Efficacy and Safety of SHR8554 on Postoperative Pain in Subjects with Moderate to Severe Acute Pain Following Orthopedic Surgery: A Multicenter, Randomized, Double-blind, Dose-explored, Active-controlled, Phase II/III Clinical Trial

Abstract

Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24hours (rSPID₂₄). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID₂₄ compared to morphine for the 0.05mg,0.1mg, and 0.2mg SHR8554 groups were 16.8 (p=0.01), 7.4 (p=0.27), and 0.2 (p=0.98), respectively. Phase III confirmed the efficacy of the 0.05mg and 0.1mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p=0.0001) and -19.8 (p<0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2mg SHR8554 group had higher incidences of TEAEs (83.3%) and AESIs (33.3%) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0%, 73.4%, and 74.1% in the 0.05 and 0.1mg SHR8554 and morphine groups, respectively, compared with 61.3% in the placebo group, while the AESIs were 29.1%, 20.3%, and 24.7% compared with 12.5% in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery. TRIAL REGISTRATION: Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.

Keywords: Phase II/III clinical trial; Postoperative; SHR8554; analgesia; biased μ-opioid receptor agonist; orthopedic surgery; patient controlled.