A Study of Ocrelizumab in Children and Adolescents With Relapsing-Remitting Multiple Sclerosis

Study Overview
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Brief Summary
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This 2-year study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic (PD) effects of ocrelizumab in children and adolescents ages ≥ 10 to ≤ 18 years with relapsing-remitting multiple sclerosis (RRMS). The data from this study will serve to determine the dosing regimen of ocrelizumab to be further investigated in the subsequent Phase III study in children and adolescents.

Official Title
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An Open-Label, Parallel-Group Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of Ocrelizumab in Children and Adolescents With Relapsing-Remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Ocrelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight >/= 25 kg Children and adolescents must have received all childhood required vaccinations Female participants of childbearing potential must agree to either remain completely abstinent or to use reliable means of contraception Diagnosis of relapsing-remitting multiple sclerosis (RRMS) Expanded Disability Status Scale (EDSS) at screening: 0-5.5, inclusive Neurologic stability for >/= 30 days prior to screening, and between screening and baseline Participants naive to prior disease-modifying therapy (DMT) Participants 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 Exclusion Criteria: Known presence or suspicion of other neurologic disorders that may mimic MS, including, but not limited to, acute disseminated encephalomyelitis, 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. Infection requiring hospitalization or treatment with IV anti-infective agents 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 History or laboratory evidence of coagulation disorders Peripheral venous access that precludes IV administration and venous blood sampling Inability to complete a magnetic resonance imaging (MRI) scan History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal antibody (mAbs) or known hypersensitivity to any component of ocrelizumab solution Previous treatment with B-cell-targeted therapies Percentage of CD4 < 30% Absolute Neutrophil Count < 1.5x1000/microliter Lymphocyte count below the lower limit of normal (LLN) for age- and sex-specific reference range

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Participants with a body weight from >/= 25 kg to < 40 kg (with at least 2 participants with a body weight from >/= 25 kg to </= 35 kg) will receive 300 milligram (mg) ocrelizumab | Drug: Ocrelizumab<br>* Ocrelizumab is administered as two infusions of half the dose given 14 days apart for the first dose, then subsequent doses are administered as a single infusion every 24 weeks. Cohort 1: total dose of 300 mg Cohort 2: total dose of 600 mg Cohort 3 and 4: additional dose level(s) may be lower than 300 mg, between 300 mg and 600 mg, or higher than 600 mg, but will be no higher than 1200 mg<br>|
| Experimental: Cohort 2<br>Participants with a body weight >/= 40 kg (with at least 2 participants with a body weight >/= 40 kg but </= 50 kg) will receive 600 mg ocrelizumab | Drug: Ocrelizumab<br>* Ocrelizumab is administered as two infusions of half the dose given 14 days apart for the first dose, then subsequent doses are administered as a single infusion every 24 weeks. Cohort 1: total dose of 300 mg Cohort 2: total dose of 600 mg Cohort 3 and 4: additional dose level(s) may be lower than 300 mg, between 300 mg and 600 mg, or higher than 600 mg, but will be no higher than 1200 mg<br>|
| Experimental: Cohort 3 (optional)<br>Based on PK, PD, safety, and tolerability data analyses of Cohorts 1 and 2, additional participants with a body weight from >/= 25 kg to < 40 kg may be enrolled and receive another dose level of ocrelizumab | Drug: Ocrelizumab<br>* Ocrelizumab is administered as two infusions of half the dose given 14 days apart for the first dose, then subsequent doses are administered as a single infusion every 24 weeks. Cohort 1: total dose of 300 mg Cohort 2: total dose of 600 mg Cohort 3 and 4: additional dose level(s) may be lower than 300 mg, between 300 mg and 600 mg, or higher than 600 mg, but will be no higher than 1200 mg<br>|
| Experimental: Cohort 4 (optional)<br>Based on PK, PD, safety, and tolerability data analyses of Cohorts 1 and 2, additional participants with a body weight >/= 40 kg may be enrolled and receive another dose level of ocrelizumab | Drug: Ocrelizumab<br>* Ocrelizumab is administered as two infusions of half the dose given 14 days apart for the first dose, then subsequent doses are administered as a single infusion every 24 weeks. Cohort 1: total dose of 300 mg Cohort 2: total dose of 600 mg Cohort 3 and 4: additional dose level(s) may be lower than 300 mg, between 300 mg and 600 mg, or higher than 600 mg, but will be no higher than 1200 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of Ocrelizumab |  | 6 months, Up to 5 years | 
| Levels of CD19+ B-cell Count in Blood |  | 6 months, Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with Adverse Events | Severity of adverse events is determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | 6 months, Up to 5 years | 
| Level of Circulating White Blood Cells (WBC) | WBC include B cells, T cells, natural killer (NK) cells and other leukocytes | 6 months, Up to 5 years | 
| Developmental Milestones - Growth velocity: Height. Change in height measured in centimeters (cm) |  | 6 months, Up to 5 years | 
| Developmental Milestones: Bone age assessment by wrist/hand radiographs | Bone age should be reported according to the Greulich and Pyle Atlas (Greulich and Pyle, 1959) | 6 months, Up to 5 years | 
| Developmental Milestones: Male and female puberty assessed by Tanner staging | Tanner stages (stages 1 to 5) (Tanner, 1986) | 6 months, Up to 5 years | 
| Developmental Milestones: Age at menarche, related with the female reproductive status | This milestone is recorded as date of menarche (day, month, year) | 6 months, Up to 5 years | 
| Non-MS Central Nervous System (CNS) Pathology as Measured by Brain Magnetic Resonance Imaging (MRI) |  | 6 months, Up to 5 years | 
| Levels of Blood Immunoglobulins |  | 6 months, Up to 5 years | 
| Antibody Titers Against Standard Vaccines | Measurement of antibody titers to common antigens (mumps, rubella, varicella, S. pneumoniae) | 6 months, Up to 5 years | 
| Percentage of Participants with Anti-Drug Antibodies (ADAs) to Ocrelizumab |  | 6 months, Up to 5 years |