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

Phase 2

Completed

Conditions: Multiple Sclerosis

Interventions: Drug: Placebo
Drug: Natalizumab (BG00002)

Registration Number: NCT01440101

Lead Sponsor: Biogen

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 106

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Double-blind Placebo	Placebo	IV infusions of placebo over 60 minutes every 4 weeks for 20 weeks
Double-blind Natalizumab 300 mg	Natalizumab (BG00002)	300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks
Open-label Natalizumab	Natalizumab (BG00002)	300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks

Primary Outcome Measures

Name	Time	Method
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.
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.

Secondary Outcome Measures

Name	Time	Method
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 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: 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: Cumulative Number of New Active Lesions Over 24 Weeks	Baseline (Week 0) to Week 24
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 B: Cumulative Number of Gd+ Lesions Over 24 Weeks	Baseline (Week 0) to Week 24
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 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 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 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: 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 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 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)