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NCT03486223

Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

Completed Phase 2 Results posted Last updated 23 March 2023
What this trial tests

Phase 2 trial testing GSK2256294 in Diabetes Mellitus in 16 participants. Completed in 18 November 2021.

Timeline
17 May 2018
Primary endpoint
18 November 2021
18 November 2021

Quick facts

Lead sponsorVanderbilt University Medical Center
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designcrossover
Maskingdouble
Primary purposeprevention
Enrollment16
Start date17 May 2018
Primary completion18 November 2021
Estimated completion18 November 2021
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

Vanderbilt University Medical Center

Who can join

Adults 21 to 50, any sex, with Diabetes Mellitus or Endocrine System Diseases. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Insulin Sensitivity Primary · 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

GroupValue95% CI
Placebo12.0± 4.3
GSK225629411.6± 3.7
Forearm Blood Flow (FBF) Secondary · Day 7

Insulin stimulated forearm blood flow determined by strain-gauge plethysmography

GroupValue95% CI
Placebo3.5± 1.9
GSK22562943.1± 1.2
Insulin Signaling in Tissue Secondary · Day 7

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.

Adipose Tissue
GroupValue95% CI
Placebo0.21± 0.14
GSK22562940.19± 0.18
Muscle Tissue
GroupValue95% CI
Placebo0.74± 0.55
GSK22562940.73± 0.58
Blood Pressure Secondary · Day 7

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

SBP
GroupValue95% CI
Placebo122.9± 11.0
GSK2256294124.3± 9.6
DBP
GroupValue95% CI
Placebo77.4± 6.8
GSK225629478.9± 8.7
Soluble Epoxide Hydrolase Activity Secondary · Day 7

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

GroupValue95% CI
Placebo4.1± 4.5
GSK22562941.9± 2.6
Renal Plasma Flow (RPF) Secondary · Day 7

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

GroupValue95% CI
Placebo648± 138
GSK2256294614± 103
Plasma Total Epoxyeicosatrienoic Acids (EETs) Secondary · Day 7

total Epoxyeicosatrienoic acids in plasma

GroupValue95% CI
Placebo21.4± 8.4
GSK225629422.4± 9.3
Plasma IL-6 Secondary · Day 7

Plasma cytokine interleukin-6 (IL-6)

GroupValue95% CI
Placebo1.48± 0.61
GSK22562941.48± 0.69
Plasma VEGF Secondary · Day 7

Plasma vascular endothelial growth factor (VEGF)

GroupValue95% CI
Placebo31.9± 18.6
GSK225629429.0± 24.4
Adipose Tissue Total Epoxyeicosatrienoic Acids (EETs) Secondary · Day 7

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

GroupValue95% CI
Placebo176± 291
GSK225629466± 44
Soluble Epoxide Hydrolase Activity in Tissue Secondary · Day 7

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

Adipose
GroupValue95% CI
Placebo2176± 965
GSK22562941280± 675
Muscle
GroupValue95% CI
Placebo3.5± 1.6
GSK22562941.9± 1.1

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline to one month post-intervention (approximately 3 months). Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 0/15 (0%)
Deaths: 0/15
GSK2256294
Serious: 0/15 (0%)
Deaths: 0/15
Other adverse events (8 terms — click to expand)

ReactionSystemPlaceboGSK2256294
Rash at biopsy dressing siteSkin and subcutaneous tissue disorders
FlushingGeneral disorders
HeadacheNervous system disorders
Increased frequency of bowel movementsGastrointestinal disorders
nauseaGastrointestinal disorders
Paresthesia of lipsNervous system disorders
PolyuriaRenal and urinary disorders
Increased thirstRenal and urinary disorders

Data from ClinicalTrials.gov NCT03486223 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets.
    Wang B, Wu L, Chen J, Dong L, et al · · 2021 · cited 900× · PMID 33637672 · DOI 10.1038/s41392-020-00443-w
  2. Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases.
    Sonnweber T, Pizzini A, Nairz M, Weiss G, et al · · 2018 · cited 319× · PMID 30360467 · DOI 10.3390/ijms19113285
  3. Small-molecule discovery through DNA-encoded libraries.
    Peterson AA, Liu DR. · · 2023 · cited 145× · PMID 37328653 · DOI 10.1038/s41573-023-00713-6
  4. The Multifaceted Role of Epoxide Hydrolases in Human Health and Disease.
    Gautheron J, Jéru I. · · 2020 · cited 77× · PMID 33374956 · DOI 10.3390/ijms22010013
  5. GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans.
    Luther JM, Ray J, Wei D, Koethe JR, et al · · 2021 · cited 32× · PMID 34455816 · DOI 10.1161/hypertensionaha.121.17659
  6. Soluble Epoxide Hydrolase Inhibition in Liver Diseases: A Review of Current Research and Knowledge Gaps.
    Warner J, Hardesty J, Zirnheld K, McClain C, et al · · 2020 · cited 22× · PMID 32545637 · DOI 10.3390/biology9060124
  7. Hematologic malignancies magnify the effect of body mass index on insulin resistance in cancer survivors.
    Sahinoz M, Luther JM, Mashayekhi M, Jung DK, et al · · 2022 · cited 9× · PMID 35130338 · DOI 10.1182/bloodadvances.2021006241
  8. The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells.
    Mashayekhi M, Wanjalla CN, Warren CM, Simmons JD, et al · · 2022 · cited 9× · PMID 34922004 · DOI 10.1016/j.prostaglandins.2021.106604

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