Pregnancy Outcomes: Effects of Metformin Study (POEM Study)

Insulin Resistance Clinical Trial

— POEM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02947503
• Other study ID #: NL 2016 POEMS
• Status: Recruiting
• Phase: Phase 3
• Start date: November 26, 2019
• Est. completion date: December 2043

Study information

• Verified date: February 2022
• Source: Bethesda Diabetes Research Center
• Contact: Adriaan Kooy, Dr
• Phone: +31528286859
• Email: a.kooy[@]treant.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: December 2043
• Est. primary completion date: December 2043
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes, Gestational
• Gestational Diabetes
• Insulin Resistance

Intervention

Drug:
• Metformin TEVA 850 mg
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.

Locations

Country	Name	City	State
Netherlands	Martini hospital Groningen	Groningen
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Treant Zorggroep	Hoogenveen, Emmen, Stadskanaal
Netherlands	Medical Center Leeuwarden	Leeuwarden

Sponsors (7)

Lead Sponsor	Collaborator
Bethesda Diabetes Research Center	Maastricht University Medical Center, Martini Hospital Groningen, Medical Centre Leeuwarden, Nij Smellinghe Hosptial, Treant Zorggroep, University Medical Center Groningen

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	30 months
Primary	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	42 months
Primary	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	282 months
Secondary	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.	30 months
Secondary	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	30 months
Secondary	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)	42 months
Secondary	Secondary outcome measures phase C	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)	282 months