Semaglutide Improves Metabolic Abnormalities and Fertility in Obese Infertile Women With Polycystic Ovary Syndrome

Study Overview
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Brief Summary
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To investigate the efficacy of semaglutide in obese infertile women of childbearing age with polycystic ovary syndrome (PCOS), we design this prospective, randomized, open and controlled study. 75 obese infertile PCOS patients will be recruited and randomized into three groups: metformin, semaglutide and metformin+semaglutide, on the basis of calorie-restricted diet and physical exercise. All subjects will be treated for 12 weeks, and then stop taking the drug for at least 8 weeks to initiate ovulation induction or ovulation induction combined with artificial insemination. All subjects will be followed up for 24 weeks for pregnancy outcome. The primary endpoint of the study is the percentage of weight loss at 12 weeks of treatment. The secondary endpoints include HOMA-IR and androgen levels at 12 weeks of treatment, ovulation rate at 24 weeks of follow-up, clinical pregnancy rate and cumulative pregnancy rate, and depression, anxiety, diet and quality of life scores at 12 weeks of treatment.

Detailed Description
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To investigate the efficacy of semaglutide in obese infertile women of childbearing age with polycystic ovary syndrome (PCOS), we design this prospective, randomized, open and controlled study. 75 obese infertile PCOS patients will be recruited and randomized into three groups: metformin, semaglutide and metformin+semaglutide, on the basis of calorie-restricted diet and physical exercise. Metformin and semaglutide will be administered in a dose increasing mode, and then maintain until the end of 12 weeks, and metabolic related indexes will be evaluated. After 12 weeks of treatment, all subjects will stop taking the drug for at least 8 weeks to initiate ovulation induction or ovulation induction combined with artificial insemination. All subjects will be followed up for 24 weeks to evaluate the fertility related indicators. The primary endpoint of the study is the percentage of weight loss at 12 weeks of treatment. The secondary endpoints include HOMA-IR and androgen levels at 12 weeks of treatment, ovulation rate at 24 weeks of follow-up, clinical pregnancy rate and cumulative pregnancy rate, and depression, anxiety, diet and quality of life scores at 12 weeks of treatment.

Official Title
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Semaglutide Improves Metabolic Abnormalities and Fertility in Obese Infertile Women With Polycystic Ovary Syndrome: a Prospective, Randomized, Open, Controlled Study

Conditions
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PCOS (Polycystic Ovary Syndrome), Semaglutide

Intervention / Treatment
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* Drug: Metformin Hydrochloride 500 MG
* Drug: Semaglutide, 1.34 mg/mL
* Drug: Semaglutide, 1.34 mg/mL and Metformin Hydrochloride 500 MG
* Behavioral: calorie-restricted diet
* Behavioral: physical exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet the PCOS diagnostic criteria (Rotterdam） Age 22-40 BMI ≥ 28 kg/m2 Infertility: having normal sexual life and failing to conceive without contraception for more than 1 year Willing to be pregnant, and her husband has no serious infertility Exclusion Criteria: History of acute pancreatitis, individual or family history of medullary thyroid cancer and multiple endocrine adenomas Type 1 diabetes and special type diabetes History of tumor Serious cardiovascular and cerebrovascular disease, mental disease, liver or kidney disease Metformin, GLP-1 RA and other drugs affecting reproductive and metabolic functions were used within 90 days before the study Known allergy to metformin, GLP-1 RA and excipients Severe endometriosis, low ovarian reserve, premature ovarian failure Inability to tolerate pregnancy and ovulation induction therapy Other conditions considered unsuitable for this study by researchers

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All subjects will be randomized into three groups: metformin single, semaglutide single, both metformin and semaglutide.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: metformin<br>About 25 subjects will be allocated to this group to receive metformin only, as the active comparator of semaglutide groups. Metformin used in this trial is Glucophage ( 500mg per tablet）produced by Bristol-Myers Squibb.The initial dose of metformin will be 500mg twice daily, which will be increased to 1000mg twice daily after two weeks, and then maintained until the end of treatment in total 12 weeks. | Drug: Metformin Hydrochloride 500 MG<br>* Metformin oral tablet (500mg per tablet) will be administered in a dose increasing mode: the initial dose will be 500mg twice daily, which will be increased to 1000mg twice daily after two weeks, and then maintained until the end of treatment in total 12 weeks.<br>* Other names: Glucophage;Behavioral: calorie-restricted diet<br>* All subjects after randomization will be reviewed and evaluated by a nutritionist, and then will receive diet guidance. The clinical nutritionist will develop a written nutrition plan for each subject. The nutrition plan of this study adopted the method of calorie restriction diet (CRD) to develop a diet, which required 83.68 kJ/kg of energy per day, 1.2 g/kg of protein per day, 40% 55% of carbohydrate energy supply ratio, and 20% 30% of fat energy supply ratio, to ensure the intake of vegetables, fruits and other rich dietary fiber, and drinking more than 1.5 L per day. The nutritionist will explain the method of food exchange in detail to enrich the food types of patients. The diet diary will be distributed to each subject, and the subjects will be required to make a return visit once every four weeks, return the diet diary each time, and receive guidance according to their compliance.<br>Behavioral: physical exercise<br>* All subjects after randomization will be reviewed and evaluated by a trainer, and then will receive guidance of physical exercise.The trainer will formulate an exercise plan for each subject. The exercise plan consists of 30 minutes of moderate and low intensity continuous aerobic exercise every day, with a frequency of 5-7 days/week. The form of exercise can be determined according to personal hobbies, such as fast walking, jogging, climbing, swimming, etc. The exercise diary will be distributed to each subject, and the subjects are required to make a return visit once every four weeks, return the exercise diary each time, and the trainer will provide guidance to the subjects according to their compliance.<br>|
| Experimental: semaglutide<br>About 25 subjects will be allocated to this group to receive semaglutide only, as one of the experimental groups. Semaglutide used in this trial is WEGOVY (semaglutide) injection produced by Novo Nordisk. Administer WEGOVY once weekly, on the same day each week, at any time of day, with or without meals. Inject subcutaneously in the abdomen, thigh or upper arm. Initiate at 0.25 mg once weekly for 4 weeks. In 4 week intervals, increase the dose until a dose of 1.0 mg is reached, and then maintained 1.0 mg until the end of treatment in total 12 weeks.. | Drug: Semaglutide, 1.34 mg/mL<br>* Inject semaglutide subcutaneously once weekly, on the same day each week, at any time of day, in a dose increasing mode: the initial dose of 0.25mg QW (once a week), increased to 0.5mg QW after 4 weeks, and increased to 1.0mg QW after another 4 weeks, and then maintained 1.0mg until the end of treatment in total 12 weeks.<br>* Other names: WEGOVY;Behavioral: calorie-restricted diet<br>* All subjects after randomization will be reviewed and evaluated by a nutritionist, and then will receive diet guidance. The clinical nutritionist will develop a written nutrition plan for each subject. The nutrition plan of this study adopted the method of calorie restriction diet (CRD) to develop a diet, which required 83.68 kJ/kg of energy per day, 1.2 g/kg of protein per day, 40% 55% of carbohydrate energy supply ratio, and 20% 30% of fat energy supply ratio, to ensure the intake of vegetables, fruits and other rich dietary fiber, and drinking more than 1.5 L per day. The nutritionist will explain the method of food exchange in detail to enrich the food types of patients. The diet diary will be distributed to each subject, and the subjects will be required to make a return visit once every four weeks, return the diet diary each time, and receive guidance according to their compliance.<br>Behavioral: physical exercise<br>* All subjects after randomization will be reviewed and evaluated by a trainer, and then will receive guidance of physical exercise.The trainer will formulate an exercise plan for each subject. The exercise plan consists of 30 minutes of moderate and low intensity continuous aerobic exercise every day, with a frequency of 5-7 days/week. The form of exercise can be determined according to personal hobbies, such as fast walking, jogging, climbing, swimming, etc. The exercise diary will be distributed to each subject, and the subjects are required to make a return visit once every four weeks, return the exercise diary each time, and the trainer will provide guidance to the subjects according to their compliance.<br>|
| Experimental: semaglutide and metformin<br>About 25 subjects will be allocated to this group to receive both semaglutide and metformin, as another of the experimental groups. Metformin used in this trial is Glucophage ( 500mg per tablet）produced by Bristol-Myers Squibb.The initial dose of metformin will be 500mg twice daily, which will be increased to 1000mg twice daily after two weeks, and then maintained until the end of treatment in total 12 weeks. Semaglutide used in this trial is WEGOVY (semaglutide) injection produced by Novo Nordisk. Administer WEGOVY once weekly, on the same day each week, at any time of day, with or without meals. Inject subcutaneously in the abdomen, thigh or upper arm. Initiate at 0.25 mg once weekly for 4 weeks. In 4 week intervals, increase the dose until a dose of 1.0 mg is reached, and then maintained 1.0 mg until the end of treatment in total 12 weeks. | Drug: Semaglutide, 1.34 mg/mL and Metformin Hydrochloride 500 MG<br>* Both Semaglutide injection and Metformin oral tablet will be administered as described above.<br>* Other names: WEGOVY and Glucophage;Behavioral: calorie-restricted diet<br>* All subjects after randomization will be reviewed and evaluated by a nutritionist, and then will receive diet guidance. The clinical nutritionist will develop a written nutrition plan for each subject. The nutrition plan of this study adopted the method of calorie restriction diet (CRD) to develop a diet, which required 83.68 kJ/kg of energy per day, 1.2 g/kg of protein per day, 40% 55% of carbohydrate energy supply ratio, and 20% 30% of fat energy supply ratio, to ensure the intake of vegetables, fruits and other rich dietary fiber, and drinking more than 1.5 L per day. The nutritionist will explain the method of food exchange in detail to enrich the food types of patients. The diet diary will be distributed to each subject, and the subjects will be required to make a return visit once every four weeks, return the diet diary each time, and receive guidance according to their compliance.<br>Behavioral: physical exercise<br>* All subjects after randomization will be reviewed and evaluated by a trainer, and then will receive guidance of physical exercise.The trainer will formulate an exercise plan for each subject. The exercise plan consists of 30 minutes of moderate and low intensity continuous aerobic exercise every day, with a frequency of 5-7 days/week. The form of exercise can be determined according to personal hobbies, such as fast walking, jogging, climbing, swimming, etc. The exercise diary will be distributed to each subject, and the subjects are required to make a return visit once every four weeks, return the exercise diary each time, and the trainer will provide guidance to the subjects according to their compliance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in bodyweight at 12 weeks for semaglutide versus metformin | Difference between body weight at 12 weeks and baseline divided by baseline body weight | at the end of 12 weeks of treatment | 
| Achievement of weight reduction of at least 5% at 12 weeks for semaglutide versus metformin | Proportion of patients with weight loss at least 5% at 12 weeks of treatment | at the end of 12 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HOMA-IR at 12 weeks of treatment | compare HOMA-IR at 12 weeks of treatment among three groups | at the end of 12 weeks of treatment | 
| testosterone level at 12 weeks of treatment | compare testosterone level at 12 weeks of treatment among three groups | at the end of 12 weeks of treatment | 
| androstenedione level at 12 weeks of treatment | compare androstenedione level at 12 weeks of treatment among three groups | at the end of 12 weeks of treatment | 
| FAI (Free Androgen Index) at 12 weeks of treatment | compare FAI at 12 weeks of treatment among three groups | at the end of 12 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCOS, semaglutide, obese, metabolic abnormality, fertility