Effect of Remimazolam With Protocolized Sedation on Critical Ill, Mechanical Ventilated Patients Compared With Midazolam

Investigational drug#remimazolam for injection Study title#Effect of Remimazolam with Protocolized Sedation on Critical Ill, Mechanical Ventilated Patients Compared with Midazolam - A parallel, Multicenter, Single-blind Randomized Controlled Trial Principal Investigator#Professor Zhanguo Liu, Dr.Jing Cai, Department of Critical Care Unit, Zhujiang Hospital, Southern Medical University Study subjects#Critical ill patients that are mechanically ventilated within the first 48h of admission to the ICU and who would remain in the ICU for over 72h are enrolled in this study. The ages of patients should be in the range from 18 to 80.

Study phase# Investigator Initiated Trial(IIT) Study objectives#The objective of the study is to determine whether remimazolam, compared with midazolam, reduces duration of ventilation in severe patients.

Study design#A parallel, Multicenter, Single-blind Randomized Controlled Trial. Medication method#Remimazolam group#Patients are administered with a bolus of remimazolam with 0.1-0.3mg/kg intravenously in 1 minute for the first time. And the maintenance dose is 0.25-0.1mg/kg/h, meanwhile the dose of remimazolam should be titrated according to Richmond Agitation Sedation Scale (RASS) scores. Nonbenzodiazepines could be administrated to the patients if sedation targets were not achieved.

Midazolam group#Patients are administered with a bolus of midazolam with 0.01-0.05mg/kg intravenously in 1 minute for the first time. And maintenance dose is 0.02-0.1mg/kg/h, meanwhile the dose of midazolam should be titrated according to Richmond Agitation Sedation Scale (RASS) scores. Nonbenzodiazepines could be administrated to the patients if sedation targets were not achieved.

Spontaneous breathing test (SBT) is conducted daily while patients are stable. Weaning would be considered after a successful SBT, and the sedation for study need to be stopped subsequently. If the weaning failed, mechanical ventilation and sedation would be used immediately according to sedation targets. Weaning success is defined as the ability to successfully complete the SBT and sustain spontaneous breathing for 48h after extubation.

Course#28days Sample size#440. Sites#15 Primary endpoint#Duration of mechanical ventilation(weaning success is typically regarded as consecutive ventilator-free over 24h following liberation from a ventilator. The duration of mechanical ventilation is from the enrollment time to the weaning time. The study and observation would be stopped due to difficult ventilator weaning, which features weaning failure repeatedly for 3 weeks.) Secondary endpoints#

1. Duration of endotracheal intubation(calculated from the time of enrollment); 2. Completion rate of sedation goals (completion rate of sedation goal = days of achieving sedation goals / total days of sedation (days from enrollment to successful ventilator withdrawal) × 100%）)； 3. Sedation remediation is defined as requiring combination with other nonbenzodiazepines sedations. 4. Length of stay in ICU and total length of stay (time from admission to discharge); 5. Others: anterograde amnesia, 28 day mortality, total cost of sedative drugs in ICU, hospitalization expenses in ICU; Anterograde amnesia used a questionnaire that is record to assess the patient's forgetfulness.

Safety endpoints#

1. Incidence of Hypotension(20% fall in systolic pressure). 2. Incidence of Delirium. 3. Incidence of spontaneous extubation. 4. Incidence of reintubation in 12h or tracheotomy. 5. Incidence of Myasthenia.(following weaning from ventilations) 6. Incidence of thrombus.(lower extremity deep venous thrombosis)

• Duration of endotracheal intubation [Time frame: From the date of enrollment until the date of pulling out the endotracheal tube, assessed up to 28 days]
• Completion rate of sedation goal [Time frame: From the date of enrollment until the date of successful ventilator withdrawal, assessed up to 28 days]
• Remediation is defined as requiring combination with other sedations [Time frame: From the date of enrollment until the date of successful ventilator withdrawal, assessed up to 28 days]
• Length of stay in ICU and total length of stay [Time frame: From the date of admission in ICU until the date of transfer from ICU]
• Anterograde amnesia [Time frame: From the date of enrollment until the date of successful ventilator withdrawal]
• 28 day mortality [Time frame: From the date of enrollment until the date of death from any cause, assessed up to 28 days]