Hyperemesis Gravidarum Risk Reduction With Metformin

NCT07129473 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: APP-25-03192
• Study Type: interventional
• Target: 224
• Locations: 1 country
• Sites: 2

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. 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. 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. 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. 4.How does pre-pregnancy metformin-XR use affect pregnancy outcomes, postpartum health, and newborn health and development?
5. 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?

Conditions

Hyperemesis Gravidarum

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

Outcome Measures

Primary Outcomes (14)

• 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.

  Baseline to 8 weeks after treatment initiation

• 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.

  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

  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.

  From confirmed pregnancy through 12 weeks of gestation

• 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.

  From confirmed pregnancy through delivery

• 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.

  At delivery

• 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.

  From confirmed pregnancy to 6 months postpartum

• 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.

  From birth to 6 months postpartum

• 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.

  From birth to 6 months postpartum

• 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.

  From birth to 6 months postpartum

• 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.

  At delivery

• 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.

  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

  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.

  Once at baseline

• 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.

  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

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

  At baseline

Study Arms (2)

Treatment Arm

EXPERIMENTAL

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

Drug: Metformin Extended Release Oral Tablet

Survey/Comparator Arm

NO INTERVENTION

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 DRUG

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).

Treatment Arm

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Southern California: lead
• The Morning Sickness & HG Clinic: collaborator

Study Sites (2)

The Morning Sickness & HG Clinic

Birmingham, Alabama, 35223, United States

NOT YET RECRUITING

University of Southern California - Keck School of Medicine

Los Angeles, California, 90033, United States

RECRUITING

Related Publications (2)

• 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.

  PMID: 38092039 BACKGROUND

• 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.

  PMID: 40588059 BACKGROUND

MeSH Terms

Conditions

Hyperemesis Gravidarum; Nausea; Vomiting; Morning Sickness

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Marlena Fejzo, PhD

  University of Southern California

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marlena Fejzo, PhD

CONTACT

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

Andrew Housholder, MD, FACEP

CONTACT

205-772-9595

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Assistant Professor of Population and Public Health Sciences in the Center for Genetic Epidemiology

Model Details: Prospective Cohort Trial with Intervention

Study Record Dates

• First Submitted: August 7, 2025
• First Posted: August 19, 2025
• Study Start: July 13, 2026
• Primary Completion (Estimated): March 1, 2031
• Study Completion (Estimated): March 1, 2031
• Last Updated: July 22, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)