Clinical Trials Register

Summary
EudraCT Number:	2006-006182-16
Sponsor's Protocol Code Number:	CENA713DES07
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:	2007-05-25
Trial results	View 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

2006-006182-16

A.3

Full title of the trial

Estudio multicéntrico, aleatorizado, abierto, para evaluar la conveniencia, en base a la seguridad, del cambio en la vía de administración de Rivastigmina (paso de la administración en forma de cápsulas a administración en forma de parches) en pacientes con Alzheimer

A.3.2

Name or abbreviated title of the trial where available

KAPA

A.4.1

Sponsor's protocol code number

CENA713DES07

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

No aplicable

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	NOVARTIS FARMACÉUTICA, 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	No
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	Rivastigmina Transdermal Patch
D.3.2	Product code	ENA713D
D.3.4	Pharmaceutical form	Transdermal patch
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rivastigmina
D.3.9.1	CAS number	123441-03-2
D.3.9.2	Current sponsor code	ENA713D
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	9,5
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	Exelon
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Exelon
D.3.2	Product code	No aplicable
D.3.4	Pharmaceutical form	Capsule, hard
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	Rivastigmina
D.3.9.1	CAS number	123441-03-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	6 to - 12
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	No
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	Rivastigmina Transdermal Patch
D.3.2	Product code	ENA713D
D.3.4	Pharmaceutical form	Transdermal patch
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rivastigmina
D.3.9.1	CAS number	123441-03-2
D.3.9.2	Current sponsor code	ENA713D
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	4,5
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

Enfermedad de Alzheimer

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

Evaluar la tolerabilidad gastrointestinal de Rivastigmina en los pacientes en los que se produce un cambio en la forma de administración (de cápsulas a parches transdérmicos) en comparación al grupo que permanece en tratamiento con Rivastigmina en forma de cápsulas durante todo el estudio, con el fin de establecer la conveniencia y el patrón de cambio del paso de la vía oral a la vía transdérmica, en pacientes con Enfermedad de Alzheimer. Se pretende evaluar si el cambio en la vía de administración precisa de un período de titulación hasta llegar a la dosis óptima o puede hacerse sin realizar dicha titulación.

E.2.2

Secondary objectives of the trial

Se evaluarán la tolerabilidad global (sistémica y cutánea), el grado de satisfacción de los pacientes/cuidadores en los distintos grupos de tratamiento y el estado cognitivo de los pacientes.

Adicionalmente, se determinarán las concentraciones plasmáticas de rivastigmina y de su metabolito ZNS114-666 (también llamado NAP226-90) en los distintos grupos de tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Hombres y mujeres (no fértiles) de edad igual o superior a 60 años. Las mujeres deberán ser postmenopáusicas (amenorrea de más de 1 año de duración) o estériles por intervención quirúrgica.
2. Pacientes que cumplan criterios del DSM-IV para una demencia del tipo Alzheimer y los criterios NINCDS-ADRDA para un Alzheimer probable o posible, con una puntuación en el MMSE mayor o igual a 10.
3. Pacientes que hayan recibido un tratamiento continuado con cápsulas de rivastigmina, a dosis superior o igual a 6 mg/día y inferior o igual a 12 mg/día (dividida en dos tomas), durante al menos los tres meses previos a la inclusión (Visita 0).
4. Pacientes dispuestos a colaborar, que quieran participar en todos los aspectos del estudio y que sean capaces de hacerlo, ya sea solos o con la ayuda de un cuidador responsable.
5. Pacientes que tengan un cuidador que acepte la responsabilidad de supervisar el tratamiento (p.ej.quitar y poner el parche cada día a la misma hora aproximadamente) y evaluar el estado del paciente durante el estudio.

E.4

Principal exclusion criteria

1. Pacientes que hayan demostrado hipersensibilidad a la Rivastigmina.
2. Pacientes que presenten una enfermedad avanzada, grave, progresiva o inestable de cualquier tipo, que pueda interferir en las evaluaciones de seguridad y tolerabilidad o poner al paciente en riesgo.
3. Pacientes que presenten una enfermedad o trastorno neurológico que, sin ser Alzheimer, justifique la demencia del paciente (p.ej. enfermedad de Huntington, enfermedad de Parkinson, resultados anormales en los exámenes de la función tiroidea, deficiencia de B12 o ácido fólico, condiciones post-traumáticas, sífilis).
4. Pacientes con diagnóstico actual de bradicardia (frecuencia cardiaca < 50 lpm), disfunción sinusal o defectos cardiacos de conducción (bloqueo sinoauricular, bloqueo aurículoventricular de segundo o tercer grado).
5. Pacientes con diagnóstico actual de una posible o probable demencia vascular según criterios del National Institute of Neurological Disorders and Stroke o de la Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN).
6. Pacientes con diagnóstico actual de depresión mayor según el DSM-IV, excepto cuando se esté tratando satisfactoriamente con dosis estables de antidepresivos sin efectos anticolinérgicos durante, al menos, las cuatro semanas previas a la inclusión.
7. Pacientes con cualquier diagnóstico del eje I según el DSM-IV que pueda interferir en la evaluación de la respuesta del paciente a la medicación del estudio, incluidas otras demencias neurodegenerativas primarias, esquizofrenia o trastorno bipolar.
8. Pacientes con diagnóstico actual de crisis convulsivas activas e incontroladas.
9. Pacientes que hayan presentado durante el último año o presenten acualmente daños cerebrovasculares (p.ej. accidente vascular cerebral, accidente isquémico transitorio, aneurisma).
10. Pacientes con diagnóstico actual de enfermedad cardiovascular grave o inestable.
11. Pacientes con diagnóstico actual de enfermedades asmáticas agudas, graves o inestables (p. ej. enfermedad pulmonar obstructiva crónica grave).
12. Pacientes con diagnóstico actual de ulceraciones pépticas activas e incontroladas o hemorragia gastrointestinal en los últimos tres meses.
13. Pacientes que presenten obstrucción urinaria clínicamente significativa.
14. Pacientes con diagnóstico actual de una enfermedad o lesión dermatológica activa que pueda impedir una evaluación precisa de la adherencia del parche y la detección de una potencial irritación tópica (p. ej. dermatitis atópica, piel herida o con rasguños en el área donde se va a aplicar el parche).
15. Pacientes que presenten alergia a productos tópicos compuestos por vitamina E.
16. Pacientes que presenten abuso o dependencia de drogas y/o alcohol.
17. Pacientes que padecen o en los que se sospechan infecciones crónicas incluyendo HIV o hepatitis B ó C.
18. Pacientes que no puedan realizar todos los procedimientos del estudio (p. ej. ceguera, sordera, dificultades del habla graves).
19. Pacientes que hayan recibido cualquier producto en investigación en las cuatro semanas previas al inicio del estudio.
20. Pacientes que hayan recibido relajantes musculares del tipo succinilcolina en las dos semanas previas al inicio del estudio.
21. Pacientes que hayan recibido fármacos colinomiméticos distintos de la rivastigmina y/o anticolinérgicos en las dos semanas previas al inicio del estudio.
22. Pacientes en tratamiento con otros fármacos antialzheimer, incluyendo otros inhibidores de la acetilcolinesterasa y la memantina en las dos semanas previas al inicio del estudio.

E.5 End points

E.5.1

Primary end point(s)

La variable principal es el porcentaje de AAs de tipo gastrointestinal recogidos durante todo el periodo de estudio, en los distintos grupos de tratamiento.

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

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)

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

uso de otra vía de administración

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

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

El final del ensayo coincide con la última visita del último paciente incluido

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

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

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Población con Alzheimer de leve a moderadamente grave

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

117

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)

No aplicable

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

2007-05-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-04-11

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

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