Metformin in Women With Type 2 Diabetes in Pregnancy Trial (MiTy)

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Metformin; Drug: Placebo Comparator

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.

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • The Centre for Mother, Infant, and Child Research, Sunnybrook Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo Comparator; 500 mg daily OD from randomisation for 2 weeks, then 1000mg BID throughout the duration of pregnancy
Active Comparator: Metformin	Drug: Metformin; 500 mg daily OD from randomisation for 2 weeks, then 1000mg BID throughout the duration of pregnancy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
A composite of: pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, and NICU admission > 24 hours.	conception to 28 days after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Large for gestational age (LGA) infants	Defined as greater than the 90th percentile for weight, based on the National canadian fetal growth standards for singleton boys and girls.	Up to 24 hours after birth
Pregnancy loss	Spontaneous abortion defined as death of a fetus at <20 weeks gestation; Stillbirth defined as death of a fetus with a birth weight ≥ 500g or at ≥ 20 wks gestational age regardless of birth weight; Neonatal death defined as death of a live born infant within the first 28 days of life or prior to hospital discharge, whichever is later.	Up to 40 weeks gestation
Preterm birth	Birth < 37 weeks gestation	Up to 37 weeks gestation
Respiratory distress	Given surfactant via an endotracheal tube and/or requiring assisted positive pressure ventilation within 72 hours after birth.	within 72 hours after birth
Neonatal hypoglycemia	A plasma glucose <2.6 mmol/L on one or more occasions, starting at 30-60 minutes after birth, and necessitating intravenous dextrose within the first 48 hours of life.	NICU admission >24 hours
NICU admission >24 hours	Admission to a neonatal intensive or special care unit for > 24 hours during the initial hospitalization after birth	NICU admission >24 hours
Cord blood gases pH <7.0		Within 4 hours of birth
Hyperinsulinemia as measured by elevated cord blood C-peptide	A cord serum C-peptide value > 1.7 ug/L (which is >90th percentile of values for the total cohort of participants in the HAPO trial) will be defined as hyperinsulinemia.	Within 4 hours of birth
Maternal glycemic control as measured by HbA1c and capillary glucose measurements.	Gestational age at testing will be recorded. All downloaded glucose results will be transmitted on a regular basis to a central site for future analysis. Monthly correlations will be done with the laboratory during routine monthly blood draws.	Up to 40 weeks gestation
Maternal hypoglycemia	Maternal hypoglycemia defined as mild (<3.6, symptomatic and asymptomatic or requiring treatment), or severe (loss of consciousness or confusion requiring assistance) will be documented at each visit.	Up to 40 weeks gestation
Maternal weight gain	The first and last weight will be obtained at the first and last visit in pregnancy, whether they be done by the endocrinologist, family physician or obstetrician.	Up to 40 weeks gestation
Maternal insulin doses	Maternal insulin doses (overall amount and number of patients that are taking 'high' insulin doses defined as 2 Units/kg or more per day)	Up to 40 weeks gestation
Pre-eclampsia, and/or gestational hypertension	Gestational hypertension: New onset of hypertension in pregnancy ≥ 20 weeks gestation in a woman with previously normal blood pressure, defined as diastolic blood pressure of ≥ 90 mmHg, taken on 2 occasions or placed on antihypertensive medication and without proteinuria. Pre-eclampsia: please refer to protocol for definition	Up to 40 weeks gestation
Sepsis	A positive blood and/or cerebral spinal fluid culture during the neonatal hospital stay.	Up to 28 days after birth
Hyperbilirubinemia	Significant jaundice was present based on bilirubin levels requiring treatment with phototherapy> 6 continuous hours, or an exchange transfusion, or receiving intravenous gamma globulin, or requiring readmission into hospital during the first 7 days of life.	First 7 days of life
Number of hospitalizations	Number of hospitalizations prior to admission for delivery and the duration of hospital stays for the mother prior to admission for delivery and associated with delivery.	Up to 40 weeks gestation
Rate of caesarean-section		Up to 40 weeks gestation
Duration of hospital stay for infant.	Duration of hospital stay for infant associated with his/her birth until the first discharge home	Up to 28 days after birth
Fetal fat mass	Fetal fat mass compared with women treated with insulin plus placebo	Up to 7 days after birth
Birth Injury	Defined as any of the following: spinal cord injury, basal skull fracture or depressed skull fracture, clavicular fracture, long bone fracture, subdural or intracerebral hemorrhage or any kind	Up to 7 days after birth
Shoulder dystocia	Documentation of any shoulder dystocia in the delivery records, plus 3 or more of the following: McRoberts maneuver, suprapubic maneuver, episiotomy, delivery of the posterior arm, Woods maneuver, Rubins maneuver, All fours Gaskins maneuver, intentional fracture of the clavicle, and/or Zavenelli maneuver.	At delivery

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: University Health Network, Toronto; Canadian Institutes of Health Research (CIHR); Sunnybrook Research Institute
• Investigators: Principal Investigator: Denice Feig, MD, Mount Sinai Hospital

Publications and helpful links

General Publications

• 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. Erratum In: Lancet Diabetes Endocrinol. 2020 Nov;8(11):e6.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2011
• Primary Completion (Actual): June 5, 2019
• Study Completion (Actual): June 5, 2019

Study Registration Dates

• First Submitted: May 2, 2011
• First Submitted That Met QC Criteria: May 12, 2011
• First Posted (Estimate): May 13, 2011

Study Record Updates

• Last Update Posted (Actual): March 3, 2020
• Last Update Submitted That Met QC Criteria: March 2, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Diabetes; MiTy; Metformin in Women; Type 2 Diabetes Pregnancy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Pregnancy in Diabetics; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: MOP-106678