CONTEXT Congenital hyperinsulinism (CHI) is characterised by dysregulated insulin secretion causing hypoglycaemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycaemia as add-on to standard of care (SoC). METHODS In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/hour) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycaemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycaemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2-4. RESULTS Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n=16) or SoC (n=16). The rate of SMPG-detected hypoglycaemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2-4 (event rate ratio: 0.85 [0.54; 1.36], p=0.5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycaemia (<3.9 mmol/L) vs. SoC alone during Weeks 2-4 (post-hoc analysis; event rate ratio: 0.57 [0.39; 0.83], p=0.0029). Dasiglucagon enabled reductions (of 37-61%) in all other measures of hypoglycaemia assessed by CGM vs. SoC alone including extent and %-time in hypoglycaemia (post-hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION Clinically meaningful reductions in all CGM-recorded measures of hypoglycaemia support using dasiglucagon as a potential treatment for CHI.

中文翻译：

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Dasiglucagon 用于治疗先天性高胰岛素血症：一项针对婴儿和儿童的随机 3 期试验。

背景 先天性高胰岛素血症 (CHI) 的特点是胰岛素分泌失调，导致低血糖和随之而来的脑损伤。Dasiglucagon 是一种胰高血糖素类似物，正在研究用于治疗 CHI。目的 评估通过持续皮下输注达西高血糖素作为标准护理 (SoC) 的补充对患有 CHI 和持续性低血糖的儿童的有效性和安全性。方法 在这项开放标签试验中，患者按 1:1 的比例随机分配至 SoC 或 SoC + dasiglucagon（10-70 µg/小时），为期 4 周。在接下来的 4 周内，所有患者均接受 dasiglucagon + SoC。通过自我监测血糖（SMPG）和盲法连续血糖监测（CGM）评估低血糖。主要终点是第 2-4 周期间每周 SMPG 检测到的低血糖发作的平均次数（SMPG <3.9 mmol/L）。结果 32 名患者（0.6-10.9 岁）被随机分配至 dasiglucagon + SoC (n=16) 或 SoC (n=16)。两组中 SMPG 检测到的低血糖发生率均较基线有所下降，但在第 2-4 周期间没有统计学显着差异（事件发生率比：0.85 [0.54；1.36]，p=0.5028）。然而，在第 2-4 周期间，与单独使用 SoC 相比，给予 dasiglucagon 导致 CGM 检测到的低血糖 (<3.9 mmol/L) 降低 43%（事后分析；事件发生率比：0.57 [0.39；0.83]，p= 0.0029）。与单独使用 SoC 相比，Dasiglucagon 使 CGM 评估的所有其他低血糖指标降低（37-61%），包括低血糖的程度和时间百分比（事后分析）。Dasiglucagon 看起来安全且耐受性良好。使用 dasiglucagon + SoC 比仅使用 SoC 时皮肤和胃肠道事件更常见。结论 使用达西高血糖素作为 CHI 的潜在治疗方法，所有 CGM 记录的低血糖测量值均出现具有临床意义的降低。