Recruiting

Phase 1

Phase 2

Metformin-XRHyperemesis Gravidarum Risk Reduction With Metformin

Sponsor:

University of Southern California

Code:

NCT07129473

Conditions

Hyperemesis Gravidarum

Eligibility Criteria

Sex: Female

Age: 18 - 49

Healthy Volunteers: Accepted

Interventions

Metformin Extended Release Oral Tablet

Study Details

Brief summary:

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

Conditions

Hyperemesis Gravidarum

Study ID

NCT07129473

Start date

Jul 13, 2026

Status verified date

Jul, 2026

Completion date

Mar, 2031

Anticipated

Primary completion date

Mar, 2031

Anticipated

Eligibility Criteria

Sex: Female

Age: 18 - 49

Healthy Volunteers: Accepted

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.

Study Design

Enrollment

224 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Prevention

Interventions and Outcome Measures

Arms

experimental: Treatment Arm

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

no intervention: Survey/Comparator Arm

Survey/Comparator Arm (N=112):

Matched controls (race/ethnicity, parity, maternal age, prior HG pregnancy (IV fluids), pregnancy intent)
No metformin treatment

Interventions

Metformin Extended Release Oral Tablet

Participants in the Treatment Arm will receive oral extended-release metformin (metformin-XR) once daily with an evening meal starting prior to conception. Daily dosing will begin at 500 mg and increase gradually over an 8-week period (+500 mg every 2 weeks, as tolerated, with increases, holds, or reductions based on symptom severity) to a maximum dose of 2,000 mg. Treatment at highest tolerated dose will continue until 2 weeks after positive pregnancy test or 12 months after cessation of birth control/contraceptive device. Participants will attend 3 clinic visits and provide blood samples at baseline, after dose escalation, and during early pregnancy to assess biomarker levels and genetic characteristics. Daily dosing, adherence, and side effects are recorded via MyCap; clinical visits include vital signs, PUQE-24/HELP scores, and blood draws. Postpartum surveys include a metformin treatment \& HG outcomes survey (REDCap) and additional measures (PES, MAPP-QOL, EPDS, PSAS, and ASQ-3).

Primary outcome measure

Adherence to Escalating Doses of Metformin-XR [ Time Frame: Baseline to 8 weeks after treatment initiation ]
Tolerability and Safety of Metformin-XR [ Time Frame: Baseline through treatment completion (up to 12 months after maintenance dose following cessation of birth control/contraceptive device or 2 weeks after confirmed pregnancy, whichever comes first) ]
Hyperemesis Gravidarum (HG) Recurrence and Severity [ Time Frame: From confirmed pregnancy through 12 weeks of gestation ]
Pregnancy & Neonatal Outcomes: Incidence of Pregnancy Complications [ Time Frame: From confirmed pregnancy through delivery ]
Pregnancy & Neonatal Outcomes: Delivery Characteristics [ Time Frame: At delivery ]
Pregnancy & Neonatal Outcomes: Assessment of Peripartum Events [ Time Frame: From confirmed pregnancy to 6 months postpartum ]
Pregnancy & Neonatal Outcomes: Maternal Postpartum Depression [ Time Frame: From birth to 6 months postpartum ]
Pregnancy & Neonatal Outcomes: Maternal Postpartum Anxiety [ Time Frame: From birth to 6 months postpartum ]
Pregnancy & Neonatal Outcomes: Maternal Postpartum Quality of Life [ Time Frame: From birth to 6 months postpartum ]
Pregnancy & Neonatal Outcomes: Neonatal Health Status [ Time Frame: At delivery ]
Pregnancy & Neonatal Outcomes: Child Developmental Status [ Time Frame: From birth to 6 months postpartum (with optional follow up until the end of the 5-year study period) ]
Indicators of Metformin Response: Genetic Factors [ Time Frame: Once at baseline ]
Indicators of Metformin Response: Circulating Biomarker Levels [ Time Frame: Once at baseline, once when participant reaches highest tolerated metformin dose (up to week 8), and once at pregnancy confirmation in participants who conceive ]
Indicators of Metformin Response: Demographic Characteristics [ Time Frame: At baseline ]

Central Contacts and Locations

Central contacts

Marlena Fejzo, PhD

310-383-3581 Marlena.Fejzo@med.usc.edu

Andrew Housholder, MD, FACEP

205-772-9595

Locations

University of Southern California - Keck School of Medicine

Recruiting

Los Angeles, California, United States, 90033

Contacts

Marlena S Fejzo, PhD

310-383-3581 marlena.fejzo@med.usc.edu

More Information

Sponsor

University of Southern California

Last update posted

Jul 22, 2026

Last verified

Jul, 2026

Keywords

Metformin
HG
Hyperemesis
Hyperemesis Gravidarum
Nausea and Vomiting of Pregnancy
NVP
severe Nausea and Vomiting of Pregnancy
sNVP
Nausea
Vomiting
Pregnancy
Pregnant
Morning Sickness

Trial information was received from ClinicalTrials.gov and was last updated on 2026-10-09. This information was provided to ClinicalTrials.gov by University of Southern California on 2026-07-22. Recruitment status is synced daily from ClinicalTrials.gov and may not reflect the sponsor's current status. Confirm during your call.