The study aims to investigate effects of inhibiting glucocorticoid activation on skin function and wound healing in patients with type 2 diabetes. Half of patients will be given a drug to inhibit glucocorticoid activation and the other half will be given a placebo.
Glucocorticoids are known to impair skin function and wound healing which are also compromised in patients with type 2 diabetes. The enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates glucocorticoids in target tissues including skin. Pre-clinical data demonstrate that 11β-HSD1 inhibition improves skin function and wound healing but this has not been investigated in man. Using the 11β-HSD1 inhibitor AZD4017, we will investigate if 1. Oral AZD4017 inhibits 11β-HSD1 activity in skin 2. AZD4017 is safe and well-tolerated in patient with T2DM 3. Oral AZD4017 regulates skin function 4. Systemic glucocorticoid levels and skin 11β-HSD1 activity, independently or in combination correlate with measures of skin function Study feasibility will also be assessed; if successful, data from this pilot study will inform power calculations for a future trial to investigate the ability of 11β-HSD1 inhibition to promote foot ulcer healing in type 2 diabetes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
28
AZD4017 is a novel orally bioavailable small molecule inhibitor of 11β-HSD1 enzyme activity. It is potent and highly selective in vitro and in vivo. The half maximal inhibitory concentration (IC50) for inhibition of 11β-HSD1 activity (cortisone to cortisol conversion) is 2nM. AZD4017 is selective (\> 2000x) for 11β-HSD1 over human recombinant 11β-HSD2 and the closely-homologous enzymes 17β-hydroxysteroid dehydrogenase 1 and 17β-hydroxysteroid dehydrogenase 3 in vitro.
Matching placebo
Leeds Teaching Hospitals Trust
Leeds, United Kingdom
Skin 11β-HSD1 activity
Enzyme activity radioassay to evaluate AZD4107 efficacy in skin
Time frame: Change between day 0 and day 28
Urinary cortisol / cortisone metabolites
Urine samples for tetrahydrocortisol / tetrahydrocortisone metabolite ratios to evaluate systemic AZD4107 efficacy
Time frame: Change between day 0 and day 35
AZD4017 in plasma
Quantification of AZD4017 concentration in plasma to evaluate systemic AZD4107 exposure
Time frame: Change between day 0 and day 28
AZD4017 in skin
Quantification of AZD4017 concentration in plasma to evaluate skin AZD4107 exposure
Time frame: Change between day 0 and day 28
Discontinuation due to Adverse Event
Adverse Event-related participant withdrawals to evaluate safety
Time frame: Day 42
Body mass index
Body mass index to evaluate safety
Time frame: Change between day 0 and day 35
Waist-hip ratio
Waist-hip ratio to evaluate safety
Time frame: Change between day 0 and day 35
Blood pressure (sphygmomanometer)
Blood pressure to evaluate safety
Time frame: Change between day 0 and day 35
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Sudomotor function
Conducted with a Sudoscan device to measure c-fiber innervation in hands and feet for skin function
Time frame: Change between day 0 and day 35
Skin hydration
Conducted with a Corneometer device to measure skin water content for skin function
Time frame: Change between day 0 and day 35
Epidermal barrier function
Conducted with a Tewameter device to measure skin trans-epidermal water loss for skin function
Time frame: Change between day 0 and day 35
Epidermal barrier integrity
Conducted by tape tripping to a pre-determined trans-epidermal water loss rate for skin function
Time frame: Change between day 0 and day 28
Skin thickness
Conducted by Optical Coherence Tomography imaging for skin function
Time frame: Change between day 0 and day 35
Wound healing
Conducted by Optical Coherence Tomography imaging for skin function
Time frame: Change between day 0 and day 2
Wound healing
Conducted by Optical Coherence Tomography imaging for skin function
Time frame: Change between day 0 and day 7
Wound healing
Conducted by Optical Coherence Tomography imaging for skin function
Time frame: Change between day 28 and day 30
Wound healing
Conducted by Optical Coherence Tomography imaging for skin function
Time frame: Change between day 28 and day 35
Skin RNA-seq gene expression profiling
For skin function
Time frame: Change between day 0 and day 28