Clinical Trials Register

Summary
EudraCT Number:	2017-004886-29
Sponsor's Protocol Code Number:	MN39158
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:	2018-04-09
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

2017-004886-29

A.3

Full title of the trial

A SINGLE ARM, OPEN LABEL MULTICENTRE EXTENSION STUDY TO EVALUATE THE EFFECTIVENESS AND SAFETY OF OCRELIZUMAB IN
PATIENTS WITH MULTIPLE SCLEROSIS PREVIOUSLY ENROLLED IN A F. HOFFMANN-LA ROCHE SPONSORED OCRELIZUMAB PHASE IIIb/IV CLINICAL TRIAL

ESTUDIO DE EXTENSIÓN MULTICÉNTRICO, ABIERTO Y DE
UN SOLO GRUPO PARA EVALUAR LA EFECTIVIDAD Y LA
SEGURIDAD DE OCRELIZUMAB EN PACIENTES CON
ESCLEROSIS MÚLTIPLE INCLUIDOS PREVIAMENTE EN UN
ENSAYO CLÍNICO DE FASE IIIb/IV DE OCRELIZUMAB
PATROCINADO POR F. HOFFMANN-LA ROCHE

A.3.1

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

A Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Patients with Multiple Sclerosis Previously Enrolled in A F. Hoffmann-la Roche Sponsored Ocrelizumab Clinical Trial

Estudio para evaluar la efectividad y la seguridad de Ocrelizumab en pacientes con esclerosis múltiple incluidos previamente en un ensayo clinico patrocinado por F. Hoffmann-la Roche

A.4.1

Sponsor's protocol code number

MN39158

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 SA (Soc unipersonal) que realiza el ensayo en España y que actúa como representante F.Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	34913257300
B.5.5	Fax number	34913248196
B.5.6	E-mail	spain.start_up_unit@roche.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	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	Ocrelizumab
D.3.2	Product code	RO4964913
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	Ocrelizumab
D.3.9.1	CAS number	637334-45-3
D.3.9.2	Current sponsor code	RO4964913
D.3.9.3	Other descriptive name	OCRELIZUMAB
D.3.9.4	EV Substance Code	SUB121707
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	30
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	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

Multiple sclerosis (MS)

Esclerosis Multiple (EM)

E.1.1.1

Medical condition in easily understood language

MS is a chronic autoimmune, inflammatory neurological disease of the central nervous system

La EM es una enfermedad neurológica inflamatoria, autoinmune crónica del sistema nervioso central

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10028245
E.1.2	Term	Multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10048393
E.1.2	Term	Multiple sclerosis relapse
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10039720
E.1.2	Term	Sclerosis multiple
E.1.2	System Organ Class	10029205 - Nervous system 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

• To evaluate the effectiveness of ocrelizumab therapy in MS patients who were previously enrolled in a Roche sponsored phase IIIb/IV-trial

-Evaluar la efectividad del tratamiento con ocrelizumab en pacientes con EM incluidos previamente en un ensayo de fase IIIb/IV patrocinado por Roche

E.2.2

Secondary objectives of the trial

• Different effectiveness measures evaluated for ocrelizumab in MS patients who were previously enrolled in a Roche sponsored phase IIIb/IV-trial
• To evaluate the safety and tolerability of ocrelizumab therapy in MS patients who were previously enrolled in a Roche sponsored phase IIIb/IV-trial

-Diferentes variables de efectividad de ocrelizumab evaluadas en pacientes con EM incluidos previamente en un ensayo de fase IIIb/IV patrocinado por Roche.
-Evaluar la seguridad y la tolerabilidad del tratamiento con ocrelizumab en pacientes con EM incluidos previamente en un ensayo de fase IIb/IV patrocinado por Roche.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Able to comply with the study protocol, in the investigator’s judgment
- Completed the treatment period of Roche sponsored ocrelizumab Parent-trial (exception for female patients who were pregnant during CASTING / MA30005 study and are still in the safety follow up period) and who in the opinion of the investigator may benefit from treatment with ocrelizumab
- Meet re-treatment criteria with ocrelizumab
- For women of childbearing potential: agreement to use an acceptable birth control method during the treatment period and for at least 6 months after the last dose of study drug

-Capacidad para cumplir el protocolo del estudio, en opinión del investigador.
-Haber completado el período de tratamiento de un ensayo original de ocrelizumab
patrocinado por Roche (a excepción de las pacientes embarazadas durante el estudio
CASTING/MA30005 que sigan en el período de seguimiento de la seguridad) y que, en
opinión del investigador, podrían beneficiarse del tratamiento con ocrelizumab
-Cumplir los criterios de retratamiento con ocrelizumab
-Mujeres en edad fértil: compromiso de utilizar un método anticonceptivo aceptable durante el período de tratamiento y durante al menos 6 meses (después de la última dosis del
fármaco del estudio.

E.4

Principal exclusion criteria

- Hypersensitivity to ocrelizumab or to any of its excipients
- Patients in a severely immunocompromised state until the condition resolves
- Evidence of any adverse event potentially attributable to ocrelizumab, for which the local label recommends permanent discontinuation
- Existence of a contra-indication as per SmPC
- Patients who discontinued ocrelizumab, exemption made for treatment discontinuation because of pregnancy and breastfeeding and continued clinical study assessments

-Hipersensibilidad al ocrelizumab o a alguno de sus excipientes
-Pacientes con inmunodepresión grave hasta su resolución
-Evidencia de cualquier acontecimiento adverso potencialmente atribuible al ocrelizumab para el que la ficha técnica recomiende la suspensión definitiva de su administración.
-Existencia de una contraindicación según la ficha técnica del producto
-Pacientes que suspendieron el tratamiento con ocrelizumab en el ensayo original, a
excepción de las pacientes que suspendieron el tratamiento por embarazo y lactancia y continuaron con las evaluaciones del estudio clínico

E.5 End points

E.5.1

Primary end point(s)

1. Evaluate clinical measures related to disease progression over two years in MS patients

1.Evaluar medidas clínicas relacionadas con la progresión de la enfermedad durante dos años en pacientes con EM

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to 2 years

1. Hasta 2 años

E.5.2

Secondary end point(s)

1. Time to onset of Confirmed disability progression (CDP) sustained for at least 24 weeks and for at least 48 weeks
2. Proportion of patients who have confirmed disability improvement (CDI), CDP for at least 24 weeks and for at least 48 weeks yearly and over the duration of the Extension study
3. Proportion of patients who have improved, stable or worsened disability compared with baseline (inclusion in Extension study) measured by expanded disability status scale (EDSS)’
4. Mean change from inclusion in Extension study in EDSS score over the course of the study
5. Time to 20% increase in timed 25-foot walk test (T25FWT); time to 20% increase in timed nine-hole peg test (9HPT) sustained for at least 24 weeks and for at least 48 weeks, and proportion of patients achieving a sustained increase assessed yearly and at the end of the Extension study
6. Time to first protocol-defined event of disease activity
7. Time to first relapse
8. Annualised relapse rate
9. Proportion of patient relapse free, yearly and over the course of the study
10. Proportion of patients with no evidence of protocol-defined disease activity (NEDA) yearly and over the course of the study
11. Proportion of patients with no evidence of progression, measured by EDSS, 9HPT and T25FW (if assessments are available)
12. Proportion of patients with no evidence of progression sustained for at least 24 weeks and no active disease (if assessments are available)
13. Change from baseline in cognitive performance as measured by the Symbol digit modalities test (SDMT)
14. Total number of T1 Gd-enhancing lesions as detected by brain MRI over time
15. Total number of new and/or enlarging T2 lesion as detected by brain MRI over time
16. Change in total T1 hypointense lesion volume over time
17. Total number of fluid-attenuated inversion-recovery (FLAIR) late enhancing lesions as detected by brain MRI over time
18. Change in brain volume (including white and grey matter fractions) as detected by brain MRI over time
19. Time to treatment discontinuation/switch
20. Employment status (Work Productivity and Activity Impairment Questionnaire [WPAI])
21. SymptoMScreen score
22. Quality of life (Multiple Sclerosis Impact Scale [MSIS]-29)
23. Evaluation of cognition as measured by SDMT assessment
24. Rate and nature of adverse events
25. Changes in vital signs, neurological examinations, clinical laboratory results, locally reviewed MRI for safety (non-MS CNS pathology) and concomitant medications

1.Tiempo transcurrido hasta la aparición de progresión confirmada de la discapacidad (PCD) mantenida durante un mínimo de 24 y de 48 semanas.
2.Proporción de pacientes que presentan una mejoría confirmada de la discapacidad (MCD), PCD durante un mínimo de 24 y de 48 semanas al año y durante todo el estudio de extensión
3 Proporción de pacientes que presenten mejoría, estabilidad o empeoramiento de la discapacidad en comparación con el momento basal (inclusión en el estudio de extensión) medido mediante la escala ampliada del estado de discapacidad (EDSS)
4.Variación media de la puntuación EDSS con respecto al momento de la inclusión en el estudio de extensión a lo largo del estudio.
5.Tiempo trascurrido hasta un aumento del 20% en la prueba de marcha de 7,6 m o 25 pies cronometrada (T25FWT);tiempo hasta un aumento del 20% en la prueba del tablero de nueve orificios (9-HPT)
cronometrada mantenido durante un mínimo de 24 y de 48 semanas, y proporción de pacientes que logren un aumento mantenido evaluado anualmente y al final del estudio de extensión.
6.Tiempo transcurrido hasta el primer episodio de actividad de la enfermedad definido en el protocolo.
7.Tiempo transcurrido hasta la primera recaída.
8.Tasa anualizada de recaídas.
9.Proporción de pacientes sin recaída, anualmente y a lo largo del estudio.
10.Proporción de pacientes sin evidencia de actividad de la enfermedad (NEDA) según la definición del protocolo anualmentea lo largo del estudio
11.Proporción de pacientes sin evidencia de progresión medidas por EDSS, 9HPT y (T25FWT),(si las valoraciones están disponibles)
12.Proporción de pacientes sin evidencia de progresión
mantenida durante un mínimo de 24 semanas y sin enfermedad activa (si las valoraciones están disponibles)
13.Variación con respecto al valor basal del rendimiento
cognitivo medido mediante la Prueba de modalidades de símbolos y dígitos (SDMT).
14.Número total de lesiones realzadas con Gd en T1 detectadas mediante RM cerebral a lo largo del tiempo
15.Número total de lesiones en T2 nuevas y/o que aumenten de tamaño detectadas mediante RM cerebral a lo largo del tiempo
16.Variación del volumen total de lesiones hipointensas
en T1 a lo largo del tiempo
17Número total de lesiones realzadas en secuencia FLAIR (inversión-recuperación con atenuación de líquidos) detectadas mediante RM cerebral a lo largo del tiempo.
18.Variación del volumen encefálico (incluidas fracciones de la sustancia blanca y gris) detectado mediante RM cerebral a lo largo del tiempo
19.Tiempo transcurrido hasta la suspensión o el cambio
de tratamiento.
20.Situación laboral (cuestionario WPAI [Cuestionario de productividad laboral y deterioro de la actividad])
21. SymptoMScreen.
22.Calidad de vida (CdV) (escala MSIS [Escala de repercusión de la esclerosis múltiple]-29).
23 Variaciones de las constantes vitales a través de SDMT
24.Tasa y naturaleza de los efectos adversos
25.Variaciones de las constantes vitales, las exploraciones neurológicas, los resultados de los análisis clínicos, la RM analizada localmente a efectos de seguridad (enfermedades en el sistema
nervioso central [SNC] distintas de la EM) y los fármacos concomitantes

E.5.2.1

Timepoint(s) of evaluation of this end point

1-24. Up to 2 years

1-24. Hasta 2 años

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

E.8.1.1

Randomised

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

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

200

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

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

Czech Republic

Denmark

Estonia

Finland

France

Ireland

Italy

Netherlands

Norway

Spain

Sweden

Turkey

United Kingdom

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

The end of the study is defined as the last patient last visit (LPLV) in the B-cell monitoring of the Follow-Up period i.e. until B-cell repletion and no longer than 2 years (If the patients are receiving other B-cell targeted therapies, then the Follow-up Period is only 48 weeks from the start of other B-cell targeted therapies).

El final del estudio se define como la última visita del último paciente durante la vigilancia de los linfocitos B del período de seguimiento, es decir, hasta que se repongan los linfocitos B y no más de dos años (si los pacientes están recibiendo otros tratamientos dirigidos a los linfocitos B, el período de seguimiento solo será de 48 semanas desde el comienzo de esos otros tratamientos).

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

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:

750

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

650

F.4.2.2

In the whole clinical trial

750

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)

The Sponsor will offer continued access to Roche IMP (ocrelizumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined in protocol section 4.3.5.

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

2018-05-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-11

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

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