A Global Multicenter, Randomized, Double-blinded, Propofol-controlled, Phase 3 Clinical Study to Evaluate the Efficacy and Safety of HSK3486 Injectable Emulsion for Induction of General Anesthesia in Adults Undergoing Elective Surgery

To demonstrate HSK3486 0.4/0.2 mg/kg (0.4 mg/kg intravenous [IV] slow injection over 30 [±5] seconds for the first dose, an additional 0.2 mg/kg if needed) is non-inferior to Propofol 2.0/1.0 mg/kg (2.0 mg/kg IV slow injection over 30 [±5] seconds for first dose, an additional 1.0 mg/kg if needed) in success of induction of general anesthesia in adults undergoing elective surgery.

开始日期2024-01-12

申办/合作机构

Haisco-Usa Pharmaceuticals Inc

NCT05614544 / Completed临床1期

A 2-Part, Dose-Finding and Human Abuse Potential Study Of HSK3486 Injection In Nondependent, Recreational Central Nervous System Depressant Users

Part 1: To determine the doses of IV HSK3486 and propofol for use in Part 2, the abuse potential part of the study.
Part 2: To evaluate the abuse potential of HSK3486 compared with propofol when administered IV to healthy nondependent, recreational CNS depressant drug users.

开始日期2022-08-16

申办/合作机构

Haisco-Usa Pharmaceuticals Inc

NCT05478174 / Completed临床3期

A Multicenter, Randomized, Double-blinded, Propofol-controlled, Phase 3 Clinical Study to Evaluate the Efficacy and Safety of HSK3486 Injectable Emulsion for Induction of General Anesthesia in Adults Undergoing Elective Surgery

To demonstrate HSK3486 0.4/0.2 mg/kg (0.4 mg/kg intravenous [IV] slow injection over 30 [±5] seconds for the first dose, an additional 0.2 mg/kg if needed) is non-inferior to propofol 2.0/1.0 mg/kg (2.0 mg/kg IV slow injection over 30 [±5] seconds for first dose, an additional 1.0 mg/kg if needed) in success of induction of general anesthesia in adults undergoing elective surgery.

开始日期2022-07-26

申办/合作机构

Haisco-Usa Pharmaceuticals Inc

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2024-04-01·Anesthesiology

Comparison of the Efficacy of HSK3486 and Propofol for Induction of General Anesthesia in Adults: A Multicenter, Randomized, Double-blind, Controlled, Phase 3 Noninferiority Trial

Article

作者: Bertoch, Todd ; Yan, Pangke ; Liu, Xiao ; Zhou, Rong ; Lai, Yu-Ling ; Gelb, Adrian W ; Essandoh, Michael ; Habib, Ashraf S ; Gan, Tong J ; Daley, William L

BackgroundPropofol is an intravenous anesthetic associated with hypotension, respiratory depression, and injection-site pain. HSK3486 injectable emulsion (ciprofol) is a 2,6-disubstituted phenol derivative with fast onset and quick, stable recovery. Previous studies support HSK3486 as an effective, safe anesthetic with substantially less injection-site pain than propofol. The primary objective of this study was to investigate the noninferiority of HSK3486 compared with propofol in successful general anesthesia induction.MethodsTwo hundred fifty-five participants were enrolled in HSK3486-304, a multicenter, randomized (2:1), double-blind, propofol-controlled, phase 3 study evaluating HSK3486 for general anesthesia induction in adults undergoing elective surgery with tracheal intubation. The primary endpoint was successful anesthesia induction, defined as 1 or less on the Modified Observer’s Assessment of Alertness/Sedation scale. Key secondary endpoints were proportion of participants with injection-site pain on the Numerical Rating Scale of 1 or greater and a composite endpoint, including the proportion of participants successfully induced while maintaining the desired anesthetic depth and without substantial cardiac and respiratory events. Safety endpoints included adverse events, abnormal vital signs, and injection-site pain.ResultsTwo hundred fifty-one participants (HSK3486, n = 168; propofol, n = 83) were included in the analyses. General anesthesia was successfully induced in 97.0% versus 97.6% of participants with HSK3486 and propofol, respectively. The difference in success rate was −0.57% (95% CI, −5.4 to 4.2%); the noninferiority boundary of −8% was not crossed. Thirty participants (18.0%) had injection-site pain with HSK3486 versus 64 (77.1%) with propofol (P < 0.0001). Eighty-one participants (48.2%) with HSK3486 versus 42 (50.6%) with propofol (P = 0.8780) satisfied the composite endpoint. When injection-site pain was excluded, the incidence of treatment-emergent adverse events related to study drug was 17.9% for HSK3486 and 14.5% for propofol.ConclusionsThe study met its primary objective and endpoint, demonstrating noninferiority of HSK3486 compared with propofol in successful anesthetic induction. Substantially less injection-site pain was associated with HSK3486 than with propofol.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

2023-04-14·Cancer Research

Abstract CT128: Phase 1 study of HSK29116, a Bruton tyrosine kinase (BTK) proteolysis-targeting chimera (PROTAC) agent, in patients with relapsed or refractory B-cell malignancies

作者: Cao, Yong ; Hu, Mengyue ; Yan, Pangke ; Xu, Wei ; Daley, William ; Li, Jianyong

AbstractBACKGROUND: BTK, a non-receptor kinase in the B-cell receptor signaling pathway, plays an essential role in B-cell development and differentiation. BTK is critical for malignant B-cell survival. Oral BTK inhibitors (BTKis), standard treatments for patients (pts) with B-cell malignancies, prevent proliferation and induce apoptosis of B cells. Currently approved BTKis covalently bind to BTK residue C481, irreversibly inhibiting phosphorylation of downstream kinases and blocking B-cell activation. Because these agents are often given continuously, their use may lead to clinical resistance and unacceptable toxicities. Indeed, acquired resistance to covalent BTKis is common and caused by the expansion of clones with a cysteine-to-serine mutation at residue 481.A novel strategy being developed to overcome BTKi resistance, is PROTAC-induced degradation of BTK. PROTACs are small molecules with one domain that binds the target protein linked to another domain that binds to ubiquitin E3 ligase, resulting in ubiquitin-dependent proteasome degradation of the target protein. HSK29116 is a small BTK PROTAC molecule that is currently undergoing clinical investigation for the treatment of B-cell malignancies. In preclinical studies, HSK29116 overcame drug resistance caused by the C481S BTK mutation. Also, HSK29116 has demonstrated inhibition of B-cell proliferation without measurable loss of other BTK-family kinase activities. This kinase selectivity may limit some of the off-target toxicities seen with currently available BTKis.METHODS: This first-in-human, multicenter, open-label, phase 1 study (NCT04861779) began recruiting in 2021 to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of oral HSK29116. Eligible pts are ≥18 years old with diagnosis of a B-cell malignancy that has relapsed or become refractory to standard therapy (≥2 prior systemic therapies, which may have included a BTKi) and for which no other treatments known to provide clinical benefit exist. Pts must have an Eastern Cooperative Oncology Group performance status ≤2 and life expectancy >3 months. Phase 1a includes dose escalation to identify dose-limiting toxicities and establish the maximum tolerated dose and/or recommended dose of HSK29116 for a phase 1b dose expansion, initiating in the US. Approximately 36 pts will be enrolled in phase 1a and 90 pts in phase 1b (≥40 pts must have previously received covalent BTKis). The primary endpoint is safety. Secondary endpoints include PK and investigator-assessed overall response rate, duration of response, time to response, and progression-free survival. Exploratory analyses will evaluate the relationship between HSK29116 anti-tumor activity and BTK gene mutations, as well as BTK protein degradation effects of HSK29116. Descriptive statistics will be used to summarize all data.Citation Format: Jianyong Li, Wei Xu, Pangke Yan, Yong Cao, Mengyue Hu, William Daley. Phase 1 study of HSK29116, a Bruton tyrosine kinase (BTK) proteolysis-targeting chimera (PROTAC) agent, in patients with relapsed or refractory B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT128.

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