Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Washington University School of Medicine
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Dominic Reeds, Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01877551
First received: June 11, 2013
Last updated: April 1, 2014
Last verified: April 2014
  Purpose

Rates of cardiovascular disease and diabetes are more than 2-fold greater in HIV infected people than the general population. Protease inhibitor booster antiretroviral therapy (PI-ART) which is used by ~50% of HIV infected people in the USA is an established risk factor for diabetes. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile salt, improves insulin sensitivity in HIV uninfected subjects, although the mechanisms for these benefits are unclear. This study will explore the hypothesis that TUDCA will improve insulin action in people with HIV who are receiving PI-ART. Further, this project will clarify the molecular mechanisms responsible for these improvements potentially benefiting society, irrespective of HIV status.


Condition Intervention
HIV Related Insulin Resistance
Protease Inhibitor Related Insulin Resistance
Endoplasmic Reticulum Stress
Drug: Tauroursodeoxycholic acid

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance".

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Insulin sensitivity [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    We will examine the ability of insulin to cause muscle to take up insulin. Each subject will receive intravenous insulin for 6 hours to see how much sugar needs to be given intravenously to keep the blood sugar normal, a measure called glucose uptake. We will compare glucose uptake during insulin infusion before and after 30 days of treatment with drug or placebo.

  • Endoplasmic reticulum stress [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    It is believed that protease inhibitors cause stress to the part of the fat cell that folds proteins; referred to as endoplasmic reticulum stress. When endoplasmic reticulum stress increases, and changes in protein levels in fat cells occur. We will measure markers of endoplasmic reticulum stress in fat samples taken from subjects before and after 30 days of treatment with TUDCA or placebo.

  • Thyroid hormone deiodinase expression in muscle [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    We will measure changes in proteins that metabolize thyroid hormone in muscle at baseline and after 30 days of treatment with TUDCA or placebo to determine if this is one of the mechanisms by which TUDCA improves how well insulin works in the body.


Secondary Outcome Measures:
  • body composition [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo.

  • liver fat [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    we will use MRI to measure the amount of fat in each subject's liver before and after 30 days of treatment. This will allow us to determine if the drug reduces liver fat.

  • liver function tests [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug.


Estimated Enrollment: 48
Study Start Date: September 2013
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: tauroursodeoxycholic acid
This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days.
Drug: Tauroursodeoxycholic acid
The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.
Other Names:
  • taurolite
  • tudcabil
Placebo Comparator: placebo
This group will receive a placebo table that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. This pill will be taken once daily for 30 days.

Detailed Description:

The purpose of this study is to determine if, and through which mechanisms, tauroursodeoxycholic acid improves insulin sensitivity in subjects with protease-inhibitor associated insulin resistance.

The investigators will perform body composition analysis by using a DEXA machine, liver fat measurement by using an MRI, and hyperinsulinemic euglycemic clamp procedures in 48 HIV infected, insulin-resistant/prediabetic subjects before and after 30 days of treatment with tauroursodeoxycholic acid or matching placebo. Biopsies of adipose tissue and skeletal muscle will be taken during fasting conditions and during insulin infusion, before and after treatment to measure markers of endoplasmic reticulum stress and thyroid hormone deiodinase.

Outcome measures:

The primary outcome measures will be change in glucose clearance during insulin infusion, change in markers of endoplasmic reticulum stress and change in content of D2 in muscle.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV+
  • receiving protease inhibitor containing antiretroviral therapy for >6 months
  • Undetectable viral load and CD4 cell count >350 cells/mm3 for >6 months
  • insulin resistant

    1. impaired fasting glucose (fasting blood glucose>100mg/dl)
    2. impaired glucose tolerance (blood glucose >140mg/dl at 2 hours during oral glucose tolerance testing.
  • abstained from medications that affect glucose (e.g. prednisone, growth hormone)
  • stable medications for >3 months

Exclusion Criteria:

  • weight loss of >5% of body weight in prior 6 months
  • active gastrointestinal disease (gallstones, pancreatitis, hepatitis, diarrhea)
  • use of antidiabetic medications
  • cardiovascular disease (uncontrolled hypertension, heart attack, heart failure, prior endocarditis)
  • history of or active substance abuse
  • blood clotting disorder or taking medications that affect blood clotting (e.g. coumadin, warfarin)
  • pregnant, planning to become pregnant or lactating
  • unable to give informed consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01877551

Contacts
Contact: Courtney Tiemann 314-362-8250 ctiemann@dom.wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Principal Investigator: Dominic N. Reeds, M.D.         
Sub-Investigator: Rachel Presti, M.D., Ph.D.         
Sub-Investigator: Brian Finck, Ph.D.         
Sub-Investigator: Zhouji Chen, Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Dominic N Reeds, M.D. Washington University School of Medicine
  More Information

Additional Information:
Publications:
Responsible Party: Dominic Reeds, Principal Investigator, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01877551     History of Changes
Other Study ID Numbers: R01DK096982
Study First Received: June 11, 2013
Last Updated: April 1, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
HIV
Protease inhibitor
insulin resistance
Tauroursodeoxycholic acid

Additional relevant MeSH terms:
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Protease Inhibitors
HIV Protease Inhibitors
Tauroursodeoxycholic acid
Taurochenodeoxycholic Acid
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Cholagogues and Choleretics
Gastrointestinal Agents

ClinicalTrials.gov processed this record on July 31, 2014