Blood Lipopolysaccharide (LPS) Rifaximin Study

Dietary Fat, Lipoprotein and Lipopolysaccharide: Role in Insulin Resistance

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.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome; Insulin Resistance; Obese
• Intervention / Treatment: Drug: Rifaximin SSD; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Center for Clinical and Translational Science

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Obese
• Insulin resistance or metabolic syndrome
• Body Mass Index between 27 and 45
• Waist circumference >40" (M) or >35" (F)
• Impaired glucose tolerance (IGT)
• Normal glucose tolerance (NGT) with at least three features of MetS
• A1C <6.5
• Blood pressure 130/85

Exclusion Criteria:

• Pregnant or breastfeeding
• Recent or unstable cardiovascular disease
• cancer,
• Renal insufficiency (GFR<30)
• Steroid use
• chronic inflammatory conditions
• Anticoagulant use
• Lipodystrophy
• Irritable Bowel Syndrome
• Allergy to local anesthetic
• Lactose intolerance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 Rifaximin SSD; Subjects randomized to this arm of the study will receive 80 mg per day Rifaximin SSD	Drug: Rifaximin SSD; Study Drug dosing will be 80 mg SSD once daily
Placebo Comparator: Arm 2 Placebo; Placebo	Other: Placebo; 80 mg placebo once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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).

Other Outcome Measures

Outcome Measure	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).	Up to 12 weeks

Collaborators and Investigators

• Sponsor: Philip Kern
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Phililp Kern, MD, University of Kentucky

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): May 31, 2019
• Study Completion (Actual): May 31, 2019

Study Registration Dates

• First Submitted: April 23, 2014
• First Submitted That Met QC Criteria: April 25, 2014
• First Posted (Estimate): April 28, 2014

Study Record Updates

• Last Update Posted (Actual): August 21, 2019
• Last Update Submitted That Met QC Criteria: August 6, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: insulin resistance; metabolic syndrome; obese
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Metabolic Syndrome; Insulin Resistance; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Rifaximin
• Other Study ID Numbers: 14-0136-F1V; UL1TR000117 (U.S. NIH Grant/Contract); 1R21DK100258-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No