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

This study has been completed.
Sponsor:
Collaborator:
Biogen Idec Japan Ltd.
Information provided by (Responsible Party):
Biogen Idec
ClinicalTrials.gov Identifier:
NCT01440101
First received: April 14, 2011
Last updated: October 20, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Multiple Sclerosis
Drug: Natalizumab (BG00002)
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Biogen Idec:

Primary Outcome Measures:
  • Part A: Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline (Week 0) to Week 24 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline (Week 0) to Week 24 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Part B: Cumulative Number of New Active Lesions Over 24 Weeks [ Time Frame: Baseline (Week 0) to Week 24 ] [ Designated as safety issue: No ]
  • Part B: Adjusted Annualized Relapse Rate Over 24 Weeks [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline (Week 0) to Week 24 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Part B: Number of Participants Who Were Relapse Free Over 24 Weeks [ Time Frame: Baseline (Week 0) to Week 24 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline (Week 0), Week 12, Week 24 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    The concentration of BG00002 in serum was determined using an Enzyme Linked Immunosorbent Assay (ELISA).

  • Part B: Concentration of Natalizumab in Serum [ Time Frame: Baseline (Week 0), Week 12, Week 24 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    Observed maximum concentration (Cmax) was calculated using non-compartmental methods.

  • Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞) [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    Volume of distribution (Vd) was calculated using non-compartmental methods.

  • Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL [ Time Frame: Dose 1/Week 0: pre-dose, post-dose and 4, 24, 48 and 96 hours post-dose ] [ Designated as safety issue: No ]
    Systemic clearance (CL) was calculated using non-compartmental methods.

  • Part B: Status of Serum Antibodies to Natalizumab [ Time Frame: Baseline (Week 0) and Week 24 ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline (Week 0) to Week 24 ] [ Designated as safety issue: Yes ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline [Week 0]); 28 days post-dose; Weeks 12, 24, and 32 (follow-up) ] [ Designated as safety issue: No ]

Enrollment: 106
Study Start Date: November 2010
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Double-blind Natalizumab 300 mg
300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks
Drug: Natalizumab (BG00002)
Other Name: Tysabri
Placebo Comparator: Double-blind Placebo
IV infusions of placebo over 60 minutes every 4 weeks for 20 weeks
Drug: Placebo
Experimental: Open-label Natalizumab
300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks
Drug: Natalizumab (BG00002)
Other Name: Tysabri

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01440101

Locations
Japan
Research Site
Chiba, Japan
Research Site
Fukuoka, Japan
Research Site
Hiroshima, Japan
Research Site
Kawagoe, Japan
Research Site
Kyoto, Japan
Research Site
Morioka, Japan
Research Site
Niigata, Japan
Research Site
Osaka, Japan
Research Site
Otaku, Japan
Research Site
Sapporo, Japan
Research Site
Sendai, Japan
Research Site
Suita, Japan
Research Site
Tokorozawa, Japan
Research Site
Tokyo, Japan
Research Site
Tsukuba, Japan
Research Site
Ube, Japan
Research Site
Yokohama, Japan
Sponsors and Collaborators
Biogen Idec
Biogen Idec Japan Ltd.
Investigators
Study Director: Medical Director Biogen Idec
  More Information

No publications provided

Responsible Party: Biogen Idec
ClinicalTrials.gov Identifier: NCT01440101     History of Changes
Other Study ID Numbers: 101MS203
Study First Received: April 14, 2011
Results First Received: September 15, 2014
Last Updated: October 20, 2014
Health Authority: Japan: Pharmaceuticals and Medical Devices Agency (PMDA)

Additional relevant MeSH terms:
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Demyelinating Autoimmune Diseases, CNS
Demyelinating Diseases
Immune System Diseases
Nervous System Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on October 23, 2014