| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing-Remitting Multiple Sclerosis |
| Sclerosi multipla recidivante-remittente |
|
| 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) |
| La SM è una mal. invalidante del cerv. e del mid. s. che interrompe il flusso di info. all'interno del cerv., caratterizzata da riacutizzaz. con periodi di remissione interm. (recidivante-remittente) |
|
| 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) |
| • Dimostrare la non inferiorità di ocrelizumab rispetto a fingolimod, sulla base del tasso di recidiva annualizzato (ARR) definito dal protocollo |
|
| 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 |
• Per dimostrare la non inferiorità di ocrelizumab rispetto a fingolimod in base al numero di lesioni iperintense in T2 nuove o in espansione (lesioni in T2) rilevate dalla risonanza magnetica cerebrale
• Dimostrare la superiorità di ocrelizumab rispetto a fingolimod in base al numero di lesioni iperintense in T2 nuove o in espansione, numero di lesioni al gadolinio in T1 e ARR definita dal protocollo
• Valutare la sicurezza di ocrelizumab somministrato per via endovenosa (IV) in infusione ogni 24 settimane rispetto a fingolimod somministrato una volta al giorno (QD) per bocca (PO)
• Per valutare la farmacocinetica di ocrelizumab in tutto bambini/adolescenti arruolati in questo studio
• Per valutare la farmacodinamica in tutti i bambini/adolescenti arruolati in questo studio, misurata dalla conta delle cellule B nel sangue
• Per valutare la risposta immunitaria a 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 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) |
Criteri generali di inclusione
• In grado di rispettare il protocollo di studio, a giudizio dello sperimentatore
• Età compresa tra >10 e <18 anni alla randomizzazione
• Peso corporeo >=25 chilogrammi
• I bambini e gli adolescenti devono aver ricevuto tutte le vaccinazioni per l'infanzia secondo le raccomandazioni locali e/o nazionali per la vaccinazione infantile contro le malattie infettive
• Le pazienti in età fertile devono accettare di rimanere in astinenza (astenersi da rapporti eterosessuali) o utilizzare contraccettivi durante il periodo di trattamento e per almeno 24 settimane dopo la dose finale di ocrelizumab/ocrelizumab placebo e per 2 mesi dopo la dose finale di fingolimod/fingolimod placebo
Criteri di inclusione relativi alla sclerosi multipla pediatrica
• Diagnosi di sclerosi multipla recidivante-remittente (SMRR) in conformità ai criteri del gruppo di studio internazionale sulla sclerosi multipla pediatrica (IPMSSG) per la SM pediatrica, versione 2012 o ai criteri McDonald 2017 (o alla revisione più recente dei criteri IPMSSG o dei criteri McDonald al momento dell'inizio dello studio)
• Conferma della diagnosi di SMRR pediatrica da parte dell'Independent Review of Eligibility Committee prima della randomizzazione
• Scala ampliata dello stato di disabilità (EDSS) allo screening: 0-5,5, entrambi inclusi
• Stabilità neurologica per >=30 giorni prima dello screening e tra lo screening e il Giorno 1
• Almeno una recidiva nell'anno precedente lo screening o due recidive nei due anni precedenti lo screening o evidenza di almeno una lesione potenziante il Gd alla risonanza magnetica entro 6 mesi prima della randomizzazione (inclusa la risonanza magnetica per lo screening) |
|
| 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 nonepileptic 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 |
Criteri generali di inclusione
• In grado di rispettare il protocollo di studio, a giudizio dello sperimentatore
• Età compresa tra >10 e <18 anni alla randomizzazione
• Peso corporeo >=25 chilogrammi
• I bambini e gli adolescenti devono aver ricevuto tutte le vaccinazioni per l'infanzia secondo le raccomandazioni locali e/o nazionali per la vaccinazione infantile contro le malattie infettive
• Le pazienti in età fertile devono accettare di rimanere in astinenza (astenersi da rapporti eterosessuali) o utilizzare contraccettivi durante il periodo di trattamento e per almeno 24 settimane dopo la dose finale di ocrelizumab/ocrelizumab placebo e per 2 mesi dopo la dose finale di fingolimod/fingolimod placebo
Criteri di inclusione relativi alla sclerosi multipla pediatrica
• Diagnosi di sclerosi multipla recidivante-remittente (SMRR) in conformità ai criteri del gruppo di studio internazionale sulla sclerosi multipla pediatrica (IPMSSG) per la SM pediatrica, versione 2012 o ai criteri McDonald 2017 (o alla revisione più recente dei criteri IPMSSG o dei criteri McDonald al momento dell'inizio dello studio)
• Conferma della diagnosi di SMRR pediatrico da parte dell'Independent Review of Eligibility Committee prima della randomizzazione
• Scala ampliata dello stato di disabilità (EDSS) allo screening: 0-5,5, entrambi inclusi
• Stabilità neurologica per >=30 giorni prima dello screening e tra lo screening e il Giorno 1
• Almeno una recidiva nell'anno precedente lo screening o due recidive nei due anni precedenti lo screening o evidenza di almeno una lesione potenziante il Gd alla risonanza magnetica entro 6 mesi prima della randomizzazione (inclusa la risonanza magnetica per lo screening) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Protocol-defined annualized relapse rate (ARR) (non-inferiority) |
| 1. Tasso di recidiva annualizzato (ARR) definito dal protocollo (non inferiorità) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 2 years |
| 1. Fino a circa 2 anni |
|
| 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 |
1. Numero di lesioni T2 nuove o in espansione rilevate dalla risonanza magnetica cerebrale durante il periodo in doppio cieco
2. Numero di lesioni T2 nuove o in espansione entro la settimana 96 (non inferiorità)
3. ARR definito dal protocollo entro la settimana 96 (non inferiorità)
4. Numero di lesioni da gadolinio (Gd) in T1 alla settimana 12
5. ARR definito dal protocollo durante il periodo in doppio cieco (superiorità)
6. Incidenza e gravità degli eventi avversi, con gravità determinata secondo i criteri comuni di terminologia per gli eventi avversi del National Cancer Institute, versione 5.0 (NCI CTCAE v5.0)
7. Variazione dal basale nei segni vitali mirati e anomalie cliniche significative nei parametri dell'elettrocardiogramma (ECG)
8. Variazione rispetto al basale nei risultati dei test di laboratorio clinici mirati
9. Concentrazioni di ocrelizumab ai tempi indicati
10. Livelli di conta delle cellule B CD19 nel sangue
11. Prevalenza di anticorpi anti-farmaco (ADA) contro ocrelizumab al basale
12. Incidenza di ADA contro ocrelizumab durante lo studio |
|
| 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 |
1. Fino a circa 2 anni
2-3. Alla settimana 96
4. Alla settimana 12
5. Fino a circa 2 anni
6. Fino a 48 settimane dalla data dell'ultima infusione di ocrelizumab
7-8. Al basale a 48 settimane dalla data dell'ultima infusione di ocrelizumab
9. Settimane 1, 2, 12, 24, 36, 48, 60, 72, 84 e 96
10. Al basale a 48 settimane dalla data dell'ultima infusione di ocrelizumab
11. Al basale (settimana da -8 a -1)
12. Settimane 1, 24, 48, 72, 96; Periodo OLE: Giorno 1 della Dose 1 e di tutte le dosi successive; Follow-up di sicurezza: 12, 36, 60, 84, 108, 132 settimane dalla data dell'ultima infusione di 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | Information not present in EudraCT |
| 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 |
| Mexico |
| Russian Federation |
| Serbia |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
| Argentina |
| Greece |
|
| 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. |
| La fine dello studio è definita come l'ultimo paziente, l'ultima visita (LPLV) dello studio o l'LPLV nel periodo di monitoraggio dell'SFU o delle cellule B dell'SFU, se successivo, o quando lo Sponsor decide di interrompere lo studio o programma di sviluppo nella SM pediatrica. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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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