Soluble Epoxide Hydrolase Inhibition and Insulin Resistance
Condition: Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; PreDiabetes; Obesity
MeSH terms: Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases
Intervention: GSK2256294; Placebo oral capsule
Intervention description: Drug will be taken daily by mouth for 7 days.; Placebo will be taken daily by mouth for 7 days.
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Arm 1 and 2 are crossover arms
Masking: Double (Participant, Investigator)
Masking description: Arms 1/2 are placebo controlled and blinded to investigator and participant
Enrollment: 16.0
Sex: All
Minimum age: 21 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers

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

Eligibility 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