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

Insulin Sensitivity Clinical Trial

— Eritoran2  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02267317
• Other study ID #: HSC20140498H
• Status: Terminated
• Phase: Phase 2
• Start date: January 2015
• Est. completion date: September 2018

Study information

• Verified date: September 2018
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

E5564 = Eritoran

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 15
• Est. completion date: September 2018
• Est. primary completion date: September 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hypersensitivity
• Insulin Resistance
• Insulin Sensitivity

Intervention

Drug:
• Eritoran
Pharmacologic inhibitor of TLR4 receptors.
• D5W
5% Dextrose Water = Vehicle

Locations

Country	Name	City	State
United States	Audie L. Murphy VA Hospital, STVHCS	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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