A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

<jats:title>Abstract</jats:title><jats:p>Chronic wounds (e.g. diabetic foot ulcers) have a major impact on quality of life, yet treatments remain limited. Glucocorticoids impair wound healing; preclinical research suggests that blocking glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves wound repair. This investigator-initiated double-blind, randomised, placebo-controlled parallel-group phase 2b pilot trial investigated efficacy, safety and feasibility of 11β-HSD1 inhibition for 35 days by oral AZD4017 (AZD) treatment in adults with type 2 diabetes (n=14) compared to placebo (PCB, n=14) in a single-centre secondary care setting. Computer-generated 1:1 randomisation was pharmacy-administered. From 300 screening invitations, 36 attended, 28 were randomised. There was no proof-of-concept that AZD inhibited 24 hour skin 11β-HSD1 activity at day 28 (primary outcome: adjusted difference AZD-PCB 90% CI (diffCI)=-3.4,5.5) but systemic 11β-HSD1 activity (median urinary [THF+alloTHF]/THE ratio) was 87% lower with AZD at day 35 (PCB 1.00, AZD 0.13, diffCI=-1.04,-0.69). Mean wound gap diameter (mm) following baseline 2mm punch biopsy was 34% smaller at day 2 (PCB 1.51, AZD 0.98, diffCI=-0.95,-0.10) and 48% smaller after repeat wounding at day 30 (PCB 1.35, AZD 0.70, diffCI=-1.15,-0.16); results also suggested greater epidermal integrity but modestly impaired barrier function with AZD. AZD was well-tolerated with minimal side effects and comparable adverse events between treatments. Staff availability restricted recruitment (2.9/month); retention (27/28) and data completeness (95.3%) were excellent. These preliminary findings suggest that AZD may improve wound healing in patients with type 2 diabetes and warrant a fully-powered trial in patients with active ulcers. [Trial Registry: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.isrctn.com/ISRCTN74621291">www.isrctn.com/ISRCTN74621291</jats:ext-link>.</jats:p><jats:sec><jats:title>Funding</jats:title><jats:p>MRC Confidence in Concept and NIHR Senior Investigator Award.]</jats:p></jats:sec><jats:sec><jats:title>Single Sentence Summary</jats:title><jats:p>AZD4017 was safe; data suggested improved skin healing / integrity, and modestly reduced epidermal barrier function in patients with type 2 diabetes.</jats:p></jats:sec><jats:sec><jats:title>Disclosure Summary</jats:title><jats:p>I certify that neither I nor my co-authors have a conflict of interest as described above that is relevant to the subject matter or materials included in this Work.</jats:p></jats:sec>