Clinical Trials Register

Summary
EudraCT Number:	2013-004838-15
Sponsor's Protocol Code Number:	ENTHERE
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-04
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

2013-004838-15

A.3

Full title of the trial

Intestinal colonization by multiresistant enterobacteria in patients with kidney and liver transplantation: multicentre cohort study and randomized, controlled, open clinical trial.

Colonización intestinal por enterobacterias multirresistentes en pacientes con trasplante renal y hepático: estudio multicéntrico de cohortes y ensayo clínico aleatorizado, controlado y abierto.

A.3.1

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

Multiresistant intestinal bacteria in patients with kidney and liver transplantation: multicenter study and clinical trial.

Enterobacterias multirresistentes en pacientes con trasplante renal y hepático: estudio multicéntrico y ensayo clínico.

A.3.2

Name or abbreviated title of the trial where available

Intestinal colonization by multiresistant enterobacteria in SOT

Colonización intestinal por enterobacterias multirresistentes en TOS

A.4.1

Sponsor's protocol code number

ENTHERE

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	Mª Carmen Fariñas Álvarez. Hospital Universitario Marques de Valdecilla
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 Salud Carlos III
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	Mª Carmen Fariñas Álvarez. Hospital Universitario Marqués de Valdecilla
B.5.2	Functional name of contact point	Infectious Diseases Unit
B.5.3	Address:
B.5.3.1	Street Address	Av. Valdecilla, s/n
B.5.3.2	Town/ city	Santander
B.5.3.3	Post code	39008
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3494220 25 20 (ext. 73263)
B.5.5	Fax number	+3494220 38 04
B.5.6	E-mail	mcfarinas@humv.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	Neomicina SALVAT
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorios SALVAT, 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	Neomycin sulfate
D.3.2	Product code	8378
D.3.4	Pharmaceutical form	Tablet
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	NEOMYCIN SULFATE
D.3.9.1	CAS number	1404-04-2
D.3.9.2	Current sponsor code	NEOMYCIN SULFATE
D.3.9.3	Other descriptive name	NEOMYCIN SULFATE
D.3.9.4	EV Substance Code	SUB03409MIG
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	1000
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	Colistina Sulfato Fagron
D.2.1.1.2	Name of the Marketing Authorisation holder	Fagron Iberica, S.A.U.
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	Colistin sulphate
D.3.2	Product code	5311054
D.3.4	Pharmaceutical form	Capsule
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	COLISTIN SULPHATE
D.3.9.1	CAS number	1264-72-8
D.3.9.2	Current sponsor code	COLISTIN SULPHATE
D.3.9.3	Other descriptive name	COLISTIN SULPHATE
D.3.9.4	EV Substance Code	SUB11844MIG
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	200
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

Colonization by multiresistant enterobacteria in patients who underwent liver and renal transplants

Colonización por enterobacterias multirresistentes en pacientes que han recibido un trasplante renal o hepatico

E.1.1.1

Medical condition in easily understood language

Bacterial Infection in patients with renal or liver transplants

Infecciones bacterianas en pacientes con trasplante Renal o Hepatico

E.1.1.2

Therapeutic area

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

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 assess whether treatment with colistin and neomycin orally for 14 days in patients with kidney and liver transplants with colonization by ESBL-producing enterobacteriaceae with chromosomal or plasmid AmpC or carbapenemases, reduces infections by these microorganisms, in the first 30 days after transplantation.

Evaluar si el tratamiento con colistina y neomicina por vía oral durante 14 días en pacientes con trasplante renal y hepático con colonización intestinal por enterobacterias productoras de BLEE, con AmpC cromosómica o plamídica o con carbapenemasas, reduce las infecciones por estos microorganismos, en los primero 30 días postrasplante.

E.2.2

Secondary objectives of the trial

1. To evaluate the treatment efficiency with oral colistin and neomycin during 14 days, in reducing the infections 1 month after treatment, in patients colonized with multiresistant enterobacteria before the transplantation (<48h).

2. To determine the security of treatment of oral colistin and neomycin during 14 days in the appearance of adverse side effects and resistance in colonized patients with multiresistant enterobacteria before the transplantation (<48h).

1. Evaluar la eficacia del tratamiento con colistina y neomicina por vía oral durante 14 días en pacientes colonizados a su ingreso (menos de 48h) para el trasplante en reducir las infecciones por estas bacterias 1 mes postratamiento.

2. Determinar la seguridad en cuanto a la aparición de efectos adversos y resistencias, del tratamiento con colistina y neomicina por vía oral durante 14 días en pacientes colonizados por enterobacterias MR a su ingreso (menos de 48h) para el trasplante.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All patients undergoing a liver or kidney transplants in the participating hospitals with a multiresistant enterobacteria positive rectal swab previous to transplant, during the study period, and sign the informed consent.

Todos los pacientes sometidos a un trasplante hepático o renal en los hospitales participantes en el proyecto durante el periodo de estudio con frotis rectal pretrasplante positivo para enterobacterias MR y que firmen el consentimiento informado.

E.4

Principal exclusion criteria

Patients aged < 18 years, hospitalized patients over 48 hours before transplantation, treated (previous week) or who are being treated with antibiotics active against multiresistant enterobacteria, presence of contraindications to the drugs used in the study, resistance of the colonizing enterobacteria strain isolated in rectal swabs to colistin (defined as MIC > 2mg/L).

Pacientes menores de 18 años, pacientes ingresados más de 48 horas previo al trasplante, tratados (semana previa) o que estén recibiendo tratamiento con antibióticos activos frente a enterobacterias MR, presencia de contraindicaciones a los fármacos usados en el estudio, resistencia de la cepa de enterobacteria aislada en el frotis rectal a la colistina (definida como CMI > 2 mg/L).

E.5 End points

E.5.1

Primary end point(s)

Infection diagnosis by multiresistant enterobacterias.

Diagnóstico de infección por enterobacterias multiresistentes.

E.5.1.1

Timepoint(s) of evaluation of this end point

Monitoring up to 45 days after transplantation: weekly until the month after the transplantation and one last visit the 45 days after transplantation (1 month after treatment).

Seguimiento hasta 45 días postrasplante: semanalmente hasta el mes postrasplante y una última visita los 45 días postrasplante (1 mes postratamiento).

E.5.2

Secondary end point(s)

Detection in swab of intestinal colonization by multiresistant enterobacteria during the monitoring.
Changes in the colistin MIC between basal swab and that one in the last visit.
Security and tolerability of the decolonized treatment studied.

Detección de colonización intestinal en frotis por enterobacterias multirresistentes durante el seguimiento.
Cambios en la CMI de la colistina entre el frotis basal y el de la visita final.
Seguridad y tolerabilidad del tratamiento descolonizador a estudio.

E.5.2.1

Timepoint(s) of evaluation of this end point

Monitoring up to 45 days after transplantation: weekly until the month after the transplantation and one last visit the 45 days after transplantation (1 month after treatment).

Seguimiento hasta 45 días postrasplante: semanalmente hasta el mes postrasplante y una última visita los 45 días postrasplante (1 mes postratamiento).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

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)

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

Yes

E.8.1.3

Single blind

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Práctica clínica habitual (ningún tratamiento)

Usual clinical practice (no treatment).

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

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:

158

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

166

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.

Nada.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Spanish Network Research in Infectious Diseases
G.4.3.4	Network Country	Spain

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-05-11

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