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

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

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%.

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: UDCA (Ursodeoxycholic acid); Drug: Metformin; Drug: Placebo

Detailed Description

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

1. 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.
2. 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.
3. 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).
4. 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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Biljana Lakic, MD; Phone Number: 101 +38765951255; Email: biljanakd@yahoo.com
• Study Contact Backup: Name: Anastasija Stokanovic, MD; Phone Number: 101 +38765825925; Email: anastasijasto@gmail.com

Study Locations

• Bosnia and Herzegovina
  • Republic Of Srpska
    • Banja Luka, Republic Of Srpska, Bosnia and Herzegovina, 78000
      • Public Health Institution Dom zdravlja Banja Luka
      • Contact: Biljana Lakic, MD; Phone Number: +387 951255; Email: biljanakd@yahoo.com
      • Principal Investigator: Biljana Lakic, MD
      • Sub-Investigator: Anastasija Stokanovic, MD
      • Principal Investigator: Ranko Skrbic, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UDCA + metformin; 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); UDCA is administered orally in addition to metformin therapy in the recommended doses in patients with type 2 diabetes mellitus.; Other Names: Ursofalk; Bilexin; Drug: Metformin; Metformin therapy is administered in the recommended dose in patients with type 2 diabetes mellitus.; Other Names: Glucophage; Siofor
Placebo Comparator: Placebo + metformin; 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: Metformin; Metformin therapy is administered in the recommended dose in patients with type 2 diabetes mellitus.; Other Names: Glucophage; Siofor; Drug: Placebo; Placebo is administered orally in addition to metformin therapy in the recommended doses in patients with type 2 diabetes mellitus.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Banja Luka
• Investigators: Study Chair: Ranko Škrbić, Professor, University of Banja Luka

Publications and helpful links

Helpful Links

• Bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment.

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2022
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: May 30, 2022
• First Submitted That Met QC Criteria: June 8, 2022
• First Posted (Actual): June 13, 2022

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Metformin; Diabetes Mellitus, Type 2; UDCA
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Cholagogues and Choleretics; Metformin; Ursodeoxycholic Acid
• Other Study ID Numbers: UDCA01T2DM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No