Safety and Efficacy of Ciprofol vs. Propofol for Sedation in Intensive Care Unit Patients with Mechanical Ventilation: A Multi-Center, Open Label, Randomized, Phase 2 Trial
Introduction
Analgesia and sedation are critical components of intensive care unit (ICU) therapies, particularly for patients undergoing mechanical ventilation. These patients often experience significant psychological stress and pain, necessitating effective sedation strategies. Currently, commonly used sedatives in ICUs include midazolam, propofol, and dexmedetomidine. Propofol is widely used due to its rapid onset, short duration of action, and dose-dependent sedation depth. However, propofol has a narrow therapeutic margin and is associated with dose-dependent side effects such as hypotension, respiratory depression, hypertriglyceridemia, and propofol-related infusion syndrome (PRIS). Midazolam, while effective, can lead to drug accumulation and prolonged mechanical ventilation. Dexmedetomidine, though it offers modest analgesic effects and potential delirium prevention, is associated with bradycardia and hypotension. Given these limitations, there is a growing need for alternative sedatives with improved safety profiles and adequate efficacy, particularly for elderly or critically ill patients.
Ciprofol (HSK3486), a novel 2,6-disubstituted phenol derivative developed by Haisco Pharmaceutical Group, has shown promise in preclinical studies. It exhibits a similar anesthetic profile to propofol but with less injection pain. Ciprofol is a gamma-aminobutyric acid type A (GABAA) receptor agonist, with a higher potency compared to propofol. This phase 2 trial aimed to evaluate the safety, efficacy, and pharmacokinetic characteristics of ciprofol for sedation in ICU patients undergoing mechanical ventilation, comparing it to propofol.
Methods
This multicenter, open-label, randomized, phase 2 trial was conducted across six research centers in China. The trial enrolled 39 ICU patients aged 18 to 80 years who required mechanical ventilation and sedation for 6 to 24 hours. Patients were randomly assigned to either the ciprofol or propofol group in a 2:1 ratio.
The trial consisted of three phases: a screening period (day -1 to day 1), a drug administration period (day 1 or day 1-2), and follow-up inspections (day 2 after drug administration). The target sedation depth was a Richmond Agitation-Sedation Scale (RASS) score of -2 to +1, in line with Chinese Society of Critical Care Medicine guidelines.
Ciprofol was administered as a loading dose of 0.1–0.2 mg/kg over 0.5–5.0 minutes, followed by a maintenance infusion rate of 0.30 mg/kg/h, adjustable between 0.06 and 0.80 mg/kg/h. Propofol was administered as a loading dose of 0.5–1.0 mg/kg over 0.5–5.0 minutes, followed by a maintenance infusion rate of 1.50 mg/kg/h, adjustable between 0.30 and 4.00 mg/kg/h. Remifentanil was used for continuous intravenous analgesia, with a loading dose of 0.5–1.0 µg/kg and a maintenance infusion rate of 0.02–0.15 µg/kg/min.
Efficacy was assessed based on the average time to sedation compliance (RASS score of -2 to +1), sedation compliance rates, and secondary endpoints such as dose adjustments, duration of drug administration, and time to full alertness. Safety was evaluated through adverse events (AEs), treatment-emergent adverse events (TEAEs), and laboratory indicators. Blood samples were collected for pharmacokinetic analysis to determine plasma concentrations of ciprofol and propofol.
Results
Of the 39 enrolled patients, 36 completed the trial. The median time to sedation compliance was 60.0 minutes for both ciprofol and propofol, with no significant difference between the two groups. Sedation compliance rates were 100% for both groups.
Secondary efficacy endpoints, including the total times of dose adjustments, duration of loading and maintenance doses, and endotracheal extubation time, were comparable between the two groups. The dosage of ciprofol was significantly lower than that of propofol, reflecting its higher potency. The total duration of drug administration was similar in both groups, with a median of 10.3 hours for ciprofol and 9.2 hours for propofol.
Safety assessments revealed that 29 patients (74.4%) experienced 87 AEs, with 17 (65.4%) in the ciprofol group and 11 (84.6%) in the propofol group. The most common TEAEs were hypotension, anemia, fever, elevated C-reactive protein, and hypokalemia. Drug-related TEAEs included hypotension (7.7% in ciprofol vs. 23.1% in propofol) and sinus bradycardia (3.8% in ciprofol vs. 7.7% in propofol). Most TEAEs were of grade 1 or 2 severity, with only five patients experiencing grade 3 TEAEs. No serious AEs or deaths were reported.
Pharmacokinetic analysis showed similar plasma concentration-time curves for ciprofol and propofol. The mean plasma concentration of ciprofol reached 153.95 ng/mL at 4 hours after the initiation of the maintenance dose and peaked at 184.51 ng/mL at 8 hours. Plasma concentrations for RASS scores of -2 to +1 were 29–185 ng/mL for ciprofol and 212–722 ng/mL for propofol.
Discussion
The results of this trial demonstrate that ciprofol is comparable to propofol in terms of efficacy for sedation in ICU patients undergoing mechanical ventilation. Both drugs achieved similar sedation compliance rates and times to sedation compliance. Ciprofol exhibited a favorable safety profile, with a lower incidence of drug-related TEAEs such as hypotension and bradycardia compared to propofol.
The lower dosage of ciprofol required for effective sedation highlights its higher potency, which may reduce the risk of side effects associated with higher doses of propofol. The pharmacokinetic profiles of ciprofol and propofol were similar, with ciprofol maintaining stable plasma concentrations throughout the drug administration period.
One limitation of this trial is the small sample size, which may have limited the statistical power to detect differences in efficacy endpoints. However, the results provide valuable data for designing future phase 3 trials. Additionally, the trial did not assess the impact of ciprofol on adrenal cortical function, which should be explored in future studies.
Conclusion
Ciprofol is a safe and effective alternative to propofol for sedation in ICU patients undergoing mechanical ventilation. It offers comparable efficacy with a potentially improved safety profile, particularly in terms of reduced hypotension and bradycardia. Further studies with larger sample sizes are warranted to confirm these findings and explore additional safety and efficacy endpoints.
doi.org/10.1097/CM9.0000000000001912
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