Clinical Trials Register

Summary
EudraCT Number:	2011-001626-15
Sponsor's Protocol Code Number:	ML27828
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:	2011-10-20
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

2011-001626-15

A.3

Full title of the trial

A multi-centre, randomized, double-blind study of the safety and efficacy of tocilizumab (TCZ) in combination with methotrexate (MTX), versus TCZ (placebo controlled) in patients with active rheumatoid arthritis (RA) with inadequate response to prior MTX treatment and low disease activity (DAS 28 ? 3.2) with the combination TCZ and MTX.

Ensayo clínico aleatorizado doble-ciego y multi-céntrico, para evaluar la seguridad y la eficacia de la combinación de tocilizumab (TCZ) y metotrexato (MTX), frente al cambio a TCZ (controlado con placebo), en pacientes con artritis reumatoide (AR) activa que manifestaron una respuesta inadecuada al tratamiento previo con MTX y han alcanzado una actividad baja de la enfermedad (DAS 28 menor o igual 3.2) con la combinación TCZ y MTX.

A.3.1

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

A study of RoActemra/Actemra (tocilizumab) in combination with methotrexate in patients with rheumatoid arthritis with inadequate response to prior treatment with methotrexate and low disease activity with the combination de RoActemra/Actemra y methotrexate.

Ensayo clínico con RoActemra/Actemra (tocilizumab) y metotrexato en pacientes con artritis reumatoide con una respuesta inadecuada al
tratamiento previo con metotrexato y una actividad baja de la enfermedad con la combinación RoActemra/Actemra y metotrexato.

A.4.1

Sponsor's protocol code number

ML27828

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	Roche Farma, 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	Roche Farma, 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	-
B.5.2	Functional name of contact point	-
B.5.3	Address:
B.5.3.1	Street Address	-
B.5.3.2	Town/ city	-
B.5.3.3	Post code	-
B.5.3.4	Country	Spain
B.5.4	Telephone number	-
B.5.5	Fax number	-
B.5.6	E-mail	Notapplicable@notapplicable.com

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	ROACTEMRA 20 mg/ml, concentrado para solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION 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.3.4	Pharmaceutical form	Concentrate 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	TOCILIZUMAB
D.3.9.3	Other descriptive name	TOCILIZUMAB
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	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	Yes
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	Anticuerpo monoclonal anti-humano recombinante humanizado, receptor de IL-6R.
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	ROACTEMRA 20 mg/ml, concentrado para solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION 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.3.4	Pharmaceutical form	Concentrate 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	TOCILIZUMAB
D.3.9.3	Other descriptive name	TOCILIZUMAB
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	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	Yes
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	Anticuerpo monoclonal anti-humano recombinante humanizado, receptor de IL-6R.
D.IMP: 3
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	Methotrexate 'Lederle' 2.5mg Tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Wyeth Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.2	Product code	Ro 002-9893/F02
D.3.4	Pharmaceutical form	Capsule, hard
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	Methotrexate Disodium
D.3.9.1	CAS number	7413345
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	2.5
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)	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid arthritis

Artritis Reumatoide

E.1.1.1

Medical condition in easily understood language

Rheumatoid arthritis

Artritis Reumatoide

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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

Evaluar el mantenimiento de la respuesta en pacientes tras el cambio a TCZ administrado en monoterapia en comparación con la continuación del tratamiento combinado de TCZ y MTX.

E.2.2

Secondary objectives of the trial

Evaluar la remisión clínica obtenida la semana 28 del ensayo.
Evaluar la mejoría de la capacidad funcional y calidad de vida.
Comparar la seguridad de TCZ en monoterapia frente a la combinación de TCZ con MTX, con respecto a la incidencia de acontecimientos adversos (AA), acontecimientos adversos graves (AAG) y las evaluaciones de laboratorio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Edad 18 años
2. Pacientes con AR activa, moderada a severa (DAS28 > 3.2) en la visita de selección.
3. Pacientes que esten recibiendo tratamiento con MTX (por vía oral o parenteral) desde hace al menos 12 semanas y que han recibido dosis estable de MTX de, al menos, 15mg/semana como mínimo (via oral o parenteral) durante las 6 semanas previas al inicio del tratamiento del estudio (día 1), con las siguientes excepciones: es aceptable una dosis de 10 mg, en vez de 15 mg, en los pacientes con un peso corporal <50 kg, toxicidad de grado bajo a MTX (por ejemplo, náuseas) o velocidad de filtración globular calculada (o aclaramiento de creatinina) < 60 ml/min. Los pacientes que hayan recibido MTX por vía parenteral (subcutánea o intramuscular) antes de la evaluación basal podrán participar en el estudio. Sin embargo, antes de iniciar el tratamiento (el día 1), estos pacientes deben haber recibido una dosis estable de MTX oral de al menos 15 mg/semana, durante un mínimo de 6 semanas.
4. Pacientes que reciben tratamiento en régimen ambulatorio.
5. Pacientes con disposición a recibir tratamiento oral con ácido fólico.
6. En caso de pacientes con tratamiento oral con corticosteroides, la dosis de corticosteroides se debe haber mantenido estable durante al menos 25 de los 28 días previos a la visita basal y se aceptará una dosis máxima de 10 mg/día.
7. Pacientes con capacidad y disposición para otorgar consentimiento informado por escrito y cumplir los requisitos del protocolo de estudio.

E.4

Principal exclusion criteria

1. Cirugía mayor en las 8 semanas previas al periodo de selección o cirugía mayor programada en los 6 meses posteriores a visita basal.
2. Enfermedad reumática autoinmune distinta de artritis reumatoide.
3. Clase funcional IV definida de acuerdo con la Clasificación del ACR del Estado Funcional en AR.
4. Historia previa o actual de enfermedad inflamatoria articular distinta de AR.
5. Pacientes con cualquiera de los siguientes tratamientos previo o concomitantes:
5.1. Agente biológico que se utilice para el tratamiento de la AR.
5.2. FAMES convencionales distintos de MTX durante el 1 mes previo a la visita basal.
5.3. Cualquier medicamento en investigación durante las 4 semanas previas al periodo de selección.
5.4. Tratamiento previo con terapia de depleción celular.
5.5. Gammaglobulina intravenosa, plasmaferesis o Prosorba Column, en los 6 meses previos a la visita basal.
5.6. Corticosteroides via intraarticular o parenteral durante las 6 semanas previas a visita basal.
5.7. Inmunización con una vacuna viva/atenuada durante las 4 semanas previas a visita basal.
5.8. Tratamiento previo con TCZ.
5.9. Cualquier tratamiento previo con agentes alquilantes.
6. Pacientes excluidos por cualquier de estos motivos de seguridad:
6.1. Mujeres embarazadas o en período de lactancia
6.2. Mujeres potencialmente fértiles que no estén utilizando un método anticonceptivos eficaz.
6.3. Antecedentes de reacciones alérgicas o anafilácticas severas a anticuerpos monoclonales humanos, humanizados o murinos.
6.4. Evidencia de anomalías clínicamente significativas en radiografía de tórax.
6.5. Evidencia de enfermedades concomitantes graves no controladas de los sistemas cardiovascular, nervioso, pulmonar, renal, hepatico, endocrino o gastrointestinal.
6.6. En pacientes con antecedentes de diverticulitis o diverticulosis que requieran tratamiento antibiótico, el médico responsable debe considerar la relación riesgo-beneficio.
6.7. Antecedentes de enfermedad ulcerativa crónica del tracto gastrointestinal (GI) inferior, que podrían predisponer a perforaciones.
6.8. Patologías no controladas, cuyas exacerbaciones se tratan normalmente con corticosteriodes orales o parenterales.
6.9. Enfermedad hepática.
6.10. Pacientes que han padecido o presentan infecciones de tipo bacteriano, vírico, fúngico, micobacteriano o de cualquier otro tipo.
6.11. Inmunodeficiencia primaria o secundaria.
6.12. Evidencia de enfermedad maligna activa, diagnosticada en los 5 años previos.
6.13. Tuberculosis (TB) activa que haya precisado tratamiento en los 3 años previos.
6.14. Pacientes con tuberculosis latente.
6.15. Pacientes VIH positivos.
6.16. Antecedentes de alcoholismo, abuso de drogas en los 6 meses previos al screening.
6.17. Neuropatías u otras afecciones que cursen con dolor que pudiesen interferir en la evaluación del dolor.
6.18. Pacientes con escaso acceso venoso periférico
6.19. Peso > 150 kg

E.5 End points

E.5.1

Primary end point(s)

Cambio en la puntuación DAS28 desde la aleatorización en semana 16 hasta el final del tratamiento en semana 28.

E.5.1.1

Timepoint(s) of evaluation of this end point

Semana 28

E.5.2

Secondary end point(s)

Not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

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

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

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.8.2.4

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

La finalización del estudio tendrá lugar cuando se realice la última visita del último paciente (UVUP). La UVUP es la fecha de la visita del último paciente en completar el estudio, o la fecha en que se recibe el último dato del último paciente, que es necesario para el análisis estadístico (es decir, los resultados de eficacia y seguridad clave para tomar una decisión), lo que ocurra más tarde.

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