Glucocorticoids and Skin Healing in Diabetes (GC-SHealD)

Diabetes Mellitus, Type 2 Clinical Trial

— GC-SHealD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03313297
• Other study ID #: ED17/93260
• Status: Completed
• Phase: Phase 2
• Start date: April 10, 2018
• Est. completion date: March 13, 2019

Study information

• Verified date: March 2019
• Source: University of Leeds
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: March 13, 2019
• Est. primary completion date: February 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• AZD4017
AZD4017 is a novel orally bioavailable small molecule inhibitor of 11ß-HSD1 enzyme activity. It is potent and highly selective in vitro and in vivo. The half maximal inhibitory concentration (IC50) for inhibition of 11ß-HSD1 activity (cortisone to cortisol conversion) is 2nM. AZD4017 is selective (> 2000x) for 11ß-HSD1 over human recombinant 11ß-HSD2 and the closely-homologous enzymes 17ß-hydroxysteroid dehydrogenase 1 and 17ß-hydroxysteroid dehydrogenase 3 in vitro.
• Placebo
Matching placebo

Locations

Country	Name	City	State
United Kingdom	Leeds Teaching Hospitals Trust	Leeds

Sponsors (1)

Lead Sponsor	Collaborator
University of Leeds

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Skin 11ß-HSD1 activity	Enzyme activity radioassay to evaluate AZD4107 efficacy in skin	Change between day 0 and day 28
Secondary	Urinary cortisol / cortisone metabolites	Urine samples for tetrahydrocortisol / tetrahydrocortisone metabolite ratios to evaluate systemic AZD4107 efficacy	Change between day 0 and day 35
Secondary	AZD4017 in plasma	Quantification of AZD4017 concentration in plasma to evaluate systemic AZD4107 exposure	Change between day 0 and day 28
Secondary	AZD4017 in skin	Quantification of AZD4017 concentration in plasma to evaluate skin AZD4107 exposure	Change between day 0 and day 28
Secondary	Discontinuation due to Adverse Event	Adverse Event-related participant withdrawals to evaluate safety	Day 42
Secondary	Body mass index	Body mass index to evaluate safety	Change between day 0 and day 35
Secondary	Waist-hip ratio	Waist-hip ratio to evaluate safety	Change between day 0 and day 35
Secondary	Blood pressure (sphygmomanometer)	Blood pressure to evaluate safety	Change between day 0 and day 35
Secondary	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
Secondary	Skin hydration	Conducted with a Corneometer device to measure skin water content for skin function	Change between day 0 and day 35
Secondary	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
Secondary	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
Secondary	Skin thickness	Conducted by Optical Coherence Tomography imaging for skin function	Change between day 0 and day 35
Secondary	Wound healing	Conducted by Optical Coherence Tomography imaging for skin function	Change between day 0 and day 2
Secondary	Wound healing	Conducted by Optical Coherence Tomography imaging for skin function	Change between day 0 and day 7
Secondary	Wound healing	Conducted by Optical Coherence Tomography imaging for skin function	Change between day 28 and day 30
Secondary	Wound healing	Conducted by Optical Coherence Tomography imaging for skin function	Change between day 28 and day 35
Secondary	Skin RNA-seq gene expression profiling	For skin function	Change between day 0 and day 28