Background & Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes including hepatic encephalopathy (HE). Androgen receptor agonists, ARAs, can address these conditions through multimodal mechanisms of action, however their safety and efficacy in patients with cirrhosis have not been well established. Approach & Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral ARA LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary endpoint was the change from baseline to 24 weeks in skeletal muscle index measured by computed tomography scan of the L3 region (L3-SMI), analyzed with a prespecified modified intent-to-treat population. The secondary endpoint was the number of overt HE events. 29 participants (mean age=59 y, MELD=17) received at least one dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary endpoint analysis demonstrated an increase in L3-SMI in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm2/m2 (95% CI, 1.3-7.4 cm2/m2, p=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (CTCAE grade ≥2; p=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

中文翻译：

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口服 LPCN 1148 改善男性肝硬化患者的肌肉减少症和肝性脑病：一项随机、安慰剂对照的 2 期试验


背景和目标：肌肉减少症在肝硬化患者中非常普遍，并与包括肝性脑病（HE）在内的不良临床结果有关。雄激素受体激动剂 ARA 可以通过多模式作用机制解决这些情况，但其在肝硬化患者中的安全性和有效性尚未得到充分证实。方法和结果：在这项多中心、双盲、2期试验中，等待肝移植的肌肉减少症和肝硬化男性被随机分配1：1接受口服ARA LPCN 1148或安慰剂治疗24周（NCT04874350）。主要终点是通过 L3 区计算机断层扫描 （L3-SMI） 测量的骨骼肌指数从基线到 24 周的变化，并使用预先指定的改良意向治疗人群进行分析。次要终点是显性 HE 事件的数量。29 名参与者 （平均年龄 = 59 岁，MELD=17） 接受了至少一剂 LPCN 1148 （n=15） 或安慰剂 （n=14）。各组之间的基线特征相似。主要终点分析显示，与安慰剂 （n=10） 相比，LPCN 1148 组 （n=15） 的 L3-SMI 增加，平均组差异为 4.4 cm2/m2 （95% CI，1.3-7.4 cm2/m2，p=0.007）。与安慰剂相比，LPCN 1148 的参与者经历的显性 HE 发作更少 （CTCAE ≥2 级;p=0.02）。两组之间治疗中出现的不良事件的数量和严重程度相似。结论： LPCN 1148 治疗改善了等待肝移植的肝硬化和肌肉减少症男性的肌肉减少症，减少了显性 HE 发作的次数。这些发现支持了关于 LPCN 1148 治疗肌肉减少症和预防 HE 复发疗效的更多研究。