E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-remitting multiple sclerosis (MS) |
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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) |
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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 |
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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 |
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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 characterize the ocrelizumab pharmacokinetic (PK) profile in children and adolescents •To evaluate relationship between drug exposure and pharmacodynamic (PD) (CD19+ B-cell count) in children and adolescents
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E.2.2 | Secondary objectives of the trial |
•To evaluate safety of ocrelizumab in children and adolescents •To assess anti-drug antibody (ADA) development to ocrelizumab
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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 at screening between >= 10 and < 18 years - Body weight >= 25 kg Note: enrollment of patients with a body weight >= 40 kg is closed. - Children and adolescents must have received all childhood required vaccinations as per local/national recommendations for childhood vaccination against infectious diseases calendar of immunization - For female patients of childbearing potential must agree to either remain completely abstinent or use two methods of contraception including at least one method with a failure rate of < 1% per year, during the treatment period and for at least 24 weeks after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required
Inclusion Criteria Related to Pediatric MS: - Diagnosis of relapsing-remitting multiple sclerosis (RRMS) in accordance with the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for pediatric MS, Version 2012, and McDonald criteria 2017 - Expanded Disability Status Scale (EDSS) at screening: 0−5.5, inclusive - Patients naïve to prior disease-modifying therapy (DMT) or patients who have had less than a total of 6 months of DMT within the past 1 year must have one of the following: o At least two relapses in the last 2 years, with at least one relapse experienced in the previous year o At least two relapses in the last 2 years and >= 1 Gd-enhancing lesion(s) (silent or not) on T1-weighted brain MRI at any time within the previous year o At least one relapse in the previous year and >= 1 Gd-enhancing lesion(s) on T1-weighted brain MRI at any time within the last year - Patients who have had at least 6 contiguous months of DMT within the past 1 year must have evidence of disease activity occurring after the full 6-month course of treatment, that is, at least one relapse or >= 1 Gd-enhancing lesion(s) on a T1-weighted brain MRI |
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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, including, but not limited to, acute disseminated encephalomyelitis, and neuromyelitis optica or neuromyelitis optica spectrum disorders and any neurologic, somatic, or metabolic condition that could interfere with brain function or normal cognitive or neurological development - Patients that are aquaporin 4 positive and myelin oligodendrocyte glycoprotein (MOG) antibody positive are not eligible to participate in the study - In case of an ADEM-like appearance of the first MS attack, a second attack with clear MS-like features is required. - Significant or uncontrolled somatic diseases or any other significant condition that may preclude patient from participating in the study - Known active bacterial, viral, fungal, mycobacterial infection, or other infection, excluding fungal infection of nail beds - Infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks prior to baseline visit or oral anti-infective agents within 2 weeks prior to baseline visit - History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis) - Receipt of a live or live-attenuated vaccine within 6 weeks prior to treatment allocation. The patient's vaccination record and a need for immunization should be carefully reviewed - History or laboratory evidence of coagulation disorders - Peripheral venous access that precludes IV administration and venous blood sampling as required per study protocol - Inability to complete a magnetic resonance imaging (MRI) scan - Teeth braces interfering with MRI acquisition - History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured) - Currently active alcohol or drug abuse or history of alcohol or drug abuse
Exclusions Related to Medications: - History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal antibody (mAbs) or known hypersensitivity to any component of ocrelizumab solution - Contraindications to or intolerance of oral or IV corticosteroids, antihistaminics, or antipyretics according to the country label - Treatment with any investigational agent within 24 weeks of screening or 5 half-lives, whichever is longer - 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 treatment allocation - Treatment with teriflunomide within 24 weeks prior to treatment allocation - Treatment with fingolimod within 6 weeks prior to treatment allocation and lymphocyte count < lower limit of normal (LLN) for age- and sexspecific reference range treatment with any other S1P receptor modulator (e.g., BAF312/siponimod) within 24 weeks prior to treatment allocation - Treatment with dimethyl fumarate within 4 weeks prior to treatment allocation and lymphocyte count < LLN for age- and sex-specific reference range - Treatment with IVIg within 12 weeks prior to treatment allocation - Treatment with plasmapheresis within 4 weeks prior to treatment allocation - Systemic corticosteroid therapy within 7 days prior to treatment allocation
Exclusions Related to Laboratory Findings: - Positive serum beta-human chorionic growth hormone (β-hCG) measured at screening or positive pregnancy test prior to the first infusion of ocrelizumab - Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA polymerase chain reaction [PCR]) or hepatitis C antibody (HepCAb) - Positive rapid plasma reagin if confirmed by microhemagglutination assay or fluorescent treponemal antibody absorption test - Percentage of CD4 < 30% (central laboratory age-specific reference range %CD4: 35%−57%) - AST or ALT levels >= 2.0 times the upper limit of normal (ULN) (value as per central laboratory) for age- and sex-specific reference range - Levels of serum IgG 18% and IgM 8% below the LLN (value as per central laboratory) for age- and sex-specific reference range - Absolute Neutrophil Count < 1.5 × 103/L - Lymphocyte count below the LLN (value as per central laboratory) for age- and sex-specific reference range |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Serum concentration of ocrelizumab 2. Levels of CD19+ B-cell count in blood
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Occurrence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v54.0 2. Change from baseline in vital signs 3. Change from baseline in clinical laboratory test results 4. Level of circulating B cells, T cells, natural killer cells, and other leukocytes 5. Developmental milestones (e.g., growth, bone age, age at menarche, Tanner staging) 6. Non-MS CNS pathology as measured by brain MRI scans 7. Levels of blood immunoglobulins 8. Antibody titers against standard vaccines 9. Presence of ADAs during the study relative to the presence of ADAs at baseline |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity and Exploratory |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Mexico |
United States |
Italy |
Poland |
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E.8.7 | Trial has a data monitoring committee | No |
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
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The end of study is defined as either the last patient, last visit (LPLV) of the study or the LPLV in the SFU period or B-cell monitoring period of the SFU period, whichever is later, or when the Sponsor decides to discontinue the study or development program in pediatric MS. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 9 |
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 | 9 |