071 pregnant women with BMI>35 were screened. 227 women were excluded - 6 were < 18 years of age, 17 had fetus with fetal defect, 66 had history of previous GDM, 18 had medical problems, 6 had gastric bypass, 68 had hyperemesis, 25 were receiving metformin, 8 could not take metformin and 13 had miscarriage

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Subject

Blinding implementation details

Central randomisation was used and patients were given consecutive numbered boxes

Are arms mutually exclusive

Yes

Metformin arm

Arm description

Metformin tablets

Arm type

Active comparator

Investigational medicinal product name

Metformin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Metfromin 500 mg started as 1 tablet twice a day and gradually increased by 1 tablet every week to acheive a maximum dose of 2 tablets 3 times a day

Placebo arm

Arm description

Placebo tablets manufactured to look identical to the active comparator Metformin

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Same as Metformin

Number of subjects in period 1	Metformin arm	Placebo arm
Started	225	225
Completed	202	198
Not completed	23	27
Consent withdrawn by subject	23	27

Baseline characteristics

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Reporting group title

Metformin arm

Reporting group description

Metformin tablets

Reporting group title

Placebo arm

Reporting group description

Placebo tablets manufactured to look identical to the active comparator Metformin

Reporting group values	Metformin arm	Placebo arm	Total
Number of subjects	225	225	450
Age categorical
Pregnant woman with BMI>35 were recruited
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	32.9 (27.3 to 36.2)	30.8 (26.6 to 34.4)	-
Gender categorical
All were female
Units: Subjects
Female	225	225	450
Male	0	0	0
Body Mass Index
All women with BMI>35 kg/m2 were recruited
Units: Kg/m2
median (inter-quartile range (Q1-Q3))	38.6 (36.5 to 41.5)	38.4 (16.3 to 41.9)	-

End points

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Reporting group title

Metformin arm

Reporting group description

Metformin tablets

Reporting group title

Placebo arm

Reporting group description

Placebo tablets manufactured to look identical to the active comparator Metformin

Primary: Median birth weight percentile

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End point title

Median birth weight percentile

End point description

End point type

Primary

End point timeframe

At the time of birth of the baby

End point values	Metformin arm	Placebo arm
Number of subjects analysed	202	198
Units: KG
median (inter-quartile range (Q1-Q3))
Reduction in birth weight centile by 0.3SD	51.8 (23.9 to 82.1)	56.6 (26.8 to 81.4)

Intention to treat

Comparison groups

Metformin arm v Placebo arm

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.66

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Primary: Median birth weight percentile

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End point title

Median birth weight percentile

End point description

The birthweight dentile of the baby is calculated for all babies

End point type

Primary

End point timeframe

End of the trial

End point values	Metformin arm	Placebo arm
Number of subjects analysed	202	198
Units: percentage
median (inter-quartile range (Q1-Q3))
Reduction in the birth weight z score by 0.3 D	51.8 (23.9 to 82.1)	56.6 (26.8 to 81.4)

Intention to treat principle

Statistical analysis description

Comparisons between groups were perfdormed with the use of Mann-Whitney U test

Comparison groups

Metformin arm v Placebo arm

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.66 ^[2]

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Confidence interval

Notes
[1] - Intention to treat analysis
[2] - Not signifiant

Adverse events

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Timeframe for reporting adverse events

Throughout the Trial

Adverse event reporting additional description

Reporting of adverse events at each visit, reporting immediately in case of hospital admission

Assessment type

Systematic

Dictionary name

Clinical terms

Dictionary version

Nil

Reporting group title

Metformin arm

Reporting group description

Metformin tablets

Reporting group title

Placebo arm

Reporting group description

Placebo tablets manufactured to look identical to the active comparator Metformin

Serious adverse events	Metformin arm	Placebo arm
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 202 (10.40%)	38 / 198 (19.19%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Pregnancy, puerperium and perinatal conditions
Fetal death
subjects affected / exposed	1 / 202 (0.50%)	5 / 198 (2.53%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 5
Fetal defect
subjects affected / exposed	3 / 202 (1.49%)	1 / 198 (0.51%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fetal disease
subjects affected / exposed	2 / 202 (0.99%)	0 / 198 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Maternal disease
subjects affected / exposed	6 / 202 (2.97%)	6 / 198 (3.03%)
occurrences causally related to treatment / all	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Preeclampsia or fetal growth restriction
subjects affected / exposed	2 / 202 (0.99%)	5 / 198 (2.53%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Preterm births
subjects affected / exposed	7 / 202 (3.47%)	10 / 198 (5.05%)
occurrences causally related to treatment / all	0 / 7	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal bleeding
subjects affected / exposed	0 / 202 (0.00%)	5 / 198 (2.53%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4.2%

Non-serious adverse events	Metformin arm	Placebo arm
Total subjects affected by non serious adverse events
subjects affected / exposed	103 / 202 (50.99%)	62 / 198 (31.31%)
General disorders and administration site conditions
Headache
subjects affected / exposed	21 / 202 (10.40%)	10 / 198 (5.05%)
occurrences all number	21	10
Lethargy, Constipation, Loss of apetite
subjects affected / exposed	15 / 202 (7.43%)	9 / 198 (4.55%)
occurrences all number	15	9
Gastrointestinal disorders
Nausea and vomiting
subjects affected / exposed	57 / 202 (28.22%)	38 / 198 (19.19%)
occurrences all number	57	38
Diarrhoea
subjects affected / exposed	35 / 202 (17.33%)	13 / 198 (6.57%)
occurrences all number	35	13
Abdominal pain or heartburn
subjects affected / exposed	14 / 202 (6.93%)	14 / 198 (7.07%)
occurrences all number	14	14

More information

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Were there any global substantial amendments to the protocol? Yes

05 Oct 2009

To make the trial a multicentre one To include blood tests like Fasting Insulin

20 Nov 2009

Increase in Sample size

20 Nov 2009

Change in the composition of the placebo

15 Jun 2010

Addition of Clinical Trial infiormation card Addition of medicine escalation sheet

25 Aug 2011

Sample size revised to 400

10 May 2013

Change of Principal Investigator at 1 site

23 Sep 2013

Shipment of blood samples from one hospital site to another for storage

20 Oct 2014

Addition of 50 more patients- Total 450 Addition of Epworth sleepiness scale

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Jan 2012	Time required for manufacture of new batch of placebo- delay in the manufacturing pharmacy unit	04 Feb 2013
24 Jan 2014	Interupption due to delay in the manufactureof placebo by the pharmacy	04 Apr 2014

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Nil

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Clinical trials

Clinical Trial Results:
Does metformin improve pregnancy outcomes [ incidence of LGA (≥90% birth weight centile) babies onset of maternal Gestational Diabetes, hypertension, PET, shoulder dystocia, admission to SCBU) in obese non-diabetic women?

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Median birth weight percentile

Primary: Median birth weight percentile

Primary: Median birth weight percentile

Primary: Median birth weight percentile

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Does metformin improve pregnancy outcomes [ incidence of LGA (≥90% birth weight centile) babies onset of maternal Gestational Diabetes, hypertension, PET, shoulder dystocia, admission to SCBU) in obese non-diabetic women?

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Median birth weight percentile

Primary: Median birth weight percentile

Primary: Median birth weight percentile

Primary: Median birth weight percentile

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Does metformin improve pregnancy outcomes [ incidence of LGA (≥90% birth weight centile) babies onset of maternal Gestational Diabetes, hypertension, PET, shoulder dystocia, admission to SCBU) in obese non-diabetic women?