The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects (Eritoran2)

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

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.

Study Overview

• Status: Terminated
• Conditions: Insulin Sensitivity
• Intervention / Treatment: Drug: D5W; Drug: Eritoran

Detailed Description

E5564 = Eritoran

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Audie L. Murphy VA Hospital, STVHCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Investigators: Principal Investigator: Nicolas Musi, MD, Audie L. Murphy VA Hospital, STVHCS San Antonio, Texas, United States 78229

Publications and helpful links

General Publications

• Liang H, Sathavarodom N, Colmenares C, Gelfond J, Espinoza SE, Ganapathy V, Musi N. Effect of acute TLR4 inhibition on insulin resistance in humans. J Clin Invest. 2022 Nov 1;132(21):e162291. doi: 10.1172/JCI162291.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: September 26, 2014
• First Submitted That Met QC Criteria: October 14, 2014
• First Posted (Estimate): October 17, 2014

Study Record Updates

• Last Update Posted (Actual): March 4, 2020
• Last Update Submitted That Met QC Criteria: February 24, 2020
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Insulin signaling and glucose disposal in muscle; Hepatic insulin sensitivity; TLR4 signaling and inflammatory gene expression; Plasma cytokine concentration; Intramyocellular diacylglycerol and ceramide content
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Insulin Resistance
• Other Study ID Numbers: HSC20140498H