The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects

Study Overview
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Brief Summary
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To determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) will reduce inflammation and improve glucose metabolism in insulin resistant (obese and T2DM) subjects.

Detailed Description
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E5564 = Eritoran

Official Title
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Phase 2 Study of The Role of Pharmacologic Inhibition of TLR4 With E5564 on Glucose Metabolism in Insulin Resistant Subjects.

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Drug: Eritoran
* Drug: D5W


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects capable of giving informed consent. lean (BMI <26 kg/m2) with normal glucose-tolerant subjects without a family history of type 2 DM obese (BMI 30-37 kg/m2) with normal glucose-tolerant subjects Type 2 DM subjects base on ADA criteria, who have HbA1c <8.5% and control with diet or sulfonylureas. Both genders. (50% males) Age = 18-65 years. Older subjects are excluded because aging is a pro-inflammatory state. All ethnic groups Premenopausal women in the follicular phase, non-lactating, and with a negative pregnancy test. Postmenopausal women on stable dose of or not exposed to hormone replacement for >=6 months. Lab: Hematocrit >=34%, serum creatinine <=1.4 mg/dL, normal electrolytes, urinalysis, and coagulation tests. Liver function tests up to 2x normal range. Stable body weight (+/-1%) for >=3 months. One or less sessions of strenuous exercise/wk for last 6 months. Exclusion Criteria: Current treatment with drugs known to affect glucose and lipid homeostasis. Subjects on a stable dose of statin (>3 months) are eligible. Non-steroidal anti-inflammatory drugs or systemic steroid use for more than 1 week within 3 months. Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsies. History of heart disease (New York Heart Classification greater than class II; more than non-specific ST-T wave changes on the ECG), peripheral vascular disease, pulmonary disease, smokers. Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg). Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and psychiatric disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Obese Group-D5W<br>Obese subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours | Drug: D5W<br>* 5% Dextrose Water = Vehicle<br>* Other names: Placebo, Vehicle;|
| Active Comparator: Obese Group - Eritoran<br>Obese subjects receive IV administration of Eritoran 12 mg every 12 hours | Drug: Eritoran<br>* Pharmacologic inhibitor of TLR4 receptors.<br>* Other names: E5564;|
| Active Comparator: Diabetes (T2DM) Group - D5W<br>T2DM subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours | Drug: D5W<br>* 5% Dextrose Water = Vehicle<br>* Other names: Placebo, Vehicle;|
| Active Comparator: Diabetes (T2DM) Group - Eritoran<br>T2DM subjects receive IV administration of Eritoran 12 mg every 12 hours | Drug: Eritoran<br>* Pharmacologic inhibitor of TLR4 receptors.<br>* Other names: E5564;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Eritoran on Muscle Insulin Sensitivity | Muscle insulin sensitivity = muscle insulin sensitivity is determined by euglycemic hyperinsulinemic clamp procedure. M value (mg glucose / kg of body weight / minute) calculated from the clamp is measured. Higher M value indicates better insulin sensitivity. There is no established reference range. | 72 hours | 
| Effect of Eritoran on Hepatic Insulin Sensitivity | Hepatic insulin sensitivity = is determined by euglycemic hyperinsulinemic clamp procedure. Endogenous glucose production or EGP (mg/kg/min) calculated from the clamp is measured. Lower EGP indicates better hepatic insulin sensitivity. There is no established reference range. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Eritoran on TLR4 Expression in Muscle Tissue | TLR4 expression in muscle tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range. | 72 hours | 
| Effect of Eritoran on TLR4 Expresison in Adipose Tissue | TLR4 expression in the adipose tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range. | 72 hours | 
| Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes | TLR4 expression in the peripheral blood monocytes is determined by flow cytometry using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range. | 72 hours | 
| Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration | TNF-alpha levels are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range. | 72 hours | 
| Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content | Intramyocellular diacylglycerol and ceramide content are determined by mass spectrometry. Higher levels have been associated with diabetes. | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin signaling and glucose disposal in muscle, Hepatic insulin sensitivity, TLR4 signaling and inflammatory gene expression, Plasma cytokine concentration, Intramyocellular diacylglycerol and ceramide content