Efficacy of Ursodeoxycholic Acid (UDCA) in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of ursodeoxycholic acid (UDCA) compared to placebo on biomarkers of oxidative stress, inflammation, and endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM) who are treated with metformin but did not meet the target HbA1C < 7%.

Detailed Description
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This is a Phase 3, randomized, double-blind, placebo-controlled, evaluation of the efficacy of UDCA on oxidative stress, inflammation, and endothelial dysfunction in combination with metformin after 8 weeks in patients with T2DM who did not meet HbA1C < 7%. Study site: a single study center (Primary Health Care Institution in Banja Luka, as recruiter center) including Center for Biomedical Research, Faculty of Medicine University of Banja Luka, as reference coordinator and research center. Sample size : 60 patients, randomized in a 1:1 allocation ratio. Objectives To investigate the effects of UDCA added to metformin on glycemia, HbA1C, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), lipoproteins, and body mass index. To investigate whether UDCA has an impact on lipid peroxidation index, nitric oxide metabolites, hydrogen peroxide (H2O2), superoxide anion radical (O2-), and total antioxidant capacity. To investigate whether UDCA has an impact on the dynamic of inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high sensitive CRP (hsCRP). To investigate whether UDCA has an impact on von Willebrand factor (vWF), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Adhesion Molecule 1 (VCAM-1), fibrinogen, homocysteine, folic acid, and vitamin D levels. Treatments arms: UDCA (1500 mg/day) + Metformin (maximum tolerated daily dose) UDCA placebo + Metformin (maximum tolerated daily dose) Treatment duration : 8 weeks Assessment - clinical and laboratory sampling: Informed consent and Screening - 7 days prior to randomization Study visits (V): V1 - Randomization and Enrollment (Baseline) V2 - 4 weeks after Baseline V3 - 8 weeks after Baseline. No interim analysis is planned. The analysis will be performed at the end of the study after data review and freezing of the database according to the intent to treat principle.

Official Title
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Randomized, Double-blind, Placebo-controlled Study of Ursodeoxycholic Acid (UDCA) Therapy on Biomarkers of Oxidative Stress, Inflammatory and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: UDCA (Ursodeoxycholic acid)
* Drug: Placebo
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Type 2 Diabetes mellitus verified at least 1 year prior to the study enrollment Treatment with metformin at a maximally tolerated dose (up to 2000 mg/day) in patients with an incomplete biochemical response showing HbA1c ≥ 6,5%. Body mass index (BMI) corresponding to overweight and obesity (≥ 25 kg/m2) Exclusion Criteria: Insulin treatment within 12 weeks prior to the study enrollment Treatment with Glucagon-like peptide 1 (GLP-1) analogs within 12 weeks prior to the study enrollment Systemic administration of glucocorticoids continuously for 10 days within 12 weeks prior to the study enrollment Prior and concomitant immunosuppressants treatment (other than glucocorticoids) History and current serious psychiatric disorders that could affect treatment adherence Co-existing uncontrolled cardiovascular disease (i.e arterial hypertension), respiratory insufficiency, acute or chronic renal failure (creatinine clearance < 60 ml/min), and liver diseases such as acute or chronic viral hepatitis, alcoholic liver disease, choledocholithiasis, autoimmune hepatitis, non-alcoholic fatty liver disease, hemochromatosis, and liver failure. Known history of cholecystitis Pregnant or lactating women Known hypersensitivity to UDCA, or other bile acids History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening) Participation in any other interventional study

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UDCA + metformin<br>UDCA in addition to Metformin Treatment All subjects will be treated with UDCA 1500 mg/day, and Metformin, up to 2000 mg/day, by oral administration, respectively, for 8 weeks. | Drug: UDCA (Ursodeoxycholic acid)<br>* UDCA is administered orally in addition to metformin therapy in the recommended doses in patients with type 2 diabetes mellitus.<br>* Other names: Bilexin;Drug: Metformin<br>* Metformin therapy is administered in the recommended dose in patients with type 2 diabetes mellitus.<br>* Other names: Glucophage;|
| Placebo Comparator: Placebo + metformin<br>Placebo of UDCA in addition to Metformin Treatment All subjects will be treated with a Placebo of UDCA, and Metformin, up to 2000 mg/day, by oral administration, respectively, for 8 weeks. | Drug: Placebo<br>* Placebo is administered orally in addition to metformin therapy in the recommended doses in patients with type 2 diabetes mellitus.<br>Drug: Metformin<br>* Metformin therapy is administered in the recommended dose in patients with type 2 diabetes mellitus.<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxidative stress biomarkers levels: superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) | ELISA assay (same units) | From Baseline and after 8 weeks | 
| Change in pro-inflammatory markers concentrations: tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) | ELISA assay (same units) | From Baseline and after 8 weeks | 
| Change in serum levels of homocystein | Detection by fluorescence polarization immunoassay | From Baseline and after 8 weeks | 
| Change in serum levels of von Willebrand factor (vWF), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Adhesion Molecule 1 (VCAM-1), and fibrinogen | ELISA assay (same units) | From Baseline and after 8 weeks | 
| Change in serum levels of Vitamin D and Folic acid | Microparticle enzyme immunoassay (same units) | From Baseline and after 8 weeks | 
| Change in Total antioxidant capacity (TAC) level | Results expressed in units μg/ml Trolox equivalents | From Baseline and after 8 weeks | 
| Change in inflammation marker level: high sensitivity CRP | Turbid metric test | From Baseline and after 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Haemoglobin A1C (HbA1C) | HbA1C level will be expressed in % | From Baseline and after 8 weeks | 
| Change in Total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides | Clinical biochemistry (colorimetric) tests, and results will be expressed in mmol/L (same units) | From Baseline and after 8 weeks | 
| Change in body weight | Weight (kg) | From Baseline and after 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Diabetes Mellitus, Type 2, UDCA