Clinical trial NCT06445946: DECIDE: A Comparative Effectiveness Trial of Metformin Versus Insulin for the Treatment of Gestational Diabetes
Official title: DECIDE: A Comparative Effectiveness Trial of Oral Metformin Versus Injectable Insulin for the Treatment of Gestational Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Gestational Diabetes Mellitus
Pregnancy, High Risk
Keywords: Insulin
Pregnancy
Glycemic control
Metformin
Gestational diabetes
Diabetes
Adverse pregnancy outcomes
Lead sponsor: Ohio State University
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
name: The George Washington University Biostatistics Center
First posted: 2024-06-06
Enrollment: 1572
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a non-inferiority patient-centered and pragmatic comparative-effectiveness pregnancy randomized controlled trial (RCT) with postpartum maternal and child follow-up through 2 years of 1,572 individuals with gestational diabetes mellitus (GDM) randomized to oral metformin versus injectable insulin.

This study will determine if metformin is not inferior to insulin in reducing adverse pregnancy outcomes, is comparably safe for exposed individuals and children, and if patient-reported factors, including facilitators of and barriers to use, differ between metformin and insulin. A total of 1,572 pregnant individuals with GDM who need pharmacotherapy will be recruited at 20 U.S. sites using consistent treatment criteria to metformin versus insulin. Participants and their children will be followed through delivery to two years postpartum.

Detailed description: Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. Glycemic control decreases the risk of adverse pregnancy outcomes for the pregnant individual with GDM and the infant exposed in utero (1). One in four individuals with GDM will require pharmacotherapy to achieve glycemic control. Insulin has been the mainstay of pharmacotherapy. Metformin is an alternative option increasingly used in clinical practice (2). Both insulin and metformin reduce the risk of adverse pregnancy outcomes, but comparative effectiveness data from a well-characterized, adequately powered, and diverse U.S. population remain lacking (3). Because metformin crosses the placenta, long-term safety data, in particular the risk of childhood obesity, from exposed children are also needed. In addition, the patient-reported experiences of individuals with GDM requiring pharmacotherapy remains to be characterized, including barriers for and facilitators of metformin versus insulin use.

In a two-arm open-label, pragmatic comparative effectiveness randomized controlled trial (RCT), the DECIDE Study will examine whether metformin is not inferior to insulin in reducing adverse pregnancy outcomes and is comparably safe for exposed mothers and children, and whether patient-reported factors, including facilitators of and barriers to use, differ between metformin versus insulin use. The DECIDE Study Consortium will recruit and retain 1,572 pregnant individuals with GDM who need pharmacotherapy at 20 U.S. sites to metformin versus insulin and follow them and their children through delivery and then to 2-years

Primary aim:

To evaluate whether outcomes in pregnant individuals randomized to metformin are not inferior to those in pregnant individuals randomized to insulin for the composite adverse neonatal outcome defined as large-for-gestational-age birthweight (LGA), hypoglycemia, hyperbilirubinemia, or death.

Secondary aims:

1. To evaluate whether mean child body mass index (BMI) at 2 years of age is higher in the offspring of pregnant individuals randomized to metformin.
2. To conduct a qualitative or mixed-methods analyses on a subgroup of participants to understand facilitators and barriers associated with metformin versus insulin use and heterogeneity of treatment effects (HTE) to facilitate evidence-based pharmacotherapy.
3. To evaluate whether pregnant individuals randomized to metformin have equivalent maternal (hypertensive disorder of pregnancy, gestational weight gain, mode of delivery, and obstetric anal sphincter injuries) and neonatal (preterm birth, mechanical ventilation, NICU admission, oxygen support, and respiratory distress syndrome) outcomes.
4. To evaluate whether pregnant individuals randomized to metformin have equivalent maternal (obesity, anthropometry, adiposity, diabetes, hypertension, cholesterol, and metabolic profile) and child (obesity, anthropometry, and adiposity) outcomes at 2-years postpartum.
5. To evaluate whether pregnant individuals randomized to metformin have equivalent patient-reported outcomes (PROs), as measured at 6 weeks postpartum and at 2 years postpartum.

Eligibility criteria: Inclusion Criteria:

* Singleton gestation. Twin reduction to singleton, either spontaneously or therapeutically, is eligible if it occurred before 14 weeks gestational age.
* Age 18 years or older
* Gestational age at randomization between 20 0/7 - 32 6/7 weeks based on project gestational age.
* GDM diagnosis less than or equal to 31 6/7 weeks based on project gestational age.
* Requires medication for glucose control defined as ≥ 30% elevated glucose values (either fasting or postprandial or both) prior to randomization per determination of the provider or documented in the medical record.
* Patient willingness and ability to attend 2-year follow-up visit.

Exclusion criteria:

* Renal disease (serum creatinine \>1.3 mg/dL) due to the potential impact of metformin on renal function.
* Major structural malformation of the fetus.
* Known fetal aneuploidy based on invasive testing or positive for aneuploidy on cell-free fetal DNA screening.
* Contraindication to metformin or insulin, including: history of lactic acidosis, intractable nausea and vomiting, prior documented allergy and/or anaphylaxis.
* For individuals with GDM diagnosed \<20 0/7 weeks, documented A1c ≥\>6.5% within prior 6 months.
* Pregestational diabetes documented in the medical record or prior A1c\>= 6.5%
* Fasting hyperglycemia \>115 mg/dl for ≥ 50% of fasting glucose values in the past week (due to the high risk of metformin failure with fasting hyperglycemia).
* Enrolled in a trial that influences primary study outcomes (composite neonatal outcome at delivery or childhood body mass index at 2 years).
* Prenatal care or delivery planned at a location where access to the complete electronic medical record will not be available to research staff.
* Language barrier (appropriate translation resources unavailable at the site)
* Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, may be included.

Primary outcomes:
measure: A neonatal composite adverse outcome of large-for-gestational-age (LGA) birthweight, hypoglycemia, hyperbilirubinemia, and/or death.
timeFrame: LGA at birth. Hypoglycemia <24 hours after birth. Hyperbilirubinemia within the first week after birth. Death between randomization to hospital discharge or 30 days postnatal.
measure: Child body mass index (BMI) at 2 years of age
timeFrame: 2 years of age.
Secondary outcomes:
measure: Hypertensive disorder of pregnancy, HDP (maternal)
timeFrame: Randomization to delivery
measure: Gestational weight gain (maternal)
timeFrame: Initiation of prenatal care to delivery
measure: Mode of delivery (maternal)
timeFrame: At birth
measure: Obstetric perineal/anal sphincter injuries (maternal)
timeFrame: At birth
measure: Preterm birth (child)
timeFrame: At birth
measure: Requiring mechanical ventilation (child)
timeFrame: <72 hours after birth
measure: NICU admission (child)
timeFrame: Birth to delivery discharge.
measure: Oxygen support (child)
timeFrame: <72 hours after birth
measure: Respiratory distress syndrome (child)
timeFrame: Anytime during the first 72 hours after birth
measure: Body mass index (BMI) (maternal)
timeFrame: 2-year follow-up
measure: Obesity overall and by class (maternal)
timeFrame: 2-year follow-up
measure: Anthropometry (maternal)
timeFrame: 2-year follow-up
measure: Anthropometry (maternal)
timeFrame: 2-year follow-up
measure: Anthropometry (maternal)
timeFrame: 2-year follow-up
measure: Adiposity (maternal)
timeFrame: 2 year follow-up
measure: Type 2 diabetes (maternal)
timeFrame: 2-year follow-up.
measure: Prediabetes (maternal)
timeFrame: 2-year follow-up.
measure: Hypertension (maternal)
timeFrame: 2-year follow-up.
measure: Cholesterol (maternal)
timeFrame: 2-year follow-up.
measure: Hemoglobin A1c (maternal)
timeFrame: 2-year follow-up.
measure: Overweight (child)
timeFrame: 2-year follow-up.
measure: Obesity (child)
timeFrame: 2-year follow-up.
measure: Anthropometry (child)
timeFrame: 2-year follow-up.
measure: Adiposity (child)
timeFrame: 2-year follow-up.
measure: Treatment Satisfaction Questionnaire for Medication (TSQM)
timeFrame: 6-weeks postpartum.
measure: Questionnaire on Acceptability of Treatment
timeFrame: 6-weeks postpartum.
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: University of Alabama
state: Alabama
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Newark
country: United States
facility: Christiana Care
state: Delaware
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Boston
country: United States
facility: Tufts University
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center OB/GYN Maternal and Fetal Medicine
state: Ohio
city: Dayton
country: United States
facility: Premier Health - Miami Valley Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Greenville
country: United States
facility: University of South Carolina Greenville
state: South Carolina
city: Austin
country: United States
facility: University of Texas Austin
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Norfolk
country: United States
facility: Eastern Virginia Medical School - Old Dominion University
state: Virginia
Study officials:
affiliation: Ohio State University
name: Kartik Venkatesh, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Venkatesh KK, Chiang CW, Castillo WC, Battarbee AN, Donneyong M, Harper LM, Costantine M, Saade G, Werner EF, Boggess KA, Landon MB. Changing patterns in medication prescription for gestational diabetes during a time of guideline change in the USA: a cross-sectional study. BJOG. 2022 Feb;129(3):473-483. doi: 10.1111/1471-0528.16960. Epub 2021 Nov 8.
citation: Venkatesh KK, Wu J, Trinh A, Cross S, Rice D, Powe CE, Brindle S, Andreatta S, Bartholomew A, MacPherson C, Costantine MM, Saade G, McAlearney AS, Grobman WA, Landon MB. Patient Priorities, Decisional Comfort, and Satisfaction with Metformin versus Insulin for the Treatment of Gestational Diabetes Mellitus. Am J Perinatol. 2024 May;41(S 01):e3170-e3182. doi: 10.1055/s-0043-1777334. Epub 2023 Dec 4.
citation: Venkatesh KK, Lynch CD, Powe CE, Costantine MM, Thung SF, Gabbe SG, Grobman WA, Landon MB. Risk of Adverse Pregnancy Outcomes Among Pregnant Individuals With Gestational Diabetes by Race and Ethnicity in the United States, 2014-2020. JAMA. 2022 Apr 12;327(14):1356-1367. doi: 10.1001/jama.2022.3189.