Comparison of ciprofol (HSK3486) versus propofol for the induction of deep sedation during gastroscopy and colonoscopy procedures: A multi‐centre, non‐inferiority, randomized, controlled phase 3 clinical trial

Li, Junxiang; Wang, Xiao; Liu, Jin; Wang, Xia; Li, Xiangkui; Wang, Yaping; Ouyang, Wen; Li, Jun; Yao, Shanglong; Zhu, Ziling; Guo, Qulian; Yu, Yonghao; Ji, Meng; Zuo, Yong

doi:10.1111/bcpt.13761

Cited by 56 publications

(69 citation statements)

References 36 publications

(50 reference statements)

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“…Satisfaction of both patients and endoscopist and patients’ willingness to repeat FB were higher in the ciprofol-remifentanil group than in the propofol-remifentanil group, which may also be due in part to the lower incidence of pain on injection. Inconsistent with the results of a previous study, the incidence of AEs, except pain on injection, was similar between the two groups ( Li et al, 2022 ). These differences may be due to small sample sizes in our trial and different anesthesia schemes.…”

Section: Discussionsupporting

confidence: 87%

“…Although the pharmacokinetic characteristics of 0.4 mg/kg of ciprofol are similar in elderly and non-elderly patients in some studies, this trial used 0.3 mg/kg of ciprofol to account for a variety of patient factors, procedure differences, and anesthesia schemes (especially the combination with remifentanil). Previous phase I–III clinical trials have reported that only 20%–25% of a ciprofol dose was needed to achieve the same anesthetic effect as propofol ( Hu et al, 2021 ; Li et al, 2022 ; Liu et al, 2022 ). Thus, this trial used 1.2 mg/kg propofol during anesthesia induction.…”

Section: Discussionmentioning

confidence: 99%

“…Ciprofol (2-[(1R)-[1-cyclopropylethyl]]-6-isopropylphenol) binds to the α1β2γ2 subtype of the gamma-aminobutyric acid (GABA)-a receptor and has improved pharmacological and physicochemical properties compared with propofol ( Qin et al, 2017 ). It is a promising anesthetic candidate; it has a rapid onset of action and, compared with propofol, has a higher therapeutic index, less respiratory depression, reduced inhibition of cardiac function, and less associated pain on injection, according to the results of several phase I–III trials in China and Australia ( Hu et al, 2021 ; Li et al, 2022 ; Liu et al, 2022 ). However, limited data are available regarding its use during FB ( Luo et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Zhu

Wang

et al. 2022

Front. Pharmacol.

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Objective: Ciprofol is a novel 2,6-disubstituted phenol derivative that has improved pharmacokinetic and pharmacodynamic properties compared with propofol. This study was conducted to compare the efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil for patients undergoing fiberoptic bronchoscopy.Methods: Overall, 92 patients undergoing fiberoptic bronchoscopy were included in this prospective, randomized, double-blind, non-inferiority trial and were equally divided into two groups (n = 46 each). Fentanyl (50 μg) was given 2 min before the intravenous infusion of 0.3 mg/kg of ciprofol or 1.2 mg/kg of propofol over a time period of 30 s. During anesthesia maintenance, 0.05–0.2 μg/kg/min of remifentanil combined with one-third to one-fourth of the initial dose of ciprofol or propofol was repeated at 2-min intervals, as required, to maintain a Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale score <3. The primary outcome was the successful rate of fiberoptic bronchoscopy. Secondary outcomes included demographic characteristics, time metrics, hemodynamics, coughing severity, intubating conditions, lowest oxygen saturation, utilization of study drug doses, number of remedies (lidocaine and vasoactive drugs) used, satisfaction scores of both patients and the endoscopist, occurrence of intraoperative awareness, patients’ willing to repeat fiberoptic bronchoscopy, and occurrence and severity of adverse events.Results: The successful completion rate of fiberoptic bronchoscopy was 91.30% (42 of 46; 95% confidence interval [CI]: 82.80%–99.80%) in the ciprofol-remifentanil group and 89.13% (41 of 46; 95% CI: 79.80%–98.50%) in the propofol-remifentanil group. Though the clinically acceptable intubating condition was improved in the ciprofol-remifentanil group, this difference has no clinical statistical difference (p > 0.05). No significant differences were noted between the two groups with respect to time metrics, consumption of fentanyl and remifentanil, or number of remedies (lidocaine and vasoactive drugs). Patients’ willingness to repeat fiberoptic bronchoscopy and the satisfaction of both patients and endoscopist were significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). Compared with patients in the propofol-remifentanil group, patients in the ciprofol-remifentanil group had more stable hemodynamics. The lowest oxygen saturation was significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). The numbers of patients who experienced pain on injection in the ciprofol-remifentanil group was significantly lower than the number in the propofol-remifentanil group (p < 0.01). Severity of coughing, clinically acceptable severity of coughing, incidence of intraoperative awareness, and other adverse events were all similar between the two groups (p > 0.05). Only four patients experienced grade 2 adverse events (severe hypotension in one patient in the ciprofol-remifentanil group and three patients in the propofol-remifentanil group; p > 0.05); they were treated with noradrenaline.Conclusion: Ciprofol-remifentanil was non-inferior to propofol-remifentanil with regard to successful sedation for flexible bronchoscopy, when used with pre-intravenous administration of 50 μg of fentanyl. At the same time, patients’ willingness to repeat flexible bronchoscopy and the satisfactions were all significantly improved.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Zhu

Wang

et al. 2022

Front. Pharmacol.

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“…A phase III clinical trial was subsequently conducted in China to compare the effects of ciprofol and propofol on inducing deep sedation during gastroscopy ( n = 30) and colonoscopy ( n = 259) procedures [ 25 ]. In this trial, the success rate of colonoscopy was 100% in the ciprofol group and 99.2% in the propofol group (mean difference, 0.8%; 95% CI: 2.2% to 4.2%); the gastroscopy success rate was 100% in both groups.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…There were no significant differences between the two groups in terms of induction time (MOAA/S ≤ 1 after administration of the initial dose), insertion time, and insertion success rates. It is worth noting that the mean time for a patient to become fully alert in the ciprofol group was longer than the propofol group in the overall analysis, and the time to discharge of the ciprofol group was significantly longer than that of the propofol group (7.4 ± 3.1 min vs. 6.0 ± 2.1 min, P < 0.001), whereas patient satisfaction scores of the ciprofol group were significantly superior to that of the propofol group (9.9 ± 0.4 vs. 9.7 ± 0.7, P = 0.001) [ 25 ]. A larger number of subjects demonstrated ciprofol 0.4 mg/kg were noninferior to 1.5 mg/kg propofol in the success rate of gastroscopy or colonoscopy.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Ciprofol: A Novel Alternative to Propofol in Clinical Intravenous Anesthesia?

Liu

et al. 2023

BioMed Research International

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Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products Administration and the information of official website, indications for ciprofol include sedation and anesthesia during the surgical/procedure of nontracheal intubation, induction and maintenance of general anesthesia, and sedation during intensive care. Ciprofol is a short-acting intravenous sedative based on the structural modification of propofol. Ciprofol has high efficacy, good selectivity, and fewer adverse reactions, indicating good clinical application potential. A series of clinical studies have been conducted to evaluate the sedative effect of ciprofol in various procedures and settings, including gastroscopy and colonoscopy, fiber-optic bronchoscopy, general anesthesia in elective surgeries, and mechanical ventilation in intensive care units. This review summarizes the chemical structure, pharmacodynamics, and pharmacokinetic properties of ciprofol. We also assessed the efficacy and safety of ciprofol by synthesizing the relevant clinical trial data.

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Model‐informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations

Zhang

Liu

et al. 2023

Biopharm & Drug Disp

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HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi-enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model-informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates.However, under the same dose, the predicted exposure of pediatric patients aged 1 month to 17 years was decreased significantly (about 21%-39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%-31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure-response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4 mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486.

show abstract

Comparison of ciprofol (HSK3486) versus propofol for the induction of deep sedation during gastroscopy and colonoscopy procedures: A multi‐centre, non‐inferiority, randomized, controlled phase 3 clinical trial

Cited by 56 publications

References 36 publications

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial

Ciprofol: A Novel Alternative to Propofol in Clinical Intravenous Anesthesia?

Model‐informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations

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