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

Primary Purpose

Acute Respiratory Failure, COVID-19, Trauma

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Remimazolam
Sponsored by
Nantes University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Acute Respiratory Failure focused on measuring Remimazolam, Sedation, Shortage, Critical care, COVID-19

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • CHU de Nantes

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Remimazolam

Arm Description

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)

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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).
Heart rate
Hemodynamic stability follow-up of heart rate, from day1 to day3.
Arterial pressure
Hemodynamic stability follow-up with systolic, diastolic and mean arterial pressure from day1 to day3.
Dose of norepinephrine
Hemodynamic stability follow-up with the dose of norepinephrine from day1 to day3.
Electrocardiogram (ECG)
Hemodynamic stability follow-up with electrocardiogram from day1 to day3.
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.
Other sedatives.
The use or switch to other sedatives (midazolam, dexmedetomidine, propofol) in case of remimazolam inefficacy, will be monitored, from day1 to day3.
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.
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).
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).
Laboratory parameters : blood gas
Routine laboratory tests for blood gas will be made within this time frame: from day0 to day3.
Laboratory parameters: haemoglobin
Routine laboratory tests for haemoglobin will be made within this time frame: from day0 to day3.
Laboratory parameters: platelet count
Routine laboratory tests for platelet count will be made within this time frame: from day0 to day3.
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.
Laboratory parameters: ionogram
Routine laboratory tests for ionogram will be made within this time frame: from day0 to day3.
Laboratory parameters: creatinine
Routine laboratory tests for creatinine will be made within this time frame: from day0 to day3.
Laboratory parameters: bilirubin
Routine laboratory tests for bilirubin will be made within this time frame: from day0 to day3.
Laboratory parameters: albumin
Routine laboratory tests for albumin will be made within this time frame: from day0 to day3.
Laboratory parameters: liver enzymes
Routine laboratory tests for liver enzymes will be made within this time frame: from day0 to day3.
Laboratory parameters: phosphorus
Routine laboratory tests for phosphorus will be made within this time frame: from day0 to day3.
Laboratory parameters: magnesium
Routine laboratory tests for magnesium will be made within this time frame: from day0 to day3.
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.
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
Death.
in the ICU or at Day-28 if the patient is not discharged

Full Information

First Posted
October 7, 2020
Last Updated
October 27, 2021
Sponsor
Nantes University Hospital
Collaborators
Paion UK Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04611425
Brief Title
REmimazolam Infusion in the Context of Hypnotic Shortage in the Critical Care Unit During the Pandemic of COVID-19: REHSCU Study
Acronym
REHSCU
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
November 30, 2020 (Actual)
Primary Completion Date
December 2, 2020 (Actual)
Study Completion Date
October 22, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nantes University Hospital
Collaborators
Paion UK Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Failure, COVID-19, Trauma, Stroke, Sepsis, Shock
Keywords
Remimazolam, Sedation, Shortage, Critical care, COVID-19

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Non-controlled
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Remimazolam
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Remimazolam
Other Intervention Name(s)
Remimazolam (CNS 7056)
Intervention Description
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.
Primary Outcome Measure Information:
Title
composite endpoint including a combination of cardio-vascular and sedation events, from baseline (before infusion) to 8 hours, after the beginning of Remimazolam infusion
Description
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).
Time Frame
8 hours after the beginning of infusion.
Secondary Outcome Measure Information:
Title
Adverse Events (all grades), related to Remimazolam.
Description
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).
Time Frame
5 days
Title
Heart rate
Description
Hemodynamic stability follow-up of heart rate, from day1 to day3.
Time Frame
3 days
Title
Arterial pressure
Description
Hemodynamic stability follow-up with systolic, diastolic and mean arterial pressure from day1 to day3.
Time Frame
3 days
Title
Dose of norepinephrine
Description
Hemodynamic stability follow-up with the dose of norepinephrine from day1 to day3.
Time Frame
3 days
Title
Electrocardiogram (ECG)
Description
Hemodynamic stability follow-up with electrocardiogram from day1 to day3.
Time Frame
3 days
Title
Sedation.
Description
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.
Time Frame
3 days
Title
Other sedatives.
Description
The use or switch to other sedatives (midazolam, dexmedetomidine, propofol) in case of remimazolam inefficacy, will be monitored, from day1 to day3.
Time Frame
3 days
Title
Wake-up time.
Description
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.
Time Frame
3 days
Title
Pharmacokinetics of Remimazolam and its metabolites (CNS 7054): Maximum Plasma Concentration.
Description
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).
Time Frame
3 days
Title
Pharmacodynamics Remimazolam and its metabolites (CNS 7054): steady state plasma levels and elimination.
Description
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).
Time Frame
3 days
Title
Laboratory parameters : blood gas
Description
Routine laboratory tests for blood gas will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: haemoglobin
Description
Routine laboratory tests for haemoglobin will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: platelet count
Description
Routine laboratory tests for platelet count will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: white blood cell count
Description
Routine laboratory tests for white blood cell count will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: ionogram
Description
Routine laboratory tests for ionogram will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: creatinine
Description
Routine laboratory tests for creatinine will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: bilirubin
Description
Routine laboratory tests for bilirubin will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: albumin
Description
Routine laboratory tests for albumin will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: liver enzymes
Description
Routine laboratory tests for liver enzymes will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: phosphorus
Description
Routine laboratory tests for phosphorus will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Laboratory parameters: magnesium
Description
Routine laboratory tests for magnesium will be made within this time frame: from day0 to day3.
Time Frame
4 days
Title
Extubation failure defined as the need to intubate a patient in the 96 hours following extubation.
Description
Extubation failure will be defined as the need to intubate a patient in the 96 hours following extubation.
Time Frame
28 days
Title
Length of Mechanical ventilation.
Description
Defined as the duration between the initiation and the successful weaning of mechanical ventilation. From Day-1 to ICU discharge or Day-28
Time Frame
28 days
Title
Death.
Description
in the ICU or at Day-28 if the patient is not discharged
Time Frame
28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raphaël CINOTTI, MD
Organizational Affiliation
Nantes University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU de Nantes
City
Nantes
Country
France

12. IPD Sharing Statement

Learn more about this trial

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

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