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

June 11, 2013
April 1, 2014
September 2013
July 2018   (final data collection date for primary outcome measure)
  • 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.
Same as current
Complete list of historical versions of study NCT01877551 on ClinicalTrials.gov Archive Site
  • 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.
Same as current
Not Provided
Not Provided
 
Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance
Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance".

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.

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.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
  • HIV Related Insulin Resistance
  • Protease Inhibitor Related Insulin Resistance
  • Endoplasmic Reticulum Stress
Drug: Tauroursodeoxycholic acid
The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.
Other Names:
  • taurolite
  • tudcabil
  • Active Comparator: tauroursodeoxycholic acid
    This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days.
    Intervention: Drug: Tauroursodeoxycholic acid
  • 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.
Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010 Aug;59(8):1899-905. doi: 10.2337/db10-0308. Epub 2010 Jun 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
48
July 2018
July 2018   (final data collection date for primary outcome measure)

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
Both
18 Years to 55 Years
No
Contact: Courtney Tiemann 314-362-8250 ctiemann@dom.wustl.edu
United States
 
NCT01877551
R01DK096982
Yes
Dominic Reeds, Washington University School of Medicine
Washington University School of Medicine
National Institutes of Health (NIH)
Principal Investigator: Dominic N Reeds, M.D. Washington University School of Medicine
Washington University School of Medicine
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP