Clinical Trials Register

Summary
EudraCT Number:	2019-004537-16
Sponsor's Protocol Code Number:	29BRC19.0280
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:	2020-09-10
Trial 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

2019-004537-16

A.3

Full title of the trial

Comparison of an inhaled sedation strategy to an intravenous sedation strategy in ICU patients treated with invasive mechanical ventilation

Comparaison d’une stratégie de sédation inhalée à une stratégie de sédation intra-veineuse chez les patients de réanimation traités par ventilation mécanique invasive

A.3.1

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

Comparison of an inhaled sedation strategy to an intravenous sedation strategy in ICU patients treated with invasive mechanical ventilation

Comparaison d’une stratégie de sédation inhalée à une stratégie de sédation intra-veineuse chez les patients de réanimation traités par ventilation mécanique invasive

A.3.2

Name or abbreviated title of the trial where available

INASED

A.4.1

Sponsor's protocol code number

29BRC19.0280

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	CHRU de Brest
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	French health ministry
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHRU de Brest
B.5.2	Functional name of contact point	Cecile DUCHIRON
B.5.3	Address:
B.5.3.1	Street Address	2 avenue Foch
B.5.3.2	Town/ city	Brest
B.5.3.4	Country	France
B.5.4	Telephone number	+33298223187
B.5.5	Fax number	+33298223183
B.5.6	E-mail	cecile.duchiron@chu-brest.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	Yes
D.2.1.1.1	Trade name	Aerrane
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Isoflurane
D.3.4	Pharmaceutical form	Solution for infusion in administration system
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation 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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Propofol 10 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Propofol
D.3.4	Pharmaceutical form	Solution for injection
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Sufentanil 50 µg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Panpharma
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Sufentanil
D.3.4	Pharmaceutical form	Solution for injection
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

Prevention of delirium

Prévention du delirium

E.1.1.1

Medical condition in easily understood language

Prevention of delirium

Prévention du delirium

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10072852
E.1.2	Term	Post-injection delirium/sedation syndrome
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the impact on the frequency of occurrence of delirium of an early inhaled sedation strategy (from induction in rapid sequence if intubation in intensive care, or from admission if intubated in pre-hospital) by ISOFLURANE ™ at using an ANACONDA ™ type system, in comparison to a conventional intravenous sedation strategy.

Déterminer l’impact sur la fréquence de survenue du délirium d’une stratégie de sédation inhalée précoce (dès l’induction en séquence rapide si intubation en réanimation, ou dès l’admission si intubé en pré-hospitalier) par ISOFLURANE™ à l’aide d’un système de type ANACONDA™, en comparaison à une stratégie de sédation conventionnelle par voie intraveineuse.

E.2.2

Secondary objectives of the trial

Determine:
• Morbidity and mortality
• The duration of hospitalization
• The number of days without mechanical ventilation
• The incidence of delirium occurring after weaning from sedation
• The quality of sedation
• Safety in use
• The dosages of pressurized amines, of vascular filling, the need to start a renal supply will be systematically collected
• The incidence of states of agitation requiring the use of a complementary drug prescription
• The physical restraint rate
• The rate of self-extubation and ablation of catheters or probes
• The rate of self-attack or hetero-aggression
• Long-term cognitive consequences
• Efficacy of sedation in a specific subgroup of "difficult to sedate" patients
• The economic value of the isoflurane inhaled sedation strategy

Déterminer :
• La morbi-mortalité
• La durée de l’hospitalisation
• Le nombre de jours sans ventilation mécanique
• L’incidence de survenue d’un delirium au décours du sevrage de la sédation
• La qualité de la sédation
• La sécurité d’utilisation
• Les posologies d’amines vasopressives, de remplissage vasculaire, la nécessité de mise en route d’une suppléance rénale seront colligés de façon systématique
• L’incidence d’états d’agitation nécessitant le recours à une prescription médicamenteuse complémentaire
• Le taux de contention physique
• Le taux d’auto-extubations et d’ablation de cathéters ou de sondes
• Le taux d’auto ou hétéro-agressions
• Les conséquences cognitives à long terme
• L’efficacité de la sédation dans un sous-groupe spécifique de patients « difficiles à sédater »
• L’intérêt économique de la stratégie de sédation inhalée par isoflurane

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patient aged 18 and over
• Patient requiring mechanical ventilation for at least 24 hours
• Consent obtained from the patient or a relative

• Patient âgé de 18 ans et plus
• Patient nécessitant une ventilation mécanique pendant au moins 24 heures
• Consentement obtenu auprès du patient ou d’un proche

E.4

Principal exclusion criteria

Patient hospitalized for the following reasons for admission:
- Cardiac arrest
- State of refractory epilepticus
- Head trauma
- Stroke
• Hearing, visual or aphasia disorders before inclusion
• Sedation started more than 24 hours ago
• Impairment of cognitive functions and / or dementia
• Contraindication to halogenated gases (personal or family history of malignant hyperthermia, acute or chronic neuromuscular disease, hepatocellular insufficiency with PT <30%)
• Severe SDRA (Berlin criteria)
• PaCO2 at inclusion> 50 mmHg
• Pregnancy in progress or lactating woman
• Patient for whom a procedure of "limitation of active therapies" is envisaged at inclusion
• Patient under guardianship or curatorship

• Patient hospitalisé pour les motifs suivants d’admission :
- Arrêt cardiaque
- Etat de mal épileptique réfractaire
- Traumatisme crânien
- Accident vasculaire cérébral
• Troubles auditifs, visuels, ou aphasie avant inclusion
• Sédation débutée depuis plus de 24h
• Atteinte des fonctions cognitives et/ou démence
• Contre-indication aux gaz halogénés (antécédents personnels ou familiaux d’hyperthermie maligne, maladie neuromusculaire aigue ou chronique, insuffisance hépato-cellulaire avec TP<30%)
• SDRA Sévère (critères de Berlin)
• PaCO2 à l’inclusion > 50 mmHg
• Grossesse en cours ou femme allaitante
• Patient pour lequel une procédure de « limitation des thérapeutiques actives » est envisagée à l’inclusion
• Patient sous tutelle ou curatelle

E.5 End points

E.5.1

Primary end point(s)

Occurrence (yes / no) of a delirium in intensive care.

Survenue (oui/non) d’un delirium en réanimation.

E.5.1.1

Timepoint(s) of evaluation of this end point

ICU exit

Sortie de réanimation

E.5.2

Secondary end point(s)

Mortality in intensive care, mortality on D28
• Duration of hospitalization in intensive care
• Number of days living without mechanical ventilation in intensive care on D28
• CAM-ICU scale (/ 8h)
The quality of sedation is defined by: compliance (yes / no) with the sedation target (sedation score set as target during prescriptions)
• Need for recourse to an additional drug prescription to alleviate a state of agitation (yes / no if yes neuroleptic, benzodiazepine, dexmedetomidine)
• Need to use additional physical restraint to overcome a state of agitation (yes / no)
• Number of accidental withdrawals by the patient of intubation tube, first vascular, nasogastric tube, urinary tube, reduced to the number of days in intensive care
• Number of auto or hetero-aggressive acts reduced to the number of days in intensive care
• Average hospital cost per patient
• Daily and cumulative dose of sedative
• The cognitive consequences will be assessed. Calculation of CDR and IQCODE scores. Evaluation within 72 hours after MMS and Trail B test extubation. Cognitive assessment (free and indexed recall, Rey figure, history recall, name and verbal fluency, TMT, SF36, PTSD Checklist, HADS, ICU memory tool) at 3 and 12 months
• PRE-DELIRIC and CIWA-Ar scores (daily Clinical Institute Withdrawal Assessment Alcohol Scale, revised).

• Mortalité en réanimation, mortalité à J28
• Durée d’hospitalisation en réanimation
• Nombre de jours vivant sans ventilation mécanique en réanimation à J28
• Echelle CAM-ICU (/8h)
La qualité de la sédation est définie par : respect (oui/non) de la cible de sédation (score de sédation fixé comme cible lors des prescriptions)
• Nécessité de recours à une prescription médicamenteuse complémentaire pour pallier à un état d’agitation (oui/non si oui neuroleptique, benzodiazépine, dexmedetomidine)
• Nécessité de recours à une contention physique complémentaire pour pallier à un état d’agitation (oui/non)
• Nombre de retraits accidentels par le patient de sonde d’intubation, d’abord vasculaire, de sonde naso-gastrique, de sonde urinaire, ramené au nombre de jour en réanimation
• Nombre d’actes auto ou hétéro-agressifs ramenés au nombre de jours en réanimation
• Le coût hospitalier moyen par patient
• Dose quotidienne et cumulée de sédatif
• Les conséquences cognitives seront évaluées. Calcul des scores CDR et IQCODE. Evaluation dans les 72 heures après l’extubation du MMS et du Trail B test. Evaluation cognitive (rappel libre et indicé, figure de Rey, rappel d’histoire, dénomination et fluence verbale, TMT, SF36, PTSD Checklist, HADS, ICU memory tool) à 3 et 12 mois
• Scores PRE-DELIRIC et CIWA-Ar (daily Clinical Institute Withdrawal Assessment Alcohol Scale, revised).

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days ou 12 months

28 jours ou 12 mois

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

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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

Yes

E.6.13.1

Other scope of the trial description

prospective strategy comparison study

etude prospective de comparaison de stratégie

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

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

The end of the trial corresponds to the last visit of the last patient followed in the protocol.

La fin de l'essai correspond à la dernière visite du dernier patient suivi dans le protocole.

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.1.3

Elderly (>=65 years)

Yes

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

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

If the patient is not in a condition to consent (intubated and ventilated patient), the consent of a family member or the confidential counselor will be obtained by the healthcare team.

Si le patient n’est pas en état de consentir (patient intubé et ventilé), le consentement d’un membre de famille ou de la personne de confiance sera recueilli par l’équipe soignante.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

250

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Aucun

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

2020-01-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-26

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

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