Clinical Trials Register

Summary
EudraCT Number:	2014-000537-24
Sponsor's Protocol Code Number:	IIS-HEPA-TEST
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:	2014-05-22
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

2014-000537-24

A.3

Full title of the trial

Pilot clinical trial phase I / IIa to determine condition, low dose and effectiveness of liver function tests (Hepatotest)

Ensayo clínico piloto fase I/IIa para determinar condiciones, dosis mínima y efectividad de un test de función hepática (Hepatotest).

A.3.1

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

Clinical trial to determine the effectiveness of a new test of liver function (HEPATOTEST)

Estudio clínico para determinar la efectividad de un nuevo test de función hepática ( HEPATOTEST).

A.3.2

Name or abbreviated title of the trial where available

IIS-HEPA-TEST

A.4.1

Sponsor's protocol code number

IIS-HEPA-TEST

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	INSTITUTO DE INVESTIGACION SANITARIA LA FE
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	INSTITUTO DE INVESTIGACION SANITARIA LA FE
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	IIS LA FE
B.5.2	Functional name of contact point	UREC
B.5.3	Address:
B.5.3.1	Street Address	Av. Fernando Abril Martorell nº106
B.5.3.2	Town/ city	VALENCIA
B.5.3.3	Post code	46026
B.5.3.4	Country	Spain
B.5.4	Telephone number	34961246611
B.5.5	Fax number	34961246620
B.5.6	E-mail	investigacion_clinica@iislafe.es

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	FRENADOL COMPLEX
D.2.1.1.2	Name of the Marketing Authorisation holder	Johnson&Jonhson 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.3.1	Product name	FRENADOL COMPLEX
D.3.4	Pharmaceutical form	Powder for oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Paracetamol
D.3.9.1	CAS number	103-90-2
D.3.9.3	Other descriptive name	PARACETAMOL
D.3.9.4	EV Substance Code	SUB09611MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	650
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DEXTROMETHORPHAN
D.3.9.1	CAS number	125-71-3
D.3.9.4	EV Substance Code	SUB07051MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	caffeine citrate
D.3.9.1	CAS number	69-22-7
D.3.9.3	Other descriptive name	CAFFEINE CITRATE
D.3.9.4	EV Substance Code	SUB13151MIG
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CHLORPHENAMINE
D.3.9.1	CAS number	132-22-9
D.3.9.4	EV Substance Code	SUB06201MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ASCORBIC ACID
D.3.9.1	CAS number	50-81-7
D.3.9.4	EV Substance Code	SUB05579MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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	ICG-PULSION
D.2.1.1.2	Name of the Marketing Authorisation holder	PULSION Medical Systems
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.3.1	Product name	ICG-PULSION
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDOCYANINE GREEN
D.3.9.1	CAS number	3599-32-4
D.3.9.3	Other descriptive name	INDOCYANINE GREEN
D.3.9.4	EV Substance Code	SUB14208MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.25 to 0.5
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

Hepatic Function.

Función Hepatica

E.1.1.1

Medical condition in easily understood language

Hepatic Function.

Función Hepatica

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

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 determine the minimum dose and pharmacokinetics (Tmax, Cmax, metabolite ratios / active ingredient in blood and urine) for each of the active ingredients of Frenadol COMPLEX ® (acetaminophen, dextromethorphan, chlorpheniramine and caffeine) in volunteer subjects. and the optimum time for taking samples (blood and urine) for the efficient determination of the metabolites
Administer the drug that is the basis of Hepatotest (Frenadol Complex) to patients who are operated on for liver surgery preoperatively, determining the presence of metabolites in blood and urine. After the taking of a tissue sample is determined activity per gram of tissue of the enzymes that are involved in the metabolism of the aforementioned drugs

Determinar la dosis mínima y la farmacocinética (Tmáx, Cmáx, ratios metabolito/principio activo en sangre y orina) para cada uno de los principios activos del FRENADOL®COMPLEX (paracetamol, dextrometorfano, clorfenamina y cafeína) en sujetos voluntarios. y el tiempo óptimo para la toma de muestras (sangre y orina), para una eficaz determinación de los metabolitos
Administrar el fármaco que constituye la base del Hepatotest (Frenadol Complex) a pacientes que sean intervenidos por una cirugía hepática antes de la intervención, determinando la presencia de metabolitos en sangre y orina. Tras la toma de una muestra de tejido se determinarán la actividad por gramo de tejido de los enzimas que están implicados en el metabolismo de los anteriormente citados fármacos

E.2.2

Secondary objectives of the trial

Establish a procedure for sampling, processing and analysis that is robust, reproducible and consistent with current clinical practice for drug administration and measurement of metabolites in blood and urine.
Development of an algorithm for correlating the results of metabolite concentrations in serum / urine with the enzymatic activities measured in liver tissue

Establecer un procedimiento para la toma de muestras, procesamiento y análisis que sea robusto, reproducible y compatible con la práctica clínica habitual, para la administración del fármaco y la medida de los metabolitos en sangre y orina.
Desarrollar de un algoritmo que permita correlacionar los resultados de concentraciones de metabolitos en suero/orina con las actividades enzimáticas medidas en tejido hepático

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Group volunteers: volunteer subjects without severe liver pathology associated.
Group patients: Patients who are to undergo abdominal surgery (liver resection preferably in the context of the underlying pathology, eg liver metastases, hepatic adenoma, cholangiocarcinoma, etc ...).

Grupo voluntarios: Sujetos voluntarios sin patología hepática grave asociada.
Grupo pacientes: Pacientes que vayan a ser sometidos a una intervención quirúrgica abdominal (preferentemente una resección hepática en el contexto de su patología de base, por ejemplo metástasis hepática, adenoma hepático, colangiocarcinoma, etc...).

E.4

Principal exclusion criteria

Group volunteers: under 18 years, pregnant and lactating women, allergy to any of the active substances or excipients, allergy to acetylsalicylic acid, liver pathology associated (cirrhosis, hepatitis, liver tumor pathology), moderate consumption of alcohol, renal failure (creatinine of 1.2mg/dl or less glomerular filtration of 90 ml / min).
Group patients: below 18, allergy to any of the active ingredients or allergy to acetylsalicylic acid, renal failure (creatinine of 1.2mg/dl or less glomerular filtration of 90 ml / min), the appearance of other pathological conditions over study that contraindicate surgery. Pregnant women and lactating.

Grupo voluntarios: Menores de 18 años, embarazadas y mujeres en periodo de lactancia, alergia a alguno de los principios activos o excipientes, alergia a ácido acetil salicílico, patología hepática asociada (cirrosis, hepatitis, patología tumoral hepática), consumo de alcohol moderado, insuficiencia renal (creatinina mayor de 1.2mg/dl o filtrado glomerular menor de 90 ml/min).
Grupo pacientes: Menores de 18 años, alergia a alguno de los principios activos o, alergia a ácido acetil salicílico, insuficiencia renal (creatinina mayor de 1.2mg/dl o filtrado glomerular menor de 90 ml/min), aparición de otras circunstancias patológicas durante el estudio que contraindiquen la cirugía. Mujeres embarazadas y en periodo de lactancia.

E.5 End points

E.5.1

Primary end point(s)

Tmax, Cmax, metabolite ratios / active substance in blood and urine
They determine the activity per gram of tissue enzymes involved in drug metabolism in liver biopsy

Tmáx, Cmáx, ratios metabolito/principio activo en sangre y orina.

Determinarán la actividad por gramo de tejido de los enzimas implicadas en el metabolismo del fármaco en biopsia hepatica

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end.

E.5.2

Secondary end point(s)

Correlation of active ingredients and metabolites in blood and urine, and liver
enzyme activity in liver biopsy

Correlación de principios activos y metabolitos en sangre y orina, y la actividad
enzimática hepática en biopsia hepática

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end.

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

Yes

E.6.6

Pharmacokinetic

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Test validation

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

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)

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.8.5

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

LVLS

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

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.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

2014-07-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-29

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

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