Zhong Yinbo, Wang Haiying, Yan Min, Yang Mengchang, Zhang Jiaqiang, Nan Ling, Wang Zhiping, Yang Jianjun, Wu Jinglei, Guo Qulian, Hu Xiaoling, Xu Hongmeng, Xu Qiang, Wang Dongxin
Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Anesthesiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Front Med (Lausanne). 2025 Jul 24;12:1604790. doi: 10.3389/fmed.2025.1604790. eCollection 2025.
This phase 2 trial comprised dose exploration (stage 1) and dose confirmation stages (stage 2) to determine the safety and efficacy of HSK21542 in patients undergoing laparoscopic abdominal surgery.
In stage 1, patients were randomly allocated at a ratio of 4:1 (12 to receive HSK21542, 3 to receive placebo) to 4 ascending dose groups in a sequential manner (group 1: preoperative HSK21542-0.4 μg/kg (or placebo) + HSK21542-0.2 μg/kg (or placebo) at postoperative 0 h, 8 h and 16 h; group 2: preoperative HSK21542-1.0 μg/kg (or placebo) + HSK21542-0.5 μg/kg (or placebo) at postoperative 0 h, 8 h and 16 h; groups 3 and 4: HSK21542-0.5 μg/kg or HSK21542-1.0 μg/kg (or placebo) at postoperative 0 h, 8 h and 16 h). In stage 2, patients received HSK21542-0.5 μg/kg, HSK21542-1.0 μg/kg or placebo postoperatively at 0 h, 8 h and 16 h in a 1:1:1 ratio. The primary endpoints in stage 1 were the safety outcomes including the incidence and severity of treatment-emergent adverse events (TEAEs) while the primary endpoint of stage 2 was the time-weighted summed pain intensity differences over 24 h (SPID ).
Stage 1 enrolled 63 patients and 57 completed the trial, while 61 patients were enrolled in stage 2, and 60 completed the trial. The most common TEAEs were fever (22.9% vs. 41.7%), nausea (25.0% vs. 33.3%) and vomiting (22.9% vs. 25.0%) in the HSK21542 and placebo groups in stage 1. HSK21542 doses of 0.5 μg/kg and 1.0 μg/kg administered postoperatively were recommended for the subsequent stage 2. The pooled results revealed a slightly lower SPID in HSK21542-1.0 μg/kg group (-1,679.8 ± 2,284.3 scores × min) than those in HSK21542-0.5 μg/kg (-1,499.4 ± 2,487.2 scores × min) and placebo groups (-435.2 ± 2,852.9 scores × min; = 0.114). A significantly higher least squares mean difference of pain intensity differences (PID) was found in HSK21542-1.0 μg/kg group compared to the placebo ( = 0.020).
HSK21542 at all dose regimens demonstrated well tolerability and safety comparable to that of the placebo among patients undergoing laparoscopic abdominal surgery in the phase 2 trial. The dosing regimen of HSK21542-1.0 μg/kg administered postoperatively at 0 h, 8 h and 16 h exhibited an acceptable efficacy, warranting its recommendation for further phase 3 trial.
https://clinicaltrials.gov/, identifier NCT04424251.
这项2期试验包括剂量探索阶段（1期）和剂量确认阶段（2期），以确定HSK21542在接受腹腔镜腹部手术患者中的安全性和有效性。
在1期，患者按4:1的比例（12例接受HSK21542，3例接受安慰剂）依次随机分配到4个递增剂量组（第1组：术前HSK21542-0.4μg/kg（或安慰剂）+术后0小时、8小时和16小时HSK21542-0.2μg/kg（或安慰剂）；第2组：术前HSK21542-1.0μg/kg（或安慰剂）+术后0小时、8小时和16小时HSK21542-0.5μg/kg（或安慰剂）；第3组和第4组：术后0小时、8小时和16小时给予HSK21542-0.5μg/kg或HSK21542-1.0μg/kg（或安慰剂））。在2期，患者术后0小时、8小时和16小时按1:1:1的比例接受HSK21542-0.5μg/kg、HSK21542-1.0μg/kg或安慰剂。1期的主要终点是安全性结果，包括治疗期间出现的不良事件（TEAE）的发生率和严重程度，而2期的主要终点是24小时内时间加权的疼痛强度总和差异（SPID ）。
1期纳入63例患者，57例完成试验，2期纳入61例患者，60例完成试验。1期HSK21542组和安慰剂组最常见的TEAE为发热（22.9%对41.7%）、恶心（25.0%对33.3%）和呕吐（22.9%对25.0%）。建议后续2期使用术后给予0.5μg/kg和1.0μg/kg的HSK21542剂量。汇总结果显示，HSK21542-1.0μg/kg组的SPID 略低于HSK21542-0.5μg/kg组（-1,679.8±2,284.3分×分钟）和安慰剂组（-435.2±2,852.9分×分钟； =0.114）。与安慰剂相比，HSK21542-1.0μg/kg组的疼痛强度差异（PID）的最小二乘均值差异显著更高（ =0.020）。
在2期试验中，所有剂量方案的HSK21542在接受腹腔镜腹部手术的患者中均表现出良好的耐受性和与安慰剂相当的安全性。术后0小时、8小时和16小时给予1.0μg/kg的HSK21542给药方案显示出可接受的疗效，值得推荐进行进一步的3期试验。
