HSK3486 (ciprofol) is a newly developed drug and a 2,6-disubstituted phenol derivative acting like propofol on gamma-aminobutyric acid-A receptors for induction and maintenance of anaesthesia and sedation which avoids the known injection pain associated with propofol aqueous phase in a lipid emulsion formulation since the aqueous phase concentration of HSK3486 in a 1% lipid emulsion is significantly less than that of propofol in a 1% lipid emulsion.
Previous studies suggested potential clinical advantages of HSK3486 as an anaesthetic agent, with no evidence of drug-related toxicity.
In this phase 3 trial the efficacy and safety of ciprofol compared to propofol for induction and maintenance of general anaesthesia has been evaluated and noninferiority in regard to its anaesthetic capability has been met.
HSK3486 (ciprofol, produced by the Haisco Pharmaceutical Group Co. Ltd, Chengdu, China), is a diastereoisomer containing two chiral centers in the R-configuration,
developed as an alternative general anesthetic to propofol. HSK3486 is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABA 1 A) receptor. In a phase 1 trial conducted in healthy patients given bolus doses (up to 0.9 mg kg 1 −1) or a continuous infusion for up to 12 h, 2 HSK3486 showed an excellent tolerance capability. HSK3486 also induced a noninferiority anaesthesia/sedation effect as did propofol during gastrointestinal endoscopy, 3 fiberoptic bronchoscopy procedures, 4 induction of general anaesthesia 5 as well as in intensive care units, 6 with stable haemodynamic characteristics. It is worth noting that pain on injection rarely occurred after a bolus injection of HSK3486 in previous studies; 7 which may be a result of the lower concentration of HSK3486 in the aqueous phase in the 1% lipid emulsion formulation. 2,8 A previous study recommended a dose of 0.3 mg kg 1,9 −1 HSK3486 for elderly patients, which produced a similarly efficacy to 0.4 mg kg −1 given to younger patients. 10
A former phase 2 trial showed that 30 patients who received a HSK3486 (0.8 mg kg
−1 h −1) infusion exhibited a 100% success rate for the maintenance of general anaesthesia, with higher satisfaction scores from anaesthesiologists, and a lower incidence of drug-related hypotension. Therefore, the present phase 3 trial was designed to involve a broader range of elective surgical patients to investigate the potential applications of HSK3486 in China. The key objective was to confirm the noninferiority of HSK3486 vs. propofol with regard to its anaesthetic capability. Secondary objectives were to evaluate the safety profiles and to determine the plasma concentrations of HSK3486 during general anaesthesia in patients who underwent nonemergency, noncardiothoracic, and nonbrain surgery. 11 Methods
Study design and participants
This was a multicentre, single-blinded, propofol-controlled, randomised, phase 3 trial involving 10 study centers, conducted from November 24, 2020 to January 25, 2021. The trial protocols were approved by the ethical committees of West China Hospital of Sichuan University, Chengdu, China, reference number HX-IRB-AF-15-V4.0 (Chairperson Prof. Yerong Yu) on September 14, 2020. All patients provided informed consent prior to enrolment, in accordance with the guidelines of each study centre. The trial was prospectively registered with clinicaltrials.gov (NCT04511728).
The centre random method was applied to competitively enrol 129 eligible patients from 10 study centres. They were randomly assigned to either the HSK3486 group or the propofol group at a ratio of 2:1 (86 patients in the HSK3486 group and 43 in the propofol group). A single-blinded design was adopted, in which patients and investigators who evaluated indicators were blinded during the whole process, while investigators in charge of drug administration and random grouping were not blinded. This study included screening period (Day −14 to Day −1), drug administration period (Day 1), postoperative observation period (Day 1) and follow-up periods (Day 2).
The inclusion criteria included: patients who underwent general anaesthesia (American Society of Anesthesiologists (ASA) classes I to II); aged ≥18 years and ≤65 years; scheduled for more than 1-h nonemergency, noncardiothoracic, and nonbrain elective surgery; and who required tracheal intubation. The key exclusion criteria included: patients with contraindications to general anaesthesia; a history of anaesthesia incidents; a disease history of cardiovascular, respiratory, neurological, psychiatric and gastrointestinal systems that could increase the risk of sedation/anaesthesia. Table 1, Supplemental Digital Content,
gives more detailed information about inclusion and exclusion criteria. https://links.lww.com/EJA/A797 Trial procedures
After baseline measurements, all eligible patients were given midazolam 0.04 mg kg
−1 and sufentanil 0.3 μg kg −1 as preanaesthetic medication. Anaesthesia induction was then initiated with either HSK3486 or propofol. After successful induction, the muscle relaxant rocuronium bromide was administered at 0.6 mg kg −1, and endotracheal intubation was performed. HSK3486 or propofol was given at appropriate doses to maintain anaesthesia after the completion of tracheal intubation. Remifentanil was administered at 0.1–0.3 μg/kg −1 min −1 for analgesia, and sufentanil and a muscle relaxant were added according to the duration and stimulation of the different surgical type. At the end of surgery, sugammadex sodium injection (2 mg kg −1) was given over 10 s for the reversal of neuromuscular blockade by rocuronium bromide. Induction of general anesthesia
The induction period of general anaesthesia was defined as the time from the injection of HSK3486 (0.4 mg kg
−1) or propofol (2.0 mg kg −1) to the completion of tracheal intubation. Within this time period, the Modified Observer's Alertness/Sedation scale (MOAA/S) was evaluated at 30 s (± 10) intervals until the time of successful induction of anesthesia (MOAA/S ≤ 1). The maximum evaluation time did not exceed 3 min (± 10 s) after the initial administration of the experimental drugs. If loss of consciousness (LOC, MOAA/S ≤ 1) had not occurred within 1 min (± 10 s) after the initial administration of experimental drugs, a top-up dose of 50% of the initial dosage was given. Thereafter, another top-up dose was administered if the LOC did not occur within 2 min (± 10 s) after the initial administration of the experimental drugs. If MOAA/S was still >1 after two top-up doses, propofol was administered for rescue induction and the failure to induce general anaesthesia was recorded. Maintenance of general anaesthesia
The maintenance was defined as the time from the completion of tracheal intubation to the discontinuation of the experimental drugs. When BIS was greater than 40, each experimental drug was infused to maintain BIS within 40–60. HSK3486 was initially given at 0.8 mg kg
−1 h −1 and the infusion rate adjusted to 0.1–0.4 mg kg −1 h −1, with a maximum allowed rate of 2.4 mg kg −1 h −1. Propofol was given initially at 5.0 mg kg −1 h −1 and the rate adjusted as appropriate (1–2 mg kg −1 h −1 per time), with minimum and maximum allowed infusion rates of 3.0 mg kg −1 h −1 and 12.0 mg kg −1 h −1, respectively. If a sedation status (BIS < 60) was not observed after delivering the maximum infusion rate of HSK3486 or propofol, the maintenance of general anaesthesia was deemed to be a failure. Then, the infusion of HSK3486 or propofol was replaced with alternative sedative agents namely propofol or inhalation anaesthetics. Experimental drug administration was stopped when surgical procedures were completed. MOAA/S was evaluated at 0 min (± 10 s), 3 min (± 10 s), 6 min (± 30 s) and 9 min (± 30 s) after the end of surgery and subsequently evaluated every 1 min (± 30 s) until signs of full alertness of patients (MOAA/S = 5 for three consecutive assessments). Bispectral index monitoring
Oxygen was inhaled by mask for 5 min before induction of anaesthesia and the average value of baseline BIS was calculated from 3 data sets recorded every 2 min prior to midazolam administration. The BIS value was recorded once every 2 min for 20 min after the first administration of experimental drug, and then recorded once every 5 min until surgical procedures were completed.
The success rate of maintenance anaesthesia was defined as the proportion of patients without intraoperative awareness who did not require rescue medication during the maintenance phase of general anaesthesia. The incidence of intraoperative awareness was assessed by a Modified Brice questionnaire 1 day after the end of surgery (Table 2, Supplemental Digital Content,
). https://links.lww.com/EJA/A797 Secondary outcomes
The proportion of patients who achieved successful induction of general anaesthesia (MOAA/S ≤ 1); time to LOS: time from the first drug administration to LOC; the proportion of time when BIS was maintained at 40–60; the percentage of patients whose BIS was maintained at 40–60 from the initial skin incision to the end of the surgical procedure; time to full alertness: the period from the discontinuation of the experimental drugs to full alertness (MOAA/S = 5 for three consecutive assessments); time to spontaneous breathing recovery (respiration rate ≥ 8 breaths per minute and tidal volume ≥ 5 ml kg
−1); and time to leaving the PACU (Aldrete score ≥ 9 for three consecutive measurements). Safety assessment
The safety assessments mainly included vital signs, laboratory measurements (routine blood, urine and stool, blood biochemistry, coagulation function), the electrocardiogram (ECG), injection pain, intraoperative awareness and reports of any treatment for emergency adverse events (TEAEs). TEAEs during the induction and maintenance phases of general anaesthesia were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 23.1) and classified according to the System Organ Class (SOC) and Preferred Term (PT). The severity of pain on injection was evaluated at least once within 15 s of the first drug administration until successful induction of general anesthesia (MOAA/S ≤ 1) based on Table 3, Supplemental Digital Content,
. The severity of all other TEAEs was classified using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). https://links.lww.com/EJA/A797 Drug-related TEAEs including TEAEs which were definitely related, probably related and possibly related to the experimental drugs during the whole phase of general anaesthesia. In addition to the vital signs recording, the area under curve (AUC) of systolic blood pressure (SBP), that is, reduction from baseline SBP over the following time points after induction was calculated in both groups: every 2 min for 20 min and then for 30, 60, 90, and 120 min. 12 Statistical analysis
Analyses were conducted using SAS software (version 9.4). Continuous variables are given as the mean ± SD; categorical variables as numbers and/or percentages. For the primary efficacy endpoint, the between-group difference in success rate was calculated with 95% confidence intervals (CIs) using the Clopper–Pearson method, with comparisons made using Fisher's exact test. The Newcombe–Wilson method was used to estimate the difference of 95% CI between groups. For secondary efficacy endpoints, the success rate of induction of anaesthesia and the between-group difference at a 95% CI were calculated. The anaesthesia-related time is reported as summary statistics and was analysed using the log-rank test. Among the other secondary efficacy endpoints and safety outcomes, continuous data were analysed using a
t-test, whereas categorical data were analysed using Fisher's exact test.
The present trial was designed as a noninferiority study and noninferiority between HSK3486, and propofol was confirmed with a lower limit of 95% CI >−8%.
Based on the results of a former phase 2 trial and a usual success rate of 99–100% for propofol maintenance in clinical practice, assuming that the success rate of maintenance anaesthesia for HSK3486 and propofol were both 99%, and a noninferiority range of 8% for the rate difference between groups, the sample size was evaluated at a one-sided 13 α level of 2.5% and power 80%. Considering a drop-out rate of 5%, a total of 129 patients with elective surgery were enrolled in the trial (86 received HSK3486, 43 propofol). Results
Patient disposition and baseline characteristics
A total of 138 patients were screened, of which 9 were not included because they did not meet the eligibility criteria (
n = 5) or had withdrawn their informed consent ( n = 4). Of the 129 patients randomly enrolled, only 1 patient in the propofol group withdrew informed consent before the first drug administration; all of the remaining 128 patients completed the trial ( Fig. 1). The baseline characteristics of patients were similar in the HSK3486 and propofol groups ( Table 1). Fig. 1:
Flow chart of the study.
Table 1 -
Demographic and baseline characteristic of enrolled patients
n = 86) Propofol (
n = 42) Total (
n = 128)
38.5 ± 10.1
40.5 ± 10.1
39.2 ± 10.1
161.6 ± 8.0
161.4 ± 8.5
161.6 ± 8.1
60.0 ± 11.1
59.3 ± 8.8
59.7 ± 10.4
BMI kg m
23.3 ± 2.8
23.3 ± 3.0
23.3 ± 2.9
Modified Mallampati score
History of anaesthesia
Previous alcohol use
Time of surgery (min)
94.6 ± 39.2
93.6 ± 35.8
94.3 ± 38.0
All data are presented as the mean ± SD or
n (%).ASA, American Society of Anesthesiologist; BMI, body mass index. Efficacy
The success rate for maintenance of general anaesthesia was 100% for both groups, without using any rescue sedatives, intraoperative awareness did not occur in any patient. The between-group difference for the success rate was 0% (95% CI −4.28% to 8.38%), and the lower limit of 95% CI was >−8%, indicating that general anaesthesia induced by HSK3486 was not inferior to that produced by propofol (
Table 2). The success rate for induction was 100% in both groups, and only one patient (HSK3486 group) required a top-up dose during the induction phase. No differences were found between the groups with regard to time to LOC, full alertness, respiratory recovery and leaving the PACU (all P > 0.05; Table 2).
Table 2 -
Summary of primary and secondary efficacy endpoints during the induction and maintenance phases of general anaesthesia in the two groups
N = 86) Propofol (
N = 42) HSK3486 vs. propofol
Difference in success rate (95% CI)
Primary efficacy outcome
Success rate for maintenance of general anaesthesia
0 (−4.28 to 8.38)
Secondary efficacy outcomes
During the induction phase of general anaesthesia
0 (−4.28 to 8.38)
Time to LOC (min)
0.8 ± 0.3
0.8 ± 0.2
During the maintenance phase of general anaesthesia
Total duration that BIS was maintained at 40 – 60 (min)
66.6 ± 37.4
65.4 ± 31.4
The proportion of time that BIS was maintained at 40–60 (%)
70.4 ± 26.1
71.6 ± 24.3
Number of patients with BIS was always maintained at 40–60
Time to fully alertness (min)
10.4 ± 3.9
10.1 ± 4.7
Time to respiratory recovery (min)
10.3 ± 4.2
9.5 ± 4.5
Time to leaving PACU (min)
22.6 ± 5.0
22.3 ± 5.4
All data are presented as the mean ± SD or
n (%).BIS, bispectral index; LOC, loss of consciousness; PACU, postanesthesia care unit.
BIS changes during the induction and maintenance phases are presented in
Fig. 2. During the induction phase, the lowest BIS value was observed at 4 min after the first drug administration in both the HSK3486 and propofol groups, with a mean (± SD) value of 34.8 (± 10.5) and 32.4 (± 9.3), respectively. During the maintenance phase, changes in BIS were not different in the two groups with regard to the similar proportion of time ( P = 0.798) and number of patients ( P = 0.625) that BIS was maintained at 40–60 ( Table 2). Fig. 2:
Changes in BIS during the induction and maintenance phases of general anaesthesia in the two groups.
The mean time of exposure to HSK3486 was similar to propofol during both induction and maintenance phases (Table 4, Supplemental Digital Content,
). With a similar general anaesthesia capability as propofol, the mean value of the infusion rate for HSK3486 was 0.9 mg kg https://links.lww.com/EJA/A797 −1 h −1, ranging from 0.4 to 1.7 mg kg −1 h −1 during the whole maintenance period. Safety
There appeared to be a comparable incidence of TEAEs (80.2% vs. 81.0%,
P = 1.000) and drug-related TEAEs (57.0% vs. 64.3%, P = 0.451) in the HSK3486 and propofol groups during the whole trial period. The severity for the majority of TEAEs was grade 1 or 2 and only one patient (HSK3486 group) had a secondary hypertriglyceridaemia exacerbation (grade 3) during the follow-up period, which was not related to HSK3486. There were no deaths, no serious AEs (SAEs) occurred, no requirement for dose adjustments or drug discontinuation because of TEAEs, or any patients withdrawing from the trial due to TEAEs.
Pain on injection and hypotension during induction were the most frequent drug-related TEAEs, with incidence of pain on injection being significantly lower in the HSK3486 group (8.1% vs. 21.4%,
P = 0.046) ( Table 3). Of note, the severity of the majority of injection site pain was mild, only 2 (2/9, 22.2%) patients in the propofol group presented with moderate pain (grade 2). The occurrence of drug-related hypotension (30.2% vs. 28.6, P = 1.000) and drug-related bradycardia (20.9% vs. 21.4% P = 1.000) during the maintenance were not statistically different between the two groups. Other drug-related TEAEs in the follow-up period including increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and a prolonged QT interval were very rare and self-curing.
Table 3 -
Summary of drug-related TEAEs termed by PT
n = 86) Propofol (
n = 42)
Drug-related TEAEs, classified by PT
Number of events
Number of patients (%)
Number of events
Number of patients (%)
Induction phase of general anaesthesia
Pain on injection
Maintenance phase of general anaesthesia
Induction + maintenance phases of general anaesthesia
Pain on injection
From the first drug administration to the end of follow-up
Pain on injection
Prolonged QT interval
ALT, alanine aminotransferase; AST, aspartate aminotransferase; PT, Preferred Term; TEAEs, treatment emergent adverse events.
Patients in the HSK3486 and propofol groups showed similar fluctuation trends in SBP, DBP, MAP, heart rate and oxygen saturation (SpO
2) during anaesthesia induction, intraoperatively and in the recovery period without significant differences (Figure 1, Supplemental Digital Content, and Table 5, Supplemental Digital Content, https://links.lww.com/EJA/A797 ). The incidence of clinically significant laboratory test abnormalities was similar between the HSK3486 and propofol groups. https://links.lww.com/EJA/A797 Discussion
The present phase 3 trial, conducted on elective surgical patients who required general anaesthesia, demonstrated that HSK3486 was not inferior to propofol regarding its capability for the induction and maintenance of general anaesthesia. The success rate for the maintenance was 100% in both arms. Propofol is well known with the advantages of rapid onset and recovery.
A single dose of HSK3486 (0.4 mg kg 14,15 −1) exhibited a similar onset of action compared to propofol (2.0 mg kg −1), with patients losing consciousness (MOAA/S ≤ 1) within 1 min. The most frequent HSK3486-related AEs were hypotension, and pain on injection observed during the induction phase, as reported for propofol induction. Of note, HSK3486 had a significant benefit on injection pain during induction, reflected by the severity and incidence of the pain elicited by HSK3486 induction, which were slightly better than propofol, findings consistent with previous HSK3486 studies. 16–18 2,8
Similar to other GABA
A receptor agonists, BIS can be used to guide the intraoperative anaesthesia depth of HSK3486 and reduce the risk of intraoperative awareness. 19 Deep anaesthesia (BIS < 40), has been shown to be linked with an increased risk of electroencephalogram burst suppression and cardiovascular dysfunctions, including myocardial infarction and stroke. 20–22 Thus, BIS was maintained at 40–60 in this trial design and HSK3486 exhibited a similar BIS pattern to propofol during the intraoperative maintenance period. 23,24
Intraoperative awareness is a very serious complication in general anaesthesia, which led patients to suffer from recurrent symptoms of anxiety, nightmares and psychological sequelae, probably resulting in the development of posttraumatic stress disorder in more severe patients.
The risk factor towards the occurrence of intraoperative awareness, mainly focus on the patient's condition, surgical type and anaesthesia depth and technology. 25 In our phase 3 trial, no intraoperative awareness occurred in either group, probably because the selected surgical procedures excluded emergency, cardiothoracic and brain surgery as well as other procedures that were scheduled for more than 4 h. 26
Evidence is growing that intraoperative hypotension is associated with increased rates of injury to vital organs such as the heart, kidneys and brain, as well as mortality in high-risk patients; some strategies have been put forward to reduce the incidence of hypotension in clinical practice.
However, in the present trial, a comparable trend in intraoperative hypotension (30.2% vs. 28.6, 27–29 P = 1.000) was found between the groups.
HSK3486 presented a comparable recovery profile to propofol, in terms of time to becoming fully alert, time to respiratory recovery and time to leaving PACU. In addition, there was no postoperative vomiting and nausea reported in the HSK3486 or propofol groups, a feature of other anaesthetic and analgesic drugs.
Delirium is a common complication in PACU and may lead to self-extubation by accident, increasing the difficulty of respiratory management, prolonging postoperative hospital stay and increasing postoperative mortality.
However, this phase 3 trial was not designed to evaluate postoperative delirium. In this phase 3 trial we adhered to routine clinical practice in China, notably: a combination anaesthetic medication regimens in addition to the experimental drugs (HSK3486 or propofol). Thus, sufentanil + midazolam (before induction) and remifentanil (intraoperative analgesia) were administered to relieve pain and discomfort. 31,32 A limitation of this study was that the procedure studied were scheduled to take less than 4 hours and excluded emergency, cardiac and brain surgery. Further clinical trials are warranted to evaluate the efficacy and safety of HSK3486 for additional patient populations, such as the elderly, children and patients requiring more extensive surgery. 33,34
In summary, we demonstrated that HSK3486 was noninferior to propofol, in terms of the induction and maintenance of general anaesthesia. In comparison to propofol, HSK3486 rarely produced pain on injection during the induction phase and exhibited a comparable intraoperative haemodynamic profile. HSK3486 is a promising drug as an alternative agent for the induction and maintenance general anaesthesia in patients undergoing elective surgery, and warrants further clinical trials.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: this study was funded by Haisco Pharmaceutical Group Co., Ltd. The funder had no role in the design of the study, collection, analysis and interpretation of data, the writing of this article, or the decision to submit it for publication.
Conflicts of interest: none.
This manuscript was handled by Dan Longrois.
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