Efficacy of Canagliflozin Versus Metformin in Women With Polycystic Ovary Syndrome

Polycystic Ovary Syndrome Clinical Trial

Official title:

Efficacy of Canagliflozin Versus Metformin in Women With Polycystic Ovary Syndrome Combined With Non-Alcoholic Fatty Liver Disease: A Single-center, Open-labeled Prospective Randomized Controlled

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06256289
• Other study ID #: FirstofShanxiMU
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: March 31, 2024
• Est. completion date: April 30, 2025

Study information

• Verified date: February 2024
• Source: The First Affiliated Hospital of Shanxi Medical University
• Contact: Ping Li, MD
• Phone: 15296791363
• Email: lp06010319[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to investigate the use of ultra-high performance liquid chromatography-mass spectrometry for metabolomics and proteomics research in patients with Polycystic Ovary Syndrome (PCOS) and Non-Alcoholic Fatty Liver Disease (NAFLD). The main questions it aims to answer are: - How can this technology help identify specific biomarkers for diagnosing PCOS combined with NAFLD? - What is the role of Canagliflozin in improving the safety and efficacy of treatment for PCOS and NAFLD patients? Participants, who are 50 non-diabetic women with PCOS, will undergo a series of assessments including cardiovascular metabolic indicators, liver NAFLD screening risk stratification, and insulin resistance index. They will be compared with 50 age and BMI-matched healthy controls. The participants will be randomized to receive either CANA/MET (Canagliflozin 100 mg daily plus Metformin 1000 mg twice daily) or MET (Metformin 1000 mg twice daily) for a continuous period of three months. The study will evaluate various parameters including menstrual patterns, anthropometric parameters, gonadal parameters, glucose-lipid homeostasis, liver enzyme indices, non-invasive hepatic fat changes, metabolomics, and NAFLD-related indicators.

Description:

Objective: 1. This study employs the latest ultra-high performance liquid chromatography-mass spectrometry platform for metabolomics and proteomics research to analyze serum samples from patients with Polycystic Ovary Syndrome (PCOS) coexisting with Non-Alcoholic Fatty Liver Disease (NAFLD). The aim is to identify specific biomarkers for the diagnosis of PCOS combined with NAFLD. At the same time, this study explores the pathogenesis and potential new therapeutic targets of PCOS combined with NAFLD at the protein and metabolic levels. 2. The study examines the role of Canagliflozin in improving the safety and efficacy of PCOS and NAFLD patients, providing evidence for the use of SGLT2 inhibitors as an effective treatment for PCOS with NAFLD. Methods: The study enrolled 50 non-diabetic PCOS women and assessed cardiovascular metabolic indicators including liver NAFLD screening risk stratification, insulin resistance index, etc. These were compared with 50 age and BMI-matched healthy controls. Utilizing the latest ultra-high performance liquid chromatography-mass spectrometry platform for metabolomics and proteomics research, a diagnostic model for PCOS coexisting with NAFLD was established and evaluated. The 50 patients were randomized 1:1 to receive Canagliflozin/Metformin or Metformin treatment. The Canagliflozin/Metformin group received Canagliflozin 100 mg once daily plus metformin 1000 mg twice daily, and the metformin group received Metformin 1000 mg twice daily, for a continuous period of three months. The study assessed the safety and efficacy of PCOS and NAFLD patients.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: April 30, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

1. aged 18-45 years old;

2. Body mass index (BMI) more than 18.5 kg / m2;

3. PCOS diagnosis meets Rotterdam 2003 criteria: at least two of the following symptoms:

menstrual menstruation / amenorrhea, hyperandrogenism, and / or biochemical and / or clinical signs of polycystic ovaries.

4. The serum pregnancy test was negative before enrollment.

5. Clinical diagnosis of fatty liver: the ratio of liver to kidney is greater than 1.0. Can understand the procedures and methods of this clinical trial, patients voluntarily participate and sign the informed consent form, willing to comply with the trial protocol requirements and cooperate with the provision of biological samples for testing as planned.

Exclusion Criteria:

1. Less than 18 years old or more than 45 years old;

2. Patients who are pregnant, intend to become pregnant, are breastfeeding or giving birth;

3. Drug history in the past three months included oral contraceptives, sodium-dependent glucose transporters 2 inhibitors, glucagon-like peptide-1 receptor agonists, thiazolidinediones, metformin, corticosteroids or traditional Chinese medicine.

4. Endocrine disorders such as hyperprolactinemia, thyroid dysfunction and diabetes, Cushing's syndrome, 21-hydroxylase deficiency, congenital adrenal hyperplasia, androgen-secreting tumors, cervical, endometrial or breast cancer.

5. Severe liver function (alanine aminase, aspartate aminase> 3 times normal value or elevation of serum bilirubin to more than 3 times the upper limit of normal) or renal impairment (eGFR <60 ml/min/1.73m2).Severe cardiopulmonary, hematopoietic and hematopoietic insufficiency.

6. Current or past (most recent three months) participation in other studies.

7. Viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, hemochromatosis, anti-trypsin defense, Wilson disease, parenteral nutrition history, use of drugs known to cause steatosis (such as valproate, amiodarone or vitamin E) or liver injury caused by drug abuse.Clinical evidence of hepatic decompensation, such as hepatic encephalopathy, ascites, and variceal bleeding.

8. drank more than 20g per day.

9. Women with persistent or recurrent symptomatic urinary tract infections (UTI), gastrointestinal (GI) problems, or any other condition that may compromise patient safety had strong fertility needs within six months of the study period.

10. Allergic or intolerant to the study drug, unable to continue treatment as required by the protocol, unwilling to complete the study or become pregnant.

11. History of mental illness within 2 years, including any suicidal behavior or major depression, depressive symptoms (defined as Patient Health Questionnaire-9 score more than 15), central nervous system disease (including but not limited to any type of seizure or stroke), and no cognitive behavior (including the investigator considers poor adherence to evaluate efficacy or is unlikely to complete the intended course and follow-up).

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Polycystic Ovary Syndrome
• Syndrome

Intervention

Drug:
• Canagliflozin 100mg Tab
Canagliflozin 100mg once daily combined Metformin 1000mg twice daily
• Metformin Hydrochloride
Metformin 1000mg twice daily

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Ping Li,MD

References & Publications (13)

Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF; Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006 Nov;91(11):4237-45. doi: 10.1210/jc.2006-0178. Epub 2006 Aug 29. — View Citation

Cai M, Shao X, Xing F, Zhang Y, Gao X, Zeng Q, Dilimulati D, Qu S, Zhang M. Efficacy of canagliflozin versus metformin in women with polycystic ovary syndrome: A randomized, open-label, noninferiority trial. Diabetes Obes Metab. 2022 Feb;24(2):312-320. doi: 10.1111/dom.14583. Epub 2021 Nov 25. — View Citation

De Sousa SM Dr, Norman RJ Prof. Metabolic syndrome, diet and exercise. Best Pract Res Clin Obstet Gynaecol. 2016 Nov;37:140-151. doi: 10.1016/j.bpobgyn.2016.01.006. Epub 2016 Feb 10. — View Citation

Itani T, Ishihara T. Efficacy of canagliflozin against nonalcoholic fatty liver disease: a prospective cohort study. Obes Sci Pract. 2018 Aug 22;4(5):477-482. doi: 10.1002/osp4.294. eCollection 2018 Oct. — View Citation

Macut D, Tziomalos K, Bozic-Antic I, Bjekic-Macut J, Katsikis I, Papadakis E, Andric Z, Panidis D. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum Reprod. 2016 Jun;31(6):1347-53. doi: 10.1093/humrep/dew076. Epub 2016 Apr 12. — View Citation

Makri E, Tziomalos K. Prevalence, etiology and management of non-alcoholic fatty liver disease in patients with polycystic ovary syndrome. Minerva Endocrinol. 2017 Jun;42(2):122-131. doi: 10.23736/S0391-1977.16.02564-5. Epub 2016 Oct 28. — View Citation

Mantovani A, Byrne CD, Scorletti E, Mantzoros CS, Targher G. Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials. Diabetes Metab. 2020 Nov;46(6):427-441. doi: 10.1016/j.diabet.2019.12.007. Epub 2020 Jan 7. — View Citation

March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010 Feb;25(2):544-51. doi: 10.1093/humrep/dep399. Epub 2009 Nov 12. — View Citation

Meyer C, McGrath BP, Teede HJ. Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. J Clin Endocrinol Metab. 2005 Oct;90(10):5711-6. doi: 10.1210/jc.2005-0011. Epub 2005 Jul 26. — View Citation

Rocha ALL, Faria LC, Guimaraes TCM, Moreira GV, Candido AL, Couto CA, Reis FM. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Invest. 2017 Dec;40(12):1279-1288. doi: 10.1007/s40618-017-0708-9. Epub 2017 Jun 13. — View Citation

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004. — View Citation

Teede HJ, Hutchison SK, Zoungas S. The management of insulin resistance in polycystic ovary syndrome. Trends Endocrinol Metab. 2007 Sep;18(7):273-9. doi: 10.1016/j.tem.2007.08.001. Epub 2007 Aug 16. — View Citation

Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1985 Nov;61(5):946-51. doi: 10.1210/jcem-61-5-946. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	liver steatosis index CAP (Controlled Attenuation Parameter) measured by FibroScan	Changes in the liver steatosis index CAP (Controlled Attenuation Parameter) as measured by transient elastography after 12 weeks of treatment.	at baseline and 12 weeks
Secondary	liver stiffness index (LS) measured by transient elastography, FibroScan	Changes in the liver stiffness index (LS) (measured by transient elastography) from baseline to 12 weeks of treatment.	at baseline and 12 weeks
Secondary	Body Composition, including total body water, muscle mass, fat mass (subcutaneous and visceral), fat-free mass detected using Bioelectrical Impedance Analysis (BIA)	Changes in Body Composition,including total body water, muscle mass, fat mass (subcutaneous and visceral), fat-free mass detected using Bioelectrical Impedance Analysis (BIA) from baseline to 12 weeks of treatment.	at baseline and 12 weeks
Secondary	selection of proteomics markers using liquid chromatography-tandem mass spectrometry (LC-MS/MS) mass spectrometry for analysis	Changes in proteomics markers from baseline to 12 weeks of treatment, involving systematic quantification of metabolites and proteins using techniques LC-MS for analysis, with chemometric methods for data interpretation, revealing metabolic pathways and biomarkers.	at baseline and 12 weeks
Secondary	selection of metabolomics markers by by liquid chromatography-tandem mass spectrometry (LC-MS/MS) mass spectrometryprecision	Changes in metabolomics markers from baseline to 12 weeks of treatment, including phosphatidylglycerol (PG), Bis(monoacylglycero)phosphate BMP, Sulfatide (sulfatide) (SL), Free fatty acids FFA, Plasmalogen ethanolamine (PE-O), Phosphatidylethanolamine (PE), Phosphatidylinositol (PI), Phosphatidylserine (PS), Monosialosyl ganglioside (GM3) plasmalogen (PCO), Phosphatidylcholine (PC), Lysophosphatidic acid (PA), Lysophosphatidylethanolamine (LPE), Lysophosphatidic acid (LPA), Lysophosphatidylinositol (LPI), Lysophosphatidylserine (LPS), Ceramide(Cer), Lysophosphatidylcholine (LPC), Plasmalogen choline (PCO), Phosphatidylcholine (PC),Sphingomyelin (SM),Sphingosine (Sph),Ceramide(Cer),Hexosylceramide (HexCer), Lactosylceramide (LacCer), Trihexosylceramide (Gb3), Acylcarnitine acylcarnitine, Monoacylglycerol (MAG), Diglyceride (DAG), Triglyceride (TAG), Cholesteryl ester (CE)	at baseline and 12 weeks
Secondary	sex hormones by liquid chromatography-tandem mass spectrometry (LC-MS/MS) mass spectrometry	Changes in sex hormones by liquid chromatography-tandem mass spectrometry (LC-MS/MS) mass spectrometry from baseline to 12 weeks of treatment, including estriol, hydrocortisone, cortisone, corticosterone, aldosterone, testosterone, 17a-Hydroxyprogesterone, 21-hydroxyprogesterone, DHEA,Estrone, androstenedione, dihydrotestosterone, estradiol,progesterone, pregnenolone, androsterone, epitestosterone, estrone sulfate, estradiol sulfate, epitestosterone sulfate, testosterone sulfate, dhea Sulfate, pregnenolone Monosulfate	at baseline and after 12 weeks
Secondary	Gut Microbiota diversity sequencing by 16s rRNA Amplicon Sequencing Analysis	Gut microbiome testing equipment includes sterile samplers for sample collection, DNA extraction kits, PCR machines for amplification, high-throughput sequencing platforms for analysis, bioinformatics software for data processing, and AI systems for advanced analysis. These tools enable precise and efficient assessment of gut microbial composition, aiding in understanding its impact on disease and informing clinical treatments.	at baseline and 12 weeks