Metformin in Women With Type 2 Diabetes in Pregnancy Trial

Study Overview
=================
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.

Official Title
-----------------
Metformin in Women With Type 2 Diabetes in Pregnancy Trial

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Placebo Comparator


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women who are between of 18-45 years of age. (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. Pregnancy gestation between 6+0-22+6 weeks. Live singleton fetus. Exclusion Criteria: 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. Diabetes diagnosed after 20 weeks gestation. Type 1 diabetes. Known intolerance to metformin. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes, MiTy, Metformin in Women, Type 2 Diabetes Pregnancy