| 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 | No |
| 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 | No |
| 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 Pediatric MS Review Committee prior to randomization
• Expanded disability status scale (EDSS) at screening: 0-5.5, both inclusive
• 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 any type of vaccine (e.g., live or live-attenuated vaccine,
non-live) 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 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 within 24 weeks prior to treatment allocation (or within 4 weeks if patients have completed an accelerated washout procedure for teriflunomide (confirmation of drug plasma level of < 0.02mg/L required))
• Treatment with 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 7 days prior to treatment allocation
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
• Medication that may prolong QTc interval and who have relevant risk factors such as hypokalemia or congenital QT prolongation 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. Until the primary analysis, which will be conducted after the last randomized patient has completed 24 weeks |
|
| 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 T1 gadolinium (Gd) lesions at Week 12
3. Protocol-defined ARR during the double-blind period (superiority)
4. 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)
5. Change from baseline in targeted vital signs and clinical significant abnormalities in electrocardiogram (ECG) parameters
6. Change from baseline in targeted clinical laboratory test results
7. Concentrations of ocrelizumab at indicated time points
8. Levels of CD19 B-cell count in blood
9. Prevalence of anti-drug antibodies (ADAs) against ocrelizumab at baseline
10. Incidence of ADAs against ocrelizumab during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Until the primary analysis, which will be conducted after the last randomized patient has completed 24 weeks
2. At Week 12
3. Until the primary analysis, which will be conducted after the last randomized patient has completed 24 weeks
4. Up to 48 weeks from the date of last infusion of ocrelizumab 5-8. Baseline to 48 weeks from the date of last infusion of ocrelizumab
9. At Baseline (Week -8 to -1)
10. Baseline to 48 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 | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | No |
| 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 |
| Switzerland |
| Ukraine |
| Australia |
| Brazil |
| Canada |
| Mexico |
| Russian Federation |
| Serbia |
| Turkey |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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