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Normally, the hormone insulin works to help keep blood sugar normal. However, as a person gains weight, insulin does not work as well and blood sugar tends to be a little higher than normal. This is called "insulin resistance".
Two investigational drugs (not approved by the Food and Drug Administration) for the treatment of high lipid levels or insulin resistance are being examined in this study: one drug is called tauroursodeoxycholic acid (TUDCA), the other is called sodium phenylbutyrate (PBA). This study is designed to test if TUDCA and/or PBA is effective in people who are obese with insulin resistance and high lipids. We hypothesize that pharmacologically-induced decreases in ER stress will improve insulin action and hepatic lipid metabolism in obese subjects.
A 4-week randomized, controlled trial will be conducted to evaluate the following specific aims in obese subjects:
Determine the effect of treatment with TUDCA or PBA on:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Subjects will be given a placebo rather than tauroursodeoxycholic acid. |
|
| tauroursodeoxycholic acid | Experimental | Subjects will receive tauroursodeoxycholic acid for four weeks. |
|
| PBA | Experimental | Subjects will receive sodium phenylbutyrate for four weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| tauroursodeoxycholic acid | Drug | 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Body Composition | Fat mass (%) | Baseline and four weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Insulin Sensitivity in the Liver | HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity. | Baseline and four weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Samuel Klein, MD | 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 | Result | 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. |
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Screening tests to determine eligibility included: medical hx & PE, blood tests, resting ECG, OGTT, MRI/MRS/MRE of abdomen/liver, and DEXA scan. Two baseline metabolism studies prior to study drug intervention. There were 67 screen fails, 4 subjects withdrew consent before beginning study intervention.
Participants will be recruited by reviewing the VFH database pf research subjects and by local postings. Potential subjects will be contacted by telephone for an initial pre-screen, at which time the study is discussed and a brief medical history and concomitant medication list is obtained. ICF will be sent to interested subjects.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks |
| FG001 | Tauroursodeoxycholic Acid | Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner. |
| FG002 | Sodium Phenylbutyrate | Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks |
| BG001 | Tauroursodeoxycholic Acid | Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Body Composition | Fat mass (%) | Posted | Mean | Standard Deviation | percentage | Baseline and four weeks |
|
Adverse event data was collected from the time participants signed the informed consent until 30 days after study completion.
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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 | Placebo | Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Samuel Klein, M.D. | Washington University School of Medicine in Saint Louis, Missouri | 314-362-8708 | sklein@wustl.edu |
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| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| D003920 | Diabetes Mellitus |
| D009765 | Obesity |
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C031655 | ursodoxicoltaurine |
| C075773 | 4-phenylbutyric acid |
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| placebo | Other | 7 pills daily for 4 weeks |
|
| sodium phenylbutyrate | Drug | 20g/day for four weeks. |
|
|
| VLDL-triglyceride (TG) Concentration | Baseline and four weeks |
| BG002 | Sodium Phenylbutyrate | Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Subjects will receive sodium phenylbutyrate for four weeks.
sodium phenylbutyrate: 20g/day for four weeks.
|
|
| Secondary | Insulin Sensitivity in the Liver | HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity. | Posted | Mean | Standard Deviation | 100/ (µmol/min * uIU/mL) | Baseline and four weeks |
|
|
|
| Secondary | VLDL-triglyceride (TG) Concentration | Posted | Mean | Standard Deviation | mmol/l | Baseline and four weeks |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Tauroursodeoxycholic Acid | Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner. | 0 | 10 | 0 | 10 | 0 | 10 |
| EG002 | Sodium Phenylbutyrate | Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks. | 0 | 6 | 0 | 6 | 0 | 6 |
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| D004700 | Endocrine System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
|
|