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

Semaglutide Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05702905
• Other study ID #: 2022CR04
• Status: Recruiting
• Phase: Phase 4
• Start date: May 9, 2023
• Est. completion date: June 30, 2025

Study information

• Verified date: March 2024
• Source: Peking University First Hospital
• Contact: Tingting Zhang, M.D.
• Phone: 86-10-83575103
• Email: cathine[@]sina.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: June 30, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 22 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Meet the PCOS diagnostic criteria (Rotterdam)

2. Age 22-40

3. BMI = 28 kg/m2

4. Infertility: having normal sexual life and failing to conceive without contraception for more than 1 year

5. Willing to be pregnant, and her husband has no serious infertility

Exclusion Criteria:

1. History of acute pancreatitis, individual or family history of medullary thyroid cancer and multiple endocrine adenomas

2. Type 1 diabetes and special type diabetes

3. History of tumor

4. Serious cardiovascular and cerebrovascular disease, mental disease, liver or kidney disease

5. Metformin, GLP-1 RA and other drugs affecting reproductive and metabolic functions were used within 90 days before the study

6. Known allergy to metformin, GLP-1 RA and excipients

7. Severe endometriosis, low ovarian reserve, premature ovarian failure

8. Inability to tolerate pregnancy and ovulation induction therapy

9. Other conditions considered unsuitable for this study by researchers

Related Conditions & MeSH terms

• Congenital Abnormalities
• Polycystic Ovary Syndrome
• Semaglutide
• Syndrome

Intervention

Drug:
• Metformin Hydrochloride 500 MG
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.
• Semaglutide, 1.34 mg/mL
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.
• Semaglutide, 1.34 mg/mL and Metformin Hydrochloride 500 MG
Both Semaglutide injection and Metformin oral tablet will be administered as described above.

Behavioral:
• calorie-restricted diet
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.
• physical exercise
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.

Locations

Country	Name	City	State
China	PekingUFH	Peking	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking University First Hospital

Country where clinical trial is conducted

China, 

References & Publications (11)

Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695-709. doi: 10.1210/clinem/dgaa285. — View Citation

Ge JJ, Wang DJ, Song W, Shen SM, Ge WH. The effectiveness and safety of liraglutide in treating overweight/obese patients with polycystic ovary syndrome: a meta-analysis. J Endocrinol Invest. 2022 Feb;45(2):261-273. doi: 10.1007/s40618-021-01666-6. Epub 2 — View Citation

Han Y, Li Y, He B. GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis. Reprod Biomed Online. 2019 Aug;39(2):332-342. doi: 10.1016/j.rbmo.2019.04.017. Epub 2019 Apr 25. — View Citation

Jensterle M, Kravos NA, Pfeifer M, Kocjan T, Janez A. A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome. — View Citation

Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrin — View Citation

Li R, Mai T, Zheng S, Zhang Y. Effect of metformin and exenatide on pregnancy rate and pregnancy outcomes in overweight or obese infertility PCOS women: long-term follow-up of an RCT. Arch Gynecol Obstet. 2022 Nov;306(5):1711-1721. doi: 10.1007/s00404-022 — View Citation

Liu X, Zhang Y, Zheng SY, Lin R, Xie YJ, Chen H, Zheng YX, Liu E, Chen L, Yan JH, Xu W, Mai TT, Gong Y. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin Endocrinol (Oxf). 2017 Dec — View Citation

Ma RL, Deng Y, Wang YF, Zhu SY, Ding XS, Sun AJ. Short-term combined treatment with exenatide and metformin for overweight/obese women with polycystic ovary syndrome. Chin Med J (Engl). 2021 Nov 3;134(23):2882-2889. doi: 10.1097/CM9.0000000000001712. — View Citation

Papaetis GS, Kyriacou A. GLP-1 receptor agonists, polycystic ovary syndrome and reproductive dysfunction: Current research and future horizons. Adv Clin Exp Med. 2022 Nov;31(11):1265-1274. doi: 10.17219/acem/151695. — View Citation

Salamun V, Jensterle M, Janez A, Vrtacnik Bokal E. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol. 2018 Jul;179(1):1-11. doi: 10.1530/EJE-1 — View Citation

Xing C, Zhao H, Zhang J, He B. Effect of metformin versus metformin plus liraglutide on gonadal and metabolic profiles in overweight patients with polycystic ovary syndrome. Front Endocrinol (Lausanne). 2022 Aug 17;13:945609. doi: 10.3389/fendo.2022.94560 — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Depression score by self-rating depression scale (SDS)at 12 weeks of treatment	Zung self-rating depression scale (SDS) contains 20 items. Each item is divided into four grades according to the frequency of symptoms, of which 10 are positive and 10 are negative. Positive scoring question rated as 1, 2, 3 and 4 in turn and reverse scoring questions rated as 4, 3, 2 and 1. Add all the scores to get the total rough score, and then multiply the rough score by 1.25 to get the integral part as the standard score. The lower the score, the better. According to the criteria of Chinese population, the cut-off value of SDS standard score is 53 points, of which 53-62 points is mild depression, 63-72 points is moderate depression, and more than 73 points is severe depression. SDS standard score = 50 indicates depressive symptoms. Depression severity is evaluated by cumulative score of each item/80. Those below 0.5 are not depressed; 0.5-0.59 is mild depression; 0.6-0.69 is moderate to severe; more than 0.7 is severe depression.	at the end of 12 weeks of treatment
Other	Anxiety score by self-rating anxiety scale (SAS)at 12 weeks of treatment	Zung self-reating anxiety scale (SAS) adopts a four-grade score, which is mainly used to assess the frequency of symptoms. The standard is: "1" means no or little time; "2" means sometimes; "3" means most of the time; "4" means most or all of the time. Of the 20 items, 15 items are stated in negative words, and scored in the order of 1-4 above. The remaining five items are stated in positive words and scored in reverse order of 4 to 1. The main statistical indicator of SAS is the total score. Add the scores of 20 items to get a rough score. Multiply the rough score by 1.25 and take the integer part to get the standard score. According to the criteria of Chinese population, the cut-off value of SAS standard score is 50 points, of which 50-59 points is mild anxiety, 60-69 points is moderate anxiety, and more than 70 points is severe anxiety.	at the end of 12 weeks of treatment
Other	Diet score by TFEQ-18 (three factor eating questionaire) at 12 weeks of treatment	The Three-Factor Eating Questionnaire Revised 18-item includes three dimensions of questions: non-controlled eating (9 items), cognitive restricted eating (6 items), and emotional eating (3 items). Uncontrolled eating refers to a tendency to lose control of excessive eating when feeling hungry or stimulated by external factors. Cognitive restriction refers to consciously limiting food intake to control weight or promote weight loss. Emotional eating refers to the tendency to overeat under some negative emotional conditions. Questions 1 to 18 are scored with 1 to 4 points. The total score of the three dimensions is the total score of the scale. The higher the score of each dimension of the questionnaire, the higher the tendency of uncontrolled eating, cognitive restriction of eating and emotional eating.	at the end of 12 weeks of treatment
Other	Quality of life score at 12 weeks of treatment	The World Health Organization Quality of Life (WHOQOL) - BREF can generate scores in four fields. The scale contains two independent analysis items: Q1 asks the individual's total subjective feelings about their own quality of life, and Q2 asks the individual's total subjective feelings about their own health status. The domain score is positive (that is, the higher the score, the better the quality of life). The domain score is obtained by calculating the average score of the items to which it belongs and multiplying by 4.	at the end of 12 weeks of treatment
Other	Ovulation rate at 24 weeks of follow-up after the end of treatment	Number of patients with ovulation after natural and ovulation induction treatment/total number of patients	at the end of 24 weeks of follow-up after the end of treatment
Other	Clinical pregnancy rate at 24 weeks of follow-up after the end of treatment	Clinical pregnancy rate=clinical pregnancy cycles/transplantation cycles	at the end of 24 weeks of follow-up after the end of treatment
Other	Cumulative pregnancy rate at 24 weeks of follow-up after the end of treatment	Cumulative pregnancy rate=number of all pregnant patients/total number of patients	at the end of 24 weeks of follow-up after the end of treatment
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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