Hyperemesis Gravidarum Risk Reduction With Metformin
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 224
- 试验地点
- 2
- 主要终点
- Tolerability and Safety of Metformin-XR
研究概览
简要总结
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:
- 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?
- 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)?
- 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?
- How does pre-pregnancy metformin-XR use affect pregnancy outcomes, postpartum health, and newborn health and development?
- 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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 49 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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)
- •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.
研究组 & 干预措施
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 as tolerated
- Continue treatment until either 2 weeks post-pregnancy confirmation or up to 12 months
干预措施: Metformin Extended Release Oral Tablet (Drug)
结局指标
主要结局
Tolerability and Safety of Metformin-XR
时间窗: 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)
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.
Adherence to Escalating Doses of Metformin-XR
时间窗: Baseline to 8 weeks after treatment initiation
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.
Tolerability and Safety of Metformin-XR
时间窗: Baseline through treatment completion (up to 12 months after treatment initiation or 2 weeks after confirmed pregnancy, whichever comes first)
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.
Hyperemesis Gravidarum (HG) Recurrence and Severity
时间窗: From confirmed pregnancy through 12 weeks of gestation
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.
Pregnancy & Neonatal Outcomes: Incidence of Pregnancy Complications
时间窗: From confirmed pregnancy through delivery
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.
Pregnancy & Neonatal Outcomes: Delivery Characteristics
时间窗: At delivery
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.
Pregnancy & Neonatal Outcomes: Assessment of Peripartum Events
时间窗: From confirmed pregnancy to 6 months postpartum
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.
Pregnancy & Neonatal Outcomes: Maternal Postpartum Depression
时间窗: From birth to 6 months postpartum
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.
Pregnancy & Neonatal Outcomes: Maternal Postpartum Anxiety
时间窗: From birth to 6 months postpartum
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.
Pregnancy & Neonatal Outcomes: Maternal Postpartum Quality of Life
时间窗: From birth to 6 months postpartum
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.
Pregnancy & Neonatal Outcomes: Neonatal Health Status
时间窗: At delivery
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.
Pregnancy & Neonatal Outcomes: Child Developmental Status
时间窗: From birth to 6 months postpartum (with optional follow up until the end of the 5-year study period)
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.
Indicators of Metformin Response: Genetic Factors
时间窗: Once at baseline
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.
Indicators of Metformin Response: Circulating Biomarker Levels
时间窗: Once at baseline, once when participant reaches highest tolerated metformin dose (up to week 8), and once at pregnancy confirmation in participants who conceive
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.
Indicators of Metformin Response: Demographic Characteristics
时间窗: At baseline
Demographic information will be collected via initial study survey and qualitatively analyzed for associations with HG and metformin response.
次要结局
未报告次要终点
研究者
Marlena Fejzo
Clinical Assistant Professor of Population and Public Health Sciences in the Center for Genetic Epidemiology
University of Southern California