Natalizumab (BG00002, Tysabri) Study in Japanese Participants With Relapsing-Remitting Multiple Sclerosis (RRMS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Multicenter Study of BG00002 in Japanese Subjects With RRMS, Consisting of a Multiple-Dose, Open-Label Evaluation of Its Safety, Tolerability, Pharmacokinetics and Pharmacodynamics (Part A) and a Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Evaluation of Safety and Efficacy (Part B)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Natalizumab (BG00002)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria Diagnosis or history of 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-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, or positive test result of 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: ALT or AST >2 times of the 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: IVIg, plasmapheresis, or cytapheresis. Treatment with immunomodulatory medications (including IFNβ and 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. NOTE: Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind Natalizumab 300 mg<br>300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks | Drug: Natalizumab (BG00002)<br> <br> * Other names: Tysabri;|
| Placebo Comparator: Double-blind Placebo<br>IV infusions of placebo over 60 minutes every 4 weeks for 20 weeks | Drug: Placebo<br> <br> |
| Experimental: Open-label Natalizumab<br>300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks | Drug: Natalizumab (BG00002)<br> <br> * Other names: Tysabri;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Week 0) to Week 24 | 
| 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. | Baseline (Week 0) to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Cumulative Number of New Active Lesions Over 24 Weeks |  | Baseline (Week 0) to Week 24 | 
| 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. | Week 24 | 
| 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 | 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. | Baseline (Week 0) to Week 24 | 
| 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.' | Baseline (Week 0), Week 12, Week 24 | 
| Part A: Concentration of Natalizumab in Serum | The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA). | 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 | 
| Part B: Concentration of Natalizumab in Serum | The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA). | Baseline (Week 0), Week 12, Week 24 | 
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Cmax | Observed maximum concentration (Cmax) was calculated using non-compartmental methods. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Vd | Volume of distribution (Vd) was calculated using non-compartmental methods. | 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 | 
| Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL | Systemic clearance (CL) was calculated using non-compartmental methods. | Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose | 
| Part B: Status of Serum Antibodies to Natalizumab | Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks. | Baseline (Week 0) and Week 24 | 
| 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. | Baseline (Week 0) to Week 24 | 
| 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. | 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 | 
| Part A: Summary of Lymphocyte Counts Over Time |  | Baseline [Week 0]); 28 days post-dose; Weeks 12, 24, and 32 (follow-up) |