Clinical Trials Register

Summary
EudraCT Number:	2013-002922-21
Sponsor's Protocol Code Number:	FOREST
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:	2014-02-18
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

2013-002922-21

A.3

Full title of the trial

Randomized, phase III, multicentre, open-labelled clinical trial, to evaluate the efficacy of fosfomycin vs meropenem in the treatment of bacteremic urinary tract infection caused by Escherichia coli producing extended-spectrum beta-lactamases (ESBL).

Ensayo clínico aleatorizado, multicéntrico, abierto, controlado, en fase III, para evaluar la eficacia de fosfomicina vs meropenem en el tratamiento dirigido de la infección urinaria bacteriémica por escherichia coli productor de betalactamasas de espectro extendido (BLEE).

A.3.1

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

Clinical study to evaluate the efficacy of fosfomycin vs meropenem in the treatment of bacteremia due to Escherichia coli (general infection caused by a specific bacteria).

Estudio clínico para evaluar la eficacia de fosfomicina vs meropenem en el tratamiento de la bacteriemia por Escherichia coli (infección generalizada causada por una bacteria específica).

A.4.1

Sponsor's protocol code number

FOREST

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	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	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	Andalusian Health Service
B.5.2	Functional name of contact point	Jesús Rodríguez Baño
B.5.3	Address:
B.5.3.1	Street Address	Avda. Dr. Fedriani, 3
B.5.3.2	Town/ city	Sevilla
B.5.3.3	Post code	41071
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034955013284
B.5.5	Fax number	0034955926552
B.5.6	E-mail	jesusrb@us.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	Disodium Fosfomycin
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS ERN, 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	Fosfomycin
D.3.4	Pharmaceutical form	Powder and solvent for 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	Fosfomycin
D.3.9.3	Other descriptive name	FOSFOMYCIN DISODIUM
D.3.9.4	EV Substance Code	SUB127116
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	4
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	Meronem
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca Farmacéutica Spain, 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	Meronem
D.3.4	Pharmaceutical form	Powder for concentrate 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	Meropenem
D.3.9.1	CAS number	96036-03-2
D.3.9.3	Other descriptive name	MEROPENEM
D.3.9.4	EV Substance Code	SUB08778MIG
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	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.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

Bacteremic urinary tract infection by Escherichia coli extended spectrum beta-lactamase (ESBL).

Infección urinaria bacteriémica por Escherichia coli productor de betalactamasas de espectro extendido (BLEE)

E.1.1.1

Medical condition in easily understood language

Bloodstream infection due to urinary tract infection by Escherichia coli

Bacterias en sangre debido a infecciòn del tracto urinario por Escherichia coli

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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10052238
E.1.2	Term	Escherichia urinary tract infection
E.1.2	System Organ Class	10021881 - Infections and infestations

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 main objective of this study is to evaluate the efficacy of intravenous fosfomycin with regard to meropenem for the treatment of bacteremic urinary tract infections caused by E. coli ESBL.

El objetivo principal de este estudio es evaluar la eficacia de fosfomicina intravenosa respecto meropenem en el tratamiento de la bacteriemia por infección del tracto urinario causada por E. coli BLEE.

E.2.2

Secondary objectives of the trial

*To evaluate the early clinical and microbiological response in both arms.
* To compare mortality and hospitalization period in the first 30 days, in patients treated with fosfomycin and meropenem.
*To evaluate the safety of intravenous fosfomycin in this treatment.
*To compare recurrent episodes rate(relapse or reinfection) in both arms.
*Pharmacokinetics of intravenous fosfomycin in patients with bacteremic urinary tract infection by E. coli extended spectrum beta-lactamase (ESBL).
*To compare the impact of fosfomycin and meropenem about the colonization in the intestinal tract by multiresistant gram-negative bacilli.
*To assess the frequency of emergence resistant strains to fosfomycin and the resistance mechanisms involved.

*Evaluar la respuesta clínica y microbiológica precoz en la prueba de curación en ambos brazos.
*Comparar la mortalidad y estancia hospitalaria en los primeros 30 días, de los pacientes tratados con fosfomicina y meropenem.
*Evaluar la seguridad de fosfomicina intravenosa en esta indicación.
*Comparar la frecuencia de recurrencias (recidivas y reinfecciones) en ambos brazos.
*Estudiar la farmacocinética de fosfomicina intravenosa en pacientes con infección urinaria bacteriémica por E. coli productor de BLEE.
*Comparar el impacto de fosfomicina y meropenem en la colonización intestinal por bacilos gram negativos multirresistentes.
*Evaluar la frecuencia de aparición de cepas resistentes a fosfomicina durante el tratamiento y los mecanismos de resistencia implicados.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Adult (over 18) hospitalized patients diagnosed with bacteremia due to urinary tract infection by E. coli extended spectrum beta-lactamase (ESBL).
*Isolation of this microorganism in blood culture with clinical sepsis without other obvious or the most likely origin of the urinary bacteremia.
*Required intravenous treatment during 5 days at least.
*Women of childbearing potential must have a negative pregnancy test.
*Signed informed consent form.

*Pacientes adultos (18 años o más) hospitalizados con bacteriemia de origen urinario por E. coli productor de BLEE sensible a fosfomicina y meropenem.
*Aislamiento en hemocultivo de este microorganismo con datos clínicos de sepsis sin otro origen evidente o probable de la bacteriemia más que el urinario.
*Necesidad estimada de tratamiento por vía intravenosa durante al menos 5 días.
*Las pacientes potencialmente fértiles deberán tener un test de gestación negativo.
*Pacientes que hayan otorgado su consentimiento informado por escrito.

E.4

Principal exclusion criteria

*Polymicrobial bacteremia.
*Undrained renal abscess or not resolved urinary tract obstruction.
*Prostatitis.
*Haematogenous or contiguous urinary infection
*Concomitant infections
*Polycystic kidney disease.
*Renal trasplantation.
*Allergy or hypersensitivity to fosfomycin or meropenem.
*Terminal condition, or life expectancy less than 90 days, or palliative treatment of the underlying disease.
*Delayed inclusion > 12 hours since the identification of E. coli ESBL in blood culture.
*Patients participating in other clinical trial.

*Bacteriemia polimicrobiana.
*Absceso renal no drenado u obstrucción de la vía urinaria no resuelta.
*Prostatitis.
*Infección urinaria hematógena o por contigüidad.
*Otra infección concomitante.
*Poliquistosis renal.
*Trasplante renal.
*Alergia o hipersensibilidad a fosfomicina o meropenem.
*Situación terminal, ó esperanza de vida estimada inferior a 90 días, o en tratamiento puramente paliativo de su enfermedad de base.
*Insuficiencia cardiaca NYHA III/IV, cirrosis hepática o insuficiencia renal que requiera tratamiento sustitutivo.
*Mujeres embarazadas o en periodo de lactancia.
*Shock séptico en el momento de la aleatorización.
*Tratamiento empírico activo >72 horas.
*Retraso en la inclusión >12 horas desde la identificación de E. coli BLEE en hemocultivo.
*Pacientes que estén participando en otro ensayo clínico con tratamiento activo.

E.5 End points

E.5.1

Primary end point(s)

Clinical and microbiological cure occurring at 5?7 days after the end of the treatment.

Curación clínica y microbiológica a los 5-7 días tras la finalización del tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

At 5?7 days after the end of the treatment.

A los 5-7 días tras la finalización del tratamiento

E.5.2

Secondary end point(s)

*Early clinical recovery.
*Early microbiological recovery.
*Recurrent episodes (relapse or reinfection) in the fisrt 60 days.
*Mortality in the first 30 days and hospitalization period.
*Frecuency and seriousness of adverse events.
*Fosfomycin plasmatic concentration in stationary phase (day 3).
*Ratio of E. coli resistant to fosfomycin and meropenem during the treatment

*Curación clínica precoz.
*Curación microbiológica precoz.
*Recurrencias (recidivas y reinfecciones) en los primeros 60 días.
*Mortalidad en los primeros 30 días y estancia hospitalaria
*Frecuencia y gravedad de efectos adversos.
*Concentraciones plasmáticas de fosfomicina en fase estacionaria (día 3).
*Proporción de E. coli resistentes a fosfomicina o meropenem durante el tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

*Day 3 (Visit 2)
*Day 5 (Visit 3)
*Day 5-7 (Visit 4)
*In the first 30 days
*In the first 60 days

*Día 3 (Visita 2)
*Día 5 (Visita 3)
*Día 5-7 (Visita 4)
*En los primeros 30 días
*En los primeros 60 días

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

Yes

E.6.4

Safety

Yes

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)

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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)

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

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

Yes

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 clinical trial is considered finished the day of the final visit of the last patient included in the study.

Se considerará final del ensayo el día de la visita final del último paciente incluido en el estudio

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 months

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:

180

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

198

F.4.2

For a multinational trial

F.4.2.1

In the EEA

198

F.4.2.2

In the whole clinical trial

198

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)

If a patient is withdrawn prematurely, he will be treated according to the clinical practice for this disease.

Si un paciente es retirado prematuramente, será tratado de acuerdo a la práctica clínica habitual para esta patología.

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	Unidad de Investigación Clínica y Ensayos Clínicos. Hospital Universitario Virgen del Rocío
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

2014-05-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-22

P. End of Trial
P.	End of Trial Status	Completed

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