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Hyperemesis GravidarumPhase 1/2NCT07129473

Hyperemesis Gravidarum Risk Reduction With Metformin

A Phase 1/2 study testing Metformin Extended Release Oral Tablet in people with Hyperemesis Gravidarum, run by University of Southern California at 2 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 49 years, women onlyHealthy volunteers can take part
Conditions the study is for
Hyperemesis Gravidarum
What is being tested?
Metformin Extended Release Oral Tablet
Could I receive a placebo?
No, everyone receives an active treatment
How many people
224 participants
Where
2 sitesUnited States
Study dates
13 Jul 2026to Mar 2031
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 49 years
  • Women only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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)
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  • 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

Who cannot join

  • 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
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  • 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 locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Marlena Fejzo, PhD contact

310-383-3581

Marlena.Fejzo@med.usc.edu

Andrew Housholder, MD, FACEP contact

205-772-9595

United States2 sites, 2 recruiting

  • The Morning Sickness & HG Clinic

    Birmingham, Alabama, 35223

    Andrew Housholder, MD, FACEP, 205-772-9595, admin@morningsicknessclinic.com

    Not yet recruiting

  • University of Southern California - Keck School of Medicine

    Los Angeles, California, 90033

    Marlena S Fejzo, PhD, 310-383-3581, marlena.fejzo@med.usc.edu

    Recruiting

Other trials in United States

About this study

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:

Read more
  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

Being tested
Metformin Extended Release Oral Tablet
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
Medical subject headings
Hyperemesis Gravidarum, Nausea, Vomiting, Morning Sickness

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Metformin Extended Release Oral TabletDrug

    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).

Study groups in NCT07129473
Study groupRoleWhat they receive
Treatment ArmExperimentalTreatment 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
Receives: Drug: Metformin Extended Release Oral Tablet
Survey/Comparator ArmNo interventionSurvey/Comparator Arm (N=112): * Matched controls (race/ethnicity, parity, maternal age, prior HG pregnancy (IV fluids), pregnancy intent) * No metformin treatment

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Adherence to Escalating Doses of Metformin-XR

    Proportion of participants in the Treatment Arm who reach and maintain each target dose level during the 8-week dose-escalation period, as recorded via MyCap survey entries.

    Measured: Baseline to 8 weeks after treatment initiation

  2. Tolerability and Safety of Metformin-XR

    Number and severity of treatment-related adverse events and dose-limiting toxicities experienced by participants during the 8-week dose-escalation period and maintenance phase. Safety assessed by participant report, clinical evaluations, and laboratory results.

    Measured: 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)

  3. Hyperemesis Gravidarum (HG) Recurrence and Severity

    Incidence and severity of HG in subsequent pregnancy, assessed using validated tools (Pregnancy-Unique Quantification of Emesis (PUQE-24), HyperEmesis Level Prediction (HELP) Score) and pregnancy experience survey responses.

    Measured: From confirmed pregnancy through 12 weeks of gestation

  4. Pregnancy & Neonatal Outcomes: Incidence of Pregnancy Complications

    Proportion of participants who experience predefined pregnancy complications (e.g., gestational diabetes, preeclampsia, gestational hypertension). Data will be abstracted from medical records and study surveys.

    Measured: From confirmed pregnancy through delivery

  5. Pregnancy & Neonatal Outcomes: Delivery Characteristics

    Proportion of participants with a favorable delivery outcome, defined as live birth at ≥37 weeks gestation. Delivery outcome will be abstracted from medical records and study surveys.

    Measured: At delivery

  6. Pregnancy & Neonatal Outcomes: Assessment of Peripartum Events

    Peripartum events will be evaluated using the validated Peripartum Events Scale (PES). PES score will be evaluated via medical record abstraction. The lowest possible PES score is zero, with higher scores corresponding to more stressful labor and delivery experiences.

    Measured: From confirmed pregnancy to 6 months postpartum

  7. Pregnancy & Neonatal Outcomes: Maternal Postpartum Depression

    Maternal mental health will be assessed using the Edinburgh Postnatal Depression Scale (EPDS). The EPDS range is 0-30, with higher scores corresponding to more severe depressive symptoms.

    Measured: From birth to 6 months postpartum

  8. Pregnancy & Neonatal Outcomes: Maternal Postpartum Anxiety

    Maternal mental health will be assessed using the Postpartum-Specific Anxiety Scale (PSAS). The PSAS range is 51-204, with higher scores corresponding to greater postpartum-specific anxiety.

    Measured: From birth to 6 months postpartum

  9. Pregnancy & Neonatal Outcomes: Maternal Postpartum Quality of Life

    Maternal postpartum quality of life will be assessed using the validated Maternal Postpartum Quality of Life (MAPP-QOL) Questionnaire. The MAPP-QOL possible total score range is 38-228, with higher scores corresponding to better quality of life.

    Measured: From birth to 6 months postpartum

  10. Pregnancy & Neonatal Outcomes: Neonatal Health Status

    Proportion of neonates who experience an adverse neonatal outcome, defined as the presence of at least one predefined adverse neonatal event, including but not limited to low birth weight (<2500 grams), preterm birth (<37 weeks gestation), admission to a neonatal intensive care unit (NICU), or low 5-minute Apgar score (<7). Data will be obtained from medical record abstraction and study surveys.

    Measured: At delivery

  11. Pregnancy & Neonatal Outcomes: Child Developmental Status

    Child development will be assessed before 6 months postpartum using the validated Ages and Stages Questionnaires, Third Edition (ASQ-3). Optionally, every 6 months up to year 5 (study completion), participants will have the opportunity to complete an additional ASQ-3 assessment corresponding to their child's age to report long-term child outcomes.

    Measured: From birth to 6 months postpartum (with optional follow up until the end of the 5-year study period)

  12. Indicators of Metformin Response: Genetic Factors

    Genotyping of variants associated with HG risk (e.g., rs1058587/GDF15, rs9312688/IGFBP7, rs12790159/PGR, and rs10948901/GFRAL) to explore their association with metformin response and pregnancy outcomes.

    Measured: Once at baseline

  13. Indicators of Metformin Response: Circulating Biomarker Levels

    Measurement of biomarker (e.g., GDF15, IGFBP7) concentrations at three timepoints in the Treatment Arm (baseline, after dose escalation, and during early pregnancy) to explore the role of each as a predictive biomarker for HG and metformin response.

    Measured: Once at baseline, once when participant reaches highest tolerated metformin dose (up to week 8), and once at pregnancy confirmation in participants who conceive

  14. Indicators of Metformin Response: Demographic Characteristics

    Demographic information will be collected via initial study survey and qualitatively analyzed for associations with HG and metformin response.

    Measured: At baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Aug 2025
  2. Study start13 Jul 2026
  3. Primary completionMar 2031 (estimated)
  4. Study completionMar 2031 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Prevention
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Prospective Cohort Trial with Intervention
Masking
None (open label)
Enrolment
224 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07129473
Sponsor's protocol ID
APP-25-03192
Status last verified
Jul 2026
First submitted
7 Aug 2025
Last updated
22 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Fejzo M, Rocha N, Cimino I, Lockhart SM, Petry CJ, Kay RG, Burling K, Barker P, George AL, Yasara N, Premawardhena A, Gong S, Cook E, Rimmington D, Rainbow K, Withers DJ, Cortessis V, Mullin PM, MacGibbon KW, Jin E, Kam A, Campbell A, Polasek O, Tzoneva G, Gribble FM, Yeo GSH, Lam BYH, Saudek V, Hughes IA, Ong KK, Perry JRB, Sutton Cole A, Baumgarten M, Welsh P, Sattar N, Smith GCS, Charnock-Jones DS, Coll AP, Meek CL, Mettananda S, Hayward C, Mancuso N, O'Rahilly S. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024 Jan;625(7996):760-767. doi: 10.1038/s41586-023-06921-9. Epub 2023 Dec 13.

    PubMed 38092039

  • Sharma N, MacGibbon KW, Brecht-Doscher A, Cortessis VK, Fejzo MS. Prepregnancy metformin use associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum. Am J Obstet Gynecol. 2025 Dec;233(6):649.e1-649.e14. doi: 10.1016/j.ajog.2025.06.055. Epub 2025 Jun 28.

    PubMed 40588059

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Metformin Extended Release Oral Tablet in people with Hyperemesis Gravidarum, run by University of Southern California at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 22 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Marlena Fejzo, PhD (310-383-3581, Marlena.Fejzo@med.usc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Adherence to Escalating Doses of Metformin-XR (time frame: Baseline to 8 weeks after treatment initiation). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07129473, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jul 2026; AzTrials last refreshed its copy on 26 Oct 2026.

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