Glyburide and Metformin for Gestational Diabetes Mellitus (GDM) (GDM)

Glyburide and Metformin for Gestational Diabetes Mellitus

This is a pharmacokinetic and pharmacodynamic study evaluating glyburide, metformin, and combination treatment for gestational diabetes mellitus.

Study Overview

• Status: Unknown
• Conditions: Gestational Diabetes Mellitus
• Intervention / Treatment: Drug: Glyburide; Drug: Metformin; Drug: Glyburide-Metformin combination

Detailed Description

Gestational diabetes mellitus (GDM) is a common complication of pregnancy. Multiple treatment regimens are currently used for the management of GDM. Following failure of diet therapy, insulin, glyburide and metformin are all used in the treatment of GDM with the oral medications providing comparable outcomes with insulin but easier route of administration and schedule. The proposed work will evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of glyburide and metformin alone and in combination in order to lay the foundation in establishing dosage and response information that could be utilized in designing a phase III randomized trial that will ultimately evaluate GDM treatment optimization.

• Study Type: Interventional
• Enrollment (Anticipated): 360
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Gestational Diabetes Subject Selection

1. Pregnant women (singleton pregnancy)
2. Gestational diabetes mellitus
3. Able to give written informed consent
4. Drug treatment is required for GDM

5. Gestational age 20-32 weeks

   • Gestational diabetes diagnosis must occur after 20 weeks and prior to 32 weeks gestation
   • Randomization and treatment initiation must occur no later than 32 weeks gestation
6. Willing to avoid ethanol
7. 18-45 years of age

Type 2 Diabetes Mellitus Subject Selection

1. Able to give written informed consent
2. New diagnosis of type 2 diabetes mellitus
3. Plan to receive metformin for treatment of type 2 diabetes mellitus
4. 18-45 years of age
5. Female
6. Negative pregnancy test
7. Hemoglobin A1C > 7%

Healthy Pregnant Women

1. Able to give written informed consent
2. Pregnant women (singleton)
3. Normal 1-hour glucose tolerance test
4. 20-32 weeks gestation
5. 18-45 years of age

Neonates: All the infants of the pregnant women participating in this study will be included

Exclusion Criteria:

Women with GDM and T2DM

1. Women taking medications expected to interact with glyburide, metformin or alter blood glucose concentrations
2. Serum creatinine > 1.2 mg/dL
3. Hematocrit < 28%
4. Allergy to glyburide, metformin or sulfa
5. Significant hepatic disease
6. Congestive heart failure or history of MI
7. Moderate to severe pulmonary disease
8. Adrenal or pituitary insufficiency

Healthy Pregnant Women

1. Receiving any hypoglycemic agents
2. Receiving corticosteroids
3. Known kidney, liver, heart, pulmonary, adrenal or pituitary disease
4. Hematocrit < 28%

Neonates

1. Infants that are not viable or too ill for blood sample collection will be included for clinical outcomes data collection, but will be excluded from other research activities.
2. Infants < 1.5 kg will be included for clinical outcomes data collection, but will be excluded from blood sample collection.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GDM Subjects; Women with GDM requiring treatment	Drug: Glyburide; Women with GDM who require treatment will be given glyburide 2.5 mg. Medication will be given at least twice daily and equal doses will be given for each dosing time for the 3 days prior to the pharmacokinetic study day.; Drug: Metformin; Women with GDM requiring treatment will be given metformin 500 mg. Medication will be administered at least twice daily and equal doses will be given for each dosing time for the 3 days prior to the pharmacokinetic study day.; Drug: Glyburide-Metformin combination; Women with GDM requiring treatment will be given glyburide 2.5 mg with metformin 500 mg. Medications will be administered at least twice daily and equal doses will be given for each dosing time 3 days prior to the pharmacokinetic study day.
No Intervention: Non-pregnant Type 2 Diabetes Milletus Subjects; Non-pregnant women with Type 2 diabetes mellitus who plan to use metformin treatment
No Intervention: Healthy Pregnant Women; Healthy pregnant women with normal 1-hour glucose tolerance test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study drug dosage in pregnancy	(1) Determination of metformin dosage in pregnancy needed to produce comparable concentrations to the approved dosage range in non-pregnant women. (2)To compare metformin apparent oral clearance in pregnant and non-pregnant women. (3)To evaluate the effect of GLY monotherapy, MET monotherapy, and GLY-MET combination on insulin sensitivity, beta-cell responsivity index and disposition index (response vectors) describing the mechanism and magnitude of effect.	Completion of data collection (4-5mnths on average in GDM and healthy pregnant women and max of 6 months in newly diagnosed T2DMs)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine GLY and MET PK parameters	Determining GLY & MET PK parameters, including AUC, max concentration, time to max & min concentrations, oral clearance, half-life, oral volume of distribution, umbilical cord plasma concentrations; correlation between CYP2C9, CYP3A5, BCRP, OATP2B1 genotypes & GLY PK/PD; GLY & MET PD parameters, including derived parameters from PK/PD modeling for pregnant & nonpregnant subjects; duration of initiation of treatment to glycemic control; effects of GDM & glycemic control on maternal & umbilical cord EPC cells & sFLT concentrations; GLY & MET half-life in neonates; efficacy & safety data.	Conclusion of data collection (up to 6 months)

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Collaborators: University of Pittsburgh; University of Washington; University of Texas; RTI International; Indiana University School of Medicine
• Investigators: Principal Investigator: Steve Caritis, MD, University of Pittsburgh; Principal Investigator: Mary F. Hebert, PharmD, FCCP, University of Washington; Principal Investigator: Gary DV Hankins, MD, University of Texas; Principal Investigator: David Flockhart, MD, PhD, Indiana University School of Medicine

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Anticipated): May 1, 2015
• Study Completion (Anticipated): June 1, 2015

Study Registration Dates

• First Submitted: March 22, 2011
• First Submitted That Met QC Criteria: April 4, 2011
• First Posted (Estimate): April 5, 2011

Study Record Updates

• Last Update Posted (Estimate): February 10, 2015
• Last Update Submitted That Met QC Criteria: February 9, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Pregnancy; Pharmacokinetics; Metformin; Pharmacodynamics; Glyburide
• 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; Glyburide
• Other Study ID Numbers: 820