Multiple Sclerosis
Conditions
Brief summary
The primary objective of Part A is to determine the safety and tolerability of natalizumab administered over 24 weeks in Japanese participants with relapsing-remitting multiple sclerosis (MS). The endpoints for this will include assessment of adverse evetns (AEs), changes in laboratory evaluations, vital signs, Expanded Disability Status Scale (EDSS) scores, and changes in physical and neurological examination findings. The secondary objectives of Part A are to characterize the pharmacokinetics (PK) profile and pharmacodynamics (PD) of natalizumab. The primary objective of Part B is to determine if natalizumab, when compared to placebo, is effective in treating Japanese participants with relapsing-remitting MS, as measured by new active lesions on cranial magnetic resonance imaging (MRI) scans over 24 weeks. New active lesions are the sum of the gadolinium-enhancing (Gd+) lesions and any new or newly-enlarging T2-hyperintense lesions that do not enhance. The primary endpoint is the rate of development of new active lesions over 24 weeks. Secondary objectives of Part B are to determine over 24 weeks whether natalizumab, when compared to placebo, is effective in reducing the frequency of clinical exacerbations, reducing the number of Gd+ lesions, reducing the number of new or newly-enlarging T2-hyperintense lesions on brain MRI scans, increasing the proportion of relapse-free participants, and improving outcomes on visual analog scale (VAS) assessing the participant's global impression of his/her well-being. Additional objectives are to assess the safety and tolerability, the incidence of serum antibodies to natalizumab and the PK profile of natalizumab.
Detailed description
This multicenter study has 2 parts and is designed to provide data in Japanese participants, as required for registration of natalizumab (BG00002) in Japan. Part A will consist of an open-label cohort of 12 participants who will receive 300 mg natalizumab intravenously (IV) every 4 weeks over a 6-month treatment period. Part B will consist of a double-blind, placebo-controlled cohort of approximately 90 participants randomized in a ratio of 1:1 to receive IV infusions of placebo or 300 mg BG00002 every 4 weeks over a 6-month period.
Interventions
DRUGNatalizumab (BG00002)
DRUGPlacebo
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Part A Key Inclusion Criteria: * Must give written informed consent and any authorizations required by local law. * Must have a diagnosis of relapsing-remitting MS, as defined by the revised McDonald criteria 1 through 4 (Polman et al, 2005). All other possible neurologic diagnoses must have been reasonably excluded by means of laboratory and/or imaging studies, in the opinion of the Investigator. * Japanese men and women aged 18 to 65, inclusive, at the time of informed consent. * All male subjects and female subjects of childbearing potential must practice effective contraception during the study and be able to continue contraception for 12 weeks after their last dose of study treatment. * Must have an Expanded Disability Status Scale (EDSS) score between 0.0 and 6.0, inclusive. * Must have experienced at least 1 medically documented clinical exacerbation within 12 months of enrollment. * Must be willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including interferon beta \[IFNβ\] and chronic systemic corticosteroids) for the duration of the study. * Must have a baseline MRI, conducted within 35 calendar days prior to enrollment. Key
Exclusion criteria
* Diagnosis or history of neuromyelitis optica (NMO), e.g., a long spinal lesion extending over 3 or more vertebral bodies was detected, or the subject has a history of positive tests for anti-aquaporin-4 (anti-AQP4) antibodies. * The subject is considered by the Investigator to be immunocompromised, based on medical history, physical examination, laboratory testing, or prior immunosuppressive or immunomodulating treatment. * An MS exacerbation (relapse) within 30 days prior to enrollment or, in the opinion of the Investigator, the subject has not stabilized from a relapse prior to enrollment at Week 0. * History of malignancy. * Known history of, or positive test result for human immunodeficiency virus (HIV) infection. * Known history of or positive test result for hepatitis C virus or hepatitis B virus within the year prior to enrollment. * History of severe allergic or anaphylactic reactions or known drug hypersensitivity. * A clinically significant infectious illness within 30 days prior to enrollment. * Abnormal liver function test results at screening: alanine aminotransferase (ALT), or aspartate aminotransferase (AST) \>2 times of the upper limit of normal (ULN) or bilirubin \>1.5 times of the ULN during screening. * Previous treatment with natalizumab, any murine protein, or any other therapeutic monoclonal antibody. * Any prior treatment with any of the following medications: total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination. * Treatment with immunosuppressant medications, e.g., azathioprine, cyclophosphamide, methotrexate, and fingolimod within 6 months prior to enrollment, or mitoxantrone and cyclosporine within 12 months prior to enrollment. * Treatment with any of the following medications or procedures within 6 months prior to enrollment: intravenous immunoglobulin (IVIg), plasmapheresis, or cytapheresis. * Treatment with immunomodulatory medications (including IFNβ and glatiramer acetate \[GA\]) within 2 weeks of enrollment. * Treatment with any of the following medications within 30 days of enrollment: intravenous corticosteroid treatment, systemic corticosteroid treatment, 4-aminopyridine or related products. * Participation in any other investigational treatment within the 6 months prior to enrollment or concurrent with this study. Part B Key Inclusion Criteria: * Must give written informed consent and any authorizations required by local law. * Must have a diagnosis of relapsing-remitting MS, as defined by the revised McDonald criteria 1 through 4 (Polman et al, 2005). All other possible neurologic diagnoses must have been reasonably excluded by means of laboratory and/or imaging studies, in the opinion of the Investigator. * Japanese men and women aged 18 to 65, inclusive, at the time of informed consent. * All male subjects and female subjects of childbearing potential must practice effective contraception during the study and be able to continue contraception for 12 weeks after their last dose of study treatment. * Must have an EDSS score between 0.0 and 5.5, inclusive. * Must have experienced at least 1 medically documented clinical exacerbation within 12 months of enrollment. * Must be willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including IFNβ and chronic systemic corticosteroids) for the duration of the study. * Prior to enrollment all subjects must have: a screening MRI, or documentation of an MRI within the subject's medical record within 1 year of the screening visit, which reveals 3 or more T2 hyperintense lesions consistent with MS, and a baseline MRI, conducted within 7 calendar days prior to enrollment, which reveals at least 1 MRI lesion consistent with MS. Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Adverse Events (AEs) | Baseline (Week 0) to Week 24 | AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. Serious AE (SAE)=any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, was a life threatening event; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; or any other medically important event that, in the opinion of the Investigator, may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as related or not related; severity was categorized as mild, moderate, or severe. |
| Part B: Rate of Development of New Active Lesions Over 24 Weeks | Baseline (Week 0) to Week 24 | New active lesions were the sum of the gadolinium-enhancing (Gd+) lesions and any new or newly enlarging T2 hyperintense lesions that did not enhance as seen on cranial magnetic resonance imaging (MRI) scans. The rate is calculated for each participant as the ordinary least squares slope of the cumulative new active lesions over time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Adjusted Annualized Relapse Rate Over 24 Weeks | Week 24 | The frequency of clinical exacerbations over 24 weeks was assessed using an annualized relapse rate that was calculated for each treatment group as the total number of relapses experienced in the group over the 24 weeks of treatment, divided by the total number of subject-years followed in the study. Obtained from a Poisson regression model, adjusted for the baseline relapse rate. |
| Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks | Baseline (Week 0) to Week 24 | — |
| Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks | Baseline (Week 0) to Week 24 | — |
| Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Baseline (Week 0) to Week 24 | Participants were categorized as relapse free=yes, relapse free=no, or relapse free=unknown. The category of relapse free=unknown includes participants who withdrew from the study and did not experience a relapse prior to withdrawal. |
| Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Baseline (Week 0), Week 12, Week 24 | The participant's self-rating of global impression of his/her well-being was assessed with a VAS. The instrument ranged from 0 to 100 (mm), where a score of 0 denoted 'poor' and a score of 100 denoted 'excellent.' |
| Part A: Concentration of Natalizumab in Serum | Week 0: pre-dose, post-dose and 2, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose; Weeks 4, 8, 12, and 16: pre-dose; Week 20 pre-dose, post-dose, and 2, 24, 48 and 96 hours post-dose; 7, 14, 21, and 28 days post-dose | The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA). |
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Cmax | Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose | Observed maximum concentration (Cmax) was calculated using non-compartmental methods. |
| Part B: Concentration of Natalizumab in Serum | Baseline (Week 0), Week 12, Week 24 | The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA). |
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2 | Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose | Time to maximum concentration (Tmax) and half-life (T1/2) were calculated using non-compartmental methods. |
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Vd | Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose | Volume of distribution (Vd) was calculated using non-compartmental methods. |
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL | Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose | Systemic clearance (CL) was calculated using non-compartmental methods. |
| Part B: Status of Serum Antibodies to Natalizumab | Baseline (Week 0) and Week 24 | Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks. |
| Part B: Number of Participants With Adverse Events (AEs) | Baseline (Week 0) to Week 24 | AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. Serious AE (SAE)=any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, was a life threatening event; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; or any other medically important event that, in the opinion of the Investigator, may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as related or not related; severity was categorized as mild, moderate, or severe. |
| Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Pre-dose; 4 hours post-dose; 7, 14, 21, and 28 days post-dose; Weeks 8, 12, and 16: pre-dose; Week 20: pre-dose; 4 hours post-dose; 7, 14, 21, and 28 days post-dose | Pharmacodynamic activity was assessed by measuring the degree of saturation by BG00002 of the very late antigen-4 (VLA-4, also known as α4β1 integrin) receptor on peripheral blood mononuclear cell populations. This was accomplished by staining cells with phycoerythrin-conjugated anti-human immunoglobulin G4 (IgG4) antibody (hIgG4-PE) to label the cell-bound BG00002, followed by flow cytometric detection and quantification. |
| Part A: Summary of Lymphocyte Counts Over Time | Baseline [Week 0]); 28 days post-dose; Weeks 12, 24, and 32 (follow-up) | — |
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞) | Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose | Area under the curve to the last measurable concentration (AUC\[0-last\]); and area under the curve extrapolated to infinity (0-AUC∞) were calculated using non-compartmental methods. |
| Part B: Cumulative Number of New Active Lesions Over 24 Weeks | Baseline (Week 0) to Week 24 | — |
Countries
Japan
Participant flow
Pre-assignment details
This was a 2-part, multicenter study, each part (open-label, double-blind) comprising discrete cohorts of BG00002-naïve participants.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Natalizumab 300 mg IV infusions of natalizumab (BG00002) over 60 minutes every 4 weeks for 20 weeks | 12 |
| Double-Blind Placebo IV infusions of placebo over 60 minutes every 4 weeks for 20 weeks | 47 |
| Double-Blind Natalizumab 300 mg IV infusions of natalizumab (BG00002) over 60 minutes every 4 weeks for 20 weeks | 47 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
| Overall Study | Other | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Open Label Natalizumab | Double-Blind Placebo | Double-Blind Natalizumab | Total |
|---|---|---|---|---|
| Age, Customized 18 to < 20 years | 0 participants | 2 participants | 0 participants | 2 participants |
| Age, Customized 20 to < 30 years | 1 participants | 8 participants | 9 participants | 18 participants |
| Age, Customized 30 to < 40 years | 6 participants | 24 participants | 18 participants | 48 participants |
| Age, Customized 40 to < 50 years | 3 participants | 10 participants | 16 participants | 29 participants |
| Age, Customized 50 to < 60 years | 1 participants | 3 participants | 3 participants | 7 participants |
| Age, Customized >/= 60 years | 1 participants | 0 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 7 Participants | 32 Participants | 34 Participants | 73 Participants |
| Sex: Female, Male Male | 5 Participants | 15 Participants | 13 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 12 | 32 / 47 | 21 / 47 |
| serious Total, serious adverse events | 2 / 12 | 11 / 47 | 7 / 47 |
Outcome results
Primary
Part A: Number of Participants With Adverse Events (AEs)
AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. Serious AE (SAE)=any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, was a life threatening event; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; or any other medically important event that, in the opinion of the Investigator, may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as related or not related; severity was categorized as mild, moderate, or severe.
Time frame: Baseline (Week 0) to Week 24
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants with an adverse event (AE) | 8 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants with a moderate or severe event | 4 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants with a severe event | 1 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants with an AE related to study drug | 3 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants with a serious event (SAE) | 2 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants with an SAE related to study drug | 1 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants discontinuing treatment due to an AE | 1 participants |
| Open Label Natalizumab | Part A: Number of Participants With Adverse Events (AEs) | Participants withdrawing from study due to an AE | 2 participants |
Primary
Part B: Rate of Development of New Active Lesions Over 24 Weeks
New active lesions were the sum of the gadolinium-enhancing (Gd+) lesions and any new or newly enlarging T2 hyperintense lesions that did not enhance as seen on cranial magnetic resonance imaging (MRI) scans. The rate is calculated for each participant as the ordinary least squares slope of the cumulative new active lesions over time.
Time frame: Baseline (Week 0) to Week 24
Population: Missing new Gd+ or new or newly-enlarging, non-enhancing T2 hyperintense lesions were imputed using linear interpolation between the 2 adjacent non-missing values. For participants who discontinued the study, linear interpolation reduced to last observation carried forward (LOCF) was used for imputing any remaining missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Natalizumab | Part B: Rate of Development of New Active Lesions Over 24 Weeks | 0.352 lesions per week over 24 weeks | Standard Deviation 0.5648 |
| Double-Blind Natalizumab | Part B: Rate of Development of New Active Lesions Over 24 Weeks | 0.058 lesions per week over 24 weeks | Standard Deviation 0.0748 |
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Part A: Concentration of Natalizumab in Serum
The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA).
Time frame: Week 0: pre-dose, post-dose and 2, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose; Weeks 4, 8, 12, and 16: pre-dose; Week 20 pre-dose, post-dose, and 2, 24, 48 and 96 hours post-dose; 7, 14, 21, and 28 days post-dose
Population: Participants who received at least 1 infusion of BG00002 with at least 1 post-baseline assessment of BG00002 serum concentration; n = the number of participants with an assessment at given timepoint. At Weeks 8, 12, and 16, one participant had values less than the lower limit of quantitation (\<LLQ) and was not counted in the n for that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 0: 24 hours post-dose; n=12 | 100.5707 µg/mL | Standard Deviation 26.17036 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 0: pre-dose; n=12 | NA µg/mL | — |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 0: post-dose; n=12 | 119.4550 µg/mL | Standard Deviation 18.86145 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 0: 4 hours post-dose; n=12 | 111.8159 µg/mL | Standard Deviation 18.35129 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 0: 48 hours post-dose; n=12 | 92.5144 µg/mL | Standard Deviation 18.26611 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 0: 96 hours post-dose; n=12 | 73.2038 µg/mL | Standard Deviation 17.02067 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | 7 days post-dose; n=12 | 62.3874 µg/mL | Standard Deviation 16.49046 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | 14 days post-dose; n=12 | 41.2363 µg/mL | Standard Deviation 12.02968 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | 21 days post-dose; n=12 | 30.9994 µg/mL | Standard Deviation 11.45474 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 4: pre-dose; n=12 | 22.5702 µg/mL | Standard Deviation 9.55131 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 8: pre-dose; n=11 | 24.7048 µg/mL | Standard Deviation 15.50352 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 12: pre-dose; n=10 | 27.9105 µg/mL | Standard Deviation 16.06085 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 16: pre-dose; n=10 | 32.9645 µg/mL | Standard Deviation 16.41578 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: pre-dose; n=10 | 36.2724 µg/mL | Standard Deviation 14.51395 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: post-dose; n=10 | 145.5353 µg/mL | Standard Deviation 38.26877 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 4 hours post-dose; n=10 | 137.6666 µg/mL | Standard Deviation 30.47429 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 24 hours post-dose; n=10 | 130.8829 µg/mL | Standard Deviation 30.17375 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 48 hours post-dose; n=10 | 120.0772 µg/mL | Standard Deviation 28.6886 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 96 hours post-dose; n=10 | 103.3549 µg/mL | Standard Deviation 26.94133 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 7 days post-dose; n=10 | 86.2563 µg/mL | Standard Deviation 24.70785 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 14 days post-dose; n=10 | 65.7307 µg/mL | Standard Deviation 24.60531 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 21 days post-dose; n=10 | 52.4002 µg/mL | Standard Deviation 21.41919 |
| Open Label Natalizumab | Part A: Concentration of Natalizumab in Serum | Week 20: 28 days post-dose; n=10 | 35.8368 µg/mL | Standard Deviation 16.33283 |
Secondary
Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC)
Pharmacodynamic activity was assessed by measuring the degree of saturation by BG00002 of the very late antigen-4 (VLA-4, also known as α4β1 integrin) receptor on peripheral blood mononuclear cell populations. This was accomplished by staining cells with phycoerythrin-conjugated anti-human immunoglobulin G4 (IgG4) antibody (hIgG4-PE) to label the cell-bound BG00002, followed by flow cytometric detection and quantification.
Time frame: Pre-dose; 4 hours post-dose; 7, 14, 21, and 28 days post-dose; Weeks 8, 12, and 16: pre-dose; Week 20: pre-dose; 4 hours post-dose; 7, 14, 21, and 28 days post-dose
Population: Participants in Part A who received a dose of BG00002 and had at least 1 post-baseline assessment of α4-integrin saturation; n=participants with an assessment at timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Pre-dose (n=12) | 6.282 percent saturation | Standard Deviation 1.645 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | 4 hours post-dose (n=12) | 88.371 percent saturation | Standard Deviation 4.6811 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | 7 days post-dose (n=12) | 85.491 percent saturation | Standard Deviation 7.1019 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | 14 days post-dose (n=12) | 77.929 percent saturation | Standard Deviation 6.8396 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | 21 days post-dose (n=12) | 71.362 percent saturation | Standard Deviation 6.8992 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | 28 days post-dose (n=12) | 69.742 percent saturation | Standard Deviation 7.3283 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 8: pre-dose (n=11) | 64.057 percent saturation | Standard Deviation 20.2412 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 12: pre-dose (n=11) | 60.615 percent saturation | Standard Deviation 22.0351 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 16: pre-dose (n=10) | 75.485 percent saturation | Standard Deviation 4.4088 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 20: pre-dose (n=10) | 75.314 percent saturation | Standard Deviation 7.1022 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 20: 4 hours post-dose (n=10) | 88.859 percent saturation | Standard Deviation 5.023 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 20: 7 days post-dose (n=10) | 83.575 percent saturation | Standard Deviation 5.9416 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 20: 14 days post-dose (n=10) | 80.376 percent saturation | Standard Deviation 5.4459 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 20: 21 days post-dose (n=10) | 80.842 percent saturation | Standard Deviation 5.5828 |
| Open Label Natalizumab | Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Week 20: 28 days post-dose (n=10) | 70.897 percent saturation | Standard Deviation 4.5757 |
Secondary
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞)
Area under the curve to the last measurable concentration (AUC\[0-last\]); and area under the curve extrapolated to infinity (0-AUC∞) were calculated using non-compartmental methods.
Time frame: Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose
Population: Randomized participants who received at least 1 infusion of BG00002 and had at least 1 post-baseline assessment of BG00002 serum concentration; n = the number of these participants with an assessment at given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞) | AUC(0-last), Dose 1/Week 0; n=12 | 31574.6 µg*h/mL |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞) | AUC(0-last), Dose 6/Week 20; n=10 | 46094.8 µg*h/mL |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞) | AUC(0-∞), Dose 1/Week 0; n=12 | 43172.6 µg*h/mL |
Secondary
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL
Systemic clearance (CL) was calculated using non-compartmental methods.
Time frame: Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose
Population: Randomized participants who received at least 1 infusion of BG00002 and had at least 1 post-baseline assessment of BG00002 serum concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL | 6.9497 mL/h |
Secondary
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Cmax
Observed maximum concentration (Cmax) was calculated using non-compartmental methods.
Time frame: Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose
Population: Randomized participants who received at least 1 infusion of BG00002 and had at least 1 post-baseline assessment of BG00002 serum concentration; n = the number of these participants with an assessment at given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Cmax | Dose 1/Week 0; n=12 | 119.58 µg/mL |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Cmax | Dose 6/Week 20; n=10 | 144.36 µg/mL |
Secondary
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2
Time to maximum concentration (Tmax) and half-life (T1/2) were calculated using non-compartmental methods.
Time frame: Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose
Population: Randomized participants who received at least 1 infusion of BG00002 and had at least 1 post-baseline assessment of BG00002 serum concentration; n = the number of these participants with an assessment at given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2 | Tmax, Dose 1/Week 0; n=12 | 1.49 hours |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2 | Tmax, Dose 6/Week 20; n=10 | 2.27 hours |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2 | T1/2, Dose 1/Week 0; n=12 | 344.9 hours |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2 | T1/2, Dose 6/Week 20; n=10 | 381.2 hours |
Secondary
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Vd
Volume of distribution (Vd) was calculated using non-compartmental methods.
Time frame: Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose; Dose 6/Week 20 pre-dose, post-dose, and 4, 24, 48 and 96 hours post-dose; 7, 14, and 21 days post-dose
Population: Randomized participants who received at least 1 infusion of BG00002 and had at least 1 post-baseline assessment of BG00002 serum concentration; n = the number of these participants with an assessment at given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Vd | Dose 1/Week 0; n=12 | 3.422 L |
| Open Label Natalizumab | Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Vd | Dose 6/Week 20; n=10 | 3.561 L |
Secondary
Part A: Summary of Lymphocyte Counts Over Time
Time frame: Baseline [Week 0]); 28 days post-dose; Weeks 12, 24, and 32 (follow-up)
Population: Participants in Part A who received a dose of BG00002 and had at least 1 post-baseline assessment of lymphocytes; n=participants with assessment at timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Natalizumab | Part A: Summary of Lymphocyte Counts Over Time | Screening; n=12 | 1708.3 cells/microliter | Standard Deviation 556.71 |
| Open Label Natalizumab | Part A: Summary of Lymphocyte Counts Over Time | Pre-dose; n=12 | 1775.0 cells/microliter | Standard Deviation 534.49 |
| Open Label Natalizumab | Part A: Summary of Lymphocyte Counts Over Time | 28 days Post-dose; n=12 | 3016.7 cells/microliter | Standard Deviation 845.13 |
| Open Label Natalizumab | Part A: Summary of Lymphocyte Counts Over Time | Week 12; n=11 | 3018.2 cells/microliter | Standard Deviation 1112.49 |
| Open Label Natalizumab | Part A: Summary of Lymphocyte Counts Over Time | Week 24; n=10 | 3340.0 cells/microliter | Standard Deviation 939.5 |
| Open Label Natalizumab | Part A: Summary of Lymphocyte Counts Over Time | Week 32 Follow-up; n=2 | 1550.0 cells/microliter | Standard Deviation 70.71 |
Secondary
Part B: Adjusted Annualized Relapse Rate Over 24 Weeks
The frequency of clinical exacerbations over 24 weeks was assessed using an annualized relapse rate that was calculated for each treatment group as the total number of relapses experienced in the group over the 24 weeks of treatment, divided by the total number of subject-years followed in the study. Obtained from a Poisson regression model, adjusted for the baseline relapse rate.
Time frame: Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open Label Natalizumab | Part B: Adjusted Annualized Relapse Rate Over 24 Weeks | 1.727 relapses per year |
| Double-Blind Natalizumab | Part B: Adjusted Annualized Relapse Rate Over 24 Weeks | 0.532 relapses per year |
Secondary
Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS)
The participant's self-rating of global impression of his/her well-being was assessed with a VAS. The instrument ranged from 0 to 100 (mm), where a score of 0 denoted 'poor' and a score of 100 denoted 'excellent.'
Time frame: Baseline (Week 0), Week 12, Week 24
Population: n = all participants with an assessment at baseline and given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Natalizumab | Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Baseline; n=47, 47 | 63.5 units on a scale | Standard Deviation 23.66 |
| Open Label Natalizumab | Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Change from Baseline at Week 12; n=47, 47 | -4.9 units on a scale | Standard Deviation 24.89 |
| Open Label Natalizumab | Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Change from Baseline at Week 24; n=44, 46 | -2.9 units on a scale | Standard Deviation 25.2 |
| Double-Blind Natalizumab | Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Baseline; n=47, 47 | 69.6 units on a scale | Standard Deviation 20.7 |
| Double-Blind Natalizumab | Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Change from Baseline at Week 12; n=47, 47 | -5.3 units on a scale | Standard Deviation 21.49 |
| Double-Blind Natalizumab | Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS) | Change from Baseline at Week 24; n=44, 46 | -4.8 units on a scale | Standard Deviation 17.4 |
Comparison: Change from Baseline to Week 12p-value: 0.729ANCOVA
Comparison: Change from Baseline at Week 24p-value: 0.942ANCOVA
Secondary
Part B: Concentration of Natalizumab in Serum
The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA).
Time frame: Baseline (Week 0), Week 12, Week 24
Population: Randomized participants who received at least 1 infusion of BG00002 and had at least 1 post-baseline assessment of BG00002 serum concentration; n = the number of these participants with an assessment at given timepoint. Participants with values \<LLQ were not counted in the n for that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open Label Natalizumab | Part B: Concentration of Natalizumab in Serum | Baseline; n=47 | NA µg/mL | — |
| Open Label Natalizumab | Part B: Concentration of Natalizumab in Serum | Week 12; n=45 | 32.6475 µg/mL | Standard Deviation 14.68246 |
| Open Label Natalizumab | Part B: Concentration of Natalizumab in Serum | Week 24; n=45 | 44.4830 µg/mL | Standard Deviation 22.53573 |
Secondary
Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks
Time frame: Baseline (Week 0) to Week 24
Population: Missing new Gd+ or new or newly-enlarging, non-enhancing T2 hyperintense lesions were imputed using linear interpolation between the 2 adjacent non-missing values. For participants who discontinued the study, linear interpolation reduced to last observation carried forward (LOCF) was used for imputing any remaining missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Natalizumab | Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks | 7.4 lesions | Standard Deviation 12.15 |
| Double-Blind Natalizumab | Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks | 1.2 lesions | Standard Deviation 1.68 |
p-value: <0.001Van Elteren test
Secondary
Part B: Cumulative Number of New Active Lesions Over 24 Weeks
Time frame: Baseline (Week 0) to Week 24
Population: Missing new Gd+ or new or newly-enlarging, non-enhancing T2 hyperintense lesions were imputed using linear interpolation between the 2 adjacent non-missing values. For participants who discontinued the study, linear interpolation reduced to last observation carried forward (LOCF) was used for imputing any remaining missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Natalizumab | Part B: Cumulative Number of New Active Lesions Over 24 Weeks | 8.5 lesions | Standard Deviation 13.35 |
| Double-Blind Natalizumab | Part B: Cumulative Number of New Active Lesions Over 24 Weeks | 1.5 lesions | Standard Deviation 2.06 |
Secondary
Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks
Time frame: Baseline (Week 0) to Week 24
Population: Missing new Gd+ or new or newly-enlarging, non-enhancing T2 hyperintense lesions were imputed using linear interpolation between the 2 adjacent non-missing values. For participants who discontinued the study, linear interpolation reduced to last observation carried forward (LOCF) was used for imputing any remaining missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Natalizumab | Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks | 1.1 lesions | Standard Deviation 1.84 |
| Double-Blind Natalizumab | Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks | 0.3 lesions | Standard Deviation 0.91 |
p-value: 0.006Wilcoxon rank sum test
Secondary
Part B: Number of Participants Who Were Relapse Free Over 24 Weeks
Participants were categorized as relapse free=yes, relapse free=no, or relapse free=unknown. The category of relapse free=unknown includes participants who withdrew from the study and did not experience a relapse prior to withdrawal.
Time frame: Baseline (Week 0) to Week 24
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open Label Natalizumab | Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Relapse free = yes | 18 participants |
| Open Label Natalizumab | Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Relapse free = no | 27 participants |
| Open Label Natalizumab | Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Relapse free = unknown | 2 participants |
| Double-Blind Natalizumab | Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Relapse free = yes | 37 participants |
| Double-Blind Natalizumab | Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Relapse free = no | 9 participants |
| Double-Blind Natalizumab | Part B: Number of Participants Who Were Relapse Free Over 24 Weeks | Relapse free = unknown | 1 participants |
Comparison: Relapse-free proportions compared using a two-sided Fisher exact test. In the analysis, participants with unknown status are considered to have relapsed.p-value: <0.00195% CI: [0.223, 0.586]Fisher Exact
Secondary
Part B: Number of Participants With Adverse Events (AEs)
AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. Serious AE (SAE)=any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, was a life threatening event; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; or any other medically important event that, in the opinion of the Investigator, may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as related or not related; severity was categorized as mild, moderate, or severe.
Time frame: Baseline (Week 0) to Week 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with an adverse event (AE) | 41 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with a moderate or severe AE | 30 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with a severe AE | 5 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with an AE related to study drug | 7 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with a serious event (SAE) | 11 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with an SAE related to study drug | 1 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants discontinuing treatment due to an AE | 1 participants |
| Open Label Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants withdrawing from study due to an AE | 1 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants withdrawing from study due to an AE | 0 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with an adverse event (AE) | 34 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with a serious event (SAE) | 7 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with a moderate or severe AE | 14 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants discontinuing treatment due to an AE | 0 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with a severe AE | 0 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with an SAE related to study drug | 1 participants |
| Double-Blind Natalizumab | Part B: Number of Participants With Adverse Events (AEs) | Participants with an AE related to study drug | 7 participants |
Secondary
Part B: Status of Serum Antibodies to Natalizumab
Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks.
Time frame: Baseline (Week 0) and Week 24
Population: Participants with one or more post-baseline screening antibody result.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open Label Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Negative at all post-dose results | 47 participants |
| Open Label Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Positive at any time | 0 participants |
| Open Label Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Positive at final evaluation | 0 participants |
| Open Label Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Persistently positive | 0 participants |
| Double-Blind Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Persistently positive | 1 participants |
| Double-Blind Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Negative at all post-dose results | 45 participants |
| Double-Blind Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Positive at final evaluation | 1 participants |
| Double-Blind Natalizumab | Part B: Status of Serum Antibodies to Natalizumab | Positive at any time | 2 participants |