Multiple Sclerosis
Conditions
Brief summary
This 12-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.
Interventions
DRUGOcrelizumab
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
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age at screening between =/\>10 to \<18 years * 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 * 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 acute disseminated encephalomyelitis (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Exploration Period: Area Under the Concentration Versus Time Curve of Ocrelizumab | Pre-dose 5- 30 minutes and post-dose 30 mins on Days 1, 15 and 169; At any time on Days 29, 57, 85 and 113 | The population PK model was used to simulate concentration-time course and predict individual area under the concentration versus time curve. The data for the PK parameter: area under the concentration versus time curve was collected and analyzed as per body weight range (\<40kg to ≥40 kg). |
| Dose Exploration Period: Maximum Concentration (Cmax) of Ocrelizumab | Pre-dose 5- 30 minutes and post-dose 30 mins on Days 1, 15 and 169; At any time on Days 29, 57, 85 and 113 | The population PK model was used to simulate concentration-time course and predict individual Cmax. The data for the PK parameter: Cmax was collected and analyzed as per body weight range (\<40kg to ≥40 kg). |
| Dose Exploration Period: Levels of CD 19+ B-cell Count in Blood | At Week 24 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Up to 12 years | An AE is untoward medical occurrence in participant administered a pharmaceutical product \& regardless of causal relationship with this treatment. An AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of investigational product, whether or not considered related to investigational product. |
| Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | At Week 24 | — |
| OOE Period: Level of Circulating T Cells and NK Cells | Up to 12 years | — |
| Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | At Week 24 | — |
| OOE Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Up to 12 years | — |
| Developmental Milestones - Growth Velocity: Change in Height | Up to 12 years | — |
| Developmental Milestones: Bone Age Assessment by Wrist/Hand Radiographs | Up to 12 years | — |
| Developmental Milestones: Male and Female Puberty Assessed by Tanner Staging | Up to 12 years | — |
| Developmental Milestones: Age at Menarche, Related With the Female Reproductive Status | Up to 12 years | — |
| Dose Exploration Period: Number of Participants With Shift From Baseline in Non-MS Central Nervous System (CNS) Pathology as Measured by Brain Magnetic Resonance Imaging (MRI) | Up to Week 24 | The change in the non-MS CNS pathology was assessed using MRI scans. |
| OOE Period: Number of Participants With Shift From Baseline in Non-MS CNS Pathology as Measured by Brain MRI | Up to 12 years | — |
| Dose Exploration Period: Levels of Blood Immunoglobulins | At Week 24 | — |
| OOE Period: Levels of Blood Immunoglobulins | Up to 12 years | — |
| Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | At Week 24 | Measurement of antibody titers to common antigens (mumps, rubella, varicella, and Streptococcus pneumoniae \[S. pneumoniae\]) were performed. |
| OOE Period: Number of Participants With Antibody Titers Against Standard Vaccines | Up to 12 years | — |
| Dose Exploration Period: Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab | At Week 24 | — |
| OOE Period: Number of Participants With ADAs to Ocrelizumab | Up to 12 years | — |
Countries
Italy, Poland, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
Participants took part in the study across 12 investigative sites in 3 countries (the United States, Poland, and Italy). This study is still ongoing.
Pre-assignment details
A total of 23 participants with relapsing-remitting multiple sclerosis (RRMS) received ocrelizumab per a weight-based dosing regimen.
Participants by arm
| Arm | Count |
|---|---|
| Ocrelizumab 300 mg Participants who weighed between 25 kg to 40 kg were administered first dose of 300 mg ocrelizumab as two IV infusions given 14 days apart i. e. 2 x 150 mg on Days 1 and 15. Participants who completed the 24-week dose exploration period were eligible to continue ocrelizumab treatment in 264-week OOE period. Ocrelizumab 300 mg was administered as a single IV infusion given 24 weeks apart. | 6 |
| Ocrelizumab 600 mg Participants who weighed 40 kg or more were administered first dose of 600 mg ocrelizumab as two IV infusions given 14 days apart i. e. 2 x 300 mg on Days 1 and 15. Participants who completed the 24-week dose exploration period were eligible to continue ocrelizumab treatment in 264-week OOE period. Ocrelizumab 600 mg was administered as a single IV infusion given 24 weeks apart. | 17 |
| Total | 23 |
Baseline characteristics
| Characteristic | Ocrelizumab 300 mg | Ocrelizumab 600 mg | Total |
|---|---|---|---|
| Age, Continuous | 11.2 years STANDARD_DEVIATION 0.8 | 15.3 years STANDARD_DEVIATION 1.8 | 14.2 years STANDARD_DEVIATION 2.4 |
| Cluster of Differentiation (CD) 19+B cells | 287 cells/microliters (cells/µL) | 234 cells/microliters (cells/µL) | 246 cells/microliters (cells/µL) |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 14 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 16 Participants | 21 Participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Male | 1 Participants | 7 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 17 |
| other Total, other adverse events | 5 / 6 | 17 / 17 |
| serious Total, serious adverse events | 1 / 6 | 4 / 17 |
Outcome results
Primary
Dose Exploration Period: Area Under the Concentration Versus Time Curve of Ocrelizumab
The population PK model was used to simulate concentration-time course and predict individual area under the concentration versus time curve. The data for the PK parameter: area under the concentration versus time curve was collected and analyzed as per body weight range (\<40kg to ≥40 kg).
Time frame: Pre-dose 5- 30 minutes and post-dose 30 mins on Days 1, 15 and 169; At any time on Days 29, 57, 85 and 113
Population: Pharmacokinetic (PK) evaluable population included all participants who were enrolled in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Area Under the Concentration Versus Time Curve of Ocrelizumab | 2187 microgram/milliters*day (µg/mL*day) |
| Body Weight ≥ 40 kg | Dose Exploration Period: Area Under the Concentration Versus Time Curve of Ocrelizumab | 3197 microgram/milliters*day (µg/mL*day) |
Primary
Dose Exploration Period: Levels of CD 19+ B-cell Count in Blood
Time frame: At Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Levels of CD 19+ B-cell Count in Blood | 91.00 cells/µL |
| Body Weight ≥ 40 kg | Dose Exploration Period: Levels of CD 19+ B-cell Count in Blood | 9.00 cells/µL |
Primary
Dose Exploration Period: Maximum Concentration (Cmax) of Ocrelizumab
The population PK model was used to simulate concentration-time course and predict individual Cmax. The data for the PK parameter: Cmax was collected and analyzed as per body weight range (\<40kg to ≥40 kg).
Time frame: Pre-dose 5- 30 minutes and post-dose 30 mins on Days 1, 15 and 169; At any time on Days 29, 57, 85 and 113
Population: PK evaluable population included all participants who were enrolled in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Maximum Concentration (Cmax) of Ocrelizumab | 106 microgram/milliters (µg/mL) |
| Body Weight ≥ 40 kg | Dose Exploration Period: Maximum Concentration (Cmax) of Ocrelizumab | 158 microgram/milliters (µg/mL) |
Secondary
Developmental Milestones: Age at Menarche, Related With the Female Reproductive Status
Time frame: Up to 7 years
Secondary
Developmental Milestones: Bone Age Assessment by Wrist/Hand Radiographs
Time frame: Up to 7 years
Secondary
Developmental Milestones - Growth Velocity: Change in Height
Time frame: Up to 7 years
Secondary
Developmental Milestones: Male and Female Puberty Assessed by Tanner Staging
Time frame: Up to 7 years
Secondary
Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte
Time frame: At Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Lymphocyte | 1.792 10^9 cells/L | Standard Deviation 0.66 |
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Neutrophil | 2.60 10^9 cells/L | Standard Deviation 0.567 |
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Monocyte | 0.328 10^9 cells/L | Standard Deviation 0.151 |
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Leukocyte | 4.87 10^9 cells/L | Standard Deviation 1.35 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Leukocyte | 5.05 10^9 cells/L | Standard Deviation 1.06 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Lymphocyte | 1.668 10^9 cells/L | Standard Deviation 0.507 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Monocyte | 0.343 10^9 cells/L | Standard Deviation 0.114 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte | Neutrophil | 2.857 10^9 cells/L | Standard Deviation 0.762 |
Secondary
Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells
Time frame: At Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | CD3+ Total T cell | 1637.67 cells/microliter (µL) | Standard Deviation 578.5 |
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | CD4+ Helper T cell | 1044.0 cells/microliter (µL) | Standard Deviation 329 |
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | CD8+ Cytotoxic T cell | 441.83 cells/microliter (µL) | Standard Deviation 180.32 |
| Body Weight < 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | NK cells | 266.5 cells/microliter (µL) | Standard Deviation 182.97 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | NK cells | 237.76 cells/microliter (µL) | Standard Deviation 118.63 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | CD3+ Total T cell | 1506.0 cells/microliter (µL) | Standard Deviation 468.68 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | CD8+ Cytotoxic T cell | 532.65 cells/microliter (µL) | Standard Deviation 218.52 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Level of Circulating T Cells and Natural Killer (NK) Cells | CD4+ Helper T cell | 889.18 cells/microliter (µL) | Standard Deviation 252.58 |
Secondary
Dose Exploration Period: Levels of Blood Immunoglobulins
Time frame: At Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Total Immunoglobulin | 11.23 gram/liter (g/L) | Standard Deviation 1.4 |
| Body Weight < 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Immunoglobulin A | 1.27 gram/liter (g/L) | Standard Deviation 0.48 |
| Body Weight < 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Immunoglobulin G | 9.25 gram/liter (g/L) | Standard Deviation 1.2 |
| Body Weight < 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Immunoglobulin M | 0.72 gram/liter (g/L) | Standard Deviation 0.26 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Immunoglobulin M | 0.61 gram/liter (g/L) | Standard Deviation 0.31 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Total Immunoglobulin | 11.86 gram/liter (g/L) | Standard Deviation 2.92 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Immunoglobulin G | 9.73 gram/liter (g/L) | Standard Deviation 2.51 |
| Body Weight ≥ 40 kg | Dose Exploration Period: Levels of Blood Immunoglobulins | Immunoglobulin A | 1.52 gram/liter (g/L) | Standard Deviation 0.61 |
Secondary
Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines
Measurement of antibody titers to common antigens (mumps, rubella, varicella, and Streptococcus pneumoniae \[S. pneumoniae\]) were performed.
Time frame: At Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Mumps | 0 Participants |
| Body Weight < 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Pneumococcal Capsular Polysaccharides | 6 Participants |
| Body Weight < 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Rubella | 0 Participants |
| Body Weight < 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Varicella-Zoster Virus | 0 Participants |
| Body Weight ≥ 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Varicella-Zoster Virus | 0 Participants |
| Body Weight ≥ 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Mumps | 0 Participants |
| Body Weight ≥ 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Rubella | 0 Participants |
| Body Weight ≥ 40 kg | Dose Exploration Period: Number of Participants With Antibody Titers Against Standard Vaccines | Pneumococcal Capsular Polysaccharides | 17 Participants |
Secondary
Dose Exploration Period: Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab
Time frame: At Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis at specified timepoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab | 0 Participants |
| Body Weight ≥ 40 kg | Dose Exploration Period: Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab | 0 Participants |
Secondary
Dose Exploration Period: Number of Participants With Shift From Baseline in Non-MS Central Nervous System (CNS) Pathology as Measured by Brain Magnetic Resonance Imaging (MRI)
The change in the non-MS CNS pathology was assessed using MRI scans.
Time frame: Up to Week 24
Population: Safety evaluable population included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Body Weight < 40 kg | Dose Exploration Period: Number of Participants With Shift From Baseline in Non-MS Central Nervous System (CNS) Pathology as Measured by Brain Magnetic Resonance Imaging (MRI) | 0 Participants |
| Body Weight ≥ 40 kg | Dose Exploration Period: Number of Participants With Shift From Baseline in Non-MS Central Nervous System (CNS) Pathology as Measured by Brain Magnetic Resonance Imaging (MRI) | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
An AE is untoward medical occurrence in participant administered a pharmaceutical product & regardless of causal relationship with this treatment. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of investigational product, whether or not considered related to investigational product.
Time frame: Up to 7 years
Secondary
OOE Period: Level of Circulating Lymphocyte, Neutrophil, Monocyte and Leukocyte
Time frame: Up to 5 years
Secondary
OOE Period: Level of Circulating T Cells and NK Cells
Time frame: Up to 5 years
Secondary
OOE Period: Levels of Blood Immunoglobulins
Time frame: Up to 5 years
Secondary
OOE Period: Number of Participants With ADAs to Ocrelizumab
Time frame: Up to 5 years
Secondary
OOE Period: Number of Participants With Antibody Titers Against Standard Vaccines
Time frame: Up to 5 years
Secondary
OOE Period: Number of Participants With Shift From Baseline in Non-MS CNS Pathology as Measured by Brain MRI
Time frame: Up to 5 years