Clinical Trials Register

Summary
EudraCT Number:	2020-000893-69
Sponsor's Protocol Code Number:	BN42082
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-07-29
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

UK - MHRA

A.2

EudraCT number

2020-000893-69

A.3

Full title of the trial

A PHASE IIIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY AND PHARMACOKINETICS OF A HIGHER DOSE OF OCRELIZUMAB IN ADULTS WITH RELAPSING MULTIPLE SCLEROSIS

A.3.1

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

A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher
Dose of Ocrelizumab in Adults with Relapsing Multiple Sclerosis

A.3.2

Name or abbreviated title of the trial where available

BN42082 Study to evaluate high dose Ocrelizumab in RMS

A.4.1

Sponsor's protocol code number

BN42082

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	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	+41616883035
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	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	Ocrevus
D.3.2	Product code	RO4964913/F07-01
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	AS2
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

Relapsing Multiple sclerosis

E.1.1.1

Medical condition in easily understood language

MS is a condition that can affect the brain and spinal cord, causing a
wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance

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	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	20.1
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 demonstrate the superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab as assessed by risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks

E.2.2

Secondary objectives of the trial

• To demonstrate superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab on the basis of time to onset of 24 week cCDP (cCDP24), CDP12, CDP24, time to >= 20% increase in 12 and 24 week confirmed timed 25 foot walk test (T25FWT), change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29), percent change in total brain volume, time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT)
• To evaluate the safety profile of a higher dose of ocrelizumab compared with the approved dose of ocrelizumab as well as the overall safety profile and safety profile by treatment arm over time
• To assess the exposure to ocrelizumab in serum in all patients in both study arms
• To characterize the ocrelizumab PD profile
• To evaluate the immune response to ocrelizumab
• To identify biomarkers that are predictive of response to a higher dose of ocrelizumab

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

A CEREBROSPINAL FLUID (CSF) BIOMARKER SUBSTUDY WITHIN BN42082 TRIAL, PHASE IIIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, CONTROLLED STUDIES TO EVALUATE THE EFFICACY, SAFETY AND PHARMACOKINETICS OF A HIGHER DOSE OF OCRELIZUMAB IN ADULTS WITH RELAPSING MULTIPLE SCLEROSIS

Version 1 Dated 19th May 2020

Primary objective
• To compare a higher dose of ocrelizumab versus the approved dose of ocrelizumab Secondary objective
• To assess the correlation between changes in CSF biomarkers with those in blood and to compare higher dose of ocrelizumab versus the approved dose of ocrelizumab
• To characterize the ocrelizumab concentration in CSF and to investigate the relationship between changes in biomarkers in CSF/blood and ocrelizumab concentration in CSF

E.3

Principal inclusion criteria

• Ages 18-55 years at time of signing ICF
• Ability to comply with the study protocol
• Diagnosis of RMS in accordance with the revised McDonald Criteria 2017
• At least two documented clinical attacks within the last 2 years prior to screening, or one clinical attack in the year prior to screening (with no relapse 30 days prior to screening and at baseline)
• Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments
• Expanded disability status scale (EDSS), at screening and baseline, from 0 to 5.5 inclusive
• Documented MRI of brain with abnormalities consistent with MS prior to screening
• Patients requiring symptomatic treatment for MS (e.g., fampridine, cannabis) and/or physiotherapy must be treated at a stable dose during the screening period prior to the initiation of study drug on Day 1 and must have a plan to remain at a stable dose for the duration of study treatment
• For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months (as applicable by the ocrelizumab [Ocrevus] local label) after the final dose of ocrelizumab.
• For female patients without reproductive potential: Females may be enrolled if post menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy).

E.4

Principal exclusion criteria

• History of primary progressive MS at screening
• Any known or suspected active infection at screening or baseline, or any major episode of infection requiring hospitalization or treatment with IV anti microbials within 8 weeks prior to and during screening or treatment with oral anti microbials within 2 weeks prior to and during screening
• History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)
• History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
• Immunocompromised state
• Receipt of a live or live attenuated vaccine within 6 weeks prior to randomization
• Inability to complete an MRI (contraindications for MRI, including but not restricted to, pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, etc.) or contraindication to gadolinium administration
• Contraindications to mandatory pre medications (i.e., corticosteroids and antihistamines) for IRRs, including uncontrolled psychosis for corticosteroids or closed angle glaucoma for antihistamines
• Known presence of other neurologic disorders
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
• Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
• History of or currently active primary or secondary (non-drug related) immunodeficiency
• Pregnant or breastfeeding or intending to become pregnant during the study or 6 or 12 months (as applicable from the local label for ocrelizumab) after final dose of the study drug
• Lack of peripheral venous access
• History of alcohol or other drug abuse within 12 months prior to screening
• Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or five half lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
• Previous use of anti-CD20s is allowed if the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy
• Previous use of mitoxantrone, cladribine, atacicept, and alemtuzumab
• Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label
• If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication. The PD effects of the previous medication must also be considered when determining the required time for washout.
• Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
• Any of previous history transplantation or anti-rejection therapy
• Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
• Systemic corticosteroid therapy within 4 weeks prior to screening
• Positive screening tests for active, latent, or inadequately treated hepatitis B
• Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab
• Any additional exclusionary criterion as per ocrelizumab (Ocrevus) local label, if more stringent than the above

E.5 End points

E.5.1

Primary end point(s)

1. Reduction in cCDP sustained for at least 12 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to Week 120 (Double blind treatment [DBT]) and Week 96 (Open label extension [OLE])

E.5.2

Secondary end point(s)

1. Time to onset of 24 week cCDP (cCDP24)
2. Time to onset of 12-week CDP (CDP12)
3. Time to onset of 24-week CDP (CDP24)
4. Time to >= 20% increase in 12 week confirmed T25FWT
5. Time to >= 20% increase in 24 week confirmed T25FWT
6. Change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29) physical scale at Week 120
7. Percent change in total brain volume from Week 24 to Week 120
8. Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT)
9. Presence, frequency, timing, outcome and severity of AEs, serious adverse events (SAE) and AEs leading to study treatment withdrawal
10. Proportion of patients with AEs and SAEs
11. Incidence and severity of adverse events, with severity determined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
12. Change from baseline in clinical laboratory test results (including hematology, chemistry, Ig levels)
13. Change from baseline in vital signs (including systolic and diastolic blood pressure, pulse rate) following study treatment administration
14. Serum concentration of ocrelizumab at specified timepoints
15. B cell levels in blood (including comparing the degree of B-cell depletion between the doses)
16. Proportion of patients achieving 5 or less B-cells per microliter of blood
17. Proportion of patients achieving 5 or less B-cells per microliter of blood in patients with the high versus low affinity Fcgamma Receptor 3A (FcgR3A) genotype per arm
18. Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study
19. Levels of soluble biomarkers
20. Levels of blood B-cells based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
21. Levels of B or T cell subsets in blood
22. DNA genotype of patients

E.5.2.1

Timepoint(s) of evaluation of this end point

1-5. Up to Week 120 (DBT) and Week 96 (OLE)
6. Baseline to Week 120
7. Week 24 to Week 120
8. Up to Week 120 (DBT) and Week 96 (OLE)
9-11. Up to Week 120 (DBT) and Week 96 (OLE)
12-13. Baseline to Week 120 (DBT) and Week 96 (OLE)
14-17. Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96
18. Week 0, 24, 48, 72, 96
19-22. DBT: Week 0, 2, 12, 24, 48, 72, 96; OLE: Week 0, 48, 96

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

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

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

Yes

E.8.2.3.1

Comparator description

Ocrelizumab approved dose compared to higher dose

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

111

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

Argentina

Australia

Belgium

Brazil

Canada

Czech Republic

Denmark

France

Germany

Greece

Hungary

Israel

Italy

Mexico

Netherlands

New Zealand

Peru

Poland

Portugal

Russian Federation

Spain

Switzerland

Turkey

Ukraine

United Kingdom

United States

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 the study will occur when all patients, who are not being treated with an alternative B cell depleting therapy, have repleted their B cells (i.e., B cell level of the patient has returned to the baseline value or the lower limit of normal, whichever is lower).

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