DECIDE: A Comparative Effectiveness Trial of Metformin Versus Insulin for the Treatment of Gestational Diabetes

Phase 4RecruitingNCT06445946

Ohio State University1,572 enrolled

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.

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

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

A neonatal composite adverse outcome of large-for-gestational-age (LGA) birthweight, hypoglycemia, hyperbilirubinemia, and/or death.

LGA will be defined as a birthweight ≥90th%tile for gestational age based on a US birth certificate reference adjusted for parity and/or fetal sex. Neonatal hypoglycemia will be defined as a blood glucose \<35 mg/dL or treatment \<24 hours after birth with either IV, PO, or gel glucose therapy. Neonatal hyperbilirubinemia will be defined as treated with phototherapy or exchange transfusion in the first postnatal week and either treatment in the first postnatal week or kernicterus. Fetal or neonatal death can be due to any indication between randomization to hospital discharge or 30 days postnatal if still hospitalized (excluding voluntary pregnancy termination).

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

Child BMI measured in kg/m2 as a continuous measure standardized using U.S. CDC reference adjusted for child sex

Time frame: 2 years of age.

Secondary Outcomes

Hypertensive disorder of pregnancy, HDP (maternal)

HDP will include either gestational hypertension or preeclampsia. Gestational hypertension will be defined as: systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure. Preeclampsia will be defined as: above blood pressure criteria AND proteinuria (300 mg or more per 24 hour urine collection, protein/creatinine ratio of 0.3 mg/dL or more, or dipstick reading of 2+) OR thrombocytopenia (platelet count less than 100 109/L), renal insufficiency (serum creatinine greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), impaired liver function (elevated blood concentrations of liver transaminases to twice normal concentration), pulmonary edema, new-onset headache or visual symptoms not attributed to other diagnoses.

Time frame: Randomization to delivery

Gestational weight gain (maternal)

Gestational weight gain between weight at first prenatal visit and weight at delivery based on z-score and defined as excess versus within Institute of Medicine (IOM) recommendations based on first pregnancy BMI.

Time frame: Initiation of prenatal care to delivery

Mode of delivery (maternal)

Cesarean delivery or vaginal delivery

Time frame: At birth

Obstetric perineal/anal sphincter injuries (maternal)

First degree: Injury to perineal skin only; Second degree: Injury to perineum involving perineal muscles but not involving anal sphincter; Third degree: Injury to perineum involving anal sphincter complex, including 3a: Less than 50% of external anal sphincter thickness torn; 3b: More than 50% external anal sphincter thickness torn; and 3c: Both external anal sphincter and internal anal sphincter torn; and Fourth degree: Injury to perineum involving anal sphincter complex (external anal sphincter and internal anal sphincter) and anal epithelium.

Time frame: At birth

Preterm birth (child)

Preterm birth \<37 weeks and \<34 weeks based on project gestational age

Time frame: At birth

Requiring mechanical ventilation (child)

Intubation, continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) for ventilation or cardiopulmonary resuscitation within first 72 hours of birth

Time frame: <72 hours after birth

NICU admission (child)

Admitted to NICU or intermediate nursery ≥72 hours, any indication

Time frame: Birth to delivery discharge.

Oxygen support (child)

Requiring oxygen support

Time frame: <72 hours after birth

Respiratory distress syndrome (child)

Signs of respiratory distress with oxygen requirement and confirmed by chest x-ray.

Time frame: Anytime during the first 72 hours after birth

Body mass index (BMI) (maternal)

Continuous measure, using standardized protocol as kg/m2.

Time frame: 2-year follow-up

Obesity overall and by class (maternal)

BMI per the following classifications: Normal or underweight: \< 25 kg/m2; Overweight: 25 to \< 30 kg/m2; Class 1: 30 to \< 35 kg/m2; Class 2: 35 to \< 40 kg/m2; and Class 3: 40 kg/m2 or greater.

Time frame: 2-year follow-up

Anthropometry (maternal)

Waist circumference, continuous measures in cm

Time frame: 2-year follow-up

Anthropometry (maternal)

Hip circumference, continuous measures in cm

Time frame: 2-year follow-up

Anthropometry (maternal)

Waist - to - hip ratio, continuous measure

Time frame: 2-year follow-up

Adiposity (maternal)

Triceps, subscapular, suprailiac skinfolds, continuous measures in cm

Time frame: 2 year follow-up

Type 2 diabetes (maternal)

A1c \> 6.5% OR fasting plasma glucose \> 126 mg/dL OR OGTT \> 200 mg/dL OR prior diagnosis per patient report

Time frame: 2-year follow-up.

Prediabetes (maternal)

A1c 5.7% to 6.4% OR fasting plasma glucose 100 mg/dl to 125 mg/dL OR OGTT 140 to 199 mg/dL

Time frame: 2-year follow-up.

Hypertension (maternal)

Per American Heart Association criteria as below and/or antihypertensive medication or prior diagnosis per patient report, and defined as: Elevated: Systolic between 120-129 and diastolic less than 80 mm Hg; Stage 1: Systolic between 130-139 or diastolic between 80-89 mm Hg; and Stage 2: Systolic at least 140 or diastolic at least 90 mm Hg.

Time frame: 2-year follow-up.

Cholesterol (maternal)

Fasting state, defined as a continuous measure and dichotomous at the following thresholds for each component: Total cholesterol: \> 200 mg/dL; LDL cholesterol: \> mg/dL; HDL cholesterol: \< 40 mg/dL; Triglycerides: \> 200 mg/dL.

Time frame: 2-year follow-up.

Hemoglobin A1c (maternal)

Continuous measure, percentage.

Time frame: 2-year follow-up.

Overweight (child)

BMI ≥85th%tile for age and sex.

Time frame: 2-year follow-up.

Obesity (child)

BMI ≥95th%tile for age and sex.

Time frame: 2-year follow-up.

Anthropometry (child)

Abdominal circumference; age- and sex-adjusted per WHO z-scores for arm circumference.

Time frame: 2-year follow-up.

Adiposity (child)

Triceps/subscapular skinfold thickness \> 90th%tile for age and sex; individual and sum of measures.

Time frame: 2-year follow-up.

Treatment Satisfaction Questionnaire for Medication (TSQM)

The TSQM (version 1.4) comprises 14 items across four domains focusing on effectiveness (three items), side effects (five items), convenience (three items), and global satisfaction (three items) of the medication over the previous 2-3 weeks. With the exception of item 4 (presence of side effects; yes or no), all items have five or seven responses, scored from one (least satisfied) to five or seven (most satisfied). Item scores are summed to give four domain scores, which are in turn transformed to a scale of 0-100. Item 4 was not included for scoring.

Time frame: 6-weeks postpartum.

Questionnaire on Acceptability of Treatment

A set of 5 questions developed in the Rowan et al. RCT assessing patient adherence, preferences, and experiences with metformin versus insulin for GDM (Rowan et al., NEJM, 2008).

Time frame: 6-weeks postpartum.

DECIDE: A Comparative Effectiveness Trial of Metformin Versus Insulin for the Treatment of Gestational Diabetes

Overview

Conditions

Interventions

Eligibility

Locations (24)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts