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The purpose of this study is to determine whether pharmacologic inhibition of Toll-like receptor 4 (TLR4) with eritoran for injection (E5564) prevents lipid-induced insulin resistance in lean, normal glucose tolerant (NGT) subjects.
E5564 = Eritoran
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| D5W (5% Dextrose in water) + Saline | Active Comparator | IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours plus Saline infusion at a rate of 30 mL/hour |
|
| D5W (5% Dextrose in water) + Intralipid | Active Comparator | IV Administration of 5% Dextrose in water /D5W (vehicle) 12 mg plus Intralipid infusion at a rate of 30 ml/hour |
|
| Eritoran + Intralipid | Active Comparator | IV administration of Eritoran 12 mg every 12 hours plus Intralipid infusion at a rate of 30 ml/hour |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Eritoran | Drug | Eritoran = E5564 Eritoran is a pharmacologic inhibitor of TLR4. |
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | TLR4 expression on 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 Cytokine Concentration |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nicolas Musi, MD | The University of Texas Health Science Center at San Antonio | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Audie L. Murphy VA Hospital, STVHCS | San Antonio | Texas | 78229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36066991 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Eritoran/Lipid Then D5W/Saline Then D5W/Lipid | Subjects randomized to receive Eritoran/Lipid first then D5W/Saline then D5W/Lipid |
| FG001 | D5W/Saline Then D5W/Lipid Then Eritoran/Lipid | Subjects randomized to receive D5W/Saline first then D5W/Lipid then Eritoran/Lipid |
| FG002 | D5W/Lipid Then D5W/Saline Then Eritoran/Lipid | Subjects randomized to receive D5W/Lipid first then D5W/Saline then Eritoran/Lipid |
| FG003 | D5W/Lipid Then Eritoran/Lipid Then D5W/Saline | Subjects randomized to receive first D5W/Lipid then Eritoran/Lipid then D5W/Saline |
| FG004 | Eritoran/Lipid Then D5W/Lipid Then D5W/Saline | Subjects randomized to receive Eritoran/Lipid then D5W/Lipid then D5W/Saline |
| FG005 | D5W/Saline Then Eritoran/Lipid Then D5W/Lipid | Subjects randomized to receive D5W/Saline then Eritoran/Lipid then D5W/Lipid |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Infusion1 |
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| Washout1 (3-4weeks Between Infusions) |
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| Infusion2 |
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| Washout2 (3-4weeks Between Infusions) |
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| Infusion3 |
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| ID | Title | Description |
|---|---|---|
| BG000 | Lean Subjects | Ten lean subjects were randomized to receive 3 infusions in different order. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Error | mg/kg/min | 72 hours |
|
Baseline to 20 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | D5W (5% Dextrose in Water) + Saline | IV administration of 5% Dextrose in water/D5W (vehicle) 12 mg every 12 hours plus Saline infusion at a rate of 30 mL/hour D5W (5% Dextrose in water): D5W = 5% Dextrose Water Vehicle |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Phlebitis Grade 1, 2, or 3 | Vascular disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Laurie Che Kelly | University of Texas Health San Antonio | 210-617-5300 | 14731 | che@uthscsa.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 10, 2016 | Jun 14, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C512420 | eritoran |
| C404742 | E5564 |
| D005947 | Glucose |
| D014867 | Water |
| ID | Term |
|---|---|
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D006878 |
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Participant, Care Provider, Investigator, Outcomes Assessor
| D5W (5% Dextrose in water) | Drug | D5W = 5% Dextrose Water Vehicle |
|
|
TNF-alpha levels (tumor necrosis factor-alpha) 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 |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| BMI | Mean | Standard Deviation | kg/m^2 |
|
| HbA1c | Mean | Standard Deviation | Percentage of glycated hemoglobin |
|
| Fasting plasma glucose | Mean | Standard Deviation | mg/dL |
|
| OG002 | Eritoran + Intralipid | IV administration of Eritoran 12 mg every 12 hours plus Intralipid infusion at a rate of 30 ml/hour Eritoran: Eritoran = E5564 Eritoran is a pharmacologic inhibitor of TLR4. |
|
|
|
| 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. | Posted | Mean | Standard Error | mg/kg/min | 72 hours |
|
|
|
| Secondary | Effect of Eritoran on TLR4 Expression on Peripheral Blood Monocytes | TLR4 expression on the peripheral blood monocytes is determined by flow cytometry using arbitrary units. Higher TLR4 expression indicates higher inflammatory response. There is no reference range. | Data from 1 subject were not collected due to instrument failure. Therefore, data from 9 subjects were reported. | Posted | Mean | Standard Error | AU | 72 hours |
|
|
|
| Secondary | Effect of Eritoran on Plasma Cytokine Concentration | TNF-alpha levels (tumor necrosis factor-alpha) are determined by ELISA. Higher level indicates higher inflammatory response. There is no established reference range. | Posted | Mean | Standard Error | pg/ml | 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. | Data were not collected due to lack of funding. | Posted | 72 hours |
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| 0 |
| 10 |
| 0 |
| 10 |
| 7 |
| 10 |
| EG001 | D5W (5% Dextrose in Water) + Intralipid | IV Administration of 5% Dextrose in water /D5W (vehicle) 12 mg plus Intralipid infusion at a rate of 30 ml/hour D5W (5% Dextrose in water): D5W = 5% Dextrose Water Vehicle | 0 | 10 | 0 | 10 | 10 | 10 |
| EG002 | Eritoran + Intralipid | IV administration of Eritoran 12 mg every 12 hours plus Intralipid infusion at a rate of 30 ml/hour Eritoran: Eritoran = E5564 Eritoran is a pharmacologic inhibitor of TLR4. | 0 | 10 | 0 | 10 | 10 | 10 |
| Bruising | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Hypokalemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Upper respiratory illness | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
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| Hydroxides |
| D000468 | Alkalies |
| D007287 | Inorganic Chemicals |
| D000838 | Anions |
| D007477 | Ions |
| D004573 | Electrolytes |
| D010087 | Oxides |
| D017601 | Oxygen Compounds |