Diabetes Mellitus, Type 2
Conditions
Keywords
skin, wound healing, 11 beta-hydroxysteroid dehydrogenase type 1
Brief summary
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
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.
Interventions
DRUGAZD4017
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.
DRUGPlacebo
Matching placebo
Sponsors
University of Leeds
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Treatment groups will be allocated in a double-blind manner. Participants will be blinded to the treatment they receive (placebo or drug) throughout all stages of the study. Investigators will also be blinded to the treatment until all samples have been collected and processed. Blinding will be generated by a dedicated trials pharmacy representative who is not otherwise associated with this study.
Intervention model description
Double-blind, randomised, parallel group, placebo-controlled phase II pilot trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able and willing to consent 2. Type 2 diabetes with HbA1c ≤11% (≤97 mmol/mol) at screening while taking standard therapy at a stable dose for ≥10 weeks
Exclusion criteria
1. Women of child-bearing potential 2. Active leg/foot ulceration 3. Clinically relevant acute electrocardiogram anomalies 4. Uncontrolled hypertension 5. Endocrine disorder (other than type 2 diabetes ), including type 1 or secondary diabetes (except treated hypothyroidism) 6. Gilbert's disease 7. Alanine aminotransferase and/or aspartate aminotransferase and/or alkaline phosphatase \>1.5x upper limit of normal (ULN) 8. Bilirubin \>1.5x ULN 9. Estimated glomerular filtration rate \<45 ml/min/m2 10. Creatine kinase \>2x ULN 11. Drug abuse within the last year 12. Any glucocorticoid treatment within 3 months of screening 13. Anti-coagulant medication 14. Probenecid therapy 15. Medical/surgical procedure or trauma during drug administration or one week after drug cessation (excluding skin biopsies) 16. Involvement in trial planning and/or conduct 17. Participation in other clinical study within 1 month 18. Deemed inappropriate to participate by the trial team
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Skin 11β-HSD1 activity | Change between day 0 and day 28 | Enzyme activity radioassay to evaluate AZD4107 efficacy in skin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AZD4017 in plasma | Change between day 0 and day 28 | Quantification of AZD4017 concentration in plasma to evaluate systemic AZD4107 exposure |
| AZD4017 in skin | Change between day 0 and day 28 | Quantification of AZD4017 concentration in plasma to evaluate skin AZD4107 exposure |
| Discontinuation due to Adverse Event | Day 42 | Adverse Event-related participant withdrawals to evaluate safety |
| Body mass index | Change between day 0 and day 35 | Body mass index to evaluate safety |
| Waist-hip ratio | Change between day 0 and day 35 | Waist-hip ratio to evaluate safety |
| Blood pressure (sphygmomanometer) | Change between day 0 and day 35 | Blood pressure to evaluate safety |
| Urinary cortisol / cortisone metabolites | Change between day 0 and day 35 | Urine samples for tetrahydrocortisol / tetrahydrocortisone metabolite ratios to evaluate systemic AZD4107 efficacy |
| Skin hydration | Change between day 0 and day 35 | Conducted with a Corneometer device to measure skin water content for skin function |
| Epidermal barrier function | Change between day 0 and day 35 | Conducted with a Tewameter device to measure skin trans-epidermal water loss for skin function |
| Epidermal barrier integrity | Change between day 0 and day 28 | Conducted by tape tripping to a pre-determined trans-epidermal water loss rate for skin function |
| Skin thickness | Change between day 0 and day 35 | Conducted by Optical Coherence Tomography imaging for skin function |
| Wound healing | Change between day 0 and day 2 | Conducted by Optical Coherence Tomography imaging for skin function |
| Skin RNA-seq gene expression profiling | Change between day 0 and day 28 | For skin function |
| Sudomotor function | Change between day 0 and day 35 | Conducted with a Sudoscan device to measure c-fiber innervation in hands and feet for skin function |
Countries
United Kingdom
Outcome results
None listed