search
Back to results

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

Primary Purpose

Insulin Sensitivity

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Eritoran
D5W
Sponsored by
The University of Texas Health Science Center at San Antonio
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Insulin Sensitivity focused on measuring Insulin signaling and glucose disposal in muscle, Hepatic insulin sensitivity, TLR4 signaling and inflammatory gene expression, Plasma cytokine concentration, Intramyocellular diacylglycerol and ceramide content

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Audie L. Murphy VA Hospital, STVHCS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Obese Group-D5W

Obese Group - Eritoran

Diabetes (T2DM) Group - D5W

Diabetes (T2DM) Group - Eritoran

Arm Description

Obese subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours

Obese subjects receive IV administration of Eritoran 12 mg every 12 hours

T2DM subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours

T2DM subjects receive IV administration of Eritoran 12 mg every 12 hours

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
September 26, 2014
Last Updated
February 24, 2020
Sponsor
The University of Texas Health Science Center at San Antonio
search

1. Study Identification

Unique Protocol Identification Number
NCT02267317
Brief Title
The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects
Acronym
Eritoran2
Official Title
Phase 2 Study of The Role of Pharmacologic Inhibition of TLR4 With E5564 on Glucose Metabolism in Insulin Resistant Subjects.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Terminated
Why Stopped
Study drug expired
Study Start Date
January 2015 (undefined)
Primary Completion Date
September 2018 (Actual)
Study Completion Date
September 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Texas Health Science Center at San Antonio

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed Description
E5564 = Eritoran

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Sensitivity
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Participant, Care Provider, Investigator, Outcomes Assessor
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Obese Group-D5W
Arm Type
Active Comparator
Arm Description
Obese subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours
Arm Title
Obese Group - Eritoran
Arm Type
Active Comparator
Arm Description
Obese subjects receive IV administration of Eritoran 12 mg every 12 hours
Arm Title
Diabetes (T2DM) Group - D5W
Arm Type
Active Comparator
Arm Description
T2DM subjects receive IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours
Arm Title
Diabetes (T2DM) Group - Eritoran
Arm Type
Active Comparator
Arm Description
T2DM subjects receive IV administration of Eritoran 12 mg every 12 hours
Intervention Type
Drug
Intervention Name(s)
Eritoran
Other Intervention Name(s)
E5564
Intervention Description
Pharmacologic inhibitor of TLR4 receptors.
Intervention Type
Drug
Intervention Name(s)
D5W
Other Intervention Name(s)
Placebo, Vehicle
Intervention Description
5% Dextrose Water = Vehicle
Primary Outcome Measure Information:
Title
Effect of Eritoran on Muscle Insulin Sensitivity
Description
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.
Time Frame
72 hours
Title
Effect of Eritoran on Hepatic Insulin Sensitivity
Description
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.
Time Frame
72 hours
Secondary Outcome Measure Information:
Title
Effect of Eritoran on TLR4 Expression in Muscle Tissue
Description
TLR4 expression in muscle tissue is determined by RNAseq using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range.
Time Frame
72 hours
Title
Effect of Eritoran on TLR4 Expresison in Adipose Tissue
Description
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.
Time Frame
72 hours
Title
Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes
Description
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.
Time Frame
72 hours
Title
Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration
Description
TNF-alpha levels are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range.
Time Frame
72 hours
Title
Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content
Description
Intramyocellular diacylglycerol and ceramide content are determined by mass spectrometry. Higher levels have been associated with diabetes.
Time Frame
72 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolas Musi, MD
Organizational Affiliation
Audie L. Murphy VA Hospital, STVHCS San Antonio, Texas, United States 78229
Official's Role
Principal Investigator
Facility Information:
Facility Name
Audie L. Murphy VA Hospital, STVHCS
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
36066991
Citation
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs