Clinical Trials Register

Summary
EudraCT Number:	2008-006333-27
Sponsor's Protocol Code Number:	105MS301
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:	2009-07-02
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

2008-006333-27

A.3

Full title of the trial

Estudio multicéntrico, aleatorizado, doble ciego, con grupos paralelos y controlado con placebo para evaluar la eficacia y la seguridad del interferón beta-1a pegilado (BIIB017) en sujetos con esclerosis múltiple recidivante.

A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of PEGylated Interferon Beta-1a (BIIB017) in Subjects with Relapsing Multiple Sclerosis.

A.3.2

Name or abbreviated title of the trial where available

ADVANCE

A.4.1

Sponsor's protocol code number

105MS301

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	Biogen Idec Limited
B.1.3.4	Country	United Kingdom
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	Interferón Beta-1a pegilado
D.3.2	Product code	BIIB017
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BIIB017
D.3.9.3	Other descriptive name	Interferón Beta-1a pegilado
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	125
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Interferón beta-1a
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	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	Interferón Beta-1a pegilado
D.3.2	Product code	BIIB017
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BIIB017
D.3.9.3	Other descriptive name	Interferón Beta-1a pegilado
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	63
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Interferón Beta-1a
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	Interferón Beta-1a pegilado
D.3.2	Product code	BIIB017
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BIIB017
D.3.9.3	Other descriptive name	Interferón Beta-1a pegilado
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	94
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Interferón Beta-1a

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Esclerosis múltiple recidivante

Relapsing Multiple Sclerosis

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10028245
E.1.2	Term	Multiple sclerosis

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

El objetivo principal de este estudio es determinar la eficacia de BIIB017 para reducir la tasa anual de recidivas (TAR) en sujetos con EMR después de un año.

E.2.2

Secondary objectives of the trial

Los objetivos secundarios de este estudio son determinar si BIIB017 después de un año, en comparación con un placebo, es eficaz para:
- Reducir el número total de lesiones hiperintensas en T2 nuevas o que han incrementado en las RMN cerebrales.
- Reducir el porcentaje de sujetos que han experimentado una recidiva.
- Mejorar la calidad de vida conforme a la puntuación física de la escala de impacto de la esclerosis múltiple de 29 ítems (MSIS-29).
- Retrasar la progresión de la discapacidad basada en un aumento de al menos 1,0 puntos en la escala ampliada del estado de discapacidad (EDSS, Expanded Disability Status Scale) con respecto a un valor basal EDSS ? 1,0 que se mantenga durante doce semanas, o un aumento de al menos 1,5 puntos en la escala EDSS con respecto a un valor basal = 0 que se mantenga durante doce semanas.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Para poder participar en este estudio, los candidatos deberán cumplir los criterios de elegibilidad siguientes en el momento de la aleatorización (día 1):
1. Capacidad de comprender el objetivo y los riesgos del estudio y de dar el consentimiento informado por escrito, firmando y fechando el documento correspondiente, así como de autorizar la utilización de información sanitaria confidencial conforme a la legislación nacional y local de confidencialidad de los datos del paciente.
2. Edad de 18 a 55 años, inclusive, en el momento de dar el consentimiento informado.
3. Deben tener un diagnóstico confirmado de EM recidivante, definida conforme a los criterios de McDonald 1-4 .
4. Deben tener una puntuación entre 0,0 y 5,0 en la escala EDSS.
5. Deben haber experimentado al menos dos recidivas, documentadas médicamente, en los tres últimos años, y al menos una de estas recidivas debe haber ocurrido en los doce meses previos a la aleatorización (día 1).
6. Todos los sujetos varones y las mujeres con capacidad de procrear deben utilizar un método anticonceptivo eficaz durante el estudio y estar dispuestos a continuar su uso durante tres meses después de la última dosis del tratamiento del estudio.

E.4

Principal exclusion criteria

No podrán entrar si alguno de los siguientes criterios de exclusión se cumple en el momento de la aleatorización (día 1):
1. EM primaria progresiva, secundaria progresiva o progresiva recidivante (conforme a definiciones de Lublin y Reingold, 1996) con un empeoramiento clínico continuo de la enfermedad durante un período de 3 meses como mínimo.
2. Antecedentes de reacciones alérgicas o anafilácticas intensas o hipersensibilidad conocida.
3. El tratamiento previo con interferón no puede ser superior a 4 semanas y los sujetos deben haber interrumpido el tratamiento con interferón 6 meses antes de la visita basal.
4. Alergia conocida a cualquier componente de la formulación de BIIB017.
5. Antecedentes de enfermedades cardíacas, endocrinas, hematológicas, hepáticas, inmunológicas, metabólicas, urológicas, pulmonares, neurológicas, dermatológicas, psiquiátricas y renales o de otras enfermedades importantes clínicamente significativas (conforme al criterio del investigador) y que impedirían la participación en un ensayo clínico.
6. Antecedentes de neoplasias malignas, incluidos tumores sólidos y neoplasias malignas hematológicas (excepto carcinomas basocelulares y espinocelulares cutáneos extirpados completamente y que se consideren curados).
7. Antecedentes de epilepsia o desmayos no explicados O antecedentes de una crisis convulsiva en los 3 meses anteriores al período basal.
8. Antecedentes de ideas suicidas en los 3 meses previos al período basal o episodio de depresión grave en los 3 meses previos al período basal. Se define depresión grave como un episodio de depresión que requiere hospitalización, o según el criterio del investigador.
9. Valores anormales clínicamente significativos en el ECG según el criterio del investigador.
10. Antecedentes conocidos o un resultado positivo en la prueba del VIH.
11. Resultado positivo en la prueba del VHC (prueba de Ab anti-VHC) o del VHB (prueba del HBsAg y/o de HBcAb).
12. Pruebas hematológicas anormales que superen cualquiera de los límites definidos a continuación, en el período de selección:
- Niveles de ALT/SGPT más de 2 veces el límite superior de la normalidad (> 2 x LSN) o AST/SGOT > 2 x LSN o bilirrubina > 1,5 x LSN.
- Recuento total de leucocitos < 3.700/mm3.
- RAN < 1.500/mm3.
- Recuento de plaquetas < 150.000/mm3.
- Hemoglobina < 10 g/dl en mujeres; < 11 g/dl en varones.
- Creatinina sérica > LSN.
- TP o TTPa > 1,2 x LSN.
13. Recidiva de la EM que ha ocurrido en los 50 días previos a la aleatorización y/o el sujeto no se ha estabilizado después de una recidiva previa antes de la aleatorización (día 1).
Antecedentes de tto.:
14. Cualquier tto. previo con BIIB017.
15. Antecedentes de hipersensibilidad o intolerancia al acetaminofén (paracetamol), ibuprofeno, naproxeno o aspirina que impedirían el uso de al menos 1 de estos fármacos durante el estudio.
16. Tto. con otros fármacos para tratar los síntomas de la EM o una enfermedad subyacente como se especifica en la tabla pág. 40:
17. Tto. con otro fármaco en investigación o con un tto. aprobado para uso en investigaciones en los 6 meses previos a la aleatorización (día 1).
Otros criterios
18. Mujeres que estén considerando la posibilidad de quedarse embarazadas durante el período del estudio.
19. No podrán participar en este estudio mujeres en edad fértil con prueba de embarazo positiva en la visita de selección o en la visita del día 1 (visita basal).
20. Mujeres embarazadas o en periodo de lactancia.
21. Antecedentes de toxicomanías o alcoholismo (conforme al criterio del investigador) en los 2 años previos al día 1.
22. Incapacidad para realizar la prueba de recorrido cronometrado de 7,6 metros (25 pies), la 9HPT con los 2 miembros superiores y la prueba PASAT 3.
23. Incapacidad para realizar pruebas de función visual.
24. Sujetos en los que la RMN esté contraindicada: pacientes con marcapasos u otros dispositivos metálicos implantados contraindicados, que sean alérgicos al gadolinio o que padezcan claustrofobia no controlable médicamente.
25. Participación actual en cualquier otro estudio con un fármaco en investigación.
26. Participación previa en este estudio.
27. Cirugía programada realizada en las 2 semanas previas a la aleatorización (día 1) o programada durante el período del estudio.
28. Negativa o imposibilidad de cumplir los requisitos del protocolo, incluida la presencia de cualquier circunstancia (física, mental o social) que pueda afectar a la capacidad del sujeto para cumplir el protocolo.
29. Cualquier otro motivo no especificado que, en opinión del investigador o de Biogen Idec, haga al sujeto no adecuado para el reclutamiento.

E.5 End points

E.5.1

Primary end point(s)

La variable principal de este estudio es determinar la eficacia de BIIB017 para reducir la tasa anual de recidivas (TAR) en sujetos con EMR al año

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

E.6.4

Safety

Yes

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Inmunogenicidad

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

170

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

1000

F.4.2.2

In the whole clinical trial

1260

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)

Como se establece en el protocolo

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

2009-09-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-07-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-10-24

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