Clinical Trials Register

Summary
EudraCT Number:	2017-003225-15
Sponsor's Protocol Code Number:	HALO-ICU
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-01
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-003225-15

A.3

Full title of the trial

Comparison between inhaled sedation with Sevoflurane vs endovenous sedation with Propofol in the Intensive Care Unit: a randomized prospective trial

Confronto tra sedazione inalatoria con Sevoflurane vs sedazione endovenosa con Propofol in Terapia Intensiva: studio prospettico randomizzato

A.3.1

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

Comparison between sedation obtained with Sevoflurane administered through inhalation and Propofol administered through intravenous infusion

Confronto tra sedazione con Sevoflurane somministrato per via inalatoria vs Propofol somministrato per via endovenosa

A.3.2

Name or abbreviated title of the trial where available

HALO-ICU

A.4.1

Sponsor's protocol code number

HALO-ICU

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	AZIENDA OSPEDALIERO-UNIVERSITARIA CAREGGI
B.1.3.4	Country	Italy
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	Pall International
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gianluca Villa
B.5.2	Functional name of contact point	SOD Anestesia Oncologica e Terapia
B.5.3	Address:
B.5.3.1	Street Address	Largo Brambilla 3
B.5.3.2	Town/ city	Firenze
B.5.3.3	Post code	50134
B.5.3.4	Country	Italy
B.5.4	Telephone number	3207615547
B.5.5	Fax number	0557946210
B.5.6	E-mail	gianluca.villa@unifi.it

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	SEVOFLURANE PIRAMAL - 100% V/V LIQUIDO PER INALAZIONE 1 FLACONE IN VETRO DA 250 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	PIRAMAL HEALTHCARE UK LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Sevoflurano
D.3.2	Product code	N01AB08
D.3.4	Pharmaceutical form	Pressurised inhalation, solution
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	SEVOFLURANO
D.3.9.1	CAS number	28523-86-6
D.3.9.2	Current sponsor code	SEVOFLURANO
D.3.9.3	Other descriptive name	Sevoflurane
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0 to 2
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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 KABI - 20MG/ML EMULSIONE INIETTABILE O PER INFUSIONE 10 FLACONCINI DA 50 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	FRESENIUS KABI ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.2	Product code	N01AX10
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 drip use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PROPOFOL
D.3.9.1	CAS number	2078-54-8
D.3.9.2	Current sponsor code	PROPOFOL
D.3.9.3	Other descriptive name	Propofol
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg/h milligram(s)/kilogram/hour
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0 to 3
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Preoperative-scheduled sedation in surgical patients admitted in the Intensive Care Unit (ICU) for postoperative monitoring

Sedazione, prevista nel preoperatorio, di pazienti chirurgici ricoverati in Unità di Terapia Intensiva (UTI) per il monitoraggio postoperatorio

E.1.1.1

Medical condition in easily understood language

Postoperative sedation in patients with indication to ICU admission.

Sedazione postoperatoria in pazienti con indicazione al ricovero in UTI.

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	LLT
E.1.2	Classification code	10049124
E.1.2	Term	Sedation during medical procedure
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

The primary objective of the study is to demonstrate the reduction of the extubation time in the Sevoflurane sedated group compared to the group of patients sedated with Propofol, starting from similar depth of sedation.

Obiettivo primario dello studio è dimostrare la riduzione dei tempi di estubazione nel gruppo di pazienti sedati con Sevoflurane rispetto al gruppo di pazienti sedati con Propofol, a partire dalla sospensione del farmaco sedativo ed a parità di profondità della sedazione.

E.2.2

Secondary objectives of the trial

Evaluate the total duration of mechanical ventilation in the ICU between the two study groups.
Evaluate the hemodynamic pattern in patients sedated with Sevoflurane compared to patients sedated with Propofol.
Evaluate the quality of waking in patients sedated with Sevoflurane compared with patients sedated with Propofol.
Assess the quality of sleep during sedation with Sevoflurane compared to Propofol.
Quantify plasma and urine inorganic fluoride concentration during sedation.
Evaluate the outcome of patients in the two study groups.
Evaluate the glicaemic stability in the two study groups.

Valutare la durata totale della ventilazione meccanica in Terapia Intensiva tra i due gruppi di studio.
Valutare l’assetto emodinamico nei pazienti sedati con Sevoflurane rispetto ai pazienti sedati con Propofol.
Valutare la qualità del risveglio nei pazienti sedati con Sevoflurane rispetto ai pazienti sedati con Propofol.
Valutare la qualità del sonno durante sedazione con Sevoflurane rispetto a Propofol.
Quantificare il fluoruro inorganico nel plasma e nelle urine durante la sedazione.
Valutare l’outcome dei pazienti nei due gruppi di studio.
Valutare la stabilità glicemica nei due gruppi

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Consent, obtained during the preoperative period, for data treatment , randomization and participation in the study.
• Age > 18 years
• Pre-operative indications for post-operative monitoring in the ICU

• Consenso, ottenuto nel periodo preoperatorio, al trattamento dei dati personali, alla randomizzazione ed alla partecipazione allo studio.
• Età > 18 anni
• Indicazione al ricovero post-operatorio in UTI

E.4

Principal exclusion criteria

• Pregnancy and breast feeding (women of childbearing age will be tested for the beta-HCG dosage to certainy exclude the pregnancy before the enrollment).
• Known hypersensitivity to propofol, soy, peanut or any of the excipients of the emulsion, as well as allergic patients to soy or peanut.
• Patients undergoing treatment with Cyclosporine.
• Severe or suspected hypersensitivity to sevoflurane or other halogenated anesthetics (eg history of liver dysfunction, fever or leukocytosis of unknown cause after anesthesia with one of these agents).
• Moderate to severe hepatic dysfunction due to jaundice, fever, and eosinophilia after Sevoflurane-induced anesthesia.
• Genetic predisposition known or suspected of malignant hyperthermia.

• Gravidanza e allattamento (le donne in età fertile saranno sottoposte prima dell’arruolamento al dosaggio delle beta-HCG ai fini di escludere con assoluta certezza lo stato gravidico).
• Ipersensibilità nota verso propofol, soia, arachidi o uno qualsiasi degli eccipienti dell’emulsione, nonché i pazienti allergici alla soia o alle arachidi.
• Pazienti in trattamento con ciclosporine.
• Ipersensibilità nota o sospetta al sevoflurano o ad altri anestetici alogenati (es. anamnesi di disfunzione epatica, febbre o leucocitosi di causa sconosciuta dopo anestesia con uno di questi agenti).
• Disfunzione epatica da moderata a severa di cui non è stata stabilita la causa, con ittero, febbre e eosinofilia dopo anestesia indotta con sevoflurano.
• Predisposizione genetica nota o sospetta a ipertermia maligna.

E.5 End points

E.5.1

Primary end point(s)

The extubation time will be evaluated quantitatively: when the ICU physician will consider the patient ready to be weaned from mechanical ventilation (according to routine clinical criteria) sedation with Propofol or Sevoflurane will be suspended. From the "stop" of sedation the time needed to allow a complite consciousness and safetly extubation will be recorded.

Il tempo di estubazione verrà valutato quantitativamente: quando il medico dell'UTI giudicherà che il paziente può essere svezzato dalla ventilazione meccanica (sulla base di criteri clinici) verrà sospesa la sedazione con Propofol o Sevoflurane. Dallo “stop” della sedazione verrà misurato il tempo necessario a consentire al paziente di raggiungere un buon grado di coscienza ed un recupero dei meccanismi di protezione delle alte vie aeree, così da consentire un ritorno alla ventilazione spontanea.

E.5.1.1

Timepoint(s) of evaluation of this end point

In the two study groups we will compare the time required from the patients to be safetly extubated from the Prpofol or Sevoflurane interruption. This data (expressed in minutes) will be reported as median and interquartile range and formaly recorded at the time of extubation.

Nei due gruppi di studio noi confronteremo il tempo intercorso da quando viene sospesa la somministrazione del farmaco a quando il paziente risulta in grado di respirare autonomamente e senza supporto meccanico. Tale dato (espresso in minuti) sarà riportato come mediana e range interquartile e registrato al momento dell’estubazione del paziente.

E.5.2

Secondary end point(s)

We will evaluate the total duration of mechanical ventilation (calcolated in minutes) between the two study groups, from the admission in the ICU to the removal of the orotracheal tube.; From the admission in the ICU systolic, diastolic and meanl arterial blood pressure will be recorded (in mmHg), as well as the heart rate (bpm) and the need for inotropic / vasopressor support (in mcg/kg/min).; The quality of patients awakening will be evaluated trought the "Richmond Agitation-Sedation Scale" after the extubation.; The quality of sleep will be evaluated in the two study groups through a sleep profiler: comparing the total sleep time (TST, in minutes) and the percentages of N1, N2 and N3 spleep compared to TST (in percentages) in the first 12 hours of sedation.; The plasmatic and urinary inorganic fluoride concentrations (in ppm) will be measured by PH-meter with ion-selective probe.; The outcome of the patients will be expressed in terms of: ICU lenght of stay (day), hospital lenght of stay (day), ICU mortality (percentage), and hospital mortality (percentage).; Glicaemic metabolic control will be expressed as glucose variability (ratio between standard deviation of glicaemia and the means observed during the sedation).

Noi valuteremo la durata totale della ventilazione meccanica (in minuti) tra i due gruppi di studio, dall’ingresso in UTI fino alla rimozione del tubo orotracheale.; Dall’ammissione in UTI saranno registrati i seguenti parametri: pressione arteriosa sistolica, diastolica e media (espressa in mmHg), frequenza cardiaca (in bpm), e l'eventuale necessità di supporto inotropo/vasopressorio (in mcg/kg/min).; Dopo l'estubazione e mediante "Richmond Agitation-Sedation Scale" (RASS) noi valuteremo la qualità del risveglio del paziente.; Noi valuteremo la qualità del sonno nei due gruppi di studio attraverso uno "sleep profiler": confrontando il "total sleep time" (TST, in minuti) e la percentuale di sonno N1, N2 ed N3 rispetto al TST (in percentuale)nelle prime 12 ore di sedazione.; In entrambi i bracci di studio, noi misureremo la concentrazione di fluoruro inorganico nel plasma e nelle urine (in ppm) mediante PH-metro con sonda iono-selettiva.; L’outcome dei pazienti sarà espresso in termini di: durata della degenza in UTI (in giorni), durata della degenza in ospedale (in giorni), mortalità in UTI (percentuali) e mortalità ospedaliera (percentuale).; La variabilità glicemica verrà espressa in termini di glucose variability (rapporto tra la deviazione standard e le medie delle glicemie osservate durante la sedazione).

E.5.2.1

Timepoint(s) of evaluation of this end point

This timing will be expressed in minutes, it will be recorde at the time of extubation and will be compared in the final analysis between the two groups. ; All these parameters will be measured hourly during the entire sedation.; This evaluation will be performed 30 minutes after the extubation.; This evaluation will be continuously performed in the first 12 hours of sedation.; These concentrations will be evaluated at the time of extubation and after 24 hours. ; These assesments will be performed at the ICU discharge and at the hospital discharge or at the patient's death.; Glucose variability will be expressed at the end of the study considering all glicaemia values observed at hemogasanalysis required for routine practice in postoperative patients.

Tale tempistica sarà espressa in minuti, verrà valutata al momento dell'estubazione e confrontata nell’analisi finale tra i due gruppi.; Noi misureremo tali parametri ogni ora durante tutta la durata della sedazione.; Noi effettueremo tale valutazione 30 minuti dopo l'estubazione.; Tale valutazione verrà effettuata in continuo nelle prime 12 ore di sedazione.; Noi misureremo queste concentrazioni al momento dell'estubazione e a distanza di 24 ore.; Noi effettueremo tale valutazione al momento della dimissione del paziente dalla UTI e dall'ospedale o al momento del decesso.; La glucose variability verrà espressa al termine dello studio considerando tutti i valori glicemici riscontrati nei vari esami emogasanalitici previsti secondo pratica clinica del centro.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Information not present in EudraCT

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 study will be concluded when the last patient enrolled will be resigned from the hospital or in case of death of this latter.

Lo studio si riterrà concluso quando l'ultimo paziente arruolato sarà dimesso dall'ospedale o in caso di eventuale decesso di questo ultimo.

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

E.8.9.2

In all countries concerned by the trial 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

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

F.3.3.6

Subjects incapable of giving consent personally

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

F.4.2.2

In the whole clinical trial

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)

Patients enrolled will be all surgical patients.
In the preoperative, we will explain to them the ways and purposes of the study and require their consent.
Patients will then be subjected to the planned surgery according to their basic pathology.
Under no circumstances the inclusion in this study will change the surgical indications and procedures already provided for the patient.
In the post-operative, patients admitted to ICU will be included in the study group or randomized control group. The

I pazienti arruolati saranno tutti pazienti chirurgici.
Nel preoperatorio saranno loro spiegate le modalità e le finalità dello studio e richiesto il loro consenso.
I pazienti verranno quindi sottoposti all’intervento chirurgico previsto secondo la loro patologia di base.
In nessun caso l’inclusione in questo studio modificherà le indicazioni e le procedure chirurgiche già previste per il paziente.
Nel post-operatorio, i pazienti ricoverati in UTI verranno inclusi nel gruppo di studio o controll

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

2017-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-19

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

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IMP with orphan designation in the indication
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