Clinical Trials Register

Summary
EudraCT Number:	2014-000906-36
Sponsor's Protocol Code Number:	GEB-IAL-2014-01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-10-03
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

2014-000906-36

A.3

Full title of the trial

Randomized, parallel, multicenter, phase IV clinical trial to assess the efficacy of hyaluronic acid/chondroitin sulfate versus fosfomycin trometamol in recurrent urinary tract infection prevention.

Ensayo clínico multicéntrico en fase IV, aleatorizado, paralelo, para valorar la eficacia del Ácido Hialurónico/Condroitín Sulfato frente a Fosfomicina trometamol en la prevención de las Infecciones Urinarias Recurrentes.

A.3.1

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

Clinical trial to compare the efficacy of two therapies (hyaluronic acid/chondroitin sulphate vs. fosfomycin trometamol) in recurrent cystitis prevention.

Ensayo Cínico para comparar la eficacia de dos terapias (ácido hialurónico/condroitín sulfato vs. fosfomicina trometamol) en la prevención de las cistitis recurrentes.

A.3.2

Name or abbreviated title of the trial where available

INURE

A.4.1

Sponsor's protocol code number

GEB-IAL-2014-01

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	Laboratorios Gebro Pharma S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Laboratorios Gebro Pharma S.A.
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	Laboratorios Gebro Pharma, S.A.
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	Av. Tibidabo, 29
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08022
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034932058686
B.5.5	Fax number	0034932058572
B.5.6	E-mail	jordi.galvan@gebro.es

D. IMP Identification
D.IMP: 1
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	Fosfomicina Kern Pharma 3g granulado para solución oral EFG
D.2.1.1.2	Name of the Marketing Authorisation holder	Kern Pharma, 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.3.4	Pharmaceutical form	Granules 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	FOSFOMYCIN TROMETAMOL
D.3.9.1	CAS number	78964-85-9
D.3.9.3	Other descriptive name	Fosfomycin trometamol
D.3.9.4	EV Substance Code	SUB02263MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	3
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	Ialuril Prefill
D.2.1.1.2	Name of the Marketing Authorisation holder	IBSA Institut Biochimique SA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Concentrate for intravesical solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use Implantation
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hyaluronic acid
D.3.9.1	CAS number	9004-61-9
D.3.9.3	Other descriptive name	HYALURONIC ACID
D.3.9.4	EV Substance Code	SUB14126MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	1.6
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CHONDROITIN SULPHATE SODIUM
D.3.9.1	CAS number	9082-07-9
D.3.9.3	Other descriptive name	CHONDROITIN SULFATE
D.3.9.4	EV Substance Code	SUB13356MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Recurrent urinary tract infections

Infecciones del tracto urinario recurrentes

E.1.1.1

Medical condition in easily understood language

Repetitive cystitis

Cistitis de repetición

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

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 the efficacy of instillations of Hyaluronic Acid in combination with Chondroitin sulfate in the presence of Calcium Chloride as excipient vs oral fosfomicyn trometamol in recurrent urinary tract infection prevention.

Evaluar la eficacia de las instilaciones de Ácido Hialurónico en combinación con Condroitín sulfato en presencia de Cloruro Cálcico como excipiente versus fosfomicina trometamol oral en la prevención de las infecciones urinarias recurrentes.

E.2.2

Secondary objectives of the trial

To assess the quality of life of patients under treatment with hyaluronic acid in combination with chondroitin sulfate in presence of calcium chloride as excipient vs oral fosfomicyn trometamol in recurrent urinary tract infection prevention.
To assess the tolerability of instillations of hyaluronic acid in combination with chondroitin sulfate in presence of calcium chloride as excipient vs oral fosfomycin in recurrent urinary tract infection prevention.

Evaluar la calidad de vida de los pacientes en tratamiento con Ácido Hialurónico en combinación con Condroitín sulfato en presencia de Cloruro Cálcico como excipiente versus fosfomicina trometamol oral en la prevención de las infecciones urinarias recurrentes.
Evaluar la tolerabilidad de las instilaciones de Ácido Hialurónico en combinación con Condroitín sulfato en presencia de Cloruro Cálcico como excipiente versus fosfomicina trometamol oral en la prevención de las infecciones urinarias recurrentes.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Females ? 18 years old
- At least 3 uncomplicated urinary infections documented by urine culture (>103 UFM/ml) in the last year
- Negative urine culture at the beginning of the trial.
- Fertile patient that agrees with abstinence or with the use of one contraceptive methods allowed during the trial. The allowed contraceptive methods are: intrauterine device (IUD), condoms, vasectomy and hormonal contraceptives.
- Females that give her written informed consent.

- Mujeres con edad ?18 años
- ?3 infecciones de orina no complicadas documentadas con cultivo de orina (>103 UFM/ml) durante el último año
- Cultivo de orina negativo al inicio del estudio.
- Paciente fértil que accede a abstenerse o a utilizar (o a que su pareja utilice) 1 método anticonceptivo permitido durante el estudio. Los métodos anticonceptivos permitidos son: dispositivo intrauterino (DIU), preservativos, vasectomía y anticonceptivos hormonales.
- Que otorguen consentimiento informado por escrito.

E.4

Principal exclusion criteria

- Any active infection at the beggining of the study.
- Infection history by fosfomycin trometamol resistant pathogens.
- Antibiotic prophylactic treatment at the moment of the inclusion.
- Treatment with HA-CS 1.6%/2.0% in the last 12 months.
- Increased postvoid residual (>100cc measured by suprapubic ecography)
- Demonstrated organic bladder pathology (bladder cancer, bladder lithiasis,?)
- Neurogenic bladder
- Urinary tract malformation.
- Pregnancy or breastfeeding.
- Use of diaphragm
- Use of spermicides
- Immunosuppression (corticoids, immunosuppressive therapy, immunosuppressive disease)
- Chronic renal failure, stage ?4.
- Allergy or intolerance to any of the studied drugs.
- Active vaginitis
- Patient with hormonal substitutive therapy and/or genital topic hormonal treatment.
- Recent urological intervention (in the last three months)
- Active neoplasic disease.

- Cualquier infección activa al empezar el estudio.
- Historia de infección por gérmenes resistentes a fosfomicina trometamol.
- Tratamiento antibiótico profiláctico en el momento de la inclusión.
- Tratamiento con AH-CS 1,6%/2.0% durante los 12 meses previos al estudio.
- Residuo postmiccional aumentado (>100cc medido por ecografía suprapúbica).
- Patología orgánica vesical demostrable (tumor vesical, litiasis vesical, ?).
- Vejiga neurógena.
- Malformación del tracto urinario.
- Embarazo o en periodo de lactancia
- Uso de diafragma
- Uso de espermicidas.
- Inmunosupresión (corticoides, inmunosupresores, enfermedad inmunosupresora).
- Insuficiencia renal crónica estadio ?4.
- Alergia o intolerancia a alguno de los fármacos en estudio.
- Vaginitis activa
- Paciente con terapia hormonal sustitutiva y/o en tratamiento hormonal genital tópico
- Paciente con intervención urológica reciente ( menos de 3 meses anterior a la visita de aleatorización)
- Enfermedad neoplásica activa

E.5 End points

E.5.1

Primary end point(s)

Time to recurrence of the infection (defined as time from the beginning of the treatment to the first recurrent infection)

Tiempo de recurrencia de la infección (definido como tiempo transcurrido desde el inicio del tratamiento hasta la primera infección recurrente)

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the study (treatment + follow-up)

Al final del estudio (tratamiento + seguimiento)

E.5.2

Secondary end point(s)

Number of UTI per patient, infection/patient/year rate, time to recurrence of the infection from completion of treatment (defined as time from the last dose of treatment taken by the patient to the first recurrent infection)changes in volume and frequency of urination (measured with the bladder diary of 3 days), impact of the treatment in the quality of life (number of sexual relationships, FSFI questionnaire) and subjective evaluation of the urinary symptoms (PUF questionnaire). Control and register of the adverse events.

Número de ITUs/paciente, tasa de infecciones/paciente/año, tiempo de recurrencia desde finalización del tratamiento (definido como el tiempo desde la toma de la última dosis de tratamiento hasta primera infección recurrente) variaciones en el volumen y frecuencia de las micciones (medido mediante diario miccional de 3 días DM3D),impacto del tratamiento en la calidad de vida con evaluación de la función sexual (número de relaciones sexuales, cuestionario FSFI) y evaluación subjetiva de los síntomas urinarios (cuestionario PUF), registro y control de los efectos adversos.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study (treatment + follow-up)

Al final del estudio (tratamiento + seguimiento)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

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

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

Ialuril Prefill (Test)

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

última visita del último paciente

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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

2014-12-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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