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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK096982 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| tauroursodeoxycholic acid | Active Comparator | This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. |
|
| placebo | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tauroursodeoxycholic acid | Drug | The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Glucose Uptake | 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 measured as the amount of 20% dextrose that is needed to keep the blood sugar at ~100mg/dl during insulin infusion before and after 30 days of treatment with drug or placebo. | Glucose uptake is measured at baseline and 30 days after study intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Body Composition | We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo. | Pre-Treatment and Post 30 day-Treatment |
| Liver Fat | We will use MRI to measure the relative (%) 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. This is calculated by subtracting the amount of fat in the liver at the beginning of the study from the amount of fat in the liver after 30 days of treatment. Subjects who have claustrophobia or are unable to undergo MRI will not have this measure performed. Due to these reasons liver MRS was only performed in 10 patients in the tauroursodeoxycholic acid group and 9 subjects in the placebo group |
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Inclusion Criteria:
HIV+
receiving protease inhibitor containing antiretroviral therapy for >6 months
Undetectable viral load
insulin resistant
abstained from medications that affect glucose (e.g. prednisone, growth hormone)
stable medications for >3 months
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dominic N. Reeds, M.D. | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20522594 | Background | 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. |
| Label | URL |
|---|---|
| Washington University AIDS Clinical Trials Unit | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Tauroursodeoxycholic Acid | This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days. |
| FG001 | 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. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Tauroursodeoxycholic Acid | This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | one subject in the control group developed influenza during the study and was excluded from final analysis |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Glucose Uptake | 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 measured as the amount of 20% dextrose that is needed to keep the blood sugar at ~100mg/dl during insulin infusion before and after 30 days of treatment with drug or placebo. | Posted | Mean | Standard Error | change in glucose infusion rate (ml/hr) | Glucose uptake is measured at baseline and 30 days after study intervention |
|
Adverse event data were taken over a 6 week period after initiation of drug or placebo
Subjects were followed for 6 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tauroursodeoxycholic Acid | This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| influenza | Infections and infestations | Non-systematic Assessment | patient contracted influenza during study |
We were unable to recruit our targeted enrollment reducing the power of the study
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Dominic Reeds | Washington University School of Medicine | 3143628430 | dreeds@wustl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 6, 2019 | Jul 15, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C031655 | ursodoxicoltaurine |
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| Placebo tablet | Other | 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. |
|
| Pre-Treatment and Post 30 day-Treatment |
| Liver Function Tests | We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug. | Pre-Treatment and Post 30 day-Treatment |
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. 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. |
| BG002 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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. 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. |
|
|
| Secondary | Body Composition | We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo. | Posted | Mean | Standard Error | percentage of body fat | Pre-Treatment and Post 30 day-Treatment |
|
|
|
| Secondary | Liver Fat | We will use MRI to measure the relative (%) 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. This is calculated by subtracting the amount of fat in the liver at the beginning of the study from the amount of fat in the liver after 30 days of treatment. Subjects who have claustrophobia or are unable to undergo MRI will not have this measure performed. Due to these reasons liver MRS was only performed in 10 patients in the tauroursodeoxycholic acid group and 9 subjects in the placebo group | Posted | Mean | Standard Error | Change in Percent liver fat | Pre-Treatment and Post 30 day-Treatment |
|
|
|
| Secondary | Liver Function Tests | We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug. | Posted | Mean | Standard Error | ALT (IU/ml) | Pre-Treatment and Post 30 day-Treatment |
|
|
|
| 0 |
| 13 |
| 0 |
| 13 |
| 1 |
| 13 |
| EG001 | 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. 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. | 0 | 14 | 0 | 14 | 0 | 14 |
|
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