SFEBES2021 Poster Presentations Metabolism, Obesity and Diabetes (78 abstracts)
A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus
Ramzi Ajjan 1,2 , Elizabeth Hensor 1,3 , Kave Shams 1,4 , Francesco Del Galdo 1,3 , Afroze Abbas 1 , Janet Woods 2 , Rebecca Fairclough 5 , Lindsay Pegg 5 , Adrian Freeman 5 , Ann Morgan 1,3 , Paul Stewart 1 , Angela Taylor 6 , Wiebke Arlt 6,7 , Abd Tahrani 6,7 , David Russell 1,2 & Ana Tiganescu 1
1University of Leeds, Leeds, United Kingdom; 2Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; 3NIHR Biomedical Research Center, Leeds, United Kingdom; 4Leeds Centre for Dermatology, Leeds, United Kingdom; 5AstraZeneca, Cambridge, United Kingdom; 6University of Birmingham, Birmingham, United Kingdom; 7University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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 3 mm 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: www.isrctn.com/ISRCTN74621291.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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