Clinical trial NCT01353391: Metformin in Women With Type 2 Diabetes in Pregnancy Trial
Official title: Metformin in Women With Type 2 Diabetes in Pregnancy Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Keywords: Diabetes
MiTy
Metformin in Women
Type 2 Diabetes Pregnancy
Lead sponsor: Mount Sinai Hospital, Canada
Sponsor class: OTHER
Collaborators: name: University Health Network, Toronto
name: Sunnybrook Research Institute
name: Canadian Institutes of Health Research (CIHR)
First posted: 2011-05-13
Enrollment: 500
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, however despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes. The investigators hypothesize that metformin use, in addition to treatment with insulin, will help with blood sugar control, lower the dose of insulin needed, lower weight gain, and improve baby outcomes.

Detailed description: Type 2 diabetes in pregnancy is increasing in prevalence and these women continue to face increased rates of adverse maternal and fetal outcomes. The investigators hypothesize that metformin use, as an adjunct to insulin, will decrease these adverse outcomes by reducing maternal hyperglycemia, high maternal insulin doses, excessive maternal weight gain and gestational hypertension/pre-eclampsia, all of which should reduce perinatal and neonatal mortality and morbidity. In addition, since metformin crosses the placenta, metformin treatment of the fetus may have a direct beneficial effect on neonatal outcomes. This study is an randomized controlled trial (RCT) that adds metformin to insulin, and is a double-blind, placebo-controlled RCT. The investigators believe that neither metformin alone nor insulin alone will effectively treat this population, and therefore our design, which includes the addition of metformin to insulin, will be the most relevant to our patients.

Eligibility criteria: Inclusion Criteria:

1. Women who are between of 18-45 years of age.
2. (i). Women diagnosed with type 2 diabetes prior to pregnancy, OR (ii). Women with undiagnosed type 2 diabetes diagnosed prior to 20 weeks gestation, defined as women presenting with gestational diabetes before 20 weeks gestation with various combinations, as per Canadian Diabetes Association, including:

   * 2 fasting glucose ≥ 7.0 mmol/L, or
   * 2 HbA1c of ≥0.065 (6.5%) performed in a laboratory using a method that is standardized to the Diabetes Control and Complications Trial (DCCT) assay, or
   * 1 fasting glucose ≥7.0 mmol/L and 1 HbA1c ≥ 0.065 (6.5%) performed in a laboratory using a method that is standardized to the DCCT assay, or
   * 1 fasting glucose ≥ 7.0 mmol/L and 1 two hour (2 hr) ≥ 11.1 on a 75 g Oral Glucose Tolerance Test (OGTT), or
   * 1 HbA1C ≥0.065 (6.5%) performed in a laboratory using a method that is standardized to the DCCT assay and 1 two hour (2 hr) ≥ 11.1 on a 75 g OGTT.
3. Pregnancy gestation between 6+0-22+6 weeks.
4. Live singleton fetus.

Exclusion Criteria:

1. Women who are not on insulin. Women who are on oral hypoglycemic agents will be taken off at the start of the trial and started on insulin prior to randomization.
2. Diabetes diagnosed after 20 weeks gestation.
3. Type 1 diabetes.
4. Known intolerance to metformin.
5. Contraindications to metformin use which include:

(i). Renal insufficiency (defined as serum creatinine of greater than 130 µmol/L or creatinine clearance \<60 ml/min) , (ii). Moderate to severe liver dysfunction (defined as liver enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) greater than 3 times the upper limit of normal), (iii). Shock or sepsis, and (iv.) Previous hypersensitivity to metformin.

f. Women with significant gastrointestinal problems such as severe vomiting requiring IV fluids or hospitalization, or active Crohn's or colitis.

g. Previous participation in the trial. h. Women who have a fetus with a known potentially lethal anomaly will be excluded. Information regarding congenital anomalies diagnosed after randomization will be recorded.

i. Known higher order pregnancies (twins, triplets, etc). These women will be excluded as they have a higher rate of adverse outcomes and we want to avoid any inequalities if they are unequally distributed between the groups.

j. Presence of acute or chronic metabolic acidosis, including diabetic ketoacidosis.

k. History of diabetic ketoacidosis or history of lactic acidosis. l. Presence of excessive alcohol intake, acute or chronic. m. Presence of congestive heart failure or history of congestive heart failure.

Primary outcomes:
measure: A composite of: pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, and NICU admission > 24 hours.
timeFrame: conception to 28 days after birth
Secondary outcomes:
measure: Large for gestational age (LGA) infants
timeFrame: Up to 24 hours after birth
measure: Pregnancy loss
timeFrame: Up to 40 weeks gestation
measure: Preterm birth
timeFrame: Up to 37 weeks gestation
measure: Respiratory distress
timeFrame: within 72 hours after birth
measure: Neonatal hypoglycemia
timeFrame: NICU admission >24 hours
measure: NICU admission >24 hours
timeFrame: NICU admission >24 hours
measure: Cord blood gases pH <7.0
timeFrame: Within 4 hours of birth
measure: Hyperinsulinemia as measured by elevated cord blood C-peptide
timeFrame: Within 4 hours of birth
measure: Maternal glycemic control as measured by HbA1c and capillary glucose measurements.
timeFrame: Up to 40 weeks gestation
measure: Maternal hypoglycemia
timeFrame: Up to 40 weeks gestation
measure: Maternal weight gain
timeFrame: Up to 40 weeks gestation
measure: Maternal insulin doses
timeFrame: Up to 40 weeks gestation
measure: Pre-eclampsia, and/or gestational hypertension
timeFrame: Up to 40 weeks gestation
measure: Sepsis
timeFrame: Up to 28 days after birth
measure: Hyperbilirubinemia
timeFrame: First 7 days of life
measure: Number of hospitalizations
timeFrame: Up to 40 weeks gestation
measure: Rate of caesarean-section
timeFrame: Up to 40 weeks gestation
measure: Duration of hospital stay for infant.
timeFrame: Up to 28 days after birth
measure: Fetal fat mass
timeFrame: Up to 7 days after birth
measure: Birth Injury
timeFrame: Up to 7 days after birth
measure: Shoulder dystocia
timeFrame: At delivery
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The Centre for Mother, Infant, and Child Research, Sunnybrook Research Institute
state: Ontario
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Denice Feig, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Feig DS, Donovan LE, Zinman B, Sanchez JJ, Asztalos E, Ryan EA, Fantus IG, Hutton E, Armson AB, Lipscombe LL, Simmons D, Barrett JFR, Karanicolas PJ, Tobin S, McIntyre HD, Tian SY, Tomlinson G, Murphy KE; MiTy Collaborative Group. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2020 Oct;8(10):834-844. doi: 10.1016/S2213-8587(20)30310-7.
citation: Feig DS, Murphy K, Asztalos E, Tomlinson G, Sanchez J, Zinman B, Ohlsson A, Ryan EA, Fantus IG, Armson AB, Lipscombe LL, Barrett JF; MiTy Collaborative Group. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial. BMC Pregnancy Childbirth. 2016 Jul 19;16(1):173. doi: 10.1186/s12884-016-0954-4.