Hyperemesis Gravidarum Risk Reduction With Metformin

University of Southern California

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Hyperemesis Gravidarum

Treatments: Drug: Metformin Extended Release Oral Tablet

Study type: Interventional

Funder types: Other

Identifiers

NCT07129473

APP-25-03192

Details and patient eligibility

About

The goal of this clinical trial is to evaluate whether daily oral metformin extended-release (metformin-XR), taken prior to and in early pregnancy, can reduce the risk and severity of Hyperemesis Gravidarum (HG), a severe nausea and vomiting condition in pregnancy, in individuals aged 18-49 who have experienced HG in a previous pregnancy and are trying to conceive. Researchers also aim to better understand which individuals may respond well - or poorly - to metformin based on biological and clinical characteristics.

The main questions this study aims to answer are:

1. Is metformin-XR well-tolerated when taken by non-pregnant individuals who have had HG in a previous pregnancy and are currently trying to conceive?
2. How safe and tolerable is metformin-XR when taken at increasing doses over an 8-week titration period and continued through early pregnancy (or for up to 12 months after reaching maintenance dose if pregnancy does not occur)?
3. Among those who become pregnant during the study, does pre-pregnancy metformin-XR use reduce the risk of HG coming back and lower the severity of nausea and vomiting symptoms?
4. How does pre-pregnancy metformin-XR use affect pregnancy outcomes, postpartum health, and newborn health and development?
5. Are there specific genetic, biomarker, demographic, or clinical features that predict whether someone is likely to benefit from metformin-XR or experience side effects that lead them to stop taking it?

Researchers will compare a metformin treatment group to a survey-only group (comparator, no study drug) to see if metformin-XR is associated with improved outcomes, including reduced HG recurrence and better maternal and neonatal health indicators.

Participants will:

Complete online questionnaires before pregnancy, during early pregnancy, and postpartum

(Treatment group only) Take daily metformin-XR and attend three brief study visits

(Treatment group only) Undergo blood draws at specified timepoints to assess safety and biological response

Enrollment: 224 estimated patients

Sex: Female

Ages: 18 to 49 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Ages 18-49
• HG in prior pregnancy (clinical criteria: intravenous (IV) fluid treatment)
• Trying to conceive
• Treatment Arm: willing to refrain from trying to conceive during their metformin dose titration period and before 2 weeks at maximum tolerated dose (up to 8 weeks total). Will use birth control or contraceptive device until maintenance dose.
• Under care of a personal OB/GYN or willing to establish care with a personal OB/GYN before study start
• Ownership of a personal scale (or willingness to obtain one for study use)
• Willing to participate in a trial that includes daily use of an oral agent prior to pregnancy
• Treatment Arm: residing in California/Alabama
• Treatment Arm: normal blood panel (CBC) (e.g., white count, hemoglobin, platelets all within the normal range)
• Treatment Arm: normal to mildly decreased creatinine levels (estimated GFR > 60 mL/min/1.73m²)
• Survey/Comparator Arm: not currently taking metformin and do not plan to take metformin prior to pregnancy
• Able and willing to provide written informed consent prior to initiation of any study procedures.
• Demonstrates understanding of the study objectives, requirements, potential risks, and willingness to comply with study procedures and follow-up.
• English speaking
• Regular cycles

Exclusion criteria

• Allergic or adverse reaction to metformin-XR
• Thalassemia
• Cirrhosis and/or hepatic impairment
• Decompensated heart failure
• Daily/regular use of medications/substances (tobacco, cyclobenzaprine, cannabis, escitalopram, sertraline, other SSRIs, Lasix)
• Treatment Arm: Use of insulin, sulfonylureas, meglitinides, or other blood sugar altering medication
• Assisted Reproductive Technology
• Excess alcohol consumption (> 7 standard drinks per week on average)
• Pregnant
• Not trying to conceive
• Treatment Arm: Residing outside California/Alabama
• Treatment Arm: abnormal blood panel (CBC) (e.g., white count or platelets not within the normal range)
• Treatment Arm: abnormal creatinine levels (estimated GFR < 60 mL/min/1.73m² excluded from the study, signs of kidney disease)
• Treatment Arm: current metformin use
• Survey/Comparator Arm: current metformin use or plans to take metformin prior to pregnancy
• Any medical/surgical condition that the investigator feels would compromise the participant's participation in the study
• Not able and willing to provide written informed consent prior to initiation of any study procedures.
• Does not demonstrate understanding of the study objectives, requirements, potential risks, and willingness to comply with study procedures and follow-up.
• Not english speaking
• Irregular cycles
• Not willing to refrain from trying to conceive/use birth control or contraceptive device until maintenance dose.

Trial design

Primary purpose: Prevention

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

224 participants in 2 patient groups

Treatment Arm

Experimental group

Description:

Treatment Arm (N=112): * Individuals with a prior HG pregnancy with intravenous (IV) fluid treatment and current pregnancy intent * Residing in California or Alabama * Daily metformin-XR, escalated from 500 mg to 2000 mg (or maximum tolerated dose) over an 8-week titration period, as tolerated * Continue treatment until either 2 weeks post-pregnancy confirmation (early pregnancy) or up to 12 months from the maintenance dose following cessation of birth control/contraceptive device if pregnancy does not occur

Treatment:

Drug: Metformin Extended Release Oral Tablet

Survey/Comparator Arm

No Intervention group

Description:

Survey/Comparator Arm (N=112): * Matched controls (race/ethnicity, parity, maternal age, prior HG pregnancy (IV fluids), pregnancy intent) * No metformin treatment