Clinical Trials Register

Summary
EudraCT Number:	2010-020338-25
Sponsor's Protocol Code Number:	WA25046
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-10-06
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

Germany - PEI

A.2

EudraCT number

2010-020338-25

A.3

Full title of the trial

A Phase III, multicenter, randomized, parallel-group, double blinded, placebo controlled study to evaluate the efficacy and safety of ocrelizumab in adults with Primary Progressive Multiple Sclerosis

A.3.1

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

A Study of Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis

A.3.2

Name or abbreviated title of the trial where available

Oratorio

A.4.1

Sponsor's protocol code number

WA25046

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	F.Hoffmann-La Roche
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 12
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@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 300mg/10 ml
D.3.2	Product code	Ro 496-4913/F07
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.3.10	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	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	Yes
D.3.11.13.1	Other medicinal product type	humanized monoclonal antibody
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	Ocrevus
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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 300mg/10 ml
D.3.2	Product code	Ro 496-4913/F07
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.3.10	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	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	Yes
D.3.11.13.1	Other medicinal product type	humanized monoclonal antibody

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	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Primary Progressive Multiple Sclerosis (PPMS)

E.1.1.1

Medical condition in easily understood language

Primary Progressive Multiple Sclerosis (PPMS)

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063401
E.1.2	Term	Primary progressive multiple sclerosis
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 investigate the efficacy of ocrelizumab compared with placebo in participants with primary progressive multiple sclerosis, as measured by the time to onset of confirmed disability progression over the treatment period, defined as an increase in EDSS that is sustained for at least 12 weeks, based on regularly scheduled visits.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of ocrelizumab compared with placebo, as reflected by the following:
• The time to onset of confirmed disability progression over the treatment period, defined as an increase in EDSS that is sustained for at least 24 weeks
• The change in 25-foot timed walk from baseline to Week 120
• The change in total volume of T2 lesions on MRI scans of the brain from baseline to week 120
• The percentage change in total brain volume as detected by brain MRI from Week 24 to Week 120
• The change in SF-36 Health Survey version 2 (SF-36v2) Physical Component Summary (PCS) score from baseline to Week 120
• To evaluate the safety and tolerability of ocrelizumab 300 mg × 2 (over 24-week treatment cycles) compared with placebo in participants with PPMS

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Optical Coherence Tomography Exploratory Substudy

This substudy is run under the main study protocol and will be used to evaluate the neuroprotective effect of ocrelizumab as measured by retinal nerve fiber layer (RNFL) thickness and macular volume in both eyes.

Optional Exploratory Substudies

Consenting patients who enrolled in the main study WA25046 and who are eligible will
be offered the opportunity to participate in optional substudies, which are run under
separate protocols.

Other exploratory substudies are run under separate study protocols:
• B cell and T cell repertoires in ocrelizumab-treated MS patients (BE29353)
• Brain myelin mapping to quantify demyelination and repair in MS in a Phase III trial of ocrelizumab (BE29340)
• Assessment of ocrelizumab treatment effects on disability of MS patients enrolled in the Phase III Orchestra program using multimodal evoked potentials (mEP) and high-resolution electroencephalogram (EEG; BE29354)
• Substudy of brain and spinal cord MRI in patients with MS participating in the OPERA clinical trial (BE29352).

Substudies will be run only at the specific assigned sites that are referred to in the substudy protocols.

E.3

Principal inclusion criteria

• Adult participants, 18-55 years of age
• Primary Progressive Multiple Sclerosis (according to revised McDonald criteria)
• Expanded Disability Status Scale (EDSS) 3.0 to 6.5 points
• Disease duration from onset of MS symptoms < 15 years if EDSS > 5.0, < 10 years if EDSS ≤ 5.0
• Sexually active male and female participants of reproductive potential must use two methods of contraception throughout the study treatment phase and for 48 weeks for females and 24 weeks for males after the last dose

Participants who meet the following entry criteria may participate in the OLE phase:
• Completed the Blinded Treatment Period of the trial and who, in the opinion of the Investigator, may benefit from treatment with ocrelizumab;
• Able and willing to provide written informed consent to participate in the OLE phase and to comply with the study protocol;
• Willing to continue to use at least two contraceptive methods
• Meet the re-treatment criteria with ocrelizumab

E.4

Principal exclusion criteria

• History of relapsing remitting multiple sclerosis, secondary progressive, or progressive relapsing multiple sclerosis at screening
• Contraindications for Magnetic Resonance Imaging (MRI)
• Known presence of other neurologic disorders
• Known active infection or history of or presence of recurrent or chronic infection
• History of cancer, including solid tumors and hematological malignancies (except for basal cell, in situ squamous cell carcinomas of the skin and in situ carcinoma of the cervix that have been excised and resolved)
• Previous treatment with B-cell targeted therapies (e.g. rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)
• Any previous treatment with lymphocyte trafficking blockers, with alemtuzumab, anti-CD4, cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study;

E.5 End points

E.5.1

Primary end point(s)

1. Efficacy: Time to onset of confirmed disability progression, defined as an increase in Expanded Disability Status Scale (EDSS) score that is sustained for at least 12 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to 11 years

E.5.2

Secondary end point(s)

1. Time to confirmed disability progression, defined as an increase in EDSS score that is sustained for at least 24 weeks
2. Change in timed 25-foot walk
3. Change in total volume of T2 lesions on magnetic resonance imaging (MRI) scans of the brain
4. Safety and tolerability: Incidence of adverse events

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to 11 years
2. From baseline to Week 120
3. From baseline to Week 120
4. Up to 11 years

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

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

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Australia

Brazil

Canada

Israel

Mexico

New Zealand

Peru

Russian Federation

Ukraine

United States

Austria

Belgium

Bulgaria

Czechia

Denmark

Finland

France

Germany

Greece

Hungary

Italy

Lithuania

Netherlands

Norway

Poland

Portugal

Slovakia

Spain

Switzerland

United Kingdom

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

The end of study is now defined as 31 December 2022 or up until the
approval of Study MN43964 (OLERO). Irrespectively, the Sponsor may
decide to terminate the study at any time. The Sponsor has decided to
provide the opportunity to all participants to rollover and continue their
treatment and/or safety follow-up under the new extension protocol.

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

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:

630

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

500

F.4.2.2

In the whole clinical trial

630

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) to
eligible participants in accordance with the Roche Global Policy on
Continued Access to IMP. A participant will be eligible to receive
ocrelizumab after completing the study if he/she decides not to
rollover to the new study (MN43964) and if all conditions are met. The
Roche Global Policy on Continued Access to IMP is available at the
following website:
www.roche.com/policy_continued_access_to_investigational_medicine
s.pdf

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

2011-04-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-06-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-12-31

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