Comparison of Insulin Alone to Insulin With Metformin to Treat Gestational Diabetes Mellitus

This study is a prospective, unmasked randomized clinical trial comparing the use of insulin vs combination insulin and metformin for treatment in women diagnosed with gestational diabetes mellitus (GDM). The investigator's hypothesis is that the combination of metformin and insulin will be superior to insulin alone to achieve tight glucose control during pregnancy.

Study Overview

• Status: Terminated
• Conditions: Gestational Diabetes
• Intervention / Treatment: Drug: Insulin; Drug: Metformin

Detailed Description

The objective of this study is to compare the effectiveness of insulin alone vs the combination of insulin and metformin in treating patients with gestational diabetes (GDM). Currently, outside of pregnancy, the treatment of type 2 diabetes mellitus (T2DM) with both metformin and insulin is superior to using insulin alone. In pregnancy, insulin alone has traditionally been used, though some advocate the use of metformin alone as primary therapy. There have been no trials published to date specifically comparing combination therapy to insulin alone. Our hypothesis is that the combination of metformin and insulin will improve overall control of blood glucose, the improvement of which has been demonstrated to improve maternal and neonatal outcomes. Control of blood glucose will be determined by hemoglobin A1c at the time of delivery.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women & Infants Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Able to read and write English and/or Spanish and give written consent
• Diagnosis of GDM, defined as an abnormal glucose tolerance test performed after 12 weeks gestation using 1 of the 2 criteria below:
• 50 gram 1 hour oral diabetes screening testing yielding a result of > 200 mg/dL
• A 100 gram 3 hour oral glucose tolerance testing yielding >2 abnormal values (normal values defined as fasting blood glucose < 95, 1 hour < 180, 2 hour < 155 and 3 hour < 140)
• Singleton gestation
• Gestational age between 12 and 34 weeks and 6 days determined by last menstrual period (LMP) confirmed by ultrasound using criteria set forth by the ACOG (Committee on Obstetric Practice). If LMP is unknown then gestational age must be set by ultrasound prior to 20 weeks gestation.

Exclusion Criteria:

• Pre-existing DM either by diagnosis preceding pregnancy or hemoglobin A1c >6.5 collected during the current pregnancy
• Uncontrolled chronic hypertension, as this may alter maternal and perinatal outcomes measured.
• Multiple gestations
• Major fetal anomalies anticipated to require NICU admission
• Contraindication to metformin (allergy, history of lactic acidosis, pre-existing renal disease (Cr >1.5 mg/dL), active liver disease, current alcohol abuse).
• Vitamin B12 deficiency, as metformin reduces intestinal absorption of vitamin B12
• Medications known to effect glucose metabolism other than insulin and metformin as this may mask any effect between the two treatments.
• Known inability to tolerate metformin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: insulin	Drug: Insulin; Weight based insulin will be calculated using 0.7 units/kg/day in the first trimester, 0.8 units/kg/day in the second trimester and 1 units/kg/day in the third trimester. This total insulin will then be divided into short acting insulin and intermediate acting insulin per provider discretion.
Active Comparator: insulin and metformin	Drug: Insulin; Weight based insulin will be calculated using 0.7 units/kg/day in the first trimester, 0.8 units/kg/day in the second trimester and 1 units/kg/day in the third trimester. This total insulin will then be divided into short acting insulin and intermediate acting insulin per provider discretion.; Drug: Metformin; Will be initiated at dose of 500 mg twice daily. If glycemic control is suboptimal, the dose of metformin will be increased to 1000 mg twice a day. Metformin will be titrated prior to increases in insulin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hgb A1c	Hgb A1c test	collected at the time of delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total daily dose of insulin	Total daily dose of insulin at the end of pregnancy	Will be recorded on hospital admission for delivery
Glucose control	Average of fasting and 2 hour postprandial glucose values	patients will collect glucose values fasting and 2 hrs postprandial every day from enrollment until delivery.
Incidence of maternal hypoglycemia	episodes of maternal hypoglycemia defined as glucose ≤70 mg/dL	patients will be screened weekly for episodes of hypoglycemia until delivery
Change in hemoglobin A1c over the course of the pregnancy	If baseline hemoglobin A1c was collected as part of routine care prior to enrollment, this value will be compared to the hemoglobin A1c collected at delivery	hemoglobin A1c will be collected at delivery (per above) and comparison performed after collection
Incidence of maternal side effects	maternal reported medication side effects (i.e. nausea, vomiting, diarrhea)	Will be assessed weekly until delivery
Treatment acceptability	determined using Diabetes Treatment Satisfaction Questionnaire. Survey includes 8 questions that are answered on a scale of 0-6; 0 indicating the least and 6 the highest level of satisfaction. The individual questions will be compared. Total satisfaction will also be compared by summing the responses to all 8 questions on a composite scale of 0-48	Will be collected postpartum after delivery
Maternal weight gain	weight gain through pregnancy	This will be calculated as the difference from the weight measured at the inital prenatal visit (the specific timing of which is patient dependant) and at the time of admission for delivery
Incidence of hypertensive disorder of pregnancy	gestational HTN, superimposed pre-eclampsia, pre-eclampsia-eclampsia	from enrollment through study completion (30 days after delivery)
Incidence of composite of adverse maternal outcomes	death, ICU admission, postpartum hemorrhage, blood transfusion, organ failure, chorioamnionitis/endometritis	from enrollment through study completion (30 days after delivery)
Breast feeding status	Whether patient is breast feeding or bottle feeding upon discharge from the hospital after delivery	Will be recorded at the time of hospital discharge after delivery (typically 2-4 days after delivery)
Mode of delivery	Mode of delivery	recorded at time of delivery
Gestational age at delivery	Gestational age at delivery	recorded at time of delivery
Infant birthweight (using age/sex matched percentiles)	Infant birthweight (using age/sex matched percentiles)	measured at time of birth
Incidence of composite neonatal morbidity	Presence of any of the following: NICU admission, hypoglycemia, hyperbilirubinemia, birth trauma, stillbirth, respiratory distress syndrome, sepsis, neonatal death prior to discharge, 5 minute Apgar score < 7, umbilical artery cord pH <7.10	from delivery through study completion (30 days after delivery)
Incidence neonatal hypoglycemia	hypoglycemia requiring intravenous treatment	from delivery through study completion (30 days after delivery)

Collaborators and Investigators

• Sponsor: Women and Infants Hospital of Rhode Island
• Investigators: Principal Investigator: Christopher Nau, MD, Women & Infants Hospital; Principal Investigator: Erika Werner, Women & Infants Hospital

Publications and helpful links

General Publications

• Committee Opinion No 700: Methods for Estimating the Due Date. Obstet Gynecol. 2017 May;129(5):e150-e154. doi: 10.1097/AOG.0000000000002046.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2018
• Primary Completion (Actual): July 30, 2019
• Study Completion (Actual): July 30, 2019

Study Registration Dates

• First Submitted: June 12, 2018
• First Submitted That Met QC Criteria: August 27, 2018
• First Posted (Actual): August 29, 2018

Study Record Updates

• Last Update Posted (Actual): July 24, 2020
• Last Update Submitted That Met QC Criteria: July 22, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: metformin
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 1099865-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes