REmimazolam Infusion in the Context of Hypnotic Shortage in the Critical Care Unit During the Pandemic of COVID-19: REHSCU Study

Study Overview
=================
Brief Summary
-----------------
The worldwide COVID-19 pandemic has led to a dramatic increase in the number of patients hospitalized in intensive care units for an acute respiratory failure in all countries. This situation has quickly led to massive shortage in masks, mechanical ventilation machines and common medications such as hypnotics. All countries over the world are currently experiencing a major shortage in basic hypnotic medications (propofol, midazolam) in the intensive care as well as in the operating theatre. The Principal Investigator proposes to perform a pilot study assessing the benefit-risk ratio of Remimazolam (a novel benzodiazepine with a short half-life) in the critical care units of Nantes University Hospital during the COVID-19 pandemic.

Detailed Description
-----------------
The worldwide COVID-19 pandemic has led to a dramatic increase in the number of patients hospitalized in intensive care units for an acute respiratory failure in all countries. This situation has quickly led to massive shortage in masks, mechanical ventilation machines and common medications such as hypnotics. The reasons for such shortage are multiple: dramatic increase of the demand, production discontinuation because of shutdowns in multiple countries, and withholding of products by producing countries. All countries over the world are currently experiencing a major shortage in basic hypnotic medications (propofol, midazolam) in the intensive care as well as in the operating theatre. Remimazolam is a novel benzodiazepine with a short half-life that has been administered in patients undergoing major surgery, as well as in the intensive care unit. The Principal Investigator proposes to perform a pilot study assessing the benefit-risk ratio of Remimazolam in the critical care units of Nantes University Hospital during the COVID-19 pandemic.

Official Title
-----------------
REmimazolam Infusion in the Context of Hypnotic Shortage in the Critical Care Unit During the Pandemic of COVID-19. The Non-randomized, Non-controlled, Pilot, Open, Mono-centric REHSCU Study

Conditions
-----------------
Sepsis, Acute Respiratory Failure, COVID-19, Trauma, Stroke, Shock

Intervention / Treatment
-----------------
* Drug: Remimazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients at least 18 years old Inclusion in the first 96 hours after ICU admission, after clinical stabilization according to the attending physician's discretion. Expected duration of general anaesthesia ≥ 24 hours Exclusion Criteria: Patients more than 85 years-old Refusal to participate Severe patients with moribund state within the 24 hours after admission to the ICU Withdrawal of Life Sustaining Therapies within the 24 hours after admission to the ICU Any pregnant or breast-feeding patient, Patients with known anaphylactic reactions to benzodiazepines, flumazenil, or a medical condition such that these agents are contraindicated (according to local label) Patients with allergy/hypersensitivity to bovine lactose, dextran or any other excipient in the remimazolam product Presence of acute alcoholic or illicit drug intoxication or benzodiazepine intoxication Inclusion in another clinical (drug) trial Patient under guardianship or trusteeship Patient under judicial protection Severe hepatic impairment defined as a Child-Pugh score > 10.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Interventional Model Description: Non-controlled
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam<br>Patients will receive an infusion of Remimazolam for a maximum duration of 48 hours. The dose of Remimazolam will be adapted according to our ICU protocol of analgesia-sedation management, based on validated scale (Richmond Assessment Sedation Scale) | Drug: Remimazolam<br>* Patients will receive an infusion of Remimazolam for a maximum duration of 48 hours. The dose of Remimazolam will be adapted according to the ICU units protocol of analgesia-sedation management, based on validated scale (Richmond Assessment Sedation Scale). Owing to previous data gathered through a previous study in Japan, the initial dose of infusion will be within a 0.2-0.5 mg/min range. The dose of Remimazolam can be increased or decreased by 0.1mg/min when needed. The maximum dose of Remimazolam will be set at 1 mg/min.<br>* Other names: Remimazolam (CNS 7056);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| composite endpoint including a combination of cardio-vascular and sedation events, from baseline (before infusion) to 8 hours, after the beginning of Remimazolam infusion | For Safety: Cardiovascular event: Hypotension will be defined as a Mean Arterial Pressure ≤65mmHg or an increase ≥50% of the dose of norepinephrine (if appropriate), sustained over one hour after the beginning of Remimazolam. For Efficacy: Sedation event: the investigator will check if Remimazolam provides an adequate level of sedation assessed with the Richmond Assessment Sedation Scale. The level of sedation will be set by the attending physician and is usually set at-1/0. The investigator will also monitor the need to use standard hypnotic drugs within this time frame as further medication (propofol, midazolam, dexmedetomidine) in case of Remimazolam inefficacy (Richmond Assessment Sedation Scale). | 8 hours after the beginning of infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (all grades), related to Remimazolam. | An exhaustive monitoring of Adverse Events will be performed from Day-0 (inclusion), Day-1 and Day-2 (during infusion), to Day-5 (3 days after discontinuation). | 5 days | 
| Heart rate | Hemodynamic stability follow-up of heart rate, from day1 to day3. | 3 days | 
| Arterial pressure | Hemodynamic stability follow-up with systolic, diastolic and mean arterial pressure from day1 to day3. | 3 days | 
| Dose of norepinephrine | Hemodynamic stability follow-up with the dose of norepinephrine from day1 to day3. | 3 days | 
| Electrocardiogram (ECG) | Hemodynamic stability follow-up with electrocardiogram from day1 to day3. | 3 days | 
| Sedation. | The level of sedation will be assessed with clinical scale (Richmond Assessment Sedation Scale, scores from -5:unarousable to+4 : Combative or Bispectral Index, index from 100 (awake subject) to 0 (very deep sleep) .From day1 to day3. | 3 days | 
| Other sedatives. | The use or switch to other sedatives (midazolam, dexmedetomidine, propofol) in case of remimazolam inefficacy, will be monitored, from day1 to day3. | 3 days | 
| Wake-up time. | In minutes, defined as Richmond Assessment Sedation Scale 4 of -1/0, only in non-neurologic patients and if general anesthesia is definitely stopped at the end of remimazolam infusion. | 3 days | 
| Pharmacokinetics of Remimazolam and its metabolites (CNS 7054): Maximum Plasma Concentration. | maximum plasma concentration of Remimazolam and its metabolites, measured during the infusion and at the end. 9 Pharmacokinetic blood samplings during the infusion, and at Day-3, after Remimazolam discontinuation. In total 9 (nine) blood samples of 2 ml will be collected during the 48-hour infusion and during elimination phase (up to 24 hours post Remimazolam infusion). | 3 days | 
| Pharmacodynamics Remimazolam and its metabolites (CNS 7054): steady state plasma levels and elimination. | measured during the infusion and at the end. 9 Pharmacodynamics blood samplings during the infusion, and at Day-3, after Remimazolam discontinuation. In total 9 (nine) blood samples of 2 ml will be collected during the 48-hour infusion and during elimination phase (up to 24 hours post Remimazolam infusion). | 3 days | 
| Laboratory parameters : blood gas | Routine laboratory tests for blood gas will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: haemoglobin | Routine laboratory tests for haemoglobin will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: platelet count | Routine laboratory tests for platelet count will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: white blood cell count | Routine laboratory tests for white blood cell count will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: ionogram | Routine laboratory tests for ionogram will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: creatinine | Routine laboratory tests for creatinine will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: bilirubin | Routine laboratory tests for bilirubin will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: albumin | Routine laboratory tests for albumin will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: liver enzymes | Routine laboratory tests for liver enzymes will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: phosphorus | Routine laboratory tests for phosphorus will be made within this time frame: from day0 to day3. | 4 days | 
| Laboratory parameters: magnesium | Routine laboratory tests for magnesium will be made within this time frame: from day0 to day3. | 4 days | 
| Extubation failure defined as the need to intubate a patient in the 96 hours following extubation. | Extubation failure will be defined as the need to intubate a patient in the 96 hours following extubation. | 28 days | 
| Length of Mechanical ventilation. | Defined as the duration between the initiation and the successful weaning of mechanical ventilation. From Day-1 to ICU discharge or Day-28 | 28 days | 
| Death. | in the ICU or at Day-28 if the patient is not discharged | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Remimazolam, Sedation, Shortage, Critical care, COVID-19