Clinical Trials Register

Summary
EudraCT Number:	2011-000972-32
Sponsor's Protocol Code Number:	P-110875-01
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:	2012-01-25
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

2011-000972-32

A.3

Full title of the trial

Estudio randomizado, abierto, con endpoint enmascarado, cruzado, de dosis única para comparar la farmacodinamia de TORASEMIDA- LP 10 mg, TORASEMIDA-LI 10 mg y FUROSEMIDA-LI 40 mg en pacientes con insuficiencia cardiaca compensada

A.4.1

Sponsor's protocol code number

P-110875-01

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	FERRER INTERNACIONAL, 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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	SUTRIL NEO 10 mg comprimidos de liberación prolongada
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS NOVAG, 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.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	TORASEMIDA
D.3.9.3	Other descriptive name	TORASEMIDE
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	10
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	SUTRIL 10 mg comprimidos
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS NOVAG, 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.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	TORASEMIDA
D.3.9.3	Other descriptive name	TORASEMIDE
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	10
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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: 3
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	SEGURIL 40 mg comprimidos
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI AVENTIS, 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.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	FUROSEMIDA
D.3.9.1	CAS number	54-31-9
D.3.9.3	Other descriptive name	FUROSEMIDE
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	40
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

INSUFICIENCIA CARDIACA COMPENSADA

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10007554
E.1.2	Term	Cardiac failure
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Explorar si torasemida de liberación prolongada (PR) es más eficiente natriuréticamente en pacientes con insuficiencia cardiaca compensada comparada con furosemida de liberación inmediata después de la administración de la dosis única

E.2.2

Secondary objectives of the trial

Los perfiles farmacocinéticos y farmacodinámicos de Torasemida LP, Torasemida IL y Furosemida IL serán explorados en pacientes con insuficiencia cardiaca compensada.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Para ser incluidos los pacientes tienen que cumplir con todos los criterios enumerados a continuación:

1. Capaz de entender la naturaleza del estudio
2. Otorgar el consentimiento informado por escrito aprobado por el Comité Ético del hospital (CEIC).
3. Hombres y mujeres, 18 años cumplidos en el momento de la firma del consentimiento informado.
4. Pacientes con insuficiencia cardiaca compensada, grado II o III, definida por la Sociedad Europea de Cardiología, con la duración de al menos 3 meses en el momento de inclusión documentada en la historia clínica del paciente o pacientes que han necesitado terapia diurética previamente.
5. Pacientes con insuficiencia cardiaca estable que están recibiendo tratamiento. Se define tratamiento estable como no haber introducido ningún medicamento nuevo para el tratamiento de la insuficiencia cardiaca durante 4 semanas previas a la inclusión. Las dosis de los medicamentos podrán ser ajustadas durante el estudio con la excepción de los diuréticos.
6. Valores de laboratorio, signos vitales y ECG dentro de los rangos de normalidad o no considerados clínicamente significativos por el investigador.
7. Sólo para mujeres, tienen que ser: a) posmenopáusicas (1 año) o esterilizadas o b) no presentar riesgo de quedarse embarazada, no ser lactante, presentar la prueba de embarazo negativa a la inclusión del estudio y no tener intención de quedarse embarazada durante el mismo, así cómo usar métodos anticonceptivos efectivos. El estado posmenopáusico se define cómo 12 meses consecutivos de amenorrea espontánea o confirmado por los resultados de hormona estimulante de folículos (FSH) > 40 mlU/mL o cómo mínimo haber pasado 6 meses después de ovariectomía (con o sin histerectomía) documentada en la historia clínica.
8. El índice de masa corporal dentro de los rangos de normalidad (Índice de Quetelet entre 19 y 30) expresado cómo peso (kg)/ altura (m2).
9. No haber donado la sangre durante las 4 semanas antes de la inclusión.

E.4

Principal exclusion criteria

No serán incluidos los pacientes a los que aplican uno o más de los siguientes criterios:

1. Hospitalización debida a insuficiencia cardiaca, síndrome agudo coronario, infarto de miocardio, cateterismo de revascularización cardiaca, arritmia cardiaca, ataque isquémico transitorio o accidente cerebrovascular, arritmia cardiaca durante los 6 meses previos a la inclusión o cirugía mayor incluyendo la torácica o cardiaca durante las 8 semanas previas a la inclusión.
2. Síntomas de angina en reposo o con actividad mínima (clase III o IV, Sociedad Canadiense Cardiovascular).
3. Estenosis aórtica o mitral severa o enfermedad valvular que puede requerir cirugía en los 12 meses posteriores a la inclusión.
4. Cardiomiopatía obstructiva hipertrófica, miocarditis activa, pericarditis constrictiva o enfermedad cardiaca congénita clínicamente significativa.
5. Necesidad de un dispositivo de asistencia ventricular, terapia inotrópica contínua o hospitalización en el caso de insuficiencia cardiaca refractaria.
6. Implantación de terapia de resincronización cardiaca en los 3 meses o de desfibrilador - cardioversión en las 4 semanas previas a la inclusión.
7. Elevada probabilidad de recibir un transplante cardiaco en los 6 meses posteriores a la inclusión.
8. Receptor de un transplante mayor de órganos (ex: pulmones, hígado, riñón, corazón, médula).
9. Tener antígenos de superficie de Hepatitis B, hepatitis C o SIDA positivos o un diagnóstico conocido de SIDA.
10. Historia de abuso de alcohol o drogas en los 3 meses previos a la inclusión.
11. Enfermedad cardiovascular concomitante que se espera que reduzca la esperanza de vida a menos de un año.
12. Infusiones iv de rutina para la IC (ex. Inotropos, vasodilatadores, diuréticos) o ultrafiltración de rutina.
13. Tratamiento con digoxina a dosis estable (aprox 6 horas post-dosis) que exceda los 1.0 ng/mL en la inclusión.
14. Terapia crónica con antiarrítmicos (con la excepción de amiodarona y betabloqueantes), antiepilépticos, antialdosterónicos (espironolactona, eplerenona)
15. Que esté tomando o haya tomado en los 14 días previos a la inclusión, un inhibidor potente del CYP2C9.
16. Que esté tomando o haya tomado en los 28 días previos a la inclusión, un inductor potente del CYP2C9.
17. Participación, en 60 días o 5 semividas previos a la inclusión, en otro ensayo clínico.
18. PAS > 150 mm Hg o PAD > 95 mm Hg, evaluada en 2 ocasiones separadas antes de la inclusión.
19. FC en supinación 100 pulsaciones / min tras 5 min de reposo o bradicardia sintomática no tratada durante el mes previo a la inclusión.
20. Bilirrubina total 1.5 veces LSN, o ALT o AST 3 veces LSN.
21. GFR estimado 30 ml / min / 1.73 m2 calculado por la modificación de la dieta en enfermedad renal (ER).
22. Tratamiento crónico con AINES (> 7 días), excepto con ácido acetilsalicílico a dosis 325 mg.
23. Diabetes insulino- dependiente no controlada.

E.5 End points

E.5.1

Primary end point(s)

La variable principal es la eficiencia natriurética expresada cómo el ratio entre natriuresis inducida por el fármaco y la cantidad del mismo recogido en la orina durante 24 horas.
La diferencia entre la eficiencia natriurética durante las 24 h después de la administración de torasemida LP y furosemida se comparará formalmente utilizando el test t de Student para muestras pareadas. El test será bilateral con un nivel de significación del 5%. Los cambios de la eficiencia a lo largo del tiempo también serán evaluados pero sin un análisis estadístico formal. Todos los análisis se harán con SPSS/WIN 18 (SPSS, Chicago, IL, USA).

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Furosemida, 40mg

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

Information not present in EudraCT

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

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	Information not present in EudraCT
F.3.3.2	Women of child-bearing potential using contraception	Information not present in EudraCT
F.3.3.3	Pregnant women	Information not present in EudraCT
F.3.3.4	Nursing women	Information not present in EudraCT
F.3.3.5	Emergency situation	Information not present in EudraCT
F.3.3.6	Subjects incapable of giving consent personally	Information not present in EudraCT
F.3.3.7	Others	Information not present in EudraCT
F.4 Planned number of subjects to be included
F.4.1	In the member state	30

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

2011-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-30

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

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