Clinical Trials Register

Summary
EudraCT Number:	2016-004833-25
Sponsor's Protocol Code Number:	UNLOCK
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-01-04
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

Spain - AEMPS

A.2

EudraCT number

2016-004833-25

A.3

Full title of the trial

Synchronous effect of anesthetics on fMRI, EEG and clinical responses. Development of a more precise system for monitoring anesthetic effect.

Efecto sincrónico de los anestésicos sobre la Resonancia Magnética Funcional, el EEG y las respuestas clínicas. Desarrollo de un sistema de monitorización anestésica más preciso.

A.3.1

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

Effect of anesthetics on fMRI, EEG and clinical responses. Development of a more precise system for monitoring anesthetic effect.

Efecto de los anestésicos sobre la Resonancia Magnética Funcional, el electroencefalograma y las respuestas clínicas. Desarrollo de un sistema de monitorización anestésica más preciso.

A.4.1

Sponsor's protocol code number

UNLOCK

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	Consorci Mar Parc de Salut de Barcelona (Parc de Salut Mar)
B.1.3.4	Country	Spain
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	Fondo de Investigación Sanitaria
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospital del Mar
B.5.2	Functional name of contact point	Servicio de Anestesia
B.5.3	Address:
B.5.3.1	Street Address	Paseo Marítimo, 25-29
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08003
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034933160785
B.5.5	Fax number	003493 2483617
B.5.6	E-mail	88143@parcdesalutmar.cat

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	Propofol Hospira 10 mg/ml emulsión para inyección y perfusión EFG
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA INVICTA, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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 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	PROPOFOL
D.3.9.1	CAS number	2078-54-8
D.3.9.3	Other descriptive name	PROPOFOL
D.3.9.4	EV Substance Code	SUB10116MIG
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: 2
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	Ultiva 1 mg polvo para concentrado para solución inyectable y para perfusión.
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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
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	REMIFENTANILO HIDROCLOCLURO
D.3.9.1	CAS number	132875-61-7
D.3.9.3	Other descriptive name	REMIFENTANIL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB04215MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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 healthy subjects

Anestesia general en voluntarios sanos

E.1.1.1

Medical condition in easily understood language

General anaesthesia in healthy subjects

Anestesia general en voluntarios sanos

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 develop a system for monitoring the effect of anesthetics on consciousness and pain, based on synchronous changes in functional neuroimaging, EEG and clinical responses.

Desarrollar un sistema de monitorización del efecto de los anestésicos sobre la consciencia y el dolor, basado en los cambios sincrónicos en la neuroimagen funcional, el EEG y las respuestas clínicas.

E.2.2

Secondary objectives of the trial

- To analyze the changes produced in the cortical connectivity map during induction of anesthesia to understand the process of "anteriorization".
- To know more precisely the neural circuits involved in propofol-induced sleep.
- To study if the application of a known pain stimulus modifies in some way (clinical, EEG or by MR) the LOC that has just been reached.
- Establish propofol dosage guidelines adjusted for each subject, studying whether they reach the LOC at "sedative" or "hypnotic" doses.
- To establish remifentanil dosing regimens by studying the concentration of remifentanil at which neuroimaging (neuronal activation-deactivation in MRF) is inhibited.
- To validate the mathematical models in relation to the plasma and brain concentrations of propofol and remifentanil.
- To validate the value of clinical signs to predict whether a subject feels the painful stimulus received.

- Analizar los cambios producidos en el mapa de conectividad cortical durante la inducción de la anestesia para entender el proceso de “anteriorización”.
- Conocer con mayor exactitud los circuitos neuronales implicados en el sueño inducido con propofol.
- Estudiar si la aplicación de un estímulo doloroso conocido modifica de alguna forma (clínica, EEG o mediante RMf) el LOC que acaba de alcanzarse.
- Establecer pautas de dosificación de propofol ajustadas a cada sujeto, estudiando si estos alcanzan el LOC a dosis “sedantes” o “hipnóticas”.
- Establecer pautas de dosificación de remifentanil, estudiando la concentración de remifentanil a la que se inhibe la respuesta del dolor en la neuroimagen (activación-desactivación neuronal en la RMf).
- Validar los modelos matemáticos en relación a las concentraciones plasmáticas y cerebrales de propofol y remifentanil.
- Validar el valor de los signos clínicos para predecir si un sujeto siente el estímulo doloroso recibido.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1- Healthy adult volunteers of both sexes between the ages of 18 and 40 at the time of the visit.
2- Physical state ASA 1
Patients who sign informed consent indicating that they have been informed of all relevant aspects of the trial.
4- Analysis of drugs in negative urine at the screening visit.

1- Adultos voluntarios sanos de ambos sexos de edad comprendida entre 18 y 40 años en el momento de la visita.
2- Estado físico ASA 1
3- Pacientes que firmen el consentimiento informado indicando que han sido informados de todos los aspectos pertinentes sobre el ensayo.
4- Análisis de drogas en orina negativo en la visita de selección.

E.4

Principal exclusion criteria

1- Cranial cutaneous or anatomical alterations.
2- Allergy to propofol, remifentanil or any of its excipients.
3 - Body mass index (BMI) <18 or> 30 kg / m2.
4- Women who test positive at the screening visit, or who are breastfeeding. Women of childbearing age (considered to be fertile after menarche and to become post-menopausal permanently unless it is sterile). They should use contraception (considered highly effective, with a failure rate of less than 1%): combined estrogen and progestogen oral contraceptives, transdermal or intravaginal. Progestin hormone contraception alone or associated with inhibition of ovulation by oral, injectable or implantable route. Intrauterine device (IUD). Intrauterine system hormone releaser (IUS). Bilateral tubal occlusion, vasectomized partner, or sexual abstinence and negative test in serum or urine to be performed on the day of selection and MRI.
5- Criteria of airway or difficult ventilation, according to the criteria of the Catalan Society of Anesthesiology, Resuscitation and Therapeutics of Pain
6- Absence of accompanying adult at the end of the study.
7- Presence of cardiac pacemakers, other electronic devices or strange ferromagnetic targets in vulnerable locations of the organism, which contraindicate the performance of MRI.
8- Background or present presence of claustrophobia. Or subjects who can not stand still for more than 25 minutes.
9- Participation in some clinical research within 3 months prior to administration of the drug.

1- Alteraciones cutáneas o anatómicas craneales.
2- Alergia al propofol, remifentanil o a alguno de sus excipientes.
3- Índice de masa corporal (IMC) < 18 o > 30 kg/m2.
4- Mujeres que den positivo en la prueba del embarazo en la visita de selección, o que se encuentren en período de lactancia materna. Las mujeres en edad fértil (se considera en edad fértil después de la menarquia y hasta convertirse en post-menopáusica de forma permanente a menos que sea estéril). Deberán utilizar contracepción (considerada altamente eficaz, con una tasa de fracaso inferior al 1%): anticonceptivos orales de estrógeno y progestágeno combinado, transdérmicos o intravaginales. Anticoncepción hormonal de progestágeno sola o asociada con la inhibición de la ovulación por vía oral, inyectable o implantable. Dispositivo intrauterino (DIU). Liberador de hormonas del sistema intrauterino (SIU). Oclusión tubárica bilateral, compañero vasectomizado, o abstinencia sexual y dar negativo en la prueba del embarazo en suero o en orina que se realizará el día de la selección y de la RMf.
5- Criterios de vía aérea o ventilación difícil, según los criterios de la Sociedad Catalana de Anestesiología, Reanimación y Terapéutica del Dolor
6- Ausencia de adulto acompañante al acabar el estudio.
7- Presencia de marcapasos cardíaco, otros dispositivos electrónicos u objetivos ferromagnéticos extraños en ubicaciones vulnerables del organismo, que contraindiquen la realización de la RM.
8- Antecedentes o presencia en la actualidad de claustrofobia. O sujetos que no puedan estar quietos por más de 25 minutos.
9- Participación en alguna investigación clínica dentro de los 3 meses anteriores a la administración del fármaco.

E.5 End points

E.5.1

Primary end point(s)

Functional Magnetic Resonance Imaging (MRI): MRI volumes with "echo planar imaging" (EPI) sequences will be acquired, the contrast of which detects changes in concentration of oxygenated and oxygenated hemoglobin in gray matter (Blood Oxygen Level Dependent, BOLD) and from there infer its metabolic dynamics and therefore also of neuronal activity.

Imágenes de Resonancia Magnética funcional (RMf): Se adquirirán en la RMf volúmenes con secuencias “echo planar imaging” (EPI), cuyo contraste permite detectar cambios de concentración de hemoglobina oxigenada y de-oxigenada en sustancia gris (señal Blood Oxygen Level Dependent, BOLD) y de ahí inferir su dinámica metabólica y por tanto también de actividad neuronal.

E.5.1.1

Timepoint(s) of evaluation of this end point

20 mins during treatment

20 mins durante la administración

E.5.2

Secondary end point(s)

Demographics: Age, sex, weight, height, dominant cerebral hemisphere, usual medication.
Categorical clinical responses:
- Abolition of response to the verbal order "open your eyes" (AOV).
- Abolition of the eye movement reflex (ARMO).
- Abolition of the eyelid reflex (ARP).
- Recovery of all these answers.

Electroencephalographic data (EEG):
- Two-channel unprocessed EEG recording.
- Parameters derived from EEG: continuous values of hypnosis index (qCON) and analgesia index (qNOX) (Monitor qCON, (Quantium Medical, Spain)
Electrodes distributed according to the international system (SI) 10/20, with the following positioning will be used: In front position, 3 electrodes (Positive in Fp, Negative in F7 / F8 and Reference in Fp1 / Fp2). In the parietal-temporal position, 3 electrodes (Positive in T6, Negative in T5 and Reference in Right Neck). The impedance will be less than 5 kOhm. The material used will be RM-compatible: the EEG collection electrodes will be AMBU WhiteSensor 4440M electrodes. The graphite cable (RM-compatible) that transmits information from the electrodes to the monitor, must be 3 meters long, to ensure that the monitor can work outside the area of influence of the magnet and no longer, to avoid loss Of signal strength. Adequate EEG channels will be assessed to obtain maximum information with minimal interference with MRI.

Map of cortical connectivity ("connectome"): At the end of the RMf session, a magnetic resonance diffusion image (DWI) of 64 gradients will be performed, from which a cortical tractography using spherical deconvolution will be calculated. The data obtained from tractography will be fused with those of the MRI to obtain a map of cortical connectivity, in which the degree of correlation between different brain regions during anesthesia will be analyzed to create a computational model of the anteriorization process.

Other secondary variables:
- Start and end of administration of propofol.
- Start and end of administration of remifentanil.
- Total dose of propofol and remifentanil.
- Hemodynamic and respiratory factors (blood pressure, heart rate, pulse oximetry and capnography).

- Registro del EEG no procesado en dos canales.
- Parámetros derivados del EEG: valores continuos de índice de hipnosis (qCON) e índice de analgesia (qNOX) (Monitor qCON, (Quantium Medical, Spain)
Se utilizarán electrodos distribuidos según el sistema internacional (SI) 10/20, con el siguiente posicionamiento: En posición frontal, 3 electrodos (Positivo en Fp, Negativo en F7/F8 y Referencia en Fp1/Fp2). En posición parietal-temporal, 3 electrodos (Positivo en T6, Negativo en T5 y Referencia en Cuello Derecho). La impedancia será inferior a 5 kOhm. El material empleado será RM-compatible: los electrodos de recogida del EEG serán electrodos AMBU WhiteSensor 4440M. El cable de grafito (RM-compatible) que trasmite la información de los electrodos al monitor, ha de tener una longitud de 3 metros, para garantizar que el monitor puede trabajar fuera del área de influencia del imán y no más largo, para evitar pérdida de intensidad de la señal. Se valorarán los canales de EEG adecuados para obtener la máxima información con una mínima interferencia con la RMf.

Mapa de conectividad cortical (“connectome”): Al finalizar la sesión de RMf se realizará una imagen de difusión por resonancia magnética (DWI) de 64 gradientes, a partir de la cual se calculará una tractografía cortical usando deconvolución esférica. Los datos obtenidos a partir de tractografía se fusionarán con los de la RMf para obtener un mapa de conectividad cortical, en el que se analizará el grado de correlación entre distintas regiones cerebrales durante la anestesia para crear un modelo computacional del proceso de anteriorización.

Otras variables secundarias:
-Inicio y finalización de la administración de propofol.
-Inicio y finalización de la administración de remifentanil.
-Dosis total de propofol y remifentanil.
-Constantes hemodinámicas y respiratorias (tensión arterial, frecuencia cardíaca, pulsioximetría y capnografía).

E.5.2.1

Timepoint(s) of evaluation of this end point

20 mins during treatment

20 mins durante la administración

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

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

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

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 visit of the last recruited healthy volunteer.

Última visita del último voluntario reclutado.

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)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

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.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

Ninguno

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

2017-03-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-27

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

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