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Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

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ClinicalTrials.gov Identifier: NCT01877551
Recruitment Status : Active, not recruiting
First Posted : June 13, 2013
Last Update Posted : May 9, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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 or disease Intervention/treatment Phase
HIV Related Insulin Resistance Protease Inhibitor Related Insulin Resistance Endoplasmic Reticulum Stress Drug: Tauroursodeoxycholic acid Other: Placebo tablet Not Applicable

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance
Study Start Date : September 2013
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
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 tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Other: Placebo tablet
The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.




Primary Outcome Measures :
  1. Insulin sensitivity [ Time Frame: 30 days ]
    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.

  2. Endoplasmic reticulum stress [ Time Frame: 30 days ]
    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.

  3. Thyroid hormone deiodinase expression in muscle [ Time Frame: 30 days ]
    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 :
  1. body composition [ Time Frame: 30 days ]
    We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo.

  2. liver fat [ Time Frame: 30 days ]
    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.

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



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV+
  • receiving protease inhibitor containing antiretroviral therapy for >6 months
  • Undetectable viral load
  • 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 anti-diabetic 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01877551


Locations
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Dominic N Reeds, M.D. Washington University School of Medicine

Additional Information:
Publications:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01877551     History of Changes
Other Study ID Numbers: 201306105
R01DK096982 ( U.S. NIH Grant/Contract )
First Posted: June 13, 2013    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2018

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
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cholagogues and Choleretics
Gastrointestinal Agents