Clinical Trials Register

Summary
EudraCT Number:	2020-000578-31
Sponsor's Protocol Code Number:	SED002
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-07-02
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

2020-000578-31

A.3

Full title of the trial

A Randomised Active-controlled Study to Compare Efficacy and Safety of Inhaled Isoflurane Delivered by the AnaConDa-S (Anaesthetic Conserving Device) to Intravenous Midazolam for Sedation in Mechanically Ventilated Paediatric Patients 3 to 17 (Less than 18) Years Old

A.3.1

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

A Study to Compare the Effect and Safety of Inhaled Isoflurane to Intravenous Midazolam for Sedation in Mechanically Ventilated Children 3-17 Years Old

A.3.2

Name or abbreviated title of the trial where available

IsoCOMFORT study

A.4.1

Sponsor's protocol code number

SED002

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/092/2019

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sedana Medical AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sedana Medical AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sedana Medical AB
B.5.2	Functional name of contact point	clinical@sedanamedical.com
B.5.3	Address:
B.5.3.1	Street Address	Vendevägen 87
B.5.3.2	Town/ city	Danderyd
B.5.3.3	Post code	182 32
B.5.3.4	Country	Sweden
B.5.6	E-mail	clinicalresearch@sedanamedical.com

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	ISOFLURANE 100% Inhalation vapour, liquid
D.2.1.1.2	Name of the Marketing Authorisation holder	Piramal Critical Care Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Inhalation vapour, liquid
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ISOFLURANE
D.3.9.1	CAS number	26675-46-7
D.3.9.4	EV Substance Code	SUB08319MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (V/V) percent volume/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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	Midazolam 1 mg/ml Solution for Injection/Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	hameln pharmaceuticals ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MIDAZOLAM
D.3.9.1	CAS number	59467-70-8
D.3.9.4	EV Substance Code	SUB08950MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Midazolam 2 mg/ml Solution for Injection/Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	hameln pharmaceuticals ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MIDAZOLAM
D.3.9.1	CAS number	59467-70-8
D.3.9.4	EV Substance Code	SUB08950MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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

Sedation in Mechanically Ventilated Paediatric Patients 3 to 17 (Less than 18) Years Old

E.1.1.1

Medical condition in easily understood language

Sedation in patients that are 3 to 17 (Less than 18) Years Old and where breathing is assisted by a Machine.

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10039897
E.1.2	Term	Sedation
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10049683
E.1.2	Term	Monitored anesthesia care sedation
E.1.2	System Organ Class	100000004865

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10062825
E.1.2	Term	Monitored anaesthesia care sedation
E.1.2	System Organ Class	100000004865

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 compare the percentage of time adequate sedation depth is maintained within the individually prescribed target range in absence of rescue sedation as assessed according to the COMFORT-B scale, in isoflurane vs midazolam treated paediatric patients for an expected minimum of 12 hours.

E.2.2

Secondary objectives of the trial

Secondary objectives, efficacy
• Compare the use of opiates, and the development of tolerance to the sedative regimen as measured by the change in dose of study drug, opiates and other analgesics, over time in isoflurane- vs midazolam-treated patients.
• Compare the need for rescue sedatives and other sedatives in isoflurane- vs midazolam-treated patients.

Secondary objectives, safety
Please see protocol

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Paediatric patients at least 3 years to 17 (less than 18) years at the time of
randomisation, admitted to an ICU/with planned ICU admission.
2. Expected mechanical (invasive) ventilation and sedation for at least 12 hours.
3. Informed consent obtained from the patient, patient’s legal guardian(s) as required
by local regulations. Where applicable, assent obtained from the patient to participate in the clinical study.

E.4

Principal exclusion criteria

1. Ongoing seizures requiring acute treatment.
2. Continuous sedation for more than 72 hours at time of randomisation.
3. Less than 24 hours post cardiopulmonary resuscitation.
4. Uncompensated circulatory shock.
5. Known hypersensitivity to isoflurane or to other halogenated anaesthetics (such as
halothane), benzodiazepines, non-investigational medicinal product(s) (analgesics, additional rescue sedatives that may be required during the study) or to any of their formulation ingredients.
6. Known or suspected genetic susceptibility to malignant hyperthermia.
7. Patients with acute asthma or obstructive lung disease symptoms requiring treatment at inclusion.
8. Patient with tidal volumes below 30 mL or above 800 mL.
9. Inability to perform reliable COMFORT-B assessment in the opinion of the Investigator e.g. due to (not limited to):
Severe traumatic brain injury, intracranial pathology (tumour, haemorrhage, infections), with a profound effect on the level of consciousness, severe mental retardation, major congenital anomalies of the central nervous system, severe myasthenia gravis, spinal muscular atrophy, or other severe neurologic disease, ongoing neuromuscular blockade which precludes COMFORT-B scoring.
10. Patients with intracranial pressure (ICP) monitoring or with suspected increase in ICP
11. Patients with treatment-induced whole-body hypothermia.
12. Patients with pheochromocytoma.
13. Patient not expected to survive next 48 hours or not committed to full medical care.
14. Female patients who are pregnant or breast-feeding.
15. Previous participation in the study (a patient can only participate once).
16. Known participation in any other clinical study that included drug treatment within three months of the first administration of the IMP.
17. Any for the study relevant medical history, or ongoing clinically significant disease, disorder or laboratory result which, in the opinion of the Investigator, precludes participation in the study for medical or ethical reasons.

E.5 End points

E.5.1

Primary end point(s)

Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 hours for a minimum of 12 hours (up to 48 hours ± 6 hours).

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint assessment will start 2 hours after initiating study sedative treatment (or in the case of ongoing sedation, 2 hours after terminating ongoing sedatives). The primary endpoint assessment will be collected either until the study treatment is replaced with the standard treatment (at 48± 6 hours from study treatment initiation) or when the wake-up for extubation is started, whichever comes first.

E.5.2

Secondary end point(s)

Secondary endpoints, efficacy
• Dose of opiates, study drugs and other analgesics required, from first blinded COMFORT-B assessment (at +2 hours) to end of study treatment period, given per 24 hours.
• Mean dose of study drugs, opiates and other analgesics required, during the last 4 hours of study treatment, as compared to the first 4 hours of study treatment after first blinded COMFORT-B assessment.
• Mean dose of rescue propofol (mg/kg/24 hours) and mean dose of rescue ketamine/es- ketamine (converted to ketamine-equivalents mg/kg/24 hours), and mean dose of α2- adrenergic agonists (mg/kg/24 hours) to maintain the COMFORT-B score in the individually prescribed range, in isoflurane- vs midazolam-treated children (time window: from 2 hours after initiating study sedative treatment to end of sedative treatment).
• Number of doses of rescue sedation (propofol, ketamine, es-ketamine) given per 24 hours from first blinded COMFORT-B assessment (at +2 hours) to end of study treatment period.
Secondary endpoints, safety
• Time from end of study drug administration to extubation if study drug is terminated for extubation.
• Proportion of observations with spontaneous breathing efforts during study treatment.
• Need for additional inotropic/vasopressor agent and change in VIS score during study treatment period compared to baseline.
• Presence of withdrawal symptoms as assessed using the SOS-PD scale in patients exposed to more than a total of 96 hours sedation (including pre-study sedation period) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.
• Presence of delirium as assessed using the SOS-PD scale in patients admitted to the ICU for at least 48 hours (including period prior to study enrolment) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.
• Proportion of patients experiencing psychomotor dysfunction or neurological symptoms during sedation and/or in the 48 hours after discontinuation of isoflurane or midazolam treatment, in relation to duration of exposure to isoflurane or midazolam,
and to cumulative midazolam mg/kg or isoflurane exposure (MAC hours).
• 30 days/hospital mortality.
• Ventilator-free days at 30 days from start of study treatment period.
• Time in intensive care unit/hospital at day 30 from start of study treatment period.
• Days alive and not in the ICU at day 30 from start of study treatment period.
• Proportion of patients with common as well as sedation-related adverse events, and frequencies of these adverse events from start of study treatment to end of 48-hour post
study treatment monitoring.
• Frequency and intensity of adverse events from start of study treatment to day 30.
• Changes in vital signs, blood gases, body temperature and urinary output from baseline
to end of study treatment.
• Changes in clinical chemistry and haematology parameters from baseline up to the 48-
hour post-study treatment monitoring.

E.5.2.1

Timepoint(s) of evaluation of this end point

per protocol

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

Yes

E.6.5

Efficacy

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

Yes

E.8.1.7.1

Other trial design description

Assessor blinded

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Last Patient Last Visit

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

160

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

140

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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 2020-07-02.

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Unconscious patients at the time of inclusion

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

160

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

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

2020-09-17

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-01-19

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