Efficacy and Safety of HSK3486 for Anesthesia/Sedation in Patients Undergoing Fiberoptic Bronchoscopy: A Multicenter, Double-Blind, Propofol-Controlled, Randomized, Phase 3 Study

Zhen Luo, Hong Tu, Xiang Zhang, Xiao Wang, Wen Ouyang, Xinchuan Wei, Xiaohua Zou, Zhaoqiong Zhu, Yalan Li, Wangning Shangguan, Hui Wu, Yaping Wang, Qulian Guo, Zhen Luo, Hong Tu, Xiang Zhang, Xiao Wang, Wen Ouyang, Xinchuan Wei, Xiaohua Zou, Zhaoqiong Zhu, Yalan Li, Wangning Shangguan, Hui Wu, Yaping Wang, Qulian Guo

Abstract

Background: Fiberoptic bronchoscopy is a complex procedure with the need for sufficient patient anesthesia/sedation while maintaining safety. This trial aimed to evaluate the efficacy, safety, and pharmacokinetics of HSK3486 during fiberoptic bronchoscopy.

Methods: This multicenter, double-blind, randomized, non-inferiority, parallel-group phase 3 trial was conducted in patients who underwent fiberoptic bronchoscopy. Patients randomly received HSK3486 0.4 mg/kg (N = 134) or propofol 2.0 mg/kg (N = 133). The primary efficacy endpoint was the successful rate of fiberoptic bronchoscopy, and secondary efficacy endpoints included successful induction of anesthesia/sedation, duration, time to being fully alert, and time to patient discharge. Safety assessments and drug concentrations were also measured.

Results: A total of 267 patients completed fiberoptic bronchoscopy, with a success rate of 100% and a 95% confidence interval of - 2.8 to 2.8% for the difference between the groups, which met the predesigned criteria of > - 8%, confirming the non-inferiority of anesthesia/sedation produced by HSK3486 compared to propofol. Among the secondary efficacy endpoints, only time to full alertness (median 8.50 vs. 6.00 min, P = 0.012) and time to discharge (median 13.00 vs. 9.87 min, P = 0.002) were slightly longer in the HSK3486 group. The incidence of adverse events was significant lower in the HSK3486 group (52.6 vs. 76.5%, P < 0.001) mainly because of less pain on injection (4.4 vs. 39.4%, P < 0.001) compared to the propofol group. HSK3486 had a similar terminal elimination half-life as propofol.

Conclusions: HSK3486 exhibited non-inferiority anesthesia/sedation compared to propofol in patients undergoing fiberoptic bronchoscopy, and had a good safety profile with a lower incidence of pain on injection.

Trial registration: Clinicaltrials.gov, NCT04111159, registered on 1 October 2019.

Conflict of interest statement

ZL, HT, XZ, XW, WOY, XCW, XHZ, ZQZ, YLL, WNSG, HW, YPW and QLG declare that they have no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Enrolment flow diagram. FAS full analysis set, PKS pharmacokinetics analysis set, SS safety set
Fig. 2
Fig. 2
The time course of median Modified Observer Assessment of Alertness/Sedation (MOAA/S) score in the two groups
Fig. 3
Fig. 3
Vital signs over time. A Systolic blood pressure (SBP), B diastolic blood pressure (DBP), C mean arterial pressure (MAP), D heart rate, E respiratory rate and F oxygen saturation (SpO2)
Fig. 4
Fig. 4
Mean plasma concentration-time curve linear plot. The plasma concentration during the first 6 h followed first-order kinetics

References

    1. Alon D, Pertzov B, Gershman E, Frishman M, Rahman NA, Rosengarten D, et al. The safety of laryngeal mask airway-assisted bronchoscopy versus standard nasal bronchoscopy. Respiration. 2017;93(4):279–284. doi: 10.1159/000456551.
    1. Wahidi MM, Jain P, Jantz M, Lee P, Mackensen GB, Barbour SY, et al. American College of Chest Physicians consensus statement on the use of topical anesthesia, analgesia, and sedation during flexible bronchoscopy in adult patients. Chest. 2011;140(5):1342–1350. doi: 10.1378/chest.10-3361.
    1. José RJ, Shaefi S, Navani N. Sedation for flexible bronchoscopy: current and emerging evidence. Eur Respir Rev. 2013;22(128):106. doi: 10.1183/09059180.00006412.
    1. Becker HD. Bronchoscopy: the past, the present, and the future. Clin Chest Med. 2010;31(1):1–18. doi: 10.1016/j.ccm.2009.11.001.
    1. Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013;68(Suppl 1):i1–i44. doi: 10.1136/thoraxjnl-2013-203618.
    1. Gonzalez R, De-La-Rosa-Ramirez I, Maldonado-Hernandez A, Dominguez-Cherit G. Should patients undergoing a bronchoscopy be sedated? Acta Anaesthesiol Scand. 2003;47(4):411–415. doi: 10.1034/j.1399-6576.2003.00061.x.
    1. Hatton MQ, Allen MB, Vathenen AS, Mellor E, Cooke NJ. Does sedation help in fibreoptic bronchoscopy? BMJ (Clin Res Ed). 1994;309(6963):1206–1207. doi: 10.1136/bmj.309.6963.1206.
    1. Goudra BG, Singh PM, Borle A, Farid N, Harris K. Anesthesia for advanced bronchoscopic procedures: state-of-the-art review. Lung. 2015;193(4):453–465. doi: 10.1007/s00408-015-9733-7.
    1. British Thoracic Society Bronchoscopy Guidelines Committee aSoSoCCoBTS British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax. 2001;56(Suppl 1):i1–21.
    1. Putinati S, Ballerin L, Corbetta L, Trevisani L, Potena A. Patient satisfaction with conscious sedation for bronchoscopy. Chest. 1999;115(5):1437–1440. doi: 10.1378/chest.115.5.1437.
    1. Matot I, Kramer MR. Sedation in outpatient bronchoscopy. Respir Med. 2000;94(12):1145–1153. doi: 10.1053/rmed.2000.0926.
    1. Clark G, Licker M, Younossian AB, Soccal PM, Frey JG, Rochat T, et al. Titrated sedation with propofol or midazolam for flexible bronchoscopy: a randomised trial. Eur Respir J. 2009;34(6):1277. doi: 10.1183/09031936.00142108.
    1. Lo Y-L, Lin T-Y, Fang Y-F, Wang T-Y, Chen H-C, Chou C-L, et al. Feasibility of bispectral index-guided propofol infusion for flexible bronchoscopy sedation: a randomized controlled trial. PLoS One. 2011;6(11):e27769-e. doi: 10.1371/journal.pone.0027769.
    1. Schlatter L, Pflimlin E, Fehrke B, Meyer A, Tamm M, Stolz D. Propofol versus propofol plus hydrocodone for flexible bronchoscopy: a randomised study. Eur Respir J. 2011;38(3):529–537. doi: 10.1183/09031936.00121610.
    1. Tan LH, Hwang NC. The effect of mixing lidocaine with propofol on the dose of propofol required for induction of anesthesia. Anesth Analg. 2003;97(2):461–464. doi: 10.1213/01.ANE.0000066357.63011.75.
    1. Desousa KA. Pain on propofol injection: causes and remedies. Indian J Pharmacol. 2016;48(6):617–623. doi: 10.4103/0253-7613.194845.
    1. Marik PE. Propofol: therapeutic indications and side-effects. Curr Pharm Des. 2004;10(29):3639–3649. doi: 10.2174/1381612043382846.
    1. Qin L, Ren L, Wan S, Liu G, Luo X, Liu Z, et al. Design, synthesis, and evaluation of novel 2,6-disubstituted phenol derivatives as general anesthetics. J Med Chem. 2017;60(9):3606–3617. doi: 10.1021/acs.jmedchem.7b00254.
    1. Bian Y, Zhang H, Ma S, Jiao Y, Yan P, Liu X, et al. Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects. Br J Clin Pharmacol. 2020;87:93–105. doi: 10.1111/bcp.14363.
    1. Hu C, Ou X, Teng Y, Shu S, Wang Y, Zhu X, et al. Sedation effects produced by a ciprofol initial infusion or bolus dose followed by continuous maintenance infusion in healthy subjects: a phase 1 trial. Adv Ther. 2021;38(11):5484–5500. doi: 10.1007/s12325-021-01914-4.
    1. Li X, Yang D, Li Q, Wang H, Wang M, Yan P, et al. Safety, pharmacokinetics, and pharmacodynamics of a single bolus of the γ-aminobutyric acid (GABA) receptor potentiator HSK3486 in healthy Chinese elderly and non-elderly. Front Pharmacol. 2021;12:2232.
    1. Teng Y, Ou M, Wang X, Zhang W, Liu X, Liang Y, et al. Efficacy and safety of ciprofol for the sedation/anesthesia in patients undergoing colonoscopy: phase IIa and IIb multi-center clinical trials. Eur J Pharm Sci. 2021;164:105904. doi: 10.1016/j.ejps.2021.105904.
    1. Common Terminology Criteria for Adverse Events (CTCAE v5.0). 2017. . Accessed 27 Nov 2017.
    1. Teng Y, Ou M, Wang X, Zhang W, Liu X, Liang Y, et al. Pharmacokinetic and pharmacodynamic properties of ciprofol emulsion in Chinese subjects: a single center, open-label, single-arm, dose-escalation phase 1 study. Am J Transl Res. 2021 (in press).
    1. Food and Drug Administration. Non-inferiority clinical trials to establish effectiveness. In: Guidance for industry. 2016.
    1. Committee for Medicinal Products for Human U, Efficacy Working P, Committee for Release for C. Committee for Medicinal Products for Human Use (CHMP) guideline on the choice of the non-inferiority margin. Stat Med. 2006;25(10):1628–38.
    1. Pastis NJ, Yarmus LB, Schippers F, Ostroff R, Chen A, Akulian J, et al. Safety and efficacy of remimazolam compared with placebo and midazolam for moderate sedation during bronchoscopy. Chest. 2019;155(1):137–146. doi: 10.1016/j.chest.2018.09.015.
    1. Silvestri GA, Vincent BD, Wahidi MM, Robinette E, Hansbrough JR, Downie GH. A phase 3, randomized, double-blind study to assess the efficacy and safety of fospropofol disodium injection for moderate sedation in patients undergoing flexible bronchoscopy. Chest. 2009;135(1):41–47. doi: 10.1378/chest.08-0623.
    1. Morgan GE, Mikhail MS, Murray MJ. Clinical anesthesiology. 3. The McGraw-Hill Companies, Inc; 2001.
    1. Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;182:335–360. doi: 10.1007/978-3-540-74806-9_16.
    1. Bergese SD, Candiotti KA, Bokesch PM, Zura A, Wisemandle W, Bekker AY. A Phase IIIb, randomized, double-blind, placebo-controlled, multicenter study evaluating the safety and efficacy of dexmedetomidine for sedation during awake fiberoptic intubation. Am J Ther. 2010;17(6):586–595. doi: 10.1097/MJT.0b013e3181d69072.
    1. Kamibayashi T, Maze M. Clinical uses of alpha2-adrenergic agonists. Anesthesiology. 2000;93(5):1345–1349. doi: 10.1097/00000542-200011000-00030.
    1. Oztürk T, Cakan A, Gülerçe G, Olgaç G, Deren S, Ozsöz A. Sedation for fiberoptic bronchoscopy: fewer adverse cardiovascular effects with propofol than with midazolam. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS. 2004;39(10):597–602. doi: 10.1055/s-2004-825919.
    1. Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg. 2000;90(4):963–969. doi: 10.1213/00000539-200004000-00035.
    1. Doenicke AW, Roizen MF, Rau J, Kellermann W, Babl J. Reducing pain during propofol injection: the role of the solvent. Anesth Analg. 1996;82(3):472–474.
    1. Klement W, Arndt JO. Pain on injection of propofol: effects of concentration and diluent. Br J Anaesth. 1991;67(3):281–284. doi: 10.1093/bja/67.3.281.
    1. Devaud JC, Berger MM, Pannatier A, Marques-Vidal P, Tappy L, Rodondi N, et al. Hypertriglyceridemia: a potential side effect of propofol sedation in critical illness. Intensive Care Med. 2012;38(12):1990–1998. doi: 10.1007/s00134-012-2688-8.
    1. Corrado MJ, Kovacevic MP, Dube KM, Lupi KE, Szumita PM, DeGrado JR. The incidence of propofol-induced hypertriglyceridemia and identification of associated risk factors. Crit Care Explor. 2020;2(12):e0282. doi: 10.1097/CCE.0000000000000282.
    1. Sebel PS, Lowdon JD. Propofol: a new intravenous anesthetic. Anesthesiology. 1989;71(2):260–277. doi: 10.1097/00000542-198908000-00015.
    1. Mankes RF. Propofol wastage in anesthesia. Anesth Analg. 2012;114(5):1091–1092. doi: 10.1213/ANE.0b013e31824ea491.
    1. Field-Ridley A, Sethi V, Murthi S, Nandalike K, Li S-TT. Utility of flexible fiberoptic bronchoscopy for critically ill pediatric patients: a systematic review. World J Crit Care Med. 2015;4(1):77–88. doi: 10.5492/wjccm.v4.i1.77.
    1. Kanaya N, Gable B, Wickley Peter J, Murray Paul A, Damron DS. Experimental conditions are important determinants of cardiac inotropic effects of propofol. Anesthesiology. 2005;103(5):1026–1034. doi: 10.1097/00000542-200511000-00017.
    1. Nagakawa T, Yamazaki M, Hatakeyama N, Stekiel TA. The mechanisms of propofol-mediated hyperpolarization of in situ rat mesenteric vascular smooth muscle. Anesth Analg. 2003;97(6):1639–1645. doi: 10.1213/01.ANE.0000087043.61777.1F.

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