Dataset Information

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.

ABSTRACT:

Background

Ciprofol (HSK3486; Haisco Pharmaceutical Group Co., Ltd., Chengdu, China), developed as a novel 2,6-disubstituted phenol derivative showed similar tolerability and efficacy characteristics as propofol when applicated as continuous intravenous infusion for 12 h maintenance sedation in a previous phase 1 trial. The phase 2 trial was designed to investigate the safety, efficacy, and pharmacokinetic characteristics of ciprofol for sedation of patients undergoing mechanical ventilation.

Methods

In this multicenter, open label, randomized, propofol positive-controlled, phase 2 trial, 39 Chinese intensive care unit patients receiving mechanical ventilation were enrolled and randomly assigned to a ciprofol or propofol group in a 2:1 ratio. The ciprofol infusion was started with a loading infusion of 0.1-0.2 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 0.30 mg·kg -1 ·h -1 , which could be adjusted to an infusion rate of 0.06 to 0.80 mg·kg -1 ·h -1 , whereas for propofol the loading infusion dose was 0.5-1.0 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 1.50 mg·kg -1 ·h -1 , which could be adjusted to 0.30-4.00 mg·kg -1 ·h -1 to achieve -2 to +1 Richmond Agitation-Sedation Scale sedation within 6-24 h of drug administration.

Results

Of the 39 enrolled patients, 36 completed the trial. The median (min, max) of the average time to sedation compliance values for ciprofol and propofol were 60.0 (52.6, 60.0) min and 60.0 (55.2, 60.0) min, with median difference of 0.00 (95% confidence interval: 0.00, 0.00). In total, 29 (74.4%) patients comprising 18 (69.2%) in the ciprofol and 11 (84.6%) in the propofol group experienced 86 treatment emergent adverse events (TEAEs), the majority being of severity grade 1 or 2. Drug- and sedation-related TEAEs were hypotension (7.7% vs. 23.1%, P = 0.310) and sinus bradycardia (3.8% vs. 7.7%, P = 1.000) in the ciprofol and propofol groups, respectively. The plasma concentration-time curves for ciprofol and propofol were similar.

Conclusions

ciprofol is comparable to propofol with good tolerance and efficacy for sedation of Chinese intensive care unit patients undergoing mechanical ventilation in the present study setting.

Trial registration

ClinicalTrials.gov, NCT04147416.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9276409 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

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.

Liu Yongjun Y Yu Xiangyou X Zhu Duming D Zeng Jun J Lin Qinhan Q Zang Bin B Chen Chuanxi C Liu Ning N Liu Xiao X Gao Wei W Guan Xiangdong X

Chinese medical journal 20220505 9

<h4>Background</h4>Ciprofol (HSK3486; Haisco Pharmaceutical Group Co., Ltd., Chengdu, China), developed as a novel 2,6-disubstituted phenol derivative showed similar tolerability and efficacy characteristics as propofol when applicated as continuous intravenous infusion for 12 h maintenance sedation in a previous phase 1 trial. The phase 2 trial was designed to investigate the safety, efficacy, and pharmacokinetic characteristics of ciprofol for sedation of patients undergoing mechanical ventila ...[more]

PMID: 34924506

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Project description:BackgroundCiprofol was approved for use in intensive care unit (ICU) patients requiring sedation during mechanical ventilation in July 2022. A pooled post-hoc analysis of phase 2 and phase 3 trials was conducted primarily to explore hypotension-free outcome in ICU patients who required mechanical ventilation and achieved the target light sedation goal at an early stage after being sedated with ciprofol or propofol.MethodsAll eligible ICU patients who were expected to require sedation for 6-24 h were randomly assigned in a 2:1 ratio to either a ciprofol or propofol group. Ciprofol or propofol was initially infused at loading doses of 0.5 or 1.0 mg/kg followed by maintenance doses of 0.3 or 1.5 mg/kg/h. Ciprofol or propofol dosages were adjusted up or down at rates of 0.05-0.10 mg/kg/h or 0.25-0.50 mg/kg/h, respectively, to achieve the target light sedation (a Richmond Agitation-Sedation Scale of -2 to + 1). The primary post-hoc outcome was the hypotension-free rate in patients who had achieved the target sedation goal after 30-min administration of ciprofol or propofol.ResultsIn total, 174 patients were enrolled for pooled post-hoc analysis, of whom 116 and 58 were assigned to the ciprofol and propofol groups, respectively. The hypotension-free rate was significantly higher in patients who achieved the target sedation goal after 30-min administration of ciprofol (93.0% vs. 81.0%, P = 0.018), and especially in the subgroups of males and patients aged < 65 years. Multivariable analysis revealed that ciprofol treatment, a younger age and lower baseline body mass index were independent favorable predictors for a higher hypotension-free rate in patients who achieved the target sedation goal after 30-min of drug administration. Moreover, hypotension-free patients who reached the target sedation level after 30 min had a more favorable short-term prognosis including a lower incidence of drug-related treatment-emergent adverse events, shorter time to extubation and fewer dose adjustments of ciprofol or propofol (all P < 0.05).ConclusionICU patients undergoing mechanical ventilation and sedated with ciprofol had significantly lower rate of hypotension during the early phase of achieving light sedation during a 6-24 h period, leading to a more favorable short-term prognosis (within 24 h).Trial registrationPhase 2 trial (clinicaltrials.gov, NCT04147416. Registered November 1, 2019, https://classic.Clinicaltrialsgov/ct2/show/NCT04147416 ) and phase 3 trial (clinicaltrials.gov, NCT04620031. Registered November 6, 2020, https://classic.Clinicaltrialsgov/ct2/show/NCT04620031 ).

Project description:IntroductionFrom previous studies of pharmacodynamic data in mice, rats, beagle dogs and mini pigs, frequently in direct comparison to induction doses of propofol, ciprofol produced a rapid onset of anesthesia/sedation.MethodsA phase 1 study suggested potential clinical advantages of ciprofol as a sedation/anesthetic agent, with no evidence of drug-related toxicity. However, the sedation effects and safety of ciprofol in intensive care unit (ICU) patients with mechanical ventilation should be further confirmed in a phase 3 study with a larger cohort of patients. During a phase 3, non-inferiority, multicenter, single-blind, randomized, propofol controlled trial, Chinese ICU patients undergoing mechanical ventilation and requiring endotracheal intubation will be sedated for 6-24 h after randomization. Considering a success rate for ICU sedation of 99% for ciprofol and the positive control drug propofol, a total sample size of 120 subjects with mechanical ventilation will be required to achieve 80% power to determine non-inferiority with a margin of 8%. Finally, taking into account 10% losses, 135 patients will be enrolled and randomly assigned to ciprofol (90 cases) and propofol (45 cases) groups in a 2:1 ratio. The primary outcome will be the success rate of sedation satisfied by the following conditions: the time within the range of Richmond Agitation and Sedation Score (+ 1 ~ - 2) must account for ≥ 70% of the study drug administration time and without other rescue treatments. Secondary outcomes will include the average time to reach the sedation goal, study drug usage, rescue medication given per unit weight, extubation time, recovery time to full consciousness and nursing scores. Safety endpoints will include adverse events (AEs), drug related AEs and serious AEs.Planned outcomesThe results of this study will provide crucial information on the use of ciprofol for sedation of patients in ICUs.Trial registrationClinicalTrials.gov identifier, NCT04620031.

Project description:ObjectivesTo determine the effectiveness and safety of ciprofol for sedating patients in ICUs who required mechanical ventilation (MV).DesignA multicenter, single-blind, randomized, noninferiority trial.SettingTwenty-one centers across China from December 2020 to June 2021.PatientsA total of 135 ICU patients 18 to 80 years old with endotracheal intubation and undergoing MV, who were expected to require sedation for 6-24 hours.InterventionsOne hundred thirty-five ICU patients were randomly allocated into ciprofol ( n = 90) and propofol ( n = 45) groups in a 2:1 ratio. Ciprofol or propofol were IV infused at loading doses of 0.1 mg/kg or 0.5 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Ciprofol or propofol were then immediately administered at an initial maintenance dose of 0.3 mg/kg/hr or 1.5 mg/kg/hr, to achieve the target sedation range of Richmond Agitation-Sedation Scale (+1 to -2). Besides, continuous IV remifentanil analgesia was administered (loading dose: 0.5-1 μg/kg, maintenance dose: 0.02-0.15 μg/kg/min).Measurements and main resultsOf the 135 patients enrolled, 129 completed the study. The primary endpoint-sedation success rates of ciprofol and propofol groups were 97.7% versus 97.8% in the full analysis set (FAS) and were both 100% in per-protocol set (PPS). The noninferiority margin was set as 8% and confirmed with a lower limit of two-sided 95% CI for the inter-group difference of -5.98% and -4.32% in the FAS and PPS groups. Patients who received ciprofol had a longer recovery time ( p = 0.003), but there were no differences in the remaining secondary endpoints (all p > 0.05). The occurrence rates of treatment-emergent adverse events (TEAEs) or drug-related TEAEs were not significantly different between the groups (all p > 0.05).ConclusionsCiprofol was well tolerated, with a noninferior sedation profile to propofol in Chinese ICU patients undergoing MV for a period of 6-24 hours.

Project description:ImportanceThe effectiveness of daily sedation interruption (DSI, defined as temporary interruption of sedation) has yet to be demonstrated in critically ill pediatric patients.ObjectiveTo compare the clinical outcomes of DSI vs continuous intravenous (IV) sedation in patients receiving invasive mechanical ventilation (MV) support in the pediatric intensive care unit (PICU).Data sourcesA systematic search for studies was conducted using predefined keywords and Medical Subject Headings in 5 major databases (PubMed, Embase, Web of Science, CINAHL [Cumulated Index to Nursing and Allied Health Literature], and Cochrane Central Register of Controlled Trials) from database inception to October 31, 2023.Study selectionRetrospective and prospective observational studies, randomized clinical trials (RCTs), and systematic reviews were assessed for inclusion. Studies were eligible if they compared DSI to continuous IV sedation in patients aged 18 years or younger requiring MV in the PICU.Data extraction and synthesisStudy characteristics, including the types of sedation, sedation protocols, and clinical outcomes, were extracted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. A random-effects model was used to pool results from articles for the meta-analysis.Main outcomes and measuresThe primary outcomes of interest were duration of MV and length of PICU stay. Secondary outcomes included total sedative dose requirement, adverse events (eg, complications associated with MV, withdrawal, and delirium), and mortality.ResultsA total of 6 RCTs with 2810 pediatric patients (1569 males [55.8%]; mean age, 26.5 [95% CI, 15.0-37.9] months) were included in the final analysis; patients had a mean PRISM (Pediatric Risk of Mortality) score of 13.68 (95% CI, 10.75-16.61). Compared with continuous IV sedation, DSI was associated with a reduction in length of PICU stay (5 studies, n = 2770; mean difference [MD], -1.45 [95% CI, -2.75 to -0.15] days; P = .03]. There was no difference in MV duration (5 studies, n = 2750; MD, -0.93 [95% CI, -1.89 to 0.04] days; P = .06), total doses of midazolam (3 studies, n = 191; MD, -1.66 [95% CI, -3.95 to 0.63] mg/kg) and morphine used (2 studies, n = 189; MD, -2.63 [95% CI, -7.01 to 1.75] mg/kg), or adverse events (risk ratio [RR], 1.03 [95% CI, 0.74-1.42]; P = .88). There was no difference in mortality between patients exposed vs not exposed to DSI (RR, 0.89 [95% CI, 0.55-1.46]; P = .65).Conclusions and relevanceThis systematic review and meta-analysis found that use of DSI in pediatric patients was associated with reduced length of PICU stay with no increase in adverse events. Further research is needed to ascertain whether this strategy is associated with improved neurodevelopmental outcomes in PICU survivors.

Project description:IntroductionPainless gastrointestinal endoscopy is being increasingly practised in the clinical field. The management and choice of sedation are important during the endoscopy procedure to reduce patient discomfort and facilitate high disease detection rates. Ciprofol is principally an agonist of the γ-aminobutyric acid type A receptor; it comprises the active ingredient HSK3486, which is similar to the currently used intravenous anaesthetic propofol in clinical practice. A systematic review and meta-analysis comparing ciprofol and propofol will be conducted to assess their efficacy and safety during endoscopy. Before starting the study, we describe the specific protocol of this systematic review.Methods and analysisThis protocol was prepared in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols 2015. The following databases will be searched: Embase, Cochrane Library, PubMed, Web of Science, Chinese Biomedical Literature Service System, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database and a clinical trial registry. The database search strategy will adopt a combination of subject words and free words. Randomised controlled trials related to ciprofol use for sedation during gastrointestinal endoscopy will also be included. Based on the inclusion and exclusion criteria, two researchers will independently screen the articles and extracted data. Following the qualitative evaluation of each study, analysis will be conducted using Review Manager software.Ethics and disseminationThe protocol for this systematic review and meta-analysis involves no individual patient data; thus, ethical approval is not required. This will be the first meta-analysis to assess the sedation efficacy of ciprofol and provide evidence to clinicians for decision-making. The results will be disseminated through conference presentations and publications in peer-review journals related to this field.Prospero registration numberCRD42022370047.

Project description:IntroductionThis randomised, open-label, multicentre study compared the safety and efficacy of an analgesia-based sedation regime using remifentanil with a conventional hypnotic-based sedation regime in critically ill patients requiring prolonged mechanical ventilation for up to 10 days.MethodsOne hundred and five randomised patients received either a remifentanil-based sedation regime (initial dose 6 to 9 microg kg(-1) h(-1) (0.1 to 0.15 microg kg(-1) min(-1)) titrated to response before the addition of midazolam for further sedation (n = 57), or a midazolam-based sedation regime with fentanyl or morphine added for analgesia (n = 48). Patients were sedated to an optimal Sedation-Agitation Scale (SAS) score of 3 or 4 and a pain intensity (PI) score of 1 or 2.ResultsThe remifentanil-based sedation regime significantly reduced the duration of mechanical ventilation by more than 2 days (53.5 hours, P = 0.033), and significantly reduced the time from the start of the weaning process to extubation by more than 1 day (26.6 hours, P < 0.001). There was a trend towards shortening the stay in the intensive care unit (ICU) by 1 day. The median time of optimal SAS and PI was the same in both groups. There was a significant difference in the median time to offset of pharmacodynamic effects when discontinuing study medication in patients not extubated at 10 days (remifentanil 0.250 hour, comparator 1.167 hours; P < 0.001). Of the patients treated with remifentanil, 26% did not receive any midazolam during the study. In those patients that did receive midazolam, the use of remifentanil considerably reduced the total dose of midazolam required. Between days 3 and 10 the weighted mean infusion rate of remifentanil remained constant with no evidence of accumulation or of a development of tolerance to remifentanil. There was no difference between the groups in SAS or PI score in the 24 hours after stopping the study medication. Remifentanil was well tolerated.ConclusionAnalgesia-based sedation with remifentanil was well tolerated; it reduces the duration of mechanical ventilation and improves the weaning process compared with standard hypnotic-based sedation regimes in ICU patients requiring long-term ventilation for up to 10 days.

Dataset Information

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.

Background

Methods

Results

Conclusions

Trial registration

Publications

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.

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