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Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

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ClinicalTrials.gov Identifier: NCT03486223
Recruitment Status : Recruiting
First Posted : April 3, 2018
Last Update Posted : May 18, 2018
Sponsor:
Information provided by (Responsible Party):
James Matt Luther, Vanderbilt University Medical Center

Brief Summary:
The purpose of this study is to test how soluble epoxide hydrolase (sEH) inhibition with GSK2256294 affects tissue sEH activity and insulin sensitivity.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders PreDiabetes Obesity Drug: GSK2256294 Drug: Placebo oral capsule Phase 2

Detailed Description:

Subjects are randomized to treatment with the sEH inhibitor GSK2256294 (10mg/day) or matching placebo for one week. On the seventh day of drug treatment, subjects will report to the CRC in the morning after an overnight fast to undergo a hyperinsulinemic-euglycemic clamp with adipose tissue biopsies.

During the Hyperinsulinemic-euglycemic clamp, insulin will be infused for 2 hours at low dose (20 mU/m2/min) and 2 hours at high dose (80 mU/m2/min) to assess insulin sensitivity. The Glucose Infusion Rate (GIR) will be adjusted to maintain glucose near 95 mg/dL. The average GIR during the final 30 minutes of the high dose period will be used as the measure of insulin sensitivity.

After completion of the study day, subjects will undergo a seven-week washout from study drug and then receive the opposite drug for one week. On the seventh day of treatment they will report to the CRC after an overnight fast and repeat the study day protocol.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Effect of Inhibition Soluble Epoxide Hydrolase on Insulin Sensitivity in Humans
Actual Study Start Date : May 17, 2018
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : October 1, 2020

Arm Intervention/treatment
Experimental: Placebo, GSK2256294
Subjects will receive placebo oral capsule daily by mouth for 7 days, then seven week washout and then GSK2256294 daily by mouth for 7 days.
Drug: GSK2256294
Drug will be taken daily by mouth for 7 days.
Other Name: GSK2256294 oral capsule

Drug: Placebo oral capsule
Placebo will be taken daily by mouth for 7 days.
Other Name: Placebo

Experimental: GSK2256294, Placebo
Subjects will receive GSK2256294 daily by mouth for 7 days, then seven week washout and then placebo oral capsule daily by mouth for 7 days.
Drug: GSK2256294
Drug will be taken daily by mouth for 7 days.
Other Name: GSK2256294 oral capsule

Drug: Placebo oral capsule
Placebo will be taken daily by mouth for 7 days.
Other Name: Placebo




Primary Outcome Measures :
  1. Change in Insulin Sensitivity [ Time Frame: After 7 days of GSK2256294 versus after 7 days of placebo ]
    Determined by Hyperinsulinemic-Euglycemic Clamp as the GIR adjusted for plasma insulin concentration during high dose insulin infusion


Secondary Outcome Measures :
  1. Forearm blood flow (FBF) [ Time Frame: Measured after 7 days of GSK2256294 versus after 7 days of placebo ]
    Insulin stimulated forearm blood flow determined by strain-gauge plethysmography

  2. Insulin signaling in adipose tissue [ Time Frame: Measured after 7 days of GSK2256294 versus after 7 days of placebo ]
    Insulin stimulated pAKT/AKT ratio in adipose tissue sample

  3. Blood Pressure [ Time Frame: Measured after 7 days of GSK2256294 versus after 7 days of placebo ]
    determined by non-invasive brachial blood pressure measurement (systolic and diastolic)


Other Outcome Measures:
  1. Plasma soluble epoxide hydrolase activity [ Time Frame: Measured after 7 days of GSK2256294 versus after 7 days of placebo ]
    Plasma epoxide hydrolase activity measured by EpOME/DHOME ratio

  2. Adipose tissue soluble epoxide hydrolase activity [ Time Frame: Measured after 7 days of GSK2256294 versus after 7 days of placebo ]
    Adipose tissue epoxide hydrolase activity measured by EpOME/DHOME ratio



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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Men and women,
  2. Age 21 to 50 years, and
  3. Pre-diabetes as defined by

    1. Fasting plasma glucose 100-125 mg/dL, or
    2. Two-hour plasma glucose 140-199 mg/dL, or
    3. HbA1c 5.7-6.4%
  4. BMI ≥ 30 kg/m2, inclusive
  5. For female subjects, the following conditions must be met:

    1. Postmenopausal status for at least one year, or
    2. Status-post surgical sterilization, or
    3. If of childbearing potential, utilization of adequate birth control and willingness to undergo serum β-hcg testing prior to drug treatment and on every study day.

Exclusion Criteria:

  1. Diabetes type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater, a two-hour plasma glucose of 200 mg/dL or greater, a HbA1c >6.4%, or the use of anti-diabetic medication
  2. Subjects who have participated in a weight-reduction program during the last six month or whose weight has increased or decreased more than two kg over the preceding six months
  3. Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control
  4. Use of spironolactone
  5. Pregnancy or breast-feeding
  6. Any history of smoking
  7. Any history of cancer including skin cancer, any history of a precancerous lesion, abnormal PSA, or lack of screening adherent to American Cancer Society Guidelines for the Early Detection of Cancer
  8. Cardiovascular disease such as myocardial infarction within six months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep-vein thrombosis, pulmonary embolism, second- or third-degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy
  9. Abnormal corrected QT interval on screening ECG (QTc).
  10. Treatment with anticoagulants
  11. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
  12. History or presence of immunological or hematological disorders
  13. Diagnosis of asthma requiring regular inhaler use
  14. Clinically significant gastrointestinal impairment that could interfere with drug absorption
  15. Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)
  16. History of gastrointestinal bleed
  17. Estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 or with an albumin-to-creatinine ratio (UACR) >300µg/mg, where eGFR is determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine is expressed in mg/dL and age in years: eGFR (mL/min/1.73m2)=186 • Scr-1.154 • age-0.203 • (1.212 if black) • (0.742 if female)
  18. Hematocrit <35%
  19. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
  20. Treatment with chronic systemic glucocorticoid therapy
  21. Treatment with lithium salts
  22. History of alcohol or drug abuse
  23. Treatment with any investigational drug in the month preceding the study
  24. Mental conditions rendering a subject unable to understand the nature, scope, and possible consequences of the study
  25. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03486223


Contacts
Contact: Robert Manning, RN 615-322-2105 robert.m.manning@Vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Robert Manning, RN    615-322-2105    robert.m.manning@Vanderbilt.edu   
Contact: Holly Waldrop       holly.waldrop@Vanderbilt.edu   
Principal Investigator: James M Luther, MD         
Sponsors and Collaborators
Vanderbilt University Medical Center
Investigators
Principal Investigator: James M Luther, MD Vanderbilt University Medical Center
Principal Investigator: Nancy J Brown, MD Vanderbilt University Medical Center

Publications:
Responsible Party: James Matt Luther, Assistant Professor of Medicine, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03486223     History of Changes
Other Study ID Numbers: 170468
First Posted: April 3, 2018    Key Record Dates
Last Update Posted: May 18, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Available upon request.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Diabetes Mellitus
Prediabetic State
Metabolic Diseases
Glucose Metabolism Disorders
Endocrine System Diseases