Clinical Trials Register

Summary
EudraCT Number:	2015-004616-37
Sponsor's Protocol Code Number:	ML29966
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:	2016-08-05
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

Germany - PEI

A.2

EudraCT number

2015-004616-37

A.3

Full title of the trial

An open-label, multicenter, biomarker study to explore the mechanism of action of ocrelizumab and B-cell biology in patients with relapsing multiple sclerosis or primary progressive multiple sclerosis.

A.3.1

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

A Study to Explore the Mechanism of Action of Ocrelizumab and B-cell Biology in Patients with Relapsing Multiple Sclerosis or Primary Progressive Multiple Sclerosis.

A.4.1

Sponsor's protocol code number

ML29966

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	GENENTECH Inc.
B.1.3.4	Country	United States
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	Genentech Inc. c/o F. Hoffman-La Roche Ltd.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Genentech Inc. c/o 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.5.6	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
D.3.2	Product code	RO4964913/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.3.9.3	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	300
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/10ml
D.3.2	Product code	RO4964913/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.3.9.3	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	300
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

- Relapsing multiple sclerosis (RMS)/Primary Progressive Multiple Sclerosis (PPMS)

E.1.1.1

Medical condition in easily understood language

RMS is the most common form of MS which causes inflammation of insulating membranes(myelin)that surround nerves. PPMS is characterized by continuous progression of disability independent from relapses

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	21.1
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	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 understand the impact of ocrelizumab treatment on neurofilament light (NfL) as a biomarker of neuronal damage in cerebrospinal fluid (CSF)
• To assess the number of cluster of differentiation (CD)19+ B cells in CSF (cell number/microliter) before and after treatment with ocrelizumab
• To assess the number of CD3+ T cells in CSF (cell number/microliter) before and after treatment with ocrelizumab

E.2.2

Secondary objectives of the trial

• The safety objective for this study, including for the Long-Term Extension, is to evaluate the safety of ocrelizumab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

General Inclusion Criteria
- Age 18 − 55 years, inclusive
- For women of childbearing potential: agreement to remain abstinent
(refrain from heterosexual intercourse) or use contraceptive methods
that result in a failure rate of < 1% per year during the treatment period
and for at least 24 weeks after the last dose of study treatment or until
their B cells have repleted, whichever is longer

Inclusion Criteria Specific to RMS Patients
- Diagnosis of RMS in accordance with the 2010 revised McDonald criteria
- Expanded Disability Status Scale (EDSS) score of 0 − 5.5 points, inclusive, at screening
- Disease duration less than 15 years in participants with an EDSS > 5.0 at screening
- Either treatment-naive or receiving treatment with disease-modifying therapies, including prior use of IFN-beta-1a (Avonex®, Rebif®), IFN-beta-1b (Betaseron®/Betaferon), or glatiramer acetate (Copaxone®)
- At least one clinically documented relapse in the past year and/or at least one T1-weighted Gd-enhancing lesion in the past year and/or at least one new T2 lesion in the past year at the time of enrollment

Inclusion Criteria Specific to RMS Cohort Arm 4
- Must meet inclusion criteria for the RMS cohort
- Separate signed Informed Consent Form for the RMS Delayed Time to
Start Control Arm (Arm 4)
- Must be willing to remain on the same dose and regimen of current
standard of care, or no treatment if treatment-naïve, for 12 weeks after
study enrollment
Inclusion Criteria Specific to primary progressive multiple sclerosis
(PPMS) Patients
- Diagnosis of PPMS in accordance with the 2010 revised McDonald
criteria
- EDSS score of 3.0 − 6.5 points, inclusive, at screening
- Disease duration from the onset of MS symptoms: Less than 10 years
in patients with an EDSS at screening ≤ 5.0
- Documented history of at least one of the following laboratory findings
in CSF:
Elevated IgG Index
One or more IgG OCBs detected by isoelectric focusing

E.4

Principal exclusion criteria

General Exclusion Criteria
- Diagnosis of primary progressive MS
- Diagnosis of secondary progressive MS (without relapses for at least 1 year)
- History or known presence of recurrent or chronic infection
- History of recurrent aspiration pneumonia requiring antibiotic therapy
- History of cancer
- History of or currently active primary or secondary immunodeficiency
- History of coagulation disorders
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- History of alcohol or other drug abuse within 24 weeks prior to enrollment
- Known presence or history of other neurologic disorders
- Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine, gastrointestinal, or any other significant disease
- Congestive heart failure
- Known active bacterial, viral, fungal, mycobacterial infection, or other infection or any major episode of infection
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants
- Contraindications for, or intolerance to, oral or intravenous (IV) corticosteroids,
- Contraindication for lumbar puncture (LP)
- Previous treatment with B cell-targeted therapies
- Previous treatment with natalizumab (Tysabri®), alemtuzumab, anti-CD4 agents, cladribine, teriflunomide, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation
- Treatment with fingolimod/Gilenya®, dimethyl fumarate/Tecfidera®, or similar treatment within 6 months prior to enrollment
- Receipt of live vaccine
- Systemic corticosteroid therapy within 4 weeks prior to baseline
- Previous or concurrent treatment with any investigational agent or treatment with any experimental procedure for MS
- Laboratory abnormalities or findings at screening
- Inability to complete Magnetic Resonance Image (MRI)
- Lack of peripheral venous access

Exclusion Criteria Specific to RMS Patients
- Diagnosis of PPMS or SPMS without relapses

E.5 End points

E.5.1

Primary end point(s)

1. Change in levels of NfL in CSF from treatment baseline to post-treatment with ocrelizumab
2. Change in number of CD19+ B cells in CSF from treatment baseline to post-treatment with ocrelizumab
3. Change in number of CD3+ T cells in CSF from treatment baseline to post-treatment with ocrelizumab

E.5.1.1

Timepoint(s) of evaluation of this end point

1-3. Treatment baseline (Day 1) and Weeks 12, 24, and 52

E.5.2

Secondary end point(s)

1. Changes in vital signs, physical findings and laboratory results
2. Incidence of AEs
3. AEs related to biomarker sample collection

E.5.2.1

Timepoint(s) of evaluation of this end point

1-3 Up to 6.5 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

E.6.4

Safety

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Explore the mechanism of action of ocrelizumab and B-cell biology
Biomarker study

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

United States

Germany

Sweden

Switzerland

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 total length of the study is expected to be approximately 2.5 years
from the first patient enrolled to LPLV, excluding any follow-up.
Patients may be consented for participation in an OLE phase if, in the
opinion of the investigator, they may benefit from treatment with
ocrelizumab. The OLE phase would continue until the Sponsor decides
to terminate the ocrelizumab program.

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:

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

F.4.2.2

In the whole clinical trial

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)

Currently, the Sponsor (Genentech, a member of the Roche Group)
does not have any plans to provide ocrelizumab or any other study
treatments or interventions to patients who have completed the study,
in accordance with the Roche Global Policy on Continued Access to
Investigational Medicinal Product, available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_
medicines.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

2016-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-04-11

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