Glucocorticoids and Skin Healing in Diabetes (GC-SHealD)

Phase 2

Completed

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Drug: AZD4017; Drug: Placebo

• Registration Number: NCT03313297
• Lead Sponsor: University of Leeds

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.

Study Timeline

• Study First Submitted: 2017-10-05
• Study First Submitted QC: 2017-10-17
• Study First Posted: 2017-10-18
• Study Start: 2018-04-10
• Primary Completion: 2019-02-27
• Status Verified: 2019-03
• Study Completion: 2019-03-13
• Last Update Submitted: 2019-03-21
• Last Update Posted: 2019-03-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AZD4017	AZD4017	400mg oral AZD4017 twice daily for 35 days
Placebo	Placebo	A placebo tablet containing microcrystalline cellulose and sodium stearyl fumarate to match the active tablets in size, shape and colour.

Primary Outcome Measures

Name	Time	Method
Skin 11β-HSD1 activity	Change between day 0 and day 28	Enzyme activity radioassay to evaluate AZD4107 efficacy in skin

Secondary Outcome Measures

Name	Time	Method
Urinary cortisol / cortisone metabolites	Change between day 0 and day 35	Urine samples for tetrahydrocortisol / tetrahydrocortisone metabolite ratios to evaluate systemic AZD4107 efficacy
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
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
Waist-hip ratio	Change between day 0 and day 35	Waist-hip ratio to evaluate safety
Body mass index	Change between day 0 and day 35	Body mass index to evaluate safety
Blood pressure (sphygmomanometer)	Change between day 0 and day 35	Blood pressure to evaluate safety
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 28 and day 35	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

Trial Locations

Locations (1)

Leeds Teaching Hospitals Trust; 🇬🇧 Leeds, United Kingdom