Clinical trial NCT02267317: The Effect of TLR4 Inhibition in Obese and Type 2 Diabetic Subjects
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
Overall status: TERMINATED
Phase: PHASE2
Conditions: 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
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
First posted: 2014-10-17
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: Effect of Eritoran on Muscle Insulin Sensitivity
timeFrame: 72 hours
measure: Effect of Eritoran on Hepatic Insulin Sensitivity
timeFrame: 72 hours
Secondary outcomes:
measure: Effect of Eritoran on TLR4 Expression in Muscle Tissue
timeFrame: 72 hours
measure: Effect of Eritoran on TLR4 Expresison in Adipose Tissue
timeFrame: 72 hours
measure: Effect of Eritoran on TLR4 Expression in Peripheral Blood Monocytes
timeFrame: 72 hours
measure: Effect of Eritoran on Plasma TNF-alpha (Tumor Necrosis Factor-alpha) Concentration
timeFrame: 72 hours
measure: Effect of Eritoran on Intramyocellular Diacylglycerol and Ceramide Content
timeFrame: 72 hours
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Audie L. Murphy VA Hospital, STVHCS
state: Texas
Study officials:
affiliation: Audie L. Murphy VA Hospital, STVHCS San Antonio, Texas, United States 78229
name: Nicolas Musi, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.