Liraglutide and Metformin Combination on Weight Loss, Metabolic - Endocrine Parameters and Pregnancy Rate in Women With PCOS, Obesity and Infertility

Sponsor

Mỹ Đức Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05952882

Collaborator

(none)

426

Enrollment

Arms

24.7

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and one of the leading causes of infertility. PCOS and obesity affect up to 12.5% - 48.3% Asian women, increase incidence of impaired glucose tolerance, type 2 diabetes and aggravate insulin resistance, cause ovulatory dysfunction and menstrual disorders, and negatively impact outcomes of Assited Reproductive Technology (ART), with higher miscarriage rate when receiving ART. Weight loss decrease insulin resistance and hyperandrogenism, improve ovulation rate and menstrual cycle, significantly higher conception and live birth rates. Weight loss prior to IVF procedures has been associated with significantly improved pregnancy rates (PR) and live birth rates. Furthermore, a decreased number of IVF cycles required to achieve a pregnancy has also been reported after weight loss interventions. Based on the principles of fetal programming, improving a lifestyle before conception might lead to improved longterm health of the offspring. Studies on the effect of anti-obesity medication combined with lifestyle changes on body weight and composition and metabolic - endocrine parameters and pregnancy rate in obese women diagnosed with PCOS are lacking. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with polycystic ovary syndrome (PCOS).

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome Obesity Infertility, Female	Drug: Liraglutide + Metformin Drug: Metformin	Phase 3

Detailed Description

The drug, liraglutide 3.0 mg was approved for chronic weight management in management in obese adults with an initial BMI of 30 kg/m2 or greater or in overweight adults BMI of 27 kg/m2 or greater with at least one weight-related co-morbid condition as an adjunct to a reduced-calorie diet and increased physical activity. Liraglutide is an acylated human glucagon-like peptide -1 (GLP-1) analog that binds to and activates the GLP-1 receptor. It lowers body weight through decreased caloric intake while stimulating insulin secretion and reducing glucagon via a glucose-dependent mechanism. For obesity management, patients may lose weight with GLP-1 receptor agonists due to other unique actions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can slow gastric emptying and increase satiety. While predictors of weight loss success for the general population are available (protein intake, weight loss medications), predictors of weight loss success may differ between normal and hyperandrogenic women. Glucagon-like peptide 1 agonists are linked with dose dependent weight lowering potential in different obesity related populations. The weight loss effects of GLP-1RAs previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to patients with PCOS. Metformin was recommended for women with PCOS and obesity (BMI ≥ 25 kg/m2) or at metabolic risks and shown beneficial effects on menstrual disorders, anovulation, hyperandrogenism, and cardiovascular abnormalities.

The aim of this study was to evaluate the impact of liraglutide in combination with metformin compared to metformin alone on weight reduction, the multifaceted metabolic - endocrine disturbances, and oocyte and embryo quality, IVF PRs and cumulative PRs (IVF and spontaneous pregnancies) in infertile obese women with PCOS who had been previously poor responders to weight reduction with lifestyle modification.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

426 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effectiveness of the Combination Liraglutide and Metformin on Weight Loss, Metabolic - Endocrine Parameters and Pregnancy Rate in Women With Polycystic Ovarian Syndrome, Obesity and Infertility

Anticipated Study Start Date :

Jul 10, 2023

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Jul 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LIME Metformin XR was initiated with a dose of 750 mg once per day for 1 week and increased to 1500 mg once per day for up to 12 weeks. Start injection liraglutide 0.6 mg subcutaneously (SC) 1week daily (QD), step up to 1.2 mg SC QD for 1week, to 1.8 mg SC QD for 1 week, 2.4 mg SC QD for 1week, to a final dose of 3.0 mg liraglutide SQ daily for up to 12 weeks.	Drug: Liraglutide + Metformin Metformin XR was initiated at 750 mg once daily and increased to 1500 mg once daily after 1 week. Concomitantly, Liraglutide was initiated at a subcutaneous dose of 0.6 mg once daily for 1 week, increased to 1.2 mg once daily for the next 1 week, increased to 1.8 mg once daily for the next 1 week, increase to 2.4 mg once daily for the next 1 week, then increase to a maintenance dose of 3.0 mg once daily for up to 12 weeks Other Names: LIME
Active Comparator: MET Metformin XR was initiated with a dose of 750 mg once per day for 1 week and increased to 1500 mg once per day for up to 12 weeks	Drug: Metformin Metformin XR was initiated at 750 mg once daily and increased to 1500 mg once daily after 1 week Other Names: MET

Arm

Intervention/Treatment

Experimental: LIME

Metformin XR was initiated with a dose of 750 mg once per day for 1 week and increased to 1500 mg once per day for up to 12 weeks. Start injection liraglutide 0.6 mg subcutaneously (SC) 1week daily (QD), step up to 1.2 mg SC QD for 1week, to 1.8 mg SC QD for 1 week, 2.4 mg SC QD for 1week, to a final dose of 3.0 mg liraglutide SQ daily for up to 12 weeks.

Drug: Liraglutide + Metformin

Metformin XR was initiated at 750 mg once daily and increased to 1500 mg once daily after 1 week. Concomitantly, Liraglutide was initiated at a subcutaneous dose of 0.6 mg once daily for 1 week, increased to 1.2 mg once daily for the next 1 week, increased to 1.8 mg once daily for the next 1 week, increase to 2.4 mg once daily for the next 1 week, then increase to a maintenance dose of 3.0 mg once daily for up to 12 weeks

Other Names:

LIME

Active Comparator: MET

Metformin XR was initiated with a dose of 750 mg once per day for 1 week and increased to 1500 mg once per day for up to 12 weeks

Drug: Metformin

Metformin XR was initiated at 750 mg once daily and increased to 1500 mg once daily after 1 week

Other Names:

MET

Outcome Measures

Primary Outcome Measures

Absolute Body Weight (BW) [12 weeks of treatment]
Treatment impact on change in body weight after 12 weeks of treatment.
Change in Percent Body Weight [12 weeks of treatment]
Treatment effect on reducing body weight expressed as percent body weight loss from baseline

Secondary Outcome Measures

Body Mass Index (BMI) [12 weeks of treatment]
Treatment effect in reducing body mass
Abdominal Adiposity (Waist Circumference [WC]) [12 weeks of treatment]
Treatment effect on loss of WC (abdominal adiposity) with drug treatment
Waist-to-Hip Ratio [12 weeks of treatment]
Change in central adiposity with treatment as measured by WHR. A reduction in ratio indicates a decrease in truncal fat.
Waist-to Height Ratio [WHtR] [12 weeks of treatment]
Treatment effect on loss of central adiposity as determined by WHt ratio. The lower the ratio indicates less abdominal adiposity.
Total Fat Mass Evaluated by BIA [12 weeks of treatment]
Treatment effect on reduction of fat mass (kg)
Total Body Fat (%) by BIA [12 weeks of treatment]
Treatment effect on reduction of percent body fat by BIA
Visceral Fat Level (VFL) [12 weeks of treatment]
Treatment effect on reduction of visceral fat level by BIA
Total lean body mass [12 weeks of treatment]
Treatment impact on total lean body mass
Glucose OGTT 0 min [12 weeks of treatment]
Treatment effect on fasting glucose prior to an oral glucose tolerance test (OGTT)
Glucose OGTT 120 min [12 weeks of treatment]
Treatment effect on glucose measured at 120 minutes of an oral glucose tolerance test (OGTT)
Insulin OGTT 0 min [12 weeks of treatment]
Treatment effect on fasting insulin prior to an oral glucose tolerance test (OGTT)
Insulin OGTT 120 min [12 weeks of treatment]
Treatment effect on insulin measured at 120 minutes of an oral glucose tolerance test (OGTT)
Fasting Insulin Sensitivity (HOMA-IR) [12 weeks of treatment]
Treatment effect on the HOMA-IR which is an insulin resistance measured derived from fasting blood glucose and insulin . The higher the number the more insulin resistant.
Matsuda Insulin Sensitivity Index Derived From the OGTT (SI OGTT) [12 weeks of treatment]
The SI OGTT is a measure of peripheral insulin sensitivity derived from the insulin and glucoses measured during an OGTT. A increase in SI OGTTindicates greater insulin sensitivity
Total Cholesterol Levels [12 weeks of treatment]
Treatment impact on improving total cholesterol levels
High Density Lipoprotein Cholesterol (HDL-C) [12 weeks of treatment]
Impact of treatment on HDL levels after 12 weeks of treatment
Triglyceride Levels (TRG) [12 weeks of treatment]
Drug effect of TRG levels after treatment
Low Density Lipoprotein Cholesterol (LDL-C) [12 weeks of treatment]
Treatment impact on improving LDL-C after treatment
Systolic Blood Pressure [12 weeks of treatment]
Treatment impact on systolic blood pressure
Diastolic Blood Pressure [12 weeks of treatment]
Treatment impact on reducing diastolic blood pressure
Menstrual Cycle Frequency [12 weeks of treatment]
Drug treatment impact on normalization of cycle frequency (cycle every 28-30 days). All cycle data is expressed as number of menses annualized to one year.
Free Androgen Index (FAI) [12 weeks of treatment]
Drug treatment effect on free androgen levels as calculated as FAI= total testosterone (T) concentrations divided by sex hormone binding globulin (SHBG) levels. A higher score indicates a worse outcome (more androgenic).
Total Testosterone Concentrations (T) [12 weeks of treatment]
Drug treatment effect on total testosterone concentrations
Sex Hormone Binding Globulin (SHBG) [12 weeks of treatment]
Drug treatment effect on SHBG
Adrenal Dehydroepiandrosterone Sulfate (DHEAS) [12 weeks of treatment]
Treatment efficacy in reducing adrenal hyperandrogenism
17(OH)-progesterone [12 weeks of treatment]
Treatment efficacy in reducing adrenal hyperandrogenism
Androstenedione [12 weeks of treatment]
Drug treatment effect on androstenedione
Progesterone [12 weeks of treatment]
Drug treatment effect on progesterone
Luteinizing Hormone (LH) [12 weeks of treatment]
Drug treatment effect on LH
Follicle Stimulating Hormone (FSH) [12 weeks of treatment]
Drug treatment effect on FSH
Ovary Volume [12 weeks of treatment]
Treatment efficacy in reducing ovary volume
Spontaneous Pregnancy Rate [12 months after treatment]
Treatment effect on spontaneous pregnancy rate
Assisted Reproductive Therapy Pregnancy Rate [12 months after treatment]
Treatment effect on Assisted Reproductive Therapy Pregnancy Rate
Cumulative Pregnancy Rate [12 months after treatment]
Treatment effect on Cumulative Pregnancy Rate
Total dosage gonadotropin (GNT) [12 weeks of treatment]
Drug treatment impact on total dosage GNT
No. of retrieved oocytes/patient [12 weeks of treatment]
Drug treatment impact on No. of retrieved oocytes/patient
No. of mature (MII) oocytes/patient [12 weeks of treatment]
Drug treatment impact on No. of mature (MII) oocytes/patient
Fertilization rate [12 weeks of treatment]
Drug treatment impact on fertilization rate
Oocyte degeneration rate [12 weeks of treatment]
Drug treatment impact on oocyte degeneration rate
Immaturity rate [12 weeks of treatment]
Drug treatment impact on immaturity rate
No. of embryos on day 5/patient [12 weeks of treatment]
Drug treatment impact on No. of embryos on day 5/patient
No. of blastocysts/patient [12 weeks of treatment]
Drug treatment impact on No. of blastocysts/patient
Blastulation rate [12 weeks of treatment]
Drug treatment impact on blastulation rate
No. of transferred embryos [12 weeks of treatment]
Drug treatment impact on No. of transferred embryos
Pregnancy rate per cycle [12 weeks of treatment]
Drug treatment impact on pregnancy rate per cycle
Pregnancy rate per Embryo Transfer (ET) [12 weeks of treatment]
Drug treatment impact on pregnancy rate per ET
Implantation rate [12 weeks of treatment]
Drug treatment impact on implantation rate
No. of cancelled fresh Embryo Transfer (ET) because of hyperstimulation risk [12 weeks of treatment]
Drug treatment impact on No. of cancelled fresh Embryo Transfer (ET because of hyperstimulation risk
Cryopreservation [12 weeks of treatment]
Drug treatment impact on cryopreservation
No. of cryopreserved embryos/patient [12 weeks of treatment]
Drug treatment impact on No. of cryopreserved embryos/patient
Ectopic Pregnancy Rate [12 weeks of treatment]
Drug treatment impact on Ectopic Pregnancy Rate
Stillbirth Rate [24 months after treatment]
Drug treatment impact on Stillbirth Rate
Abortion Rate [24 months after treatment]
Drug treatment impact on Abortion Rate
Gestational Diabetes Mellitus Rate [24 months after treatment]
Drug treatment impact on Gestational Diabetes Mellitus Rate
Gestational hypertensive disorder (GHD) Rate [24 months after treatment]
Drug treatment impact on Gestational hypertensive disorder (GHD) Rate
Live Birth Rate [24 months after treatment]
Drug treatment impact on Live Birth Rate
Gestational age at birth [24 months after treatment]
Drug treatment impact on gestational age at birth
Type of Delivery Method [24 months after treatment]
Drug treatment impact on Type of Delivery Method

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Female gender
18-65 years of age
Diagnosis of polycystic ovary syndrome according to the revised Rotterdam criteria (2003)
BMI ≥ 25 kg/m2
Infertility
Agree to participate in the study

Exclusion Criteria:

Type 1 or type 2 diabetes.
History of acute or chronic pancreatitis.
Family or individual history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
Known hypersensitivity or contraindication to the use of GLP-1 receptor agonists.
Used of hormonal drugs, drugs causing clinically significant weight changes and drugs affecting glucose tolerance for at least 8 weeks.
Used a anti-androgen drugs for at least 4 weeks.
History of malignancy requiring chemotherapy.
History of taking antidiabetic drugs other than gestational diabetes or weight-loss drugs discontinued for at least 4 weeks.
History of gastrectomy or device-based intervention to manage obesity
Eating disorders (anorexia or bulimia) or digestive disorders.
Substance abuse (Tobacco or alcohol)
History of major depression or other serious mental disorder.
Inability or refusal to adhere treatment regimens.