Clinical Trials Register

Summary
EudraCT Number:	2020-005448-48
Sponsor's Protocol Code Number:	CN42097
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-05
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

Czechia - SUKL

A.2

EudraCT number

2020-005448-48

A.3

Full title of the trial

A PHASE III, NON-INFERIORITY, RANDOMIZED, OPEN-LABEL, PARALLEL GROUP, MULTICENTER STUDY TO INVESTIGATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND RADIOLOGICAL AND CLINICAL EFFECTS OF SUBCUTANEOUS OCRELIZUMAB VERSUS INTRAVENOUS OCRELIZUMAB IN PATIENTS WITH MULTIPLE SCLEROSIS

RANDOMIZOVANÉ, OTEVŘENÉ, MULTICENTRICKÉ KLINICKÉ HODNOCENÍ NON-INFERIORITY, S PARALELNÍMI SKUPINAMI, FÁZE III, ZKOUMAJÍCÍ FARMAKOKINETIKU, FARMAKODYNAMIKU, BEZPEČNOST, RADIOLOGICKÉ A KLINICKÉ ÚČINKY OCRELIZUMABU PODÁVANÉHO SUBKUTÁNNĚ OPROTI OCRELIZUMABU PODÁVANÉMU INTRAVENÓZNĚ U PACIENTŮ S ROZTROUŠENOU SKLERÓZOU

A.3.1

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

A Study to Investigate the Pharmacokinetics, Pharmacodynamics, Safety and Radiological and Clinical Effects of Subcutaneous (SC) Ocrelizumab versus Intravenous (IV) Ocrelizumab in Patients with Multiple Sclerosis

KLINICKÉ HODNOCENÍ ZKOUMAJÍCÍ FARMAKOKINETIKU, FARMAKODYNAMIKU, BEZPEČNOST, RADIOLOGICKÉ A KLINICKÉ ÚČINKY OCRELIZUMABU PODÁVANÉHO SUBKUTÁNNĚ OPROTI OCRELIZUMABU PODÁVANÉMU INTRAVENÓZNĚ U PACIENTŮ S ROZTROUŠENOU SKLERÓZOU

A.4.1

Sponsor's protocol code number

CN42097

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 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. Hoffman-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.5.6	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	ocrelizumab
D.3.2	Product code	RO4964913
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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	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	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
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/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

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)

E.1.1.1

Medical condition in easily understood language

Multiple sclerosis is a long-term disease that attacks the central nervous system, affecting the brain, spinal cord, and optic nerves.

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.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10080700
E.1.2	Term	Relapsing 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 demonstrate pharmacokinetics (PK) non-inferiority of the SC formulation of ocrelizumab in patients with MS

E.2.2

Secondary objectives of the trial

• To determine the maximum serum concentration (Cmax) of ocrelizumab SC in patients with MS
• To evaluate the radiological effects of ocrelizumab SC compared with ocrelizumab IV in patients with MS
• To evaluate and compare the safety profile after administration of ocrelizumab SC versus ocrelizumab IV and to assess the safety of ocrelizumab SC at the selected dose in patients with MS
• To evaluate the immune response to ocrelizumab SC and IV, and rHuPH0
• To evaluate the effect of ocrelizumab SC compared with IV ocrelizumab on the pharmacodynamics (PD) marker for the mechanism of action of ocrelizumab (i.e. B cell depletion)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Diagnosis of primary progressive multiple sclerosis (PPMS) or relapsing multiple sclerosis (RMS) according to the revised McDonald 2017 criteria
• Age 18-65 years, inclusive, at time of signing Informed Consent Form
• Ability to comply with the study protocol and schedule of protocol assessments, in the investigator's judgment
• Expanded disability status scale (EDSS) score, 0-6.5, inclusive, at screening.
• Neurological stability for >=30 days prior to both screening and baseline
• Disease duration from onset of MS symptoms of less than 15 years for patients with EDSS score <2.0 at screening
• Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for 6 months or 12 months (as applicable by the ocrelizumab IV [Ocrevus] local label) after the final dose of ocrelizumab
• Female patients without reproductive potential 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

• Any known or suspected active infection at screening or baseline (except nailbed infections), 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 attenuated vaccine within 6 weeks prior to randomization
• Inability to complete an MRI or contraindication to gadolinium administration
• Contraindications to mandatory pre-medications (i.e., corticosteroids and antihistamines) for infusion-related reaction (IRRs), including closed angle glaucoma for antihistamines
• Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
• Any concomitant disease that may require chronic treatment with systemic corticosteroids (e.g., mineralocorticoids and glucocorticoids) 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 and 6 or 12 months (as applicable by the ocrelizumab [Ocrevus] local label) after last administration 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 or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS
• Patients who have previously received anti-CD20s (including ocrelizumab) if the last treatment was less than 2 years before screening, and/or if B-cell count is below lower limit of normal, and/or the discontinuation of the treatment was due to safety reasons or lack of efficacy
• Previous treatment with cladribine, atacicept, and alemtuzumab
• Previous treatment with fingolimod, siponimod, ponesimod, or ozanimod within 6 weeks of baseline
• Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
• Previous treatment with natalizumab within 4.5 months of baseline
• Treatment with mitoxantrone within 2 years prior to baseline visit or evidence of cardiotoxicity following mitoxantrone use or a cumulative lifetime dose of more than 60 milligrams per meter square (mg/m^2)
• 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 5 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 previous history of transplantation or anti-rejection therapy
• Treatment with IV immunoglobulin (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. Serum ocrelizumab area under the concentration-time curve (AUC[w1-12]) after SC administration compared to IV infusion from Day 1 to Week 12

E.5.1.1

Timepoint(s) of evaluation of this end point

1. At Week 1 (Days 1, 2, 3, 5, 7, and 10), Weeks 2, 4, 8 and 12

E.5.2

Secondary end point(s)

1. Maximum serum concentration (Cmax) of ocrelizumab SC in patients with MS
2. Total number of T1Gd+ lesions as detected by brain magnetic resonance imaging (MRI) at Weeks 8 and 24
3. Total number of new or enlarging T2 lesions as detected by brain MRI at Weeks 12 and 24 relative to the previous scan
4. Incidence and severity of adverse events, with severity determined according to the national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0
5. Change from baseline in targeted vital signs
6. Change from baseline in targeted clinical laboratory test results
7. Incidence of treatment-emergent antidrug antibodies (ADAs) to ocrelizumab after SC or IV administration relative to the presence of ADAs at baseline
8. Relationship between ADA status to ocrelizumab and pharmacokinetics, pharmacodynamics, and safety
9. Incidence of treatment-emergent antibodies to rHuPH20 after SC administration relative to the presence at baseline
10. Relationships between antibodies to rHuPH20 and safety
11. Percentage of patients achieving CD19+ B cell level <5 cells/microliter at Weeks 12 and 24

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At Weeks 1, 2, 4, 8, 12, 16, 24 and 48
2. At Weeks 8 and 24
3. At Weeks 12 and 24
4. Up to approximately 48 Weeks
5. Baseline (Day 1), Weeks 2, 12, 24, 48 and safety follow up visit (every 24 weeks until 28 weeks after the last dose)
6. Baseline (Day 1), Weeks 12, 22, 46 and safety follow up visit (every 24 weeks until 28 weeks after the last dose)
7-10. Baseline (Day 1), Weeks 24, 48 and safety follow up visit (every 24 weeks until 28 weeks after the last dose)
11. At Weeks 12 and 24

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

immunogenicity, radiological and clinical effects of SC administration.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ocrelizumab, Concentrate for Solution for Infusion, 300mg

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

New Zealand

United States

France

Spain

Czechia

Italy

Russian Federation

Turkey

Ukraine

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

LVLS

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:

232

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

200

F.4.2.2

In the whole clinical trial

232

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)

Protocol Section 4.3.4: The Roche Global Policy on Continued Access to Investigational Medicinal Product is available at the following website:
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

2022-03-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-19

P. End of Trial
P.	End of Trial Status	Ongoing

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