Efficacy and safety of peripherally-restricted κ-opioid receptor agonist-HSK21542 for postoperative analgesia in patients undergoing laparoscopic abdominal surgery: a randomized, placebo-controlled phase 2 trial

Yinbo Zhong¹Haiying Wang¹Min Yan^1*Mengchang Yang²Jiaqiang Zhang³Ling Nan⁴Zhiping Wang⁵Jianjun Yang⁶Jinglei Wu⁷Qulian Guo⁸Xiaoling Hu⁹Hongmeng Xu¹⁰Qiang Xu¹¹Dongxin Wang¹²

• ¹Department of Anesthesiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
• ²Department of Anesthesiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
• ³Department of Anesthesiology, Pain and Perioperative Medicine, Henan Provincial People's Hospital, Zhengzhou, China
• ⁴Department of Anesthesiology, The First Bethune Hospital of Jilin University, Changchun, China
• ⁵Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
• ⁶Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
• ⁷Department of Anesthesiology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, China
• ⁸Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, China
• ⁹Department of Anesthesiology, First Affiliated Hospital, University of South China, Hengyang, Hunan Province, China
• ¹⁰Department of Anesthesiology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
• ¹¹Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
• ¹²Department of Anesthesiology, Peking University First Hospital, Beijing, China

Background: 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. Methods: 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 0h, 8h and 16h; group 2: preoperative HSK21542-1.0 μg/kg (or placebo)+HSK21542-0.5 μg/kg (or placebo) at postoperative 0h, 8h and 16h; groups 3 and 4: HSK21542-0.5 μg/kg or HSK21542-1.0 μg/kg (or placebo) at postoperative 0h, 8h and 16h). 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 (SPID0-24h). Results: 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 SPID0-24h 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; P=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 (P=0.020). Conclusion: 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.