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| ID | Type | Description | Link |
|---|---|---|---|
| UL1TR000117 | U.S. NIH Grant/Contract | View source | |
| 1R21DK100258-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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Metabolic syndrome is a condition involving elevated levels of fat in the blood, a tendency towards diabetes, hypertension, and too much fat around the abdomen (an increased waistline). Individuals with metabolic syndrome often have impaired glucose tolerance, which is a condition where blood sugar is normal when fasting (before eating), but is too high after drinking a sugary drink. This is due to an abnormality in the body's sensitivity to insulin (insulin resistance), which is due in part to an inability of the muscle to take up glucose.
People with metabolic syndrome have inflammation in their fat tissue and in their blood stream, and the changes in the level of inflammatory chemicals produced by cells in your fat tissues will be studied. One possible source of the inflammation may be the bacteria in the intestine. When individuals eat fatty foods, some of the bacterial products become attached to the fat in their blood and then get directed to fat tissue. The investigators wish to determine whether individuals have an excessive amount of inflammation in their fat tissues, and whether this inflammation comes from the bacteria in their intestines. To determine this, the investigators wish to treat individuals with an antibiotic that reduces the bacteria in their intestines and in their blood, and determine whether this reduces their overall level of inflammation.
This is a randomized, placebo-controlled proof of concept study that will examine the investigational drug Rifaximin Soluble Solid Dispersion (SSD) ability to reduce gut microbiota and thereby reduce adipose inflammation and improve insulin resistance.
Each subject enrolled will undergo a fat tolerance test with a high-fat meal, an oral glucose tolerance test, a fat biopsy, and a euglycemic clamp. Following their successful completion of those procedures subjects will be randomized to study treatment. That treatment will involve receiving the investigational drug,80 mg per day of rifaximin-soluble solid dispersion (SDD), or placebo for 12 weeks. All procedures will be performed on the Clinical Services Core of the CCTS. The initial visit will involve informed consent, and routine labs (comprehensive metabolic panel, lipid panel, TSH, CBC with platelets). These routine labs are for safety purposes and to rule out exclusionary disorders. A stool sample will also be collected and frozen for possible future analysis of bacterial microflora.
Subjects will be asked to allow the principal investigator to bank blood and tissue samples collected during this study that are not used for other study-related tests. No additional blood or tissue samples will be collected. If the subject agrees to the banking of their blood and tissue samples they will be stored in the Principal Investigator's laboratory at the University of Kentucky for an indefinite period of time or until they are used up. Stored samples will be used for future research testing to learn about how to prevent, detect, or treat insulin resistance, metabolic syndrome, diabetes or other health problems.
Each subject will undergo total body composition testing using a total body dual-energy x-ray absorptiometry (DXA) scan. The DXA scan measures the subject's bond density and body fat.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 Rifaximin SSD | Experimental | Subjects randomized to this arm of the study will receive 80 mg per day Rifaximin SSD |
|
| Arm 2 Placebo | Placebo Comparator | Placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifaximin SSD | Drug | Study Drug dosing will be 80 mg SSD once daily |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Circulating LPS | Plasma lipopolysaccharide (LPS) will be measured both in the fasting state and after a lipid-rich meal in obese subjects (Pre-Treatment: 0, 4 and 8 hr timepoints). The subjects will then be treated with the antibiotic rifaximin for 12 weeks to substantially reduce gut bacteria. LPS measurements at fasting and after a lipid-rich meal will be repeated (Post-Treatment: 0, 4 and 8 hr timepoints). The lipid tolerance tests before and after treatment with rifaximin will be assessed to determine whether there is a reduction in post-prandial LPS. LPS measurements were obtained using a modified LAL Assay. | 0, 4 and 8 hours at Baseline, and 0, 4 and 8 hours after 12 weeks of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Tissue Inflammation | Subjects will undergo a baseline fat biopsy (pre-treatment). They will then be treated with rifaximin for 12 weeks and biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation. Data are reported as normalized mRNA expression levels (arbitrary units) of TNFalpha. | Pre-Treatment (baseline) and Post-Treatment (12 weeks after baseline). |
| Measure | Description | Time Frame |
|---|---|---|
| Improved Insulin Sensitivity | We hypothesize that a change in the microbial flora with rifaximin will alter plasma LPS, adipose tissue inflammation, and insulin sensitivity. Therefore, we will examine, before and after rifaximin/placebo treatment: 1. LPS associated with lipoproteins, 2. insulin sensitivity and hepatic glucose production, 3. plasma inflammatory markers (TNFα, IL-6, MCP-1, adiponectin), 4. adipose inflammatory markers (CD68, MCP1, TNFα, PAI1, IL12, IL10, TLR4 and others). |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Phililp Kern, MD | University of Kentucky | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Kentucky Center for Clinical and Translational Science | Lexington | Kentucky | 40536 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1 Rifaximin SSD | Subjects randomized to this arm of the study will receive 80 mg per day Rifaximin SSD Rifaximin SSD: Study Drug dosing will be 80 mg SSD once daily |
| FG001 | Arm 2 Placebo | Placebo Placebo: 80 mg placebo once daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm 1 Rifaximin SSD | Subjects randomized to this arm of the study will receive 80 mg per day Rifaximin SSD Rifaximin SSD: Study Drug dosing will be 80 mg SSD once daily |
| BG001 | Arm 2 Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Circulating LPS | Plasma lipopolysaccharide (LPS) will be measured both in the fasting state and after a lipid-rich meal in obese subjects (Pre-Treatment: 0, 4 and 8 hr timepoints). The subjects will then be treated with the antibiotic rifaximin for 12 weeks to substantially reduce gut bacteria. LPS measurements at fasting and after a lipid-rich meal will be repeated (Post-Treatment: 0, 4 and 8 hr timepoints). The lipid tolerance tests before and after treatment with rifaximin will be assessed to determine whether there is a reduction in post-prandial LPS. LPS measurements were obtained using a modified LAL Assay. | Posted | Mean | Standard Error | EU/mL | 0, 4 and 8 hours at Baseline, and 0, 4 and 8 hours after 12 weeks of treatment |
|
24 months
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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 | Arm 1 Rifaximin SSD | Subjects randomized to this arm of the study will receive 80 mg per day Rifaximin SSD Rifaximin SSD: Study Drug dosing will be 80 mg SSD once daily |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Philip Kern | University of Kentucky | 859-323-2232 | pake222@uky.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 | May 17, 2016 | Jun 11, 2019 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 17, 2016 | Jun 11, 2019 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| D007333 | Insulin Resistance |
| D024821 | Metabolic Syndrome |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| Placebo |
| Other |
80 mg placebo once daily |
|
| Up to 12 weeks |
Placebo
Placebo: 80 mg placebo once daily
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
|
| OG001 | Arm 2 Placebo | Placebo Placebo: 80 mg placebo once daily |
|
|
|
| Secondary | Tissue Inflammation | Subjects will undergo a baseline fat biopsy (pre-treatment). They will then be treated with rifaximin for 12 weeks and biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation. Data are reported as normalized mRNA expression levels (arbitrary units) of TNFalpha. | Posted | Mean | Standard Error | arbitrary units | Pre-Treatment (baseline) and Post-Treatment (12 weeks after baseline). |
|
|
|
|
| Other Pre-specified | Improved Insulin Sensitivity | We hypothesize that a change in the microbial flora with rifaximin will alter plasma LPS, adipose tissue inflammation, and insulin sensitivity. Therefore, we will examine, before and after rifaximin/placebo treatment: 1. LPS associated with lipoproteins, 2. insulin sensitivity and hepatic glucose production, 3. plasma inflammatory markers (TNFα, IL-6, MCP-1, adiponectin), 4. adipose inflammatory markers (CD68, MCP1, TNFα, PAI1, IL12, IL10, TLR4 and others). | Not Posted | Up to 12 weeks | Participants |
| 0 |
| 6 |
| 0 |
| 6 |
| 0 |
| 6 |
| EG001 | Arm 2 Placebo | Placebo Placebo: 80 mg placebo once daily | 0 | 6 | 0 | 6 | 0 | 6 |
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |