Clinical Trials Register

Summary
EudraCT Number:	2020-003689-37
Sponsor's Protocol Code Number:	RC20_0319
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-01
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2020-003689-37

A.3

Full title of the trial

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.

Administration de Remimazolam dans le contexte d’une pénurie de médicaments Hypnotiques en réanimation pendant la pandémie du Coronavirus COVID-19. Étude REHSCU pilote non-contrôlée, non-randomisée, ouverte.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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.

A.3.2

Name or abbreviated title of the trial where available

REHSCU

A.4.1

Sponsor's protocol code number

RC20_0319

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CHU de Nantes
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	PAION
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU de Nantes
B.5.2	Functional name of contact point	Direction Recherche et Innovation
B.5.3	Address:
B.5.3.1	Street Address	5 Allée de l'île Gloriette
B.5.3.2	Town/ city	Nantes
B.5.3.3	Post code	44093
B.5.3.4	Country	France
B.5.4	Telephone number	00330253482835
B.5.5	Fax number	00330253482836
B.5.6	E-mail	bp-prom-regl@chu-nantes.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Remimazolam
D.3.2	Product code	PRD2518686
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

general anaesthesia in ICU

anesthésie générale en unité de soins intensifs

E.1.1.1

Medical condition in easily understood language

general anaesthesia in ICU

anesthésie générale en unité de soins intensifs

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10021723
E.1.2	Term	Induction and maintenance of anaesthesia
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

to assess the balance safety-efficacy of Remimazolam in the ICU during the first 8 hours after the beginning of infusion.

évaluer la balance sécurité-efficacité du Remimazolam administré en soins intensifs pendant les 8 premières heures après le début de la perfusion.

E.2.2

Secondary objectives of the trial

-Adverse Events (all grades), related to Remimazolam
-hemodynamic stability
-the level of sedation
-the necessity to use or switch to other sedatives during the 48-hour time-frame
-laboratory parameters
-length of mechanical ventilation
-extubation failure
-steady state plasma levels and elimination of Remimazolam and its main metabolite
-wake-up time (if applicable)
-in-ICU mortality or at Day-28 if the patient is not discharged.

-Évènements indésirables (tous grades), liés au Remimazolam
-Stabilité cardio-circulatoire
-Niveau de sédation
-L’utilisation d’autres médicaments hypnotiques pendant les 48 heures d’utilisation du Remimazolam
-Biologie
-Durée de ventilation mécanique
-Échecs d’extubation
-Pharmacocinétique et pharmacodynamique du Remimazolam et de ses métabolites
-Durée de réveil (si applicable)
-Mortalité en réanimation ou à J28 si le patient n’est toujours pas sorti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

PRE-INCLUSION CRITERIA
- Next-of-kin, Legal representative written informed consent
- affiliation with French social security system or beneficiary from such system

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

Critères de pré-inclusion
- Consentement d’un proche ou de la personne de confiance
- Affiliation au regime de Sécurité Sociale ou bénéficiaire de ce système

Critères d’inclusion
- Patients âgés de 18 ans et plus
- Inclusion dans les 96 heures suivant l’admission en réanimation, après stabilisation de l’état clinique selon le médecin en charge du patient
- Durée prévisible de l’anesthésie générale ≥ 24 heures

E.4

Principal 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.

- Patients âgés de 85 ans et plus
- Refus de participation
- Patient dont l’état Clinique est jugé moribond dans les 24 heures suivant l’admission en réanimation
- Limitation des thérapeutiques actives de reanimation dans les 24 heures suivant l’admission
- Femme enceinte ou allaitante
- Patients avec des reactions anaphylactiques connues aux benzodiazépines, flumazemil ou situation clinique pour laquelle les benzodiazépines sont contre-indiquées
- Patients avec une allergie/hypersensibilité au lactose, dextran ou autre excipient du Remimazolam
- Intoxication aiguë à l’alcool, drogue ou aux benzodiazépines
- Inclusion dans une autre étude portant sur un médicament
- Patient sous tutelle, curatelle, ou un régime de protection spéciale
- Insuffisance hépatique sévère définie par un Child-Pugh score > 10.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is a composite endpoint including a combination of cardio-vascular and sedation events, from baseline (before infusion) to 8 hours, after the beginning of Remimazolam infusion. Since the patient’s clinical situation could rapidly evolved in the ICU, we chose to assess these endpoints during a short time-frame.
1) 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.
2) Efficacy. Sedation event. We 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. We will also monitor the need to use standard hypnotic drugs within this time frame as rescue medication in case of Remimazolam inefficacy (propofol, midazolam, dexmedetomidine).

Le critère d'évaluation principal est un critère d'évaluation composite comprenant une combinaison d'événements cardio-vasculaires et de sédation, depuis la ligne de base (avant la perfusion) jusqu'à 8 heures après le début de la perfusion de Remimazolam.
1) Événement cardiovasculaire. L'hypotension sera définie comme une pression artérielle moyenne ≤ 65 mmHg ou une augmentation ≥ 50% de la dose de norépinéphrine (le cas échéant), maintenue plus d'une heure après le début du Remimazolam.
2) Événement de sédation. Nous surveillerons si le Remimazolam fournit n niveau adéquat de sédation évalué avec l'échelle d'évaluation de la sédation de Richmond,. Le niveau de sédation sera fixé par le médecin traitant et est généralement fixé à-1/0. Nous surveillerons également la nécessité d'utiliser des médicaments hypnotiques standards dans ce laps de temps comme médicament de secours en cas d'inefficacité du Remimazolam (propofol, midazolam, dexmédétomidine).

E.5.1.1

Timepoint(s) of evaluation of this end point

from baseline (before infusion) to 8 hours, after the beginning of Remimazolam infusion

de la ligne de base (avant la perfusion) à 8 heures, après le début de la perfusion de Remimazolam

E.5.2

Secondary end point(s)

The secondary endpoints will be assessed as follows. These endpoints will be assessed the day of the initiation of Remimazolam, during the infusion, and at various time-points during the ICU.
-Adverse Events observed during the 48-hour infusion and up to 3 days after end of dosing
Adverse Event of Special Interest that will be monitored are the cardio-vascular events (hypotension, bradycardia), from the beginning to the end of Remimazolam infusion.
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). Owing to the very short half-life of Remimazolam, only adverse reaction monitoring will be performed afterwards.
-Hemodynamic stability. Heart rate, systolic, diastolic and mean arterial pressure, dose of norepinephrine, modification of ECG. From Day-1 to Day-3 (ie 24 hours after the end of infusion).
-Sedation. The level of sedation will be assessed with clinical scales such as Richmond Assessment Sedation Scale, Bispectral Index (when available). The monitoring with Bispectral Index, will be left at the attending physician’s discretion. From Day-1 to Day-3 (ie 24 hours after the end of infusion).
-Other sedatives. During the infusion, the dose of Remimazolam will be monitored. The necessity to use or switch to other sedatives (midazolam, dexmedetomidine, propofol) in case of remimazolam inefficacy, will be monitored. From Day-1 to Day-3 (ie 24 hours after the end of infusion).
-We will collect the 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. From Day-1 to Day-3 (ie 24 hours after the end of infusion).
-Pharmacokinetics and pharmacodynamics of Remimazolam and its metabolites, will be measured during the infusion and at the end. We will perform 9 Pharmocokinetic 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. Routine laboratory tests will be made within this time frame: blood gas, haemoglobin, platelet count, white blood cell count, ionogram, creatinine, bilirubin, albumin, liver enzymes, phosphorus, magnesium. Day-0 to Day-3 (ie 24 hours after the end of infusion).
-Extubation failure. Extubation failure will be defined as the need to intubate a patient in the 96 hours following extubation. From Day-1 to ICU discharge or Day-28
-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.

Critères de jugement secondaires (ces critères seront évalués le jour de l’initiation, pendant l’administration, avec des fenêtres de surveillance variable après l’arrêt de la perfusion) :
- Evénements indésirables observés pendant la perfusion de 48 heures et jusqu'à 3 jours après l'arrêt de la perfusion.
Les événements indésirables d'intérêt particulier qui seront surveillés sont les événements cardio-vasculaires (hypotension, bradycardie), du début à la fin de la perfusion de Remimazolam. Une surveillance exhaustive des événements indésirables sera effectuée du jour 0 (inclusion), du jour 1 et du jour 2 (pendant la perfusion) au jour 5 (3 jours après l'arrêt). En raison de la demi-vie très courte du remimazolam, un suivi moins fréquent des événements sera effectué par la suite.
-Stabilité cardio-circulatoire. fréquence cardiaque, pression artérielle systolique diastolique et moyenne, dose de noradrénaline, ECG. (jusqu’à 24 heures après l’arrêt, soit J3)
-Niveau de Sédation. Le niveau de Sédation sera évalué par l’échelle de Richmond (Richmond Assessment Sedation Scale), l’index Bispectral le cas échéant (jusqu’à 24 heures après l’arrêt, soit J3)
-Durée de réveil: durée entre l’arrêt du Remimazolam et l’obtention d’un score de RASS à -1/0 (uniquement chez les patients sans atteinte neurologique et pour lesquels l’anesthésie générale est définitivement arrêtée à l’issue de l’administration du Remimazolam). (jusqu’à 24 heures après l’arrêt, soit J3)
-Sédatifs. La dose de Remimazolam sera recensée. La nécessité d’utiliser d’autres sédatifs sera également recensée (midazolam, dexmedetomidine, propofol). (jusqu’à 24 heures après l’arrêt, soit J3)
-Biologie. Des prélèvements biologiques de routine seront réalisés : bilan gazeux, bilan hématique, ionogramme, urée, créatinine, phosphore, magnesium, albumine. (jusqu’à 24 heures après l’arrêt, soit J3)
-Pharmacocinetique, pharmacodynamique du Remimazolam et des metabolites, mesuré pendant la perfusion et à la fin. Nous effectuerons 9 prélèvements sanguins pharmacocinétiques pendant la perfusion et au jour 3, après l'arrêt du remimazolam. Au total, 9 (neuf) échantillons sanguins de 2 ml seront prélevés pendant la perfusion de 48 heures et pendant la phase d'élimination (jusqu'à 24 heures après la perfusion de Remimazolam).
-Échec d’extubation. Il sera défini comme la nécessité de ré-intuber un patient dans les 96 heures suivant l’extubation. (jusqu’à la sortie de réanimation ou J28 au maximum)
-Durée de ventilation mécanique invasive définie comme la durée (en jours) entre l’intubation et le sevrage réussi de la ventilation mécanique. (jusqu’à la sortie de réanimation ou J28 au maximum)
-Mortalité en réanimation ou à J28 si le patient n’est toujours pas sorti.

E.5.2.1

Timepoint(s) of evaluation of this end point

ICU length of stay (or until Day 5 in case the patient is discharged from the ICU before). Maximum day-28 after inclusion if the patient is not discharged from the ICU.

durée de séjour en réanimation ou jusqu’à J5 si le patient sort de réanimation avant le J5. La période maximale de suivi sera fixée à J28 après l’inclusion, si le patient n’est toujours pas sortie de la réanimation.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Dernière visite du dernier patient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-10-01.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patient’s will not be in a position to receive information and provide consent (general anaesthesia). Consent from the patient’s next-of-kin or legal representative. Retrospective consent once the patient has recovered, if condition compatible.

Patient non en mesure de recevoir de donner son consentement éclairé (anesthésie générale). Consentement du plus proche parent ou du représentant légal du patient. Consentement rétrospectif patient une fois le patient guéri, si l'état est compatible.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-10-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-10

P. End of Trial
P.	End of Trial Status	Ongoing

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