Clinical Trials Register

Summary
EudraCT Number:	2017-003127-29
Sponsor's Protocol Code Number:	ENDOKINETIC-CEF
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:	2017-12-21
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

2017-003127-29

A.3

Full title of the trial

Phase II clinical trial to evaluate an antibiotic regimen pharmacokinetic applicable to outpatient parenteral antimicrobial therapy in Enterococcus faecalis infective endocarditis

Ensayo clínico Fase II para evaluar la farmacocinética y de una pauta antibiótica aplicable al tratamiento antibiótico intravenoso domiciliario de la endocarditis infecciosa por Enterococcus faecalis

A.3.1

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

Phase II clinical trial to evaluate an antibiotic regimen pharmacokinetic applicable to outpatient parenteral antimicrobial therapy in Enterococcus faecalis infective endocarditis

Ensayo clínico fase II para evaluar la farmacocinética y de una pauta antibiótica aplicable al tratamiento antibiótico intravenoso domiciliario de la endocarditis infecciosa por Enterococcus faecalis

A.4.1

Sponsor's protocol code number

ENDOKINETIC-CEF

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	Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla. (FISEVI)
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	University Hospital Virgen del Rocío
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	Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla. (FISEVI)
B.5.2	Functional name of contact point	Laura Herrera Hidalgo
B.5.3	Address:
B.5.3.1	Street Address	University Hospital Virgen del Rocío. General Hospital, Pharmacy. Manuel Siurot avenue s/n
B.5.3.2	Town/ city	Sevilla
B.5.3.3	Post code	41013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34955012095
B.5.6	E-mail	laura.herrera.sppa@juntadeandalucia.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	Ceftriaxona
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorio Ramón Sala, S.L.
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	Ceftriaxone
D.3.4	Pharmaceutical form	Powder for 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	CEFTRIAXONE
D.3.9.1	CAS number	73384-59-5
D.3.9.4	EV Substance Code	SUB07431MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	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	Ceftriaxona
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorio Ramón Sala, S.L.
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	Ceftriaxone
D.3.4	Pharmaceutical form	Powder for 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	CEFTRIAXONE
D.3.9.1	CAS number	73384-59-5
D.3.9.4	EV Substance Code	SUB07431MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	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

Healthy volunteers (Enterococcus faecalis infective endocarditis)

Voluntarios sanos (endocarditis infecciosa por Enterococcus faecalis)

E.1.1.1

Medical condition in easily understood language

Healthy volunteers (Enterococcus faecalis infective endocarditis)

Voluntarios sanos (endocarditis infecciosa por Enterococcus faecalis)

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10014892
E.1.2	Term	Enterococcus faecalis endocarditis
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10053349
E.1.2	Term	Pharmacokinetic study
E.1.2	System Organ Class	100000004848

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 determinate whether 24 hours after the administration of 4 grams of ceftriaxone in a single short infusion, serums levels would be higher than 5 micrograms per mililitre

Determinar si concentración plasmática de ceftriaxona 24 horas después de la administración de 4 gramos en una infusión corta única es superior a 5 microgramos por mililitro.

E.2.2

Secondary objectives of the trial

1. To compare the 24 hours area under the curve (AUC) after the administration of 4 grams of ceftriaxone in a single short infusion and the administration of 2 grams of ceftriaxone in a two short infusions separated for 12 hours.
2. To determinate all dose-dependants pharmacokinetics parameters after the administration of 4 grams of ceftriaxone in a single short infusion.
3. To determinate the safety of the administration of 4 grams of ceftriaxone in a single short infusion

1.Comparar el Área bajo la curva (AUC) 24 horas de ceftriaxona mediante la administración de 4 gramos en una infusión corta única con el AUC 24 horas de la administración de 2 gramos cada 12 horas (dos dosis) en una infusión corta.
2. Determinar los parámetros farmacocinéticos dosis dependiente de ceftriaxona tras la administración de 4 gramos en infusión corta.
3. Determinar la seguridad de la administración de 4 gramos de ceftriaxona en infusión corta.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female adults subjects.
2. Weight between 40 and 18 kilograms, both included, and body mass index lower than 34 kilograms per square meter.
3. The subjetct (or his/her "trusted representative") must have given his/her informed and signed consent approved by an Ethical Committee.
4. The subjetc must have normal analytical values or abnormal without clinical significance of biochemical parameters, liver and kidney function panel test, hemogram and album level. A medical check will be run by workers of Infectious Diseases Department.
5. The subjetc must have a normal physical examination or abnormal without clinical significance. A medical check will be run by workers of Infectious Diseases Department.
6. The medication taken usually by the subjects will be check by the Pharmacy Department in order to find possible interactions with ceftriaxone.

1. Sujetos, hombres o mujeres adultos.
2. Peso mínimo de 40 kg y máximo de 105 kg ambos incluidos e índice de masa corporal (IMC) menor de 34 kg /m2.
3. El sujeto o su representante deben firmar un documento de consentimiento informadoaprobado por el Comité Ético de Ensayos Clínicos.
4. Los sujetos deben tener unos valores analíticos normales o anormales sin relevancia clínica, que incluyan parámetros bioquímicos, perfil hepático, perfil renal, hemograma y albúmina. Los pacientes serán examinados por personal del Servicio de Enfermedades Infecciosas.
5. Los sujetos deben tener una exploración física inicial normal o con hallazgos anormales sin relevancia clínica. Los pacientes serán examinados por personal del Servicio de Enfermedades Infecciosas.
6. El tratamiento habitual que el sujeto tenga prescrito será evaluado por personal del Servicio de Farmacia para valorar posibles interacciones con la ceftriaxona.

E.4

Principal exclusion criteria

1. Subjects with clinically significant abnormalities in laboratory test or physical exploration. A medical check will be run by workers of Infectious Diseases Department.
2. Subjects undergoing an active infection find at the screening.
3. Subjects with any clinical or surgery condition which contraindicate his/her inclusion, check by workers of Infectious Diseases Department.
4. Subjects who has recieved treatment with cephalosporins 21 days before the trial starts or during the trial (apart from the protocol treatment).
5. Subjects hypersensitive or allergic to cephalosporines or penicillins.
6. Subjetcs undergoing chronic or acute cutaneous diseases which prevent the treatment administration.
7. Subjetct not giving his/her informed and signed consent approved by an Ethical Committee.

1. Los sujetos con anormalidades clínicamente significativas en los análisis de laboratorio o en la exploración física inicial. Los pacientes serán examinados por personal del Servicio de Enfermedades Infecciosas.
2. Los sujetos con presencia de infección activa en el momento del screening.
3. Los sujetos que presenten alguna condición clínica o quirúrgica que contraindique su inclusión a juicio del personal del Servicio de Enfermedades Infecciosas.
4. Los sujetos que hayan recibido tratamiento con cefalosporinas en los 21 días previos al inicio del ensayo o durante el mismo (fuera de lo establecido en el protocolo).
5. Los sujetos con alergia o hipersensibilidad a cefalosporinas y penicilinas.
6. Los sujetos con enfermedades cutáneas crónicas o agudas que no permitan la administración del tratamiento.
7. Los sujetos que no firmen por escrito un documento de consentimiento informado aprobado por el Comité Ético de Ensayos Clínicos.

E.5 End points

E.5.1

Primary end point(s)

Serums levels of ceftriaxone 24 hours after the administration of 4 grams of ceftriaxone in a single short infusion.

Concentración plasmática de ceftriaxona 24 horas después de la administración de 4 gramos en una infusión corta única.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 hours after the administration of ceftriaxone

24 horas después de la administración de ceftriaxona

E.5.2

Secondary end point(s)

1. Serums levels of ceftriaxone 0.5, 1, 2, 3, 6, 8, 10, 12, 16 y 20 and 24 hours after the administration of 4 grams of ceftriaxone in a single short infusion.
2. Dose-dependants pharmacokinetics parameters after the administration of 4 grams of ceftriaxone in a single short infusion: plasma clearance and volume of distribution.
3. Significant differences between serums levels of ceftriaxone 24 hours after the administration of 4 grams of ceftriaxone in a single short infusion and serums levels of ceftriaxone 24 hours after the administration of 2 grams of ceftriaxone in two short infusion separated for 12 hours.
4. Number of adverse reactions after the administration of 4 grams of ceftriaxone in a single short infusion.
5. Frequency and importance of adverse reactions.

1. Concentraciones plasmáticas de ceftriaxona a las 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20 y 24 horas después de la administración de 4 gramos en una infusión corta única.
2. Parámetros farmacocinéticos dosis dependiente de ceftriaxona tras la administración de 4 gramos en infusión corta: aclaramiento y volumen de distribución
3. Diferencias significativas entre la concentración plasmática de ceftriaxona 24 horas después de la administración de 4 gramos en una infusión corta única con la concentración plasmática 24 horas después de la administración de 2 gramos cada 12 horas (dos dosis) en una infusión corta.
4. Número de reacciones adversas tras de la administración de 4 gramos de ceftriaxona en infusión corta.
5. Frecuencia y gravedad de las reacciones adversas.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20 and 24 hours after the administration of ceftriaxone.
2 and 3. 24 hours after the administration of ceftriaxone .
4 and 5. 24 hours, 1 week and 1 month after the administration of ceftriaxone .

1. 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20 y 24 horas después de la administración de ceftriaxona.
2 y 3. 24 horas después de la administración de ceftriaxona.
4 y 5. 24 horas, 1 semana y 1 mes después de la administración de ceftriaxona.

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

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)

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

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Ceftriaxona 2 gramos cada 12 horas (2 infusiones cortas)

Ceftriaxone 2 grams each 12 hours (2 short infusions)

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

Última visita del último sujeto

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)

1. Medical consultation 1 week after the administration of ceftriaxone
2. Telephone medical consultation 1 month after the administration of ceftriaxone.

1. Consulta de evaluación 1 semana después de la administración de ceftriaxona.
2. Consulta telefónica 1 mes después de la administración de ceftriaxona.

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

2018-02-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-26

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

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