Effect of Metformin on Healthy Live Birth in Women With Prediabetes

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of metformin pretreatment on reproductive outcomes in infertile women with prediabetes.

Detailed Description
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To evaluate the efficacy and safety of metformin pretreatment on reproductive outcomes in infertile women with prediabetes and to determine whether either starting metformin pretreatment before ovarian stimulation (aiming at improving the quality of oocyte/embryo) or starting before frozen embryo transfer (FET) (aiming at improving the receptivity of endometrium) could increase the chance of a healthy live birth compared with placebo.

Official Title
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Effect of Metformin on Healthy Live Birth After In-vitro Fertilization in Women With Prediabetes Mellitus: a Multicenter Double-blind Placebo Controlled Randomized Trial

Conditions
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Metformin, Prediabetes, In-Vitro Fertilization

Intervention / Treatment
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* Drug: Metformin pretreatment before ovarian stimulation
* Drug: Placebo pretreatment before ovarian stimulation
* Drug: Metformin pretreatment before endometrial preparation for frozen embryo transfer
* Drug: Placebo pretreatment before endometrial preparation for frozen embryo transfer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who are diagnosed with prediabetes by ADA criteria, including either IFG, IGT, or HbA1C 5.7-6.4%. Women aged 20-40 years. Women who plan to undergo a new cycle of IVF, ICSI, or PGT-A. Exclusion Criteria: Women who are diagnosed with diabetes according to the ADA criteria11,12, which is meeting one of the following criteria: fasting plasma glucose ≥7.0mmol/L, 2-h plasma glucose during 75-g OGTT ≥11.1mmol/L, HbA1c≥6.5%, or a random plasma glucose≥11.1mmol/L. Women who are taking medicine that interfere with glucose metabolism, such as metformin, oral anti-diabetic agents (sulfonylureas, glinides, thiazolidinediones, α-glycosidase inhibitors, GLP-1 receptor agonist, etc.), weight loss drugs (i.e.orlistat, etc.), glucocorticoids, and growth hormones within 2 months before enrollment. Women with un-corrected hyperthyroidism or hypothyroidism. Women with congenital or acquired abnormal uterine cavity including septate uterus, unicornous uterus, uterus duplex, and intrauterine adhesions. Women with a diagnosis of adenomyosis. Women with untreated hydrosalpinx. Women who plan to undergo PGT-SR or PGT-M. Women with major medical comorbidities, such as known liver disease, known renal disease, or known significant anemia.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin-Metformin Group<br>Metformin pretreatment before ovarian stimulation till oocyte retrieval and cryopreservation of all embryos, and followed by metformin pretreatment before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer. | Drug: Metformin pretreatment before ovarian stimulation<br>* The enrolled patients will be prescribed metformin 850mg twice daily for at least 4 weeks prior to ovarian stimulation till oocyte retrieval.<br>* Other names: Metformin before ovarian stimulation;Drug: Metformin pretreatment before endometrial preparation for frozen embryo transfer<br>* After oocyte retrieval, the enrolled patients will be prescribed metformin 850mg twice daily for at least 4 weeks before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer.<br>* Other names: Metformin before endometrial preparation;|
| Experimental: Metformin-Placebo Group<br>Metformin pretreatment before ovarian stimulation till oocyte retrieval and cryopreservation of all embryos, and followed by placebo pretreatment before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer. | Drug: Metformin pretreatment before ovarian stimulation<br>* The enrolled patients will be prescribed metformin 850mg twice daily for at least 4 weeks prior to ovarian stimulation till oocyte retrieval.<br>* Other names: Metformin before ovarian stimulation;Drug: Placebo pretreatment before endometrial preparation for frozen embryo transfer<br>* After oocyte retrieval, the enrolled patients will be prescribed placebo 850mg twice daily for at least 4 weeks before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer.<br>* Other names: Placebo before endometrial preparation;|
| Experimental: Placebo-Metformin Group<br>Placebo pretreatment before ovarian stimulation till oocyte retrieval and cryopreservation of all embryos, and followed by metformin pretreatment before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer. | Drug: Placebo pretreatment before ovarian stimulation<br>* The enrolled patients will be prescribed placebo 850mg twice daily for at least 4 weeks prior to ovarian stimulation till oocyte retrieval.<br>* Other names: Placebo before ovarian stimulation;Drug: Metformin pretreatment before endometrial preparation for frozen embryo transfer<br>* After oocyte retrieval, the enrolled patients will be prescribed metformin 850mg twice daily for at least 4 weeks before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer.<br>* Other names: Metformin before endometrial preparation;|
| Experimental: Placebo-Placebo Group<br>Placebo pretreatment before ovarian stimulation till oocyte retrieval and cryopreservation of all embryos, and followed by placebo pretreatment before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer. | Drug: Placebo pretreatment before ovarian stimulation<br>* The enrolled patients will be prescribed placebo 850mg twice daily for at least 4 weeks prior to ovarian stimulation till oocyte retrieval.<br>* Other names: Placebo before ovarian stimulation;Drug: Placebo pretreatment before endometrial preparation for frozen embryo transfer<br>* After oocyte retrieval, the enrolled patients will be prescribed placebo 850mg twice daily for at least 4 weeks before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer.<br>* Other names: Placebo before endometrial preparation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| healthy live birth | defined as a singleton live birth at ≥37 weeks, with infant birth weight between 2500 and 4000g and without a major congenital anomaly. | From the date of randomization until delivery after the first embryo transfer, up to 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BMI | change in body mass index (BMI) from baseline to the establishment of clinical pregnancy. | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | 
| Change in fasting glucose level | change in fasting glucose level from baseline to the establishment of clinical pregnancy. | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | 
| Change in fasting insulin level | change in fasting insulin level from baseline to the establishment of clinical pregnancy. | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | 
| Change in 2-h levels of glucose after 75-g OGTT | change in 2-h levels of glucose after 75-g OGTT from baseline to the establishment of clinical pregnancy. | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | 
| Change in 2-h levels of insulin after 75-g OGTT | change in 2-h levels of insulin after 75-g OGTT from baseline to the establishment of clinical pregnancy. | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | 
| Days of ovarian stimulation | the duration of ovarian stimulation by exogenous gonadotropin | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | 
| Total dose of gonadotropins | the total dose of exogenous gonadotropin used during ovarian stimulation | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | 
| Peak estradiol level | the estradiol level on the day of hCG trigger | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | 
| Number of oocyte retrieved | the number of oocyte retrieved | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | 
| Number of good-score embryos | the number of good-score embryos | From the date of randomization until the third day after oocyte retrieval, up to 12 weeks | 
| Number of euploid embryos | the number of euploid embryos | From the date of randomization until the initiation of endometrial preparation for frozen embryo transfer, up to 20 weeks | 
| OHSS | ovarian hyperstimulation syndrome was defined according to the Golan criteria | From the day of oocyte retrieved until the initiation of endometrial preparation for the first frozen embryo transfer, up to 8 weeks | 
| Clinical pregnancy | defined as the ultrasound confirmation of at least one intrauterine gestational sac | 30-35 days after the first frozen embryo transfer | 
| Singleton or twin pregnancy | the number of intrauterine gestational sacs | 30-35 days after the first frozen embryo transfer | 
| Pregnancy loss | defined as pregnancies that eventuate in a spontaneous abortion or therapeutic abortion that occurred throughout pregnancy. | From the date of confirmation of pregnancy until the date of pregnancy loss, up to 9 months | 
| Live birth | defined as the delivery of any neonate with signs of life at ≥ 28 weeks of gestation | From the date of randomization until delivery after the first embryo transfer, up to 16 months | 
| Incidences of obstetric and neonatal complications | including gestational diabetes mellitus, pre-eclampsia, premature rupture of membrane, placenta previa, placental abruption, congenital anomalies, postpartum hemorrhage, stillbirth, neonatal respiratory distress syndrome, neonatal jaundice, neonatal infection, neonatal death. | From the establishment of clinically recognized pregnancy until six weeks after delivery after the first embryo transfer, up to 11 months | 
| Gestational weight gain | maternal weight gain during pregnancy | at delivery | 
| Birth weight | birth weight of the newborn at delivery | at delivery | 
| LGA | defined as the birthweight above the 90th percentile for gestational age based on a sex-specific reference | at delivery | 
| SGA | defined as the birthweight below the 10th percentile for gestational age based on a sex-specific reference | at delivery | 
| LBW | the infant born weighing less than 2500g | at delivery | 
| Macrosomia | the infant born weighing larger than 4000g | at delivery | 
| Adverse events | adverse event (AE) and serious adverse event (SAE) | From the date of randomization until six weeks after delivery after the first embryo transfer, up to 18 months | 
| Cumulative live birth | define as women achieving live birth after all the cycles of embryo transfer per oocyte retrieval that performed within one year after randomization. | From the date of randomization until delivery, up to 28 months |