Clinical Trials Register

Summary
EudraCT Number:	2020-004128-41
Sponsor's Protocol Code Number:	WN42086
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-12-10
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-004128-41

A.3

Full title of the trial

A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY STUDY TO EVALUATE SAFETY AND EFFICACY OF OCRELIZUMAB IN COMPARISON WITH FINGOLIMOD IN CHILDREN AND ADOLESCENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS

A.3.1

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

A Study to Evaluate Safety and Efficacy of Ocrelizumab in Comparison with Fingolimod in Children and Adolescents with Relapsing-Remitting Multiple Sclerosis

A.4.1

Sponsor's protocol code number

WN42086

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/493/2020

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.5.6	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.3.4	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.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	Gilenya
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	United States
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fingolimod
D.3.9.1	CAS number	162359-55-9
D.3.9.2	Current sponsor code	RO7079904
D.3.9.3	Other descriptive name	FINGOLIMOD
D.3.9.4	EV Substance Code	SUB31908
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	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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
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
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsing-Remitting Multiple Sclerosis

E.1.1.1

Medical condition in easily understood language

Multiple sclerosis is a disabling disease of brain and spinal cord that disrupts flow of information within brain, characterized by flare-ups with periods of remission in between (relapsing remitting)

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	10063399
E.1.2	Term	Relapsing-remitting 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 non-inferiority of ocrelizumab compared with fingolimod, based on Protocol-defined annualized relapse rate (ARR)

E.2.2

Secondary objectives of the trial

• To demonstrate non-inferiority of ocrelizumab compared with fingolimod based on the number of new or enlarging T2-hyperintense lesions (T2 lesions) as detected by brain MRI
• To demonstrate the superiority of ocrelizumab versus fingolimod based on the number of new or enlarging T2-hyperintense lesions, number of T1 gadolinium lesions and protocol-defined ARR
• To evaluate the safety of ocrelizumab administered by intravenous (IV) infusion every 24-weeks compared with fingolimod administered once a day (QD) by mouth (PO)
• To assess the pharmacokinetics of ocrelizumab in all children/adolescents enrolled in this study
• To assess the pharmacodynamics in all children/adolescents enrolled in this study, as measured by blood B-cell count
• To evaluate the immune response to ocrelizumab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

General Inclusion Criteria
• Able to comply with the study protocol, in the investigator's judgment
• Age between >10 to <18 years at randomization
• Body weight >=25 kilograms
• Children and adolescents must have received all childhood vaccinations as per local and/or national recommendations for childhood vaccination against infectious diseases
• Female patients of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 24 weeks after the final dose of ocrelizumab/ocrelizumab placebo and for 2 months after the final dose of fingolimod/fingolimod placebo
Inclusion Criteria Related to Pediatric Multiple Sclerosis
• Diagnosis of relapsing-remitting multiple sclerosis (RRMS) in accordance with the international pediatric multiple sclerosis study group (IPMSSG) criteria for pediatric MS, Version 2012, or McDonald criteria 2017 (or the most current revision of the IPMSSG criteria or McDonald criteria at the time of study start)
• Confirmation of the diagnosis of Pediatric RRMS by the Independent Review of Eligibility Committee prior to randomization
• Expanded disability status scale (EDSS) at screening: 0-5.5, both inclusive
• Neurologic stability for >=30 days prior to screening, and between screening and Day 1
• At least one relapse during the year prior to screening or two relapses in the previous two years prior to screening or evidence of at least one Gd enhancing lesion on MRI within 6 months prior to randomization (including screening MRI)

E.4

Principal exclusion criteria

Exclusions Related to General Health
• Pregnancy or lactation
• Known presence or suspicion of other neurologic disorders that may mimic MS
• Aquaporin-4 positive and/or myelin oligodendrocyte glycoprotein antibody positive at screening
• Clinical or laboratory findings at first presentation not typically for MS
• Abnormal findings in the cerebrospinal fluid at first presentation
• Atypical magnetic resonance imaging (MRI) findings
• Significant uncontrolled somatic diseases or any other significant condition
• Known active bacterial, viral, fungal, mycobacterial infection, or other infection
• Infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks prior to Day 1 visit or oral anti-infective agents within 2 weeks prior to Day 1 visit
• History or known presence of recurrent or chronic infection
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to treatment allocation
• History or laboratory evidence of clinically significant coagulation disorders
• Peripheral venous access that precludes IV administration and venous blood sampling
• Inability to complete MRI scan
• Teeth braces interfering with MRI acquisition
• History of cancer
• Currently active or history of alcohol or drug abuse
Exclusion Criteria Related to General Health Specific to Fingolimod Treatment
• History of symptomatic bradycardia, recurrent syncope, significant QT prolongation. Patients having risk factors for QT prolongation such as hypokalemia or congenital QT prolongation, and uncontrolled hypertension
• Patients who in the previous 6 months had myocardial infarction, unstable angina pectoris, stroke/transient ischemic attack, decompensated heart failure, or New York Heart Association Class III/IV heart failure
• Patients with severe cardiac arrhythmias
• Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, sick-sinus syndrome or sinoatrial heart block
• Patients with a baseline QTc interval >=500 milliseconds
• Presence of macular edema
• Presence of any pulmonary conditions, as determined by the investigator
• History of any type of epileptic seizure(s) as well as psychogenic non-epileptic seizure(s) during the past 12 months before screening
• Patients with chronic liver or biliary disease, acute or chronic pancreatitis
Exclusion Criteria Related to Medications
• History of a severe allergic or anaphylactic reaction to humanized or murine MAbs or known hypersensitivity to any component of ocrelizumab solution
• Contraindications to or intolerance of oral or IV corticosteroids, antihistamines, or antipyretics
• Treatment with any investigational agent within 24 weeks of screening or 5 half-lives
• Previous treatment with B-cell−targeted therapies
• Any previous treatment with alemtuzumab, anti-CD4, cladribine, mitoxantrone, daclizumab, laquinimod, total body irradiation, or bone marrow transplantation
• Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, or methotrexate within 24 months prior to treatment allocation
• Treatment with natalizumab within 12 months prior to randomization
• Previous treatment with fingolimod
• Treatment with teriflunomide or any other S1P receptor modulator within 24 weeks prior to treatment allocation
• Treatment with dimethyl fumarate within 4 weeks prior to treatment allocation
• Treatment with intravenous immunoglobulin within 12 weeks prior to treatment allocation
• Treatment with plasmapheresis within 4 weeks prior to treatment allocation
• Completion of systemic corticosteroid therapy within 30 days prior to screening
Exclusion Criteria Related to Medications Specific to Fingolimod Treatment
• History of a severe allergic reaction or known hypersensitivity to any component of fingolimod tablet
• Treatment with beta-blockers or calcium-channel blockers
• Patient treated with digoxin, anticholinesteratic agents, pilocarpine
• Anti-arrhythmic drugs of Class Ia and III
Exclusion Criteria Related to Laboratory Findings
• Positive screening tests for serum beta-human chorionic growth hormone (beta-hCG) or hepatitis B or hepatitis B core antibody or hepatitis C antibody or rapid plasma reagin
• Positive serological testing for myelin oligodendrocyte glycoprotein (MOG) antibody, human immunodeficiency virus (HIV), tuberculosis
• Positive pregnancy test
• Negative serological testing for varicella zoster
• CD4: <30%, Serum IgG: 18% below the lower limit of normal (LLN), Serum IgM: 8% below the LLN, Neutrophil Count <1.5*10^3 per microliter, Lymphocyte: below the LLN
• Patients with ALT, AST, Alkaline phosphatase, y-GGT> 2x Upper Limit of Normal range for age

E.5 End points

E.5.1

Primary end point(s)

1. Protocol-defined annualized relapse rate (ARR) (non-inferiority)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to approximately 2 years

E.5.2

Secondary end point(s)

1. Number of new or enlarging T2 lesions as detected by brain MRI during the double-blind period
2. Number of new or enlarging T2 lesions by Week 96 (non-inferiority)
3. Protocol-defined ARR by Week 96 (non-inferiority)
4. Number of T1 gadolinium (Gd) lesions at Week 12
5. Protocol-defined ARR during the double-blind period (superiority)
6. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
7. Change from baseline in targeted vital signs and clinical significant abnormalities in electrocardiogram (ECG) parameters
8. Change from baseline in targeted clinical laboratory test results
9. Concentrations of ocrelizumab at indicated time points
10. Levels of CD19 B-cell count in blood
11. Prevalence of anti-drug antibodies (ADAs) against ocrelizumab at baseline
12. Incidence of ADAs against ocrelizumab during the study

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to approximately 2 years
2-3. At Week 96
4. At Week 12
5. Up to approximately 2 years
6. Up to 48 weeks from the date of last infusion of ocrelizumab
7-8. Baseline to 48 weeks from the date of last infusion of ocrelizumab
9. Weeks 1, 2, 12, 24, 36, 48, 60, 72, 84 and 96
10. Baseline to 48 weeks from the date of last infusion of ocrelizumab
11. At Baseline (Week -8 to -1)
12. Weeks 1, 24, 48, 72, 96; OLE Period: Day 1 of Dose 1 and of all doses afterword’s; Safety Follow up: 12, 36, 60, 84, 108, 132 weeks from the date of last infusion of ocrelizumab

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

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

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

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.8.5

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

Mexico

Serbia

Turkey

Argentina

Austria

Belgium

Brazil

Bulgaria

Canada

Czechia

Denmark

Germany

Greece

Hungary

Italy

Netherlands

Poland

Portugal

Romania

Russian Federation

Spain

Switzerland

Ukraine

United Kingdom

United States

France

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 defined as either the last patient, last visit (LPLV) of the study or the LPLV in the SFU or B-cell monitoring period of the SFU, whichever is later, or when the Sponsor decides to discontinue the study or development program in pediatric MS.

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

Yes

F.1.1

Number of subjects for this age range:

233

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

210

F.1.2

Adults (18-64 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Informed consent for study participation signed by the parents or a legal guardian, with patient assent obtained verbally and when possible, in writing, from all pediatric patients old enough to fully comprehend the assent document

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

115

F.4.2.2

In the whole clinical trial

233

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 does not have any plans to provide ocrelizumab or any other study treatments to patients who have completed the study. The Sponsor may evaluate whether to continue providing ocrelizumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, 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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Connect4Children (C4C)
G.4.3.4	Network Country	United Kingdom

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-12-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-10

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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