Trial Outcomes & Findings for Soluble Epoxide Hydrolase Inhibition and Insulin Resistance (NCT NCT03486223)

NCT ID: NCT03486223

Last Updated: 2023-03-23

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 16 participants
• Primary outcome timeframe: Day 7
• Results posted on: 2023-03-23

Participant Flow

35 volunteers were screened for inclusion

16 individuals were randomized. Of those not randomized, 19 did not meet inclusion criteria and were excluded. 1 participant was randomized but was excluded due to illness prior to receiving any study intervention.

Participant milestones

Measure	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. GSK2256294: Drug will be taken daily by mouth for 7 days. Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	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. GSK2256294: Drug will be taken daily by mouth for 7 days. Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.
Intervention 1 STARTED	8	8
Intervention 1 COMPLETED	8	7
Intervention 1 NOT COMPLETED	0	1
Washout STARTED	8	7
Washout COMPLETED	8	7
Washout NOT COMPLETED	0	0
Intervention 2 STARTED	8	7
Intervention 2 COMPLETED	8	7
Intervention 2 NOT COMPLETED	0	0

Reasons for withdrawal

Measure	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. GSK2256294: Drug will be taken daily by mouth for 7 days. Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	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. GSK2256294: Drug will be taken daily by mouth for 7 days. Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.
Intervention 1 received oral steroids for sinus infection; randomized but did not receive intervention	0	1

Baseline Characteristics

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

Baseline characteristics by cohort

Measure	Placebo Then GSK2256294 n=8 Participants 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. GSK2256294: Drug will be taken daily by mouth for 7 days. Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 Then Placebo n=8 Participants 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. GSK2256294: Drug will be taken daily by mouth for 7 days. Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	Total n=16 Participants Total of all reporting groups
Age, Continuous	45 years STANDARD_DEVIATION 8 • n=5 Participants	48 years STANDARD_DEVIATION 10 • n=7 Participants	47 years STANDARD_DEVIATION 9 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	8 participants n=5 Participants	8 participants n=7 Participants	16 participants n=5 Participants
Glucose	97 mg/dl STANDARD_DEVIATION 8 • n=5 Participants	96 mg/dl STANDARD_DEVIATION 8 • n=7 Participants	97 mg/dl STANDARD_DEVIATION 8 • n=5 Participants
Body mass index	39 kg/m^2 STANDARD_DEVIATION 7 • n=5 Participants	43 kg/m^2 STANDARD_DEVIATION 9 • n=7 Participants	41 kg/m^2 STANDARD_DEVIATION 8 • n=5 Participants
Waist circumference	112 cm STANDARD_DEVIATION 14 • n=5 Participants	121 cm STANDARD_DEVIATION 24 • n=7 Participants	116 cm STANDARD_DEVIATION 20 • n=5 Participants
HDL Cholesterol	50 mg/dl STANDARD_DEVIATION 11 • n=5 Participants	47 mg/dl STANDARD_DEVIATION 7 • n=7 Participants	48 mg/dl STANDARD_DEVIATION 9 • n=5 Participants
Triglycerides	117 mg/dl STANDARD_DEVIATION 48 • n=5 Participants	128 mg/dl STANDARD_DEVIATION 65 • n=7 Participants	122 mg/dl STANDARD_DEVIATION 55 • n=5 Participants

PRIMARY outcome

Timeframe: Day 7

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

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Insulin Sensitivity	12.0 mg/kg/FFM/min Standard Deviation 4.3	11.6 mg/kg/FFM/min Standard Deviation 3.7

SECONDARY outcome

Timeframe: Day 7

Population: Unable to obtain FBF measurement during 2 Placebo study days

Insulin stimulated forearm blood flow determined by strain-gauge plethysmography

Outcome measures

Measure	Placebo n=13 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Forearm Blood Flow (FBF)	3.5 ml/min/100ml Standard Deviation 1.9	3.1 ml/min/100ml Standard Deviation 1.2

SECONDARY outcome

Timeframe: Day 7

Population: Unable to obtain adipose sample for pAKT measurement during 2 Placebo study days

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.

Outcome measures

Measure	Placebo n=13 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Insulin Signaling in Tissue Adipose Tissue	0.21 pAKT/pAKT ratio Standard Deviation 0.14	0.19 pAKT/pAKT ratio Standard Deviation 0.18
Insulin Signaling in Tissue Muscle Tissue	0.74 pAKT/pAKT ratio Standard Deviation 0.55	0.73 pAKT/pAKT ratio Standard Deviation 0.58

SECONDARY outcome

Timeframe: Day 7

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

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Blood Pressure DBP	77.4 mmHg Standard Deviation 6.8	78.9 mmHg Standard Deviation 8.7
Blood Pressure SBP	122.9 mmHg Standard Deviation 11.0	124.3 mmHg Standard Deviation 9.6

SECONDARY outcome

Timeframe: Day 7

Population: Unable to obtain RBF measurement in 8 participants due to availability of PAH

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

Outcome measures

Measure	Placebo n=7 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=8 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Renal Plasma Flow (RPF)	648 ml/min/per 1.73 m^2 Standard Deviation 138	614 ml/min/per 1.73 m^2 Standard Deviation 103

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 7

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

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Soluble Epoxide Hydrolase Activity	4.1 pmol 14,15-DHET/ml/hr Standard Deviation 4.5	1.9 pmol 14,15-DHET/ml/hr Standard Deviation 2.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 7

Population: Adequate sample not available in 1 participant during GSK

total Epoxyeicosatrienoic acids in plasma

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=14 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Plasma Total Epoxyeicosatrienoic Acids (EETs)	21.4 pmol/mL Standard Deviation 8.4	22.4 pmol/mL Standard Deviation 9.3

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 7

Plasma cytokine interleukin-6 (IL-6)

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Plasma IL-6	1.48 pmol/ml Standard Deviation 0.61	1.48 pmol/ml Standard Deviation 0.69

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 7

Plasma vascular endothelial growth factor (VEGF)

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Plasma VEGF	31.9 pg/ml Standard Deviation 18.6	29.0 pg/ml Standard Deviation 24.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 7

Population: Adequate sample not available in 1 participant during GSK

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

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=14 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs)	176 pmol/mg Standard Deviation 291	66 pmol/mg Standard Deviation 44

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 7

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

Outcome measures

Measure	Placebo n=15 Participants Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 Participants GSK2256294: Drug will be taken daily by mouth for 7 days.
Soluble Epoxide Hydrolase Activity in Tissue Adipose	2176 pmol 14,15-DHET/mg tissue/hr Standard Deviation 965	1280 pmol 14,15-DHET/mg tissue/hr Standard Deviation 675
Soluble Epoxide Hydrolase Activity in Tissue Muscle	3.5 pmol 14,15-DHET/mg tissue/hr Standard Deviation 1.6	1.9 pmol 14,15-DHET/mg tissue/hr Standard Deviation 1.1

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

GSK2256294

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Placebo n=15 participants at risk Placebo oral capsule: Placebo will be taken daily by mouth for 7 days.	GSK2256294 n=15 participants at risk GSK2256294: Drug will be taken daily by mouth for 7 days.
General disorders Flushing	0.00% 0/15 • Baseline to one month post-intervention (approximately 3 months)	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)
Nervous system disorders Headache	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)
Gastrointestinal disorders Increased frequency of bowel movements	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)
Gastrointestinal disorders nausea	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)	0.00% 0/15 • Baseline to one month post-intervention (approximately 3 months)
Nervous system disorders Paresthesia of lips	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)	0.00% 0/15 • Baseline to one month post-intervention (approximately 3 months)
Skin and subcutaneous tissue disorders Rash at biopsy dressing site	13.3% 2/15 • Number of events 2 • Baseline to one month post-intervention (approximately 3 months)	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)
Renal and urinary disorders Polyuria	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)	0.00% 0/15 • Baseline to one month post-intervention (approximately 3 months)
Renal and urinary disorders Increased thirst	0.00% 0/15 • Baseline to one month post-intervention (approximately 3 months)	6.7% 1/15 • Number of events 1 • Baseline to one month post-intervention (approximately 3 months)

Additional Information

Dr. James M Luther

Vanderbilt University Medical Center

Phone: 6153223353

Email: james.luther@vumc.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place