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Pregnancy Outcomes: Effects of Metformin Study (POEM Study) (POEM)

Primary Purpose

Gestational Diabetes, Insulin Resistance

Status

Recruiting

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

Metformin TEVA 850 mg

About this trial

This is an interventional treatment trial for Gestational Diabetes focused on measuring Gestational Diabetes, Insulin Resistance, Metformin, Hyperinsulinaemia, Prevention of Complications, Long Term Study, Mother and Child, Health Benefits

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Pregnant women with GDM defined as a Fasting Plasma Glucose (FPG) > 5,3 mMol and/or an Oral Glucose Tolerance test (OGTT) with a Plasma glucose (PG) > 7,8 mMol, two hours after the oral intake of 75 gram glucose
Written informed consent
Age 18-45 years
Gestational age at inclusion 16-32 weeks
Glycohemoglobin test (HbA1c) at inclusion ≤ 48 mmol/mol (6.5% Hb)

Exclusion Criteria:

Diabetes mellitus before pregnancy, except previous GDM
Proteinuria: Urine Albumin-to-Creatinine Ratio (UACR) > 35 mg/mmol at screening
Malignancy during the last 5 years before inclusion, except non-melanoma skin cancer
Psychiatric and/or mood disorder potentially affecting compliance of treatment
Chronic liver disease and/or Alanine aminotransferase aspartate transaminase (ASAT) and/or Alanine aminotransferase (ALAT) > 3x Upper Limit of Normal (ULN).
Chronic renal failure with a Glomerular filtration rate (GFR) < 45 ml/min/1.73m2
Chronic pulmonary failure with hypoxia
Significantly uncontrolled hypertension - Systolic blood pressure (SBP) > 160 mm Hg despite medical treatment
Chronic treatment with corticosteroids
Intolerance for metformin and/or earlier use of metformin in this pregnancy
Membership of the POEM study group
Severe foetal anomaly at inclusion - like major neural tube and/or cardiac malformation
Ruptured membranes
Multiple pregnancy
Inability to understand or read the Dutch language
Bariatric surgery in medical history
Hyperemesis gravidarum

Sites / Locations

Martini hospital GroningenRecruiting
University Medical Center GroningenRecruiting
Treant ZorggroepRecruiting
Medical Center LeeuwardenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

Metformin on top of usual care

Usual care

Arm Description

Metformin TEVA 850 mg (1-3 times daily) added to usual care from start of the diagnosis GDM. Usual care has been defined as intensive counselling for diet and lifestyle plus insulin therapy if needed. Intervention: metformin TEVA 850 mg (1-3 times daily) on top of usual care.

Usual care from start of the diagnosis GDM. Control group without metformin. Usual care has been defined as intensive counselling for diet and lifestyle plus insulin therapy if needed. Intervention: usual care.

Outcomes

Primary Outcome Measures

GDM Outcome Score (GOS) in Phase A

An aggregate score of eight clinically relevant endpoints, as previously defined: pregnancy related hypertension, including (pre-) eclampsia, according validated guidelines, large for gestational age baby (LGA) at delivery according validated guidelines, premature delivery with a gestational age < 37 weeks, instrumental delivery, caesarean delivery, birth trauma, like fractures of clavicle and humerus, subdural / intracerebral haemorrhage, neonatal hypoglycaemia, defined as blood glucose < 2.6 mmol/l, admission for neonatal intensive care.

T2D and obesity at the end of Phase B

Incidence of maternal T2DM Weight (kg) and BMI (category) development mother Weight (kg) and BMI (percentile) development child

Development of T2D and obesity during Phase C

Incidence of maternal T2DM Weight (kg) and BMI (category) development mother Weight (kg) and BMI (percentile) development child

Secondary Outcome Measures

Secondary Outcome measures phase A mother

Maternal outcome score (MOS) Caesarean delivery (yes=1, no=0) (Pre-)eclampsia, HELPP and PIH (if at least one is diagnosed=yes=1,no=0) Maternal mortality (yes=1, no=0) Postpartum haemorrhage (blood loss > 1000 ml)(yes=1, no=0) Thrombosis (yes=1, no=0) For each individual component applies: if occured=1 point. If not occured =0 points. A total score per individual will be calculated (0-5 for MOS). Each component on its own is also a secondary outcome measure.

Secondary Outcome measures phase A child

Neonatal outcome score (NOS)** IRDS requiring oxygen therapy (CPAP, optiflow, mechanical ventilation or surfactant) (yes=1, no=0) Stillbirth or neonatal death (yes=1, no=0) Preterm birth <37 weeks (yes=1, no=0) Shoulder dystocia (yes=1, no=0) Instrumental delivery (yes=1, no=0) Caesarean delivery (yes=1, no=0) Neonatal hypoglycaemia < 2.6 mml/l (yes=1, no=0) Neonatal jaundice needing phototherapy (yes=1, no=0) NICU admission (yes=1, no=0) Apgar score < 7 at 5 minutes (yes=1, no=0) Congenital anomaly (to a list, if one anomaly = yes = 1, no=0) For each individual component applies: if occured=1. If not occured=0. A total score per individual will be calculated (0-11 for NOS). Each component on its own is also a secondary outcome measure. Apgar score as a variable (1-10) at 1, 5, 10 min Foetal weight at delivery in grams

Secondary outcome measures phase B

Hypertension development (yes/no) Thrombotic and CVD events (yes/no) Development of chronic disease (according to list - yes/no) Gonadal and gender development (to be determined: question(naires) + potentially additional measurements from research blood panel) Puberty and maturation (to be determined: question(naires) + potentially additional measurements from research blood panel) Educational and intellectual development (levels of education completed) Development of chronic disease (according to list - yes/no)

Secondary outcome measures phase C

Full Information

NCT ID

NCT02947503

First Posted

October 20, 2016

Last Updated

February 7, 2022

Sponsor

Bethesda Diabetes Research Center

Collaborators

Maastricht University Medical Center, University Medical Center Groningen, Medical Centre Leeuwarden, Martini Hospital Groningen, Treant Zorggroep, Nij Smellinghe Hosptial

1. Study Identification

Unique Protocol Identification Number

NCT02947503

Brief Title

Pregnancy Outcomes: Effects of Metformin Study (POEM Study)

Acronym

POEM

Official Title

Pregnancy Outcomes: Effects of Metformin Study (POEM Study), a Long Term Randomized Controlled Study in Gestational Diabetes

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 26, 2019 (Actual)

Primary Completion Date

December 2043 (Anticipated)

Study Completion Date

December 2043 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bethesda Diabetes Research Center

Collaborators

Maastricht University Medical Center, University Medical Center Groningen, Medical Centre Leeuwarden, Martini Hospital Groningen, Treant Zorggroep, Nij Smellinghe Hosptial

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

One approach to prevent the rising burden of diabetes is to address the issue of gestational diabetes mellitus (GDM). GDM has a growing prevalence up to 5-10% (and even higher in specific subgroups), with a pregnant population becoming older and more obese worldwide. GDM increases the risks of complications during pregnancy, at delivery and on the longer term, like type 2 diabetes (T2D) and persistent obesity, in mother and child. Moreover, insulin added to diet as the standard care for GDM has disadvantages for mother (maintenance of hyperinsulinaemia, increasing weight and blood pressure) and child (macrosomia, hypoglycaemia) with related adverse pregnancy outcomes. Metformin, as an insulin sensitizer targeting the cause of GDM, may have essential benefits, as suggested by observational studies. However, RCTs with metformin (early positioned in the treatment of GDM) are still lacking. The POEM study is the first Randomized controlled trial (RCT) in GDM to test the hypothesis that metformin, early given from the start of the diagnosis GDM, on top of diet and lifestyle improves clinically relevant pregnancy outcomes in mother and child during pregnancy, at delivery and on the longer term - up to 20 years after birth.

Detailed Description

The POEM study was designed to investigate the effects of metformin on top of diet and lifestyle (with insulin rescue if needed) in GDM on eight clinically relevant pregnancy outcomes at delivery, summarized by means of an integrated, newly developed score, the GDM Outcome Score (GOS), and on other relevant outcomes on the longer term in mother and child. The investigators hypothesize that metformin given to women with GDM from the start of the diagnosis reduces risks resulting in relevant health benefits for mother and child during pregnancy, at delivery, and many years thereafter. The POEM study is a randomized controlled intervention study, consisting of three phases: Phase A - from inclusion until six weeks after delivery; intervention study with and without exposure of metformin in mother and (unborn) child: two arms after randomization with 1:1 allocation to Diet + Lifestyle + Metformin (DLM) or Diet + Lifestyle (DL); Phase B - from six weeks until 1 year after delivery; intervention study with exposure of DLM vs DL in mother; Phase C - from 1 until 20 years after delivery; observational extension study of mother and child without study medication.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Gestational Diabetes, Insulin Resistance

Keywords

Gestational Diabetes, Insulin Resistance, Metformin, Hyperinsulinaemia, Prevention of Complications, Long Term Study, Mother and Child, Health Benefits

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

500 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Metformin on top of usual care

Arm Type

Active Comparator

Arm Description

Arm Title

Usual care

Arm Type

No Intervention

Arm Description

Intervention Type

Drug

Intervention Name(s)

Metformin TEVA 850 mg

Other Intervention Name(s)

Metformin

Intervention Description

At inclusion, patients (N=500) will be randomized 1:1 to metformin vs usual care (850 mg tablets, 3 times daily or, if tolerance is suboptimal, a lower maximally tolerated dose, 1-2 times daily), on top of diet and lifestyle, with an insulin rescue in both arms if needed.

Primary Outcome Measure Information:

Title

GDM Outcome Score (GOS) in Phase A

Description

Time Frame

30 months

Title

T2D and obesity at the end of Phase B

Description

Incidence of maternal T2DM Weight (kg) and BMI (category) development mother Weight (kg) and BMI (percentile) development child

Time Frame

42 months

Title

Development of T2D and obesity during Phase C

Description

Incidence of maternal T2DM Weight (kg) and BMI (category) development mother Weight (kg) and BMI (percentile) development child

Time Frame

282 months

Secondary Outcome Measure Information:

Title

Secondary Outcome measures phase A mother

Description

Time Frame

30 months

Title

Secondary Outcome measures phase A child

Description

Time Frame

30 months

Title

Secondary outcome measures phase B

Description

Time Frame

42 months

Title

Secondary outcome measures phase C

Description

Time Frame

282 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Pregnant women with GDM defined as a Fasting Plasma Glucose (FPG) > 5,3 mMol and/or an Oral Glucose Tolerance test (OGTT) with a Plasma glucose (PG) > 7,8 mMol, two hours after the oral intake of 75 gram glucose Written informed consent Age 18-45 years Gestational age at inclusion 16-32 weeks Glycohemoglobin test (HbA1c) at inclusion ≤ 48 mmol/mol (6.5% Hb) Exclusion Criteria: Diabetes mellitus before pregnancy, except previous GDM Proteinuria: Urine Albumin-to-Creatinine Ratio (UACR) > 35 mg/mmol at screening Malignancy during the last 5 years before inclusion, except non-melanoma skin cancer Psychiatric and/or mood disorder potentially affecting compliance of treatment Chronic liver disease and/or Alanine aminotransferase aspartate transaminase (ASAT) and/or Alanine aminotransferase (ALAT) > 3x Upper Limit of Normal (ULN). Chronic renal failure with a Glomerular filtration rate (GFR) < 45 ml/min/1.73m2 Chronic pulmonary failure with hypoxia Significantly uncontrolled hypertension - Systolic blood pressure (SBP) > 160 mm Hg despite medical treatment Chronic treatment with corticosteroids Intolerance for metformin and/or earlier use of metformin in this pregnancy Membership of the POEM study group Severe foetal anomaly at inclusion - like major neural tube and/or cardiac malformation Ruptured membranes Multiple pregnancy Inability to understand or read the Dutch language Bariatric surgery in medical history Hyperemesis gravidarum

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Adriaan Kooy, Dr

Phone

+31528286859

a.kooy@treant.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Louise Smit

l.ismit@treant.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Adriaan Kooy, Dr.

Organizational Affiliation

BDRC

Official's Role

Principal Investigator

Facility Information:

Facility Name

Martini hospital Groningen

City

Groningen

Country

Netherlands

Individual Site Status

Recruiting

Facility Name

University Medical Center Groningen

City

Groningen

Country

Netherlands

Individual Site Status

Recruiting

Facility Name

Treant Zorggroep

City

Hoogenveen, Emmen, Stadskanaal

Country

Netherlands

Individual Site Status

Recruiting

Facility Name

Medical Center Leeuwarden

City

Leeuwarden

Country

Netherlands

Individual Site Status

Recruiting

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

IPD will be available upon reasonable request. The study protocol will be submitted for publication in a peer reviewed journal.

IPD Sharing Time Frame

Within one year

IPD Sharing Access Criteria

Access to detailed information and IPD will be upon request. The PI and project team will evaluate the request based on the submission of an official request with details on what, why and how.

Citations:

PubMed Identifier

35354633

Citation

van Hoorn EGM, van Dijk PR, Prins JR, Lutgers HL, Hoogenberg K, Erwich JJHM, Kooy A. Pregnancy Outcomes: Effects of Metformin (POEM) study: a protocol for a long-term, multicentre, open-label, randomised controlled trial in gestational diabetes mellitus. BMJ Open. 2022 Mar 30;12(3):e056282. doi: 10.1136/bmjopen-2021-056282.

Results Reference

derived

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Pregnancy Outcomes: Effects of Metformin Study (POEM Study)

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