Long-term Sedation With Remimazolam Besylate in Critically Ill Patients

Study Overview
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Brief Summary
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A randomized non-inferior trial comparing remimazolam besylate with propofol for long-term sedation during invasive mechanical ventilation in critically ill patients

Official Title
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Long-term Sedation With Remimazolam Besylate Versus Propofol in Critically Ill Patients During Invasive Mechanical Ventilation: a Randomized Non-inferior Trial

Conditions
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Light Sedation, Mechanical Ventilation

Intervention / Treatment
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* Drug: Remimazolam besylate
* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 80 years; Intubated and mechanically ventilated ≤96 hours before enrollment； Expected to require continuous invasive ventilation and sedation ≥24 hours; Requirement for light to moderate sedation (a RASS score of -3 to 0) Exclusion Criteria: Body mass index (BMI) <18 or >30 kg/m2; Allergy or unsuitabilty to any composition of study drugs or remifentanil; Living expectancy less than 48 hours； Possible surgey in the operating room in 24 hours； Myasthenia gravis; Serious hepatic dysfunction (CTP 10-15); Chronic kidney disease with glomerular filtration rate (GFR) < 29 ml/min/1.73m2; Systolic blood pressure less than 90 mm Hg after appropriate intravenous volume replacement and continuous infusions of 2 vasopressors; Acute severe neurological disorder and any other condition interfering with RASS assessment; Pregnancy or lactation; Unstable angina or acute myocardial infarction; Left ventricular ejection fraction less than 30%; Heart rate less than 50 beats/min; Grade 2 , second degree or third degree atrioventricular block in the absence of a pacemaker; Abuse of controlled substances or alcohol; Other conditions deemed unsuitable to be included;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam besylate<br>Remimazolam besylate at an initial infusion rate of 0.15 mg/kg/h and adjusted (maximum of 0.3 mg/kg/h) to maintain a RASS score between - 3 and 0 | Drug: Remimazolam besylate<br>* Sedation drug<br>|
| Active Comparator: Propofol<br>Propofol intravenously at an initial infusion rate of 2.0 mg/kg/h and adjusted (maximum of 4.0 mg/kg/h) to maintain a RASS score between - 3 and 0 | Drug: Propofol<br>* Propofol. Sedation drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of time in the target sedation range without rescue sedation | The percentage of time in the target sedation range without rescue sedation | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive ventilator free time | Hours of time free from invasive ventilator | From start of study to 7 days | 
| Successful extubation rate | Extubation of endotracheal tube for the first time in 7 days without reintubation or switching to tracheostomy within the following 48 hours | From start of study to 7 days | 
| Length of ICU stay | Length of ICU stay | From start of study to 28 days | 
| Mortality | Mortality | From start of study to 28 days | 
| Length of hospitalization | Length of hospitalization | From start of study to 28 days | 
| weaning time | weaning time in minutes between continuous discontinuation of the study drug and extubation in patients with successful extubation | From start of study to 7 days | 
| Rate of hypotension | Systolic blood pressure less than 80 mmHg or diastolic blood pressure less than 50 mmHg for 5 minutes or treated with vasopressors | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of hypertension | systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mmHg for 5 minutes or treated with vasodilators | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of bradycardia | heart rate less than 50 bpm for 5 minutes or treated with medication to increase heart rate | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of tachycardia | heart rate greater than 120 bpm for 5 minutes or treated with medication to decrease heart rate | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of unplanned extubation of endotracheal tube | unplanned extubation of endotracheal tube | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of shock | New-onset shock | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of hospital-acquired pneumonia | hospital-acquired pneumonia | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of myocardial infarction | myocardial infarction | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of cerebral ischemic stroke | cerebral ischemic stroke | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of cerebral hemorrhagic stroke | Rate of cerebral hemorrhagic stroke | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of pulmonary embolism | pulmonary embolism | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of upper digestive tract ulcer confirmed endoscopically | upper digestive tract ulcer confirmed endoscopically | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of more than 500 milliliters of bloody stool | more than 500 milliliters of bloody stool | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of delirium | delirium | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| delta SOFA | defined as the difference between SOFA when each patient stops receiving the study drug and SOFA at inclusion | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first | 
| Rate of withdraw from the trial because of intolerance, severe adverse events or other safety concerns | rate of withdraw from the trial because of intolerance, severe adverse events or other safety concerns | 7 days after enrollment, or when patients decease, require deep sedation, are scheduled for surgery, are discontinued from the study drug for at least 12 hours, are discharged from ICU, or are withdrawn from the trial, whichever comes first |