A randomised controlled pilot trial of oral 11ß-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus
A randomised controlled pilot trial of oral 11ß-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus
复制标题
口服 11-HSD1 抑制剂 AZD4017 用于 2 型糖尿病成人伤口愈合的随机对照试验
DOI：
10.1101/2021.03.23.21254200
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ajjan R
中科院分区：
文献类型：
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作者：
Ajjan R
< jats: title> 摘要< jats: p> 慢性伤口（例如糖尿病足溃疡）对生活质量有重大影响，但治疗方法仍然有限。糖皮质激素会损害伤口愈合；临床前研究表明，通过 11β-羟基类固醇脱氢酶 1 型 (11β-HSD1) 阻断糖皮质激素的激活可以改善伤口修复。这项由研究者发起的双盲、随机、安慰剂对照平行组 2b 期先导试验研究了在单中心二级护理机构中，与安慰剂（PCB，n= 14）相比，通过口服 AZD4017 (AZD) 治疗 35 天的 2 型糖尿病成人 (n= 14) 抑制 11β-HSD1 的有效性、安全性和可行性。计算机生成的 1:1 随机化由药房管理。从 300 份筛选邀请中，36 人参加，28 人随机分配。没有概念证明表明 AZD 在第 28 天抑制 24 小时皮肤 11β-HSD1 活性（主要结果：调整差异 AZD-PCB 90% CI (diffCI)=-3.4, 5.5），但在第 35 天使用 AZD 时全身 11β-HSD1 活性（中位尿 [THF+ alloTHF]/THE 比率）降低 87%（PCB 1.00，AZD 0.13， diffCI=-1.04,-0.69)。基线 2mm 穿刺活检后的平均伤口间隙直径 (mm) 在第 2 天缩小了 34%（PCB 1.51，AZD 0.98，diffCI=-0.95，-0.10），在第 30 天重复受伤后缩小了 48%（PCB 1.35，AZD 0.70，diffCI=-1.15，-0.16）；结果还表明，AZD 可以提高表皮完整性，但屏障功能略有受损。 AZD 具有良好的耐受性，副作用极小，治疗之间的不良事件也相当。人员可用性限制招聘（2.9/月）；保留率 (27/28) 和数据完整性 (95.3%) 非常出色。这些初步研究结果表明，AZD 可以改善 2 型糖尿病患者的伤口愈合，并需要对活动性溃疡患者进行全面的试验。[试验登记处：< 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: sec>< jats: title> 资金< jats: p> MRC 概念信心和 NIHR 高级研究员奖。]< jats: sec>< jats: title> 单句摘要< jats: p> AZD4017 是安全的；数据表明，2 型糖尿病患者的皮肤愈合/完整性得到改善，表皮屏障功能略有降低。< jats: sec>< jats: title> 披露摘要< jats: p> 我证明，我和我的合著者均不存在与本作品中包含的主题或材料相关的上述利益冲突。
< jats: title> Abstract< jats: p> Chronic wounds (eg 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: sec>< jats: title> Funding< jats: p> MRC Confidence in Concept and NIHR Senior Investigator Award.]< jats: sec>< jats: title> Single Sentence Summary< jats: p> AZD4017 was safe; data suggested improved skin healing/integrity, and modestly reduced epidermal barrier function in patients with type 2 diabetes.< jats: sec>< jats: title> Disclosure Summary< 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.