CompletedNCT03486223Updated Mar 23, 2023Results posted

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

A Phase 2 interventional study of GSK2256294 and Placebo oral capsule in Diabetes Mellitus, Endocrine System Diseases and Glucose Metabolism Disorders, sponsored by Vanderbilt University Medical Center. Completed at 1 site in United States. Open to participants aged 21 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-03-23.

Sponsored by Vanderbilt University Medical Center · Phase 2, Interventional, and Prevention

Phase: Phase 2
Study type: Interventional
Enrollment: 16
Allocation: Randomized
Ages: 21 Years to 50 Years
Sex: All

Study summary

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

Read the detailed description

We will test the hypothesis that soluble epoxide hydrolase (sEH) inhibition with GSK2256294 improves insulin sensitivity using the gold-standard, hyperinsulinemic-euglycemic clamps, with stable isotope dilution to assess hepatic gluconeogenesis. We will assess insulin-stimulated vasodilation in the forearm using plethysmography and in the renal vasculature using para-aminohippurate (PAH, IND#133828) clearance. We will obtain adipose and muscle tissue before and after clamp to assess insulin signaling in these tissues.

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.

Conditions studied

Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
PreDiabetes
Obesity

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Who can participate

Ages eligible: 21 Years to 50 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Men and women,
Age 21 to 50 years, and
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%
BMI ≥ 30 kg/m2, inclusive
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

Exclusion Criteria:

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
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
Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control
Use of spironolactone
Pregnancy or breast-feeding
Any history of smoking
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
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
Abnormal corrected QT interval on screening ECG (QTc).
Treatment with anticoagulants
History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
History or presence of immunological or hematological disorders
Diagnosis of asthma requiring regular inhaler use
Clinically significant gastrointestinal impairment that could interfere with drug absorption
Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)
History of gastrointestinal bleed
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)
Hematocrit \<35%
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
Treatment with chronic systemic glucocorticoid therapy
Treatment with lithium salts
History of alcohol or drug abuse
Treatment with any investigational drug in the month preceding the study
Mental conditions rendering a subject unable to understand the nature, scope, and possible consequences of the study
Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Study design

Phase: Phase 2
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Double (Participant, Investigator)
Enrollment: 16 participants (actual)

Study arms

Experimental
Placebo then 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: Placebo oral capsule
Experimental
GSK2256294 then 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: Placebo oral capsule

Interventions

DrugGSK2256294
Drug will be taken daily by mouth for 7 days.
Also known as: GSK2256294 10mg oral capsule
DrugPlacebo oral capsule
Placebo will be taken daily by mouth for 7 days.
Also known as: Placebo

What researchers measure

Primary outcomes

Insulin Sensitivity
Insulin sensitivity determined by Hyperinsulinemic-Euglycemic Clamp as the glucose infusion rate (GIR) per fat-free-mass (FFM) during high dose insulin infusion
Time frame: Day 7

Secondary outcomes

Forearm Blood Flow (FBF)
Insulin stimulated forearm blood flow determined by strain-gauge plethysmography
Time frame: Day 7
Insulin Signaling in Tissue
Insulin stimulated phosphorylated AKT to total AKT ratio (pAKT/AKT) in adipose and muscle tissue sample. AKT is an insulin sensitive serine/threonine kinase also known as protein kinase B.
Time frame: Day 7
Blood Pressure
determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP)
Time frame: Day 7
Renal Plasma Flow (RPF)
Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m\^2 body surface area
Time frame: Day 7

Other outcomes

Soluble Epoxide Hydrolase Activity
soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in plasma
Time frame: Day 7
Plasma Total Epoxyeicosatrienoic Acids (EETs)
total Epoxyeicosatrienoic acids in plasma
Time frame: Day 7
Plasma IL-6
Plasma cytokine interleukin-6 (IL-6)
Time frame: Day 7
Plasma VEGF
Plasma vascular endothelial growth factor (VEGF)
Time frame: Day 7
Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)
total Epoxyeicosatrienoic acids in adipose tissue (pmol per mg tissue)
Time frame: Day 7
Soluble Epoxide Hydrolase Activity in Tissue
soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in adipose and muscle, per mg tissue
Time frame: Day 7

Results

Posted Mar 23, 2023

Limitations and caveats

Enrollment was not sufficient for subgroup analysis for race and gender, due to drug expiration.

Participant flow

35 volunteers were screened for inclusion

Intervention 1

Participant flow — Intervention 1
Milestone	Placebo Then GSK2256294	GSK2256294 Then Placebo
Started	8	8
Completed	8	7
Not completed	0	1
Withdrew: Received oral steroids for sinus infection; randomized but did not receive intervention	0	1

Washout

Participant flow — Washout
Milestone	Placebo Then GSK2256294	GSK2256294 Then Placebo
Started	8	7
Completed	8	7
Not completed	0	0

Intervention 2

Participant flow — Intervention 2
Milestone	Placebo Then GSK2256294	GSK2256294 Then Placebo
Started	8	7
Completed	8	7
Not completed	0	0

Outcome measures

PrimaryInsulin Sensitivity

Insulin sensitivity determined by Hyperinsulinemic-Euglycemic Clamp as the glucose infusion rate (GIR) per fat-free-mass (FFM) during high dose insulin infusion

Time frame:: Day 7
Reported as:: Mean · mg/kg/FFM/min

Insulin Sensitivity
mg/kg/FFM/min	Placebo	GSK2256294
Insulin Sensitivity	12.0 ± 4.3	11.6 ± 3.7

Statistical analysis

Placebo vs GSK2256294 · Wilcoxon (Mann-Whitney) · p = 0.71 (Wilcoxon signed-rank test was used for the within-subject comparison of GSK2256294 versus placebo.)

SecondaryForearm Blood Flow (FBF)

Insulin stimulated forearm blood flow determined by strain-gauge plethysmography

Time frame:: Day 7
Reported as:: Mean · ml/min/100ml

Forearm Blood Flow (FBF)
ml/min/100ml	Placebo	GSK2256294
Forearm Blood Flow (FBF)	3.5 ± 1.9	3.1 ± 1.2

SecondaryInsulin Signaling in Tissue

Insulin stimulated phosphorylated AKT to total AKT ratio (pAKT/AKT) in adipose and muscle tissue sample. AKT is an insulin sensitive serine/threonine kinase also known as protein kinase B.

Time frame:: Day 7
Reported as:: Mean · pAKT/pAKT ratio

Insulin Signaling in Tissue
pAKT/pAKT ratio	Placebo	GSK2256294
Adipose Tissue	0.21 ± 0.14	0.19 ± 0.18
Muscle Tissue	0.74 ± 0.55	0.73 ± 0.58

SecondaryBlood Pressure

determined by non-invasive brachial blood pressure measurement (systolic blood pressure, SBP; diastolic blood pressure, DBP)

Time frame:: Day 7
Reported as:: Mean · mmHg

Blood Pressure
mmHg	Placebo	GSK2256294
SBP	122.9 ± 11.0	124.3 ± 9.6
DBP	77.4 ± 6.8	78.9 ± 8.7

Other pre-specifiedSoluble Epoxide Hydrolase Activity

soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in plasma

Time frame:: Day 7
Reported as:: Mean · pmol 14,15-DHET/ml/hr

Soluble Epoxide Hydrolase Activity
pmol 14,15-DHET/ml/hr	Placebo	GSK2256294
Soluble Epoxide Hydrolase Activity	4.1 ± 4.5	1.9 ± 2.6

SecondaryRenal Plasma Flow (RPF)

Renal plasma flow determined by PAH infusion, ml/min/per 1.73 m\^2 body surface area

Time frame:: Day 7
Reported as:: Mean · ml/min/per 1.73 m^2

Renal Plasma Flow (RPF)
ml/min/per 1.73 m^2	Placebo	GSK2256294
Renal Plasma Flow (RPF)	648 ± 138	614 ± 103

Other pre-specifiedPlasma Total Epoxyeicosatrienoic Acids (EETs)

total Epoxyeicosatrienoic acids in plasma

Time frame:: Day 7
Reported as:: Mean · pmol/mL

Plasma Total Epoxyeicosatrienoic Acids (EETs)
pmol/mL	Placebo	GSK2256294
Plasma Total Epoxyeicosatrienoic Acids (EETs)	21.4 ± 8.4	22.4 ± 9.3

Other pre-specifiedPlasma IL-6

Plasma cytokine interleukin-6 (IL-6)

Time frame:: Day 7
Reported as:: Mean · pmol/ml

Plasma IL-6
pmol/ml	Placebo	GSK2256294
Plasma IL-6	1.48 ± 0.61	1.48 ± 0.69

Other pre-specifiedPlasma VEGF

Plasma vascular endothelial growth factor (VEGF)

Time frame:: Day 7
Reported as:: Mean · pg/ml

Plasma VEGF
pg/ml	Placebo	GSK2256294
Plasma VEGF	31.9 ± 18.6	29.0 ± 24.4

Other pre-specifiedAdipose Tissue Total Epoxyeicosatrienoic Acids (EETs)

total Epoxyeicosatrienoic acids in adipose tissue (pmol per mg tissue)

Time frame:: Day 7
Reported as:: Mean · pmol/mg

Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)
pmol/mg	Placebo	GSK2256294
Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)	176 ± 291	66 ± 44

Other pre-specifiedSoluble Epoxide Hydrolase Activity in Tissue

soluble epoxide hydrolase (sEH) activity measured by 14,15-DHET conversion rate in adipose and muscle, per mg tissue

Time frame:: Day 7
Reported as:: Mean · pmol 14,15-DHET/mg tissue/hr

Soluble Epoxide Hydrolase Activity in Tissue
pmol 14,15-DHET/mg tissue/hr	Placebo	GSK2256294
Adipose	2176 ± 965	1280 ± 675
Muscle	3.5 ± 1.6	1.9 ± 1.1

Adverse events

Collected over Baseline to one month post-intervention (approximately 3 months). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Placebo	0/15 (0%)	0/15 (0%)	2/15 (13.3%)
GSK2256294	0/15 (0%)	0/15 (0%)	2/15 (13.3%)

Most frequent other events

Most frequent other events
Event	Placebo	GSK2256294
Rash at biopsy dressing siteSkin and subcutaneous tissue disorders	2/15	1/15
FlushingGeneral disorders	0/15	1/15
HeadacheNervous system disorders	1/15	1/15
Increased frequency of bowel movementsGastrointestinal disorders	1/15	1/15
nauseaGastrointestinal disorders	1/15	0/15
Paresthesia of lipsNervous system disorders	1/15	0/15
PolyuriaRenal and urinary disorders	1/15	0/15
Increased thirstRenal and urinary disorders	0/15	1/15

Baseline characteristics

1 participant included here (in GSK-then-placebo arm) was randomized but did not receive intervention or complete a study day

Age, Continuous
Age, Continuous(years)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
Mean	45 ± 8	48 ± 10	47 ± 9

Sex: Female, Male
Sex: Female, Male(Participants)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
Female	8	6	14
Male	0	2	2

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
Hispanic or Latino	0	0	0
Not Hispanic or Latino	8	8	16
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	1	2	3
White	5	6	11
More than one race	2	0	2
Unknown or Not Reported	0	0	0

Region of Enrollment
Region of Enrollment(participants)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
United States	8	8	16

Glucose
Glucose(mg/dl)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
Mean	97 ± 8	96 ± 8	97 ± 8

Body mass index
Body mass index(kg/m^2)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
Mean	39 ± 7	43 ± 9	41 ± 8

Waist circumference
Waist circumference(cm)	Placebo Then GSK2256294	GSK2256294 Then Placebo	Total
Mean	112 ± 14	121 ± 24	116 ± 20

2 further baseline measures are reported on the registry.

Study locations

1 site

Vanderbilt University Medical Center
Nashville, Tennessee 37232, United States

References and documents

Publications

Luther JM, Brown NJ. Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat. 2016 Sep;125:2-7. doi: 10.1016/j.prostaglandins.2016.07.010. Epub 2016 Jul 19. PubMed 27448715 ↗
Gangadhariah MH, Dieckmann BW, Lantier L, Kang L, Wasserman DH, Chiusa M, Caskey CF, Dickerson J, Luo P, Gamboa JL, Capdevila JH, Imig JD, Yu C, Pozzi A, Luther JM. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017 Jun;60(6):1066-1075. doi: 10.1007/s00125-017-4260-0. Epub 2017 Mar 28. PubMed 28352940 ↗
Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28. PubMed 25173047 ↗
Luther JM, Ray J, Wei D, Koethe JR, Hannah L, DeMatteo A, Manning R, Terker AS, Peng D, Nian H, Yu C, Mashayekhi M, Gamboa J, Brown NJ. GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans. Hypertension. 2021 Sep;78(4):1092-1102. doi: 10.1161/HYPERTENSIONAHA.121.17659. Epub 2021 Aug 30. PubMed 34455816 ↗

Study documents

Study protocol · Aug 11, 2021
Statistical analysis plan · Aug 11, 2021
Informed consent form · Aug 11, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — Available upon request.

Registry details

Key details

Study ID: NCT03486223
Lead sponsor: Vanderbilt University Medical Center
Collaborators: National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Responsible party: James Matt Luther (Associate Professor of Medicine, Vanderbilt University Medical Center) — Principal investigator
First posted: Apr 3, 2018
Start date: May 17, 2018
Primary completion: Nov 18, 2021
Completion: Nov 18, 2021
Results posted: Mar 23, 2023
Last update: Mar 23, 2023

Study contacts

James M Luther, MD

principal investigator · Vanderbilt University Medical Center

Nancy J Brown, MD

principal investigator · Vanderbilt University Medical Center

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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