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

Overview

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.

Interventions

• Drug Metformin
  Individuals randomized to this arm will receive oral metformin tablets for their Gestational diabetes mellitus treatment.
• Drug Insulin
  Individuals randomized to this arm will receive injectable insulin for their Gestational diabetes mellitus treatment.

Primary outcome measures

• A neonatal composite adverse outcome of large-for-gestational-age (LGA) birthweight, hypoglycemia, hyperbilirubinemia, and/or death. [Time frame: 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.]
• Child body mass index (BMI) at 2 years of age [Time frame: 2 years of age.]

Secondary outcome measures (12)

• Hypertensive disorder of pregnancy, HDP (maternal) [Time frame: Randomization to delivery]
• Gestational weight gain (maternal) [Time frame: Initiation of prenatal care to delivery]
• Mode of delivery (maternal) [Time frame: At birth]
• Obstetric perineal/anal sphincter injuries (maternal) [Time frame: At birth]
• Preterm birth (child) [Time frame: At birth]
• Requiring mechanical ventilation (child) [Time frame: <72 hours after birth]
• NICU admission (child) [Time frame: Birth to delivery discharge.]
• Oxygen support (child) [Time frame: <72 hours after birth]
• Respiratory distress syndrome (child) [Time frame: Anytime during the first 72 hours after birth]
• Body mass index (BMI) (maternal) [Time frame: 2-year follow-up]
• Obesity overall and by class (maternal) [Time frame: 2-year follow-up]
• Anthropometry (maternal) [Time frame: 2-year follow-up]

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 - 33 6/7 weeks based on project gestational age.
• GDM diagnosis less than or equal to 33 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 24 centers

• University of Alabama — Tuscaloosa
• Cedars Sinai Medical Center — Los Angeles
• University of California San Francisco — San Francisco
• Christiana Care — Newark
• University of South Florida — Tampa
• Tufts University — Boston
• Massachusetts General Hospital — Boston
• Beth Israel Deaconess Medical Center — Boston
• … and 16 more centers

Publications

• 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. PMID 34605130
• 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 PMID 38049101
• 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. PMID 35412565
• Venkatesh KK, MacPherson C, Clifton RG, Powe CE, Bartholomew A, Gregory D, Trinh A, McAlearney AS, Fiechtner LG, Catalano P, Rice D, Cross S, Kutay H, Gabbe S, Grobman WA, Costantine MM, Battarbee AN, Boggess K, Katukuri V, Eichelberger K, Esakoff T, Feghali MN, Harper L, Kaimal A, Kole-White M, Mendez-Figueroa H, Mlynarczyk M, Sciscione A, Shook L, Sobhani NC, Stamilio DM, Werner E, Wiegand S, Ze PMID 39317491

Identifiers

NCT: NCT06445946 · 2024H0193

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗