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Glucocorticoids and Skin Healing in Diabetes (GC-SHealD) (GC-SHealD)

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ClinicalTrials.gov Identifier: NCT03313297
Recruitment Status : Completed
First Posted : October 18, 2017
Last Update Posted : March 22, 2019
Sponsor:
Information provided by (Responsible Party):
Ana Tiganescu, PhD, 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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: AZD4017 Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, randomised, parallel group, placebo-controlled phase II pilot trial
Masking: Quadruple (Participant, Care Provider, 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.
Primary Purpose: Treatment
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
Actual Study Start Date : April 10, 2018
Actual Primary Completion Date : February 27, 2019
Actual Study Completion Date : March 13, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Steroids

Arm Intervention/treatment
Active Comparator: AZD4017
400mg oral AZD4017 twice daily for 35 days
Drug: AZD4017
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.

Placebo Comparator: Placebo
A placebo tablet containing microcrystalline cellulose and sodium stearyl fumarate to match the active tablets in size, shape and colour.
Drug: Placebo
Matching placebo




Primary Outcome Measures :
  1. Skin 11β-HSD1 activity [ Time Frame: Change between day 0 and day 28 ]
    Enzyme activity radioassay to evaluate AZD4107 efficacy in skin


Secondary Outcome Measures :
  1. Urinary cortisol / cortisone metabolites [ Time Frame: Change between day 0 and day 35 ]
    Urine samples for tetrahydrocortisol / tetrahydrocortisone metabolite ratios to evaluate systemic AZD4107 efficacy

  2. AZD4017 in plasma [ Time Frame: Change between day 0 and day 28 ]
    Quantification of AZD4017 concentration in plasma to evaluate systemic AZD4107 exposure

  3. AZD4017 in skin [ Time Frame: Change between day 0 and day 28 ]
    Quantification of AZD4017 concentration in plasma to evaluate skin AZD4107 exposure

  4. Discontinuation due to Adverse Event [ Time Frame: Day 42 ]
    Adverse Event-related participant withdrawals to evaluate safety

  5. Body mass index [ Time Frame: Change between day 0 and day 35 ]
    Body mass index to evaluate safety

  6. Waist-hip ratio [ Time Frame: Change between day 0 and day 35 ]
    Waist-hip ratio to evaluate safety

  7. Blood pressure (sphygmomanometer) [ Time Frame: Change between day 0 and day 35 ]
    Blood pressure to evaluate safety

  8. Sudomotor function [ Time Frame: Change between day 0 and day 35 ]
    Conducted with a Sudoscan device to measure c-fiber innervation in hands and feet for skin function

  9. Skin hydration [ Time Frame: Change between day 0 and day 35 ]
    Conducted with a Corneometer device to measure skin water content for skin function

  10. Epidermal barrier function [ Time Frame: Change between day 0 and day 35 ]
    Conducted with a Tewameter device to measure skin trans-epidermal water loss for skin function

  11. Epidermal barrier integrity [ Time Frame: Change between day 0 and day 28 ]
    Conducted by tape tripping to a pre-determined trans-epidermal water loss rate for skin function

  12. Skin thickness [ Time Frame: Change between day 0 and day 35 ]
    Conducted by Optical Coherence Tomography imaging for skin function

  13. Wound healing [ Time Frame: Change between day 0 and day 2 ]
    Conducted by Optical Coherence Tomography imaging for skin function

  14. Wound healing [ Time Frame: Change between day 0 and day 7 ]
    Conducted by Optical Coherence Tomography imaging for skin function

  15. Wound healing [ Time Frame: Change between day 28 and day 30 ]
    Conducted by Optical Coherence Tomography imaging for skin function

  16. Wound healing [ Time Frame: Change between day 28 and day 35 ]
    Conducted by Optical Coherence Tomography imaging for skin function

  17. Skin RNA-seq gene expression profiling [ Time Frame: Change between day 0 and day 28 ]
    For skin function



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03313297


Locations
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United Kingdom
Leeds Teaching Hospitals Trust
Leeds, United Kingdom, LS9 7TF
Sponsors and Collaborators
University of Leeds

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Responsible Party: Ana Tiganescu, PhD, Scientific Lead, University of Leeds
ClinicalTrials.gov Identifier: NCT03313297     History of Changes
Other Study ID Numbers: ED17/93260
First Posted: October 18, 2017    Key Record Dates
Last Update Posted: March 22, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ana Tiganescu, PhD, University of Leeds:
skin
wound healing
11 beta-hydroxysteroid dehydrogenase type 1
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Niacinamide
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs