CRD vs. Met in Patients With Obese PCOS Infertility

• ClinicalTrials.gov Identifier: NCT06049186
• Recruitment Status: Recruiting
• First Posted: September 22, 2023
• Last Update Posted: September 22, 2023
• Sponsor: Shanghai First Maternity and Infant Hospital
• Collaborators: RenJi Hospital; Shanghai 10th People's Hospital
• Information provided by (Responsible Party): Shanghai First Maternity and Infant Hospital

Study Description

Brief Summary:

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disease and a major cause of anovulatory infertility in reproductive-aged women. From 2010 to 2020, it was found that the prevalence of PCOS in reproductive-aged women in China reached 7.8%, an increase of 65% over 10 years ago. Many of them are overweight or obese. Weight loss including diet modifications can significantly reduce reproductive and metabolic disorders of PCOS and is recommended as a first step in the treatment of overweight or obese women with PCOS. Many weight loss programs have been proposed, including calorie-restriction diet (CRD) intervention. Whether CRD intervention prior to ovulation induction therapy could improve live birth rates in overweight/obese PCOS women has not been illustrated.

Condition or disease	Intervention/treatment	Phase
Polycystic Ovary Syndrome	Behavioral: CRD; Drug: Metformin	Not Applicable

Detailed Description:

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disease and a major cause of anovulatory infertility in reproductive-aged women. Rotterdam criteria state the definition of PCOS is that women must present with two of the following three signs/symptoms-hyperandrogenism, chronic anovulation/oligomenorrhea, and polycystic ovaries-in the absence of other diseases that promote these symptoms. From 2010 to 2020, it was found that the prevalence of PCOS in reproductive-aged women in China reached 7.8%, an increase of 65% over 10 years ago. Many of them are overweight or obese. Weight loss including diet modifications can significantly reduce reproductive and metabolic disorders of PCOS and is recommended as a first step in the treatment of overweight or obese women with PCOS. Many weight loss programs have been proposed, including calorie-restriction diet (CRD) intervention. Whether CRD intervention prior to ovulation induction therapy could improve live birth rates in overweight/obese PCOS women has not been illustrated. This research is aimed to evaluate whether CRD intervention prior to ovulation induction could promote reproductive health in overweight or obese PCOS women with fertility requirements and provide an evidence-based nutrition advice for clinical practice.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 406 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Comparison of live birth rates between calorie-restricted diets and metformin interventions prior to ovulation induction therapy in patients with overweight/obese polycystic ovary syndrome combined with Infertility.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Comparison of Live Birth Rates Between Calorie-restricted Diets and Metformin Interventions Prior to Ovulation Induction Therapy in Patients With Overweight/Obese Polycystic Ovary Syndrome Combined With Infertility
• Estimated Study Start Date: September 15, 2023
• Estimated Primary Completion Date: January 1, 2026
• Estimated Study Completion Date: March 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: CRD group; Patients in the calorie-restricted diet (CRD) group will have strict calorie-restriction diets for 8 weeks and then weight stability for 4 weeks.	Behavioral: CRD; During the initial 8 weeks of the trial, polycystic ovary syndrome (PCOS) patients are instructed to follow a diet of 1200 to 1500 kcal per day supervised by dietitians. The CRD includes a combination of 40 to 55% of calories from carbohydrates, 15 to 20% from protein, and 20 to 30% from fat; this regimen represented approximately 75% of the participants' daily caloric intake at baseline. All the participants receive dietary counseling daily during the trial.; Other Name: Calorie-restricted diet
Active Comparator: Control group; Patients in the control group will receive regular diets and metformin 1500 mg daily for 12 weeks. Participants allocated to the control group are followed by the conventional approach (usual care) based on regular visits respecting the usual schedule dictated by the rules of general practice.	Drug: Metformin; After randomization, patients entering the metformin group will be given 1500 mg daily (bid/tid) metformin and regular diets as control. Participants allocated to the control group are followed by the conventional approach (usual care) based on regular visits respecting the usual schedule dictated by the rules of general practice.; Other Name: Metformin treatment

Outcome Measures

Primary Outcome Measures :

1. Live birth during the period of ovulation induction [ Time Frame: 18 months ]
   Live birth will be defined as the delivery of one or more living infants (≥22 week's gestation or birth weight more than 500g). The outcome could be assessed by clinical data and clinical diagnosis.

Secondary Outcome Measures :

1. Fasting blood glucose (FBG) [ Time Frame: Baseline period and 3 months ]
   A laboratory test that determines the level of glucose in the blood after an overnight fast, used especially to diagnose diabetes and prediabetes. The normal interval is 3.9-6.1mmol/L. The outcome could be assessed by clinical data and clinical test.
2. Fasting insulin (FINS) [ Time Frame: Baseline period and 3 months ]
   The level of insulin in the blood during fasting (usually in the morning when fasting). The normal interval is 5~20 μIU. The outcome could be assessed by clinical data and clinical test.
3. Oral glucose tolerance test (OGTT) [ Time Frame: Baseline period and 3 months ]
   An oral glucose tolerance test (OGTT) is a diagnostic tool used to evaluate how an individual's body metabolizes sugar. Often used to diagnose diabetic conditions, an oral glucose tolerance test requires minimal preparatory measures and may be safely administered during pregnancy. The outcome could be assessed by clinical data and clinical test.
4. Insulin release test (IRT) [ Time Frame: Baseline period and 3 months ]
   Quantitative oral glucose during fasting increases blood glucose and stimulates pancreatic β cells to release insulin. By measuring plasma insulin levels during fasting and 0.5h, 1h, 2h, and 3h after taking sugar, we can understand the secretion and reserve function of pancreatic β cells, which is also helpful for the classification of diabetes mellitus and guide treatment. The outcome could be assessed by clinical data and clinical test.
5. Blood lipid [ Time Frame: Baseline period and 3 months ]
   Lipid related indicators include cholesterol, triglycerides. The outcome could be assessed by clinical data and clinical test.
6. Kidney function index [ Time Frame: Baseline period and 3 months ]
   Blood tests that are included in the kidney function test include measuring for creatinine and blood urea nitrogen (BUN). The outcome could be assessed by clinical data and clinical test.
7. Liver function index [ Time Frame: Baseline period and 3 months ]
   Liver function index includes alanine aminotransferase (ALT), alkaline phosphatase (ALP) . The outcome could be assessed by clinical data and clinical test.
8. Free testosterone (FT) [ Time Frame: Baseline period and 3 months ]
   The average serum testosterone concentration is 0.43ng/ml, the high limit is 0.68ng/ml, if more than 0.7ng/m1 (equal to 2.44nmol/L), it is called hypertestosterone, or hyperandrogenemia. The outcome could be assessed by clinical data and clinical test.
9. Total testosterone (TT) [ Time Frame: Baseline period and 3 months ]
   The normal range of female testosterone is 0.1-0.75ng /ml, testosterone is the main sex hormone of the human body, men and women have secretion, male testosterone secretion is 20-30 times the amount of female testosterone secretion, it is very important to maintain the second sexual characteristics, bone and muscle strength. The outcome could be assessed by clinical data and clinical test.
10. Sex Hormone Binding Globulin (SHBG) [ Time Frame: Baseline period and 3 months ]
    A globulin synthesized by liver cells that can bind sex hormones, also known as testosterone - estrogen binding globulin or steroidal binding protein, is an important carrier of sex hormones, which can have an important impact on the regulation of sex hormone levels and bioavailability in the body. Clinical detection of SHBG level can provide scientific reference value for disease detection and judgment. The normal interval is 20-130nmol/L for women. The outcome could be assessed by clinical data and clinical test.
11. Liver transient elastography(TE) [ Time Frame: Baseline period and 3 months ]
    TE may be used to monitor disease progression or regression via serial measurements and to guide further management including treatment. The outcome could be assessed by clinical data and clinical test.
12. Weight [ Time Frame: Baseline period and 3 months ]
    Unit: kilogram (kg). The outcome could be assessed by clinical data and clinical test.
13. Height [ Time Frame: Baseline period and 3 months ]
    Unit: meter (m). The outcome could be assessed by clinical data and clinical test.
14. Body Mass Index (BMI) [ Time Frame: Baseline period and 3 months ]
    BMI = weight (in kg)/ height^2 (in m^2).
15. Waist circumference [ Time Frame: Baseline period and 3 months ]
    Unit: centimeter (cm). The outcome could be assessed by clinical data and clinical test.
16. Body fat [ Time Frame: Baseline period and 3 months ]
    Body fat is measured by body fat scale. The outcome could be assessed by clinical data and clinical test.
17. Lean body weight [ Time Frame: Baseline period and 3 months ]
    Lean body weight refers to the total weight of organs, bones, and muscles. The outcome could be assessed by clinical data and clinical test.
18. Blood pressure (BP) [ Time Frame: Baseline period and 3 months ]
    Blood pressure is a measurement of the force of blood against the arterial walls when the heart pumps. The pressure is measured in millimeters of mercury (mmHg) and is expressed as two numbers. For example, the optimal BP for an adult is 120 over 80, or 120/80. A pressure reading of 120 over 80 or lower is considered healthy. If the systolic number ranges above 120 to 139 or the diastolic number ranges above 80 to 89, a person is considered to have pre-hypertension. Systolic readings from 140 to 159 or diastolic readings from 90 to 99 are classified as stage 1 hypertension. Systolic measurements of 160 or above or diastolic measurements of 100 or above indicate the severe condition of stage 2 hypertension. The outcome could be assessed by clinical data and clinical test.
19. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline period and 3 months ]
    The purpose of the HADS was to screen for clinically significant anxiety and depressive symptoms in medically ill patients. Content The HADS-A includes specific items that assess generalized anxiety including tension, worry, fear, panic, difficulties in relaxing, and restlessness. The total score for the HADS-A can range from 0 to 21. The following guidelines are recommended for the interpretation of scores: 0-7 for normal or no anxiety, 8-10 for mild anxiety, 11-14 for moderate anxiety, and 12-21 for severe anxiety.
20. Biochemical pregnancy [ Time Frame: 8 months ]
    A pregnancy diagnosed only by the detection of beta hCG in serum or urine. The outcome could be assessed by clinical data and clinical diagnosis.
21. Ectopic pregnancy [ Time Frame: 8 months ]
    Ectopic pregnancy (EP) is defined as the implantation and development of a fertilized ovum anywhere outside of the uterine cavity. The outcome could be assessed by clinical data and clinical diagnosis.
22. Pregnancy failure [ Time Frame: 8 months ]
    Pregnancy failure, otherwise termed as pregnancy loss or miscarriage, can occur at different stages during this process and many different pathophysiological mechanisms may be implicated. The outcome could be assessed by clinical data and clinical diagnosis.
23. Birth weight [ Time Frame: 18 months ]
    Macrosomia is defined in a newborn as a birth weight more than two standard deviations above the mean percentile for gestational age, >90th percentile weight for gestational age, or a birth weight greater than 4000g at term. The outcome could be assessed by clinical data and clinical diagnosis.
24. Neonatal complications [ Time Frame: 18 months ]
    Neonatal complications include intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, bronchopulmonary dysplasia, jaundice. The outcome could be assessed by clinical data and clinical diagnosis.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 40 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. a diagnosis of polycystic ovary syndrome (PCOS) based on the Rotterdam diagnostic criteria;
2. age 20-35 years old;
3. a body-mass index over 23;
4. have requirements for fertility.

Exclusion Criteria:

1. acute or chronic viral hepatitis;
2. serious liver dysfunction or chronic kidney disease;
3. serious cardiovascular or cerebrovascular disease;
4. patients with a history of acute/chronic infection, severe cardiovascular and cerebrovascular diseases, and malignant tumors;
5. have drugs for PCOS such as glucocorticoids and anti-androgen drugs (spironolactone, cyproterone acetate, flutamide, etc.) within 3 months;
6. congenital or secondary uterine abnormalities;
7. use of medications that affect weight or energy balance such as Metformin within 3 months;
8. undergoing weight loss treatment (weight change greater than 5% in the past 3 months) or have a history of gastrointestinal surgery;
9. tubal obstruction;
10. the total number of motile sperm of male partner is less than 10 million;
11. any other situations that might affect the trial.

Contacts and Locations

Contacts

Contact: Miaoxin Chen, Dr; 20261000; chenmiaoxin@51mch.com

Locations

China, Shanghai

Shanghai First Maternity and Infant Hospital; Recruiting

Shanghai, Shanghai, China, 201204

Contact: Miao Chen, Dr 20261000 chenmiaoxin@51mch.com

Sponsors and Collaborators

Shanghai First Maternity and Infant Hospital

RenJi Hospital

Shanghai 10th People's Hospital

Investigators

• Study Chair: Miaoxin Chen, Dr; Shanghai First Maternity and Infant Hospital

More Information

Publications:

Yang R, Li Q, Zhou Z, Qian W, Zhang J, Wu Z, Jin L, Wu X, Zhang C, Zheng B, Tan J, Hao G, Li S, Tian T, Hao Y, Zheng D, Wang Y, Norman RJ, Li R, Liu P, Qiao J. Changes in the prevalence of polycystic ovary syndrome in China over the past decade. Lancet Reg Health West Pac. 2022 May 31;25:100494. doi: 10.1016/j.lanwpc.2022.100494. eCollection 2022 Aug.

Lie Fong S, Douma A, Verhaeghe J. Implementing the international evidence-based guideline of assessment and management of polycystic ovary syndrome (PCOS): how to achieve weight loss in overweight and obese women with PCOS? J Gynecol Obstet Hum Reprod. 2021 Jun;50(6):101894. doi: 10.1016/j.jogoh.2020.101894. Epub 2020 Aug 16.

Shahid R, Iahtisham-Ul-Haq, Mahnoor, Awan KA, Iqbal MJ, Munir H, Saeed I. Diet and lifestyle modifications for effective management of polycystic ovarian syndrome (PCOS). J Food Biochem. 2022 Jul;46(7):e14117. doi: 10.1111/jfbc.14117. Epub 2022 Feb 24.

Szczuko M, Kikut J, Szczuko U, Szydlowska I, Nawrocka-Rutkowska J, Zietek M, Verbanac D, Saso L. Nutrition Strategy and Life Style in Polycystic Ovary Syndrome-Narrative Review. Nutrients. 2021 Jul 18;13(7):2452. doi: 10.3390/nu13072452.

Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. J Transl Med. 2020 Feb 27;18(1):104. doi: 10.1186/s12967-020-02277-0.

• Responsible Party: Shanghai First Maternity and Infant Hospital
• ClinicalTrials.gov Identifier: NCT06049186
• Other Study ID Numbers: CRD vs. Met in PCOS
• First Posted: September 22, 2023
• Last Update Posted: September 22, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Infertility; Syndrome; Disease; Pathologic Processes; Genital Diseases; Urogenital Diseases; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Gonadal Disorders; Endocrine System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs