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

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

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.

Study Overview

• Status: Completed
• Conditions: Stroke; COVID-19; Sepsis; Shock; Trauma; Acute Respiratory Failure
• Intervention / Treatment: Drug: Remimazolam

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Nantes, France
    • CHU de Nantes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Remimazolam; 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; 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.; 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

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: Paion UK Ltd.
• Investigators: Principal Investigator: Raphaël CINOTTI, MD, CHU de Nantes

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2020
• Primary Completion (Actual): December 2, 2020
• Study Completion (Actual): October 22, 2021

Study Registration Dates

• First Submitted: October 7, 2020
• First Submitted That Met QC Criteria: October 30, 2020
• First Posted (Actual): November 2, 2020

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; Critical care; Sedation; Remimazolam; Shortage
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Insufficiency
• Other Study ID Numbers: RC20_0319

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No