Glucocorticoids and Skin Healing in Diabetes (GC-SHealD)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 Oral AZD4017 inhibits 11β-HSD1 activity in skin AZD4017 is safe and well-tolerated in patient with T2DM Oral AZD4017 regulates skin function 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.

Official Title
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A Double-blind, Randomized, Placebo-controlled Phase II Pilot Trial Investigating Efficacy, Safety and Feasibility of 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition by AZD4017 to Improve Skin Function and Wound Healing in Patients With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: AZD4017
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to consent Type 2 diabetes with HbA1c ≤11% (≤97 mmol/mol) at screening while taking standard therapy at a stable dose for ≥10 weeks Exclusion Criteria: Women of child-bearing potential Active leg/foot ulceration Clinically relevant acute electrocardiogram anomalies Uncontrolled hypertension Endocrine disorder (other than type 2 diabetes ), including type 1 or secondary diabetes (except treated hypothyroidism) Gilbert's disease Alanine aminotransferase and/or aspartate aminotransferase and/or alkaline phosphatase >1.5x upper limit of normal (ULN) Bilirubin >1.5x ULN Estimated glomerular filtration rate <45 ml/min/m2 Creatine kinase >2x ULN Drug abuse within the last year Any glucocorticoid treatment within 3 months of screening Anti-coagulant medication Probenecid therapy Medical/surgical procedure or trauma during drug administration or one week after drug cessation (excluding skin biopsies) Involvement in trial planning and/or conduct Participation in other clinical study within 1 month Deemed inappropriate to participate by the trial team

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, randomised, parallel group, placebo-controlled phase II pilot trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AZD4017<br>400mg oral AZD4017 twice daily for 35 days | Drug: AZD4017<br>* 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.<br>|
| Placebo Comparator: Placebo<br>A placebo tablet containing microcrystalline cellulose and sodium stearyl fumarate to match the active tablets in size, shape and colour. | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin 11β-HSD1 activity | Enzyme activity radioassay to evaluate AZD4107 efficacy in skin | Change between day 0 and day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary cortisol / cortisone metabolites | Urine samples for tetrahydrocortisol / tetrahydrocortisone metabolite ratios to evaluate systemic AZD4107 efficacy | Change between day 0 and day 35 | 
| AZD4017 in plasma | Quantification of AZD4017 concentration in plasma to evaluate systemic AZD4107 exposure | Change between day 0 and day 28 | 
| AZD4017 in skin | Quantification of AZD4017 concentration in plasma to evaluate skin AZD4107 exposure | Change between day 0 and day 28 | 
| Discontinuation due to Adverse Event | Adverse Event-related participant withdrawals to evaluate safety | Day 42 | 
| Body mass index | Body mass index to evaluate safety | Change between day 0 and day 35 | 
| Waist-hip ratio | Waist-hip ratio to evaluate safety | Change between day 0 and day 35 | 
| Blood pressure (sphygmomanometer) | Blood pressure to evaluate safety | Change between day 0 and day 35 | 
| Sudomotor function | Conducted with a Sudoscan device to measure c-fiber innervation in hands and feet for skin function | Change between day 0 and day 35 | 
| Skin hydration | Conducted with a Corneometer device to measure skin water content for skin function | 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 | 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 | Change between day 0 and day 28 | 
| Skin thickness | Conducted by Optical Coherence Tomography imaging for skin function | Change between day 0 and day 35 | 
| Wound healing | Conducted by Optical Coherence Tomography imaging for skin function | Change between day 0 and day 2 | 
| Wound healing | Conducted by Optical Coherence Tomography imaging for skin function | Change between day 0 and day 7 | 
| Wound healing | Conducted by Optical Coherence Tomography imaging for skin function | Change between day 28 and day 30 | 
| Wound healing | Conducted by Optical Coherence Tomography imaging for skin function | Change between day 28 and day 35 | 
| Skin RNA-seq gene expression profiling | For skin function | Change between day 0 and day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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skin, wound healing, 11 beta-hydroxysteroid dehydrogenase type 1