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CompletedNCT01440101Tysabri JapanUpdated Oct 21, 2014Results posted

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

A Phase 2/3 interventional study of Natalizumab (BG00002) and Placebo in Multiple Sclerosis, sponsored by Biogen. Completed at 17 sites in Japan. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2014-10-21.

Sponsored by Biogen · Phase 2/3, Interventional, and Treatment

Phase
Phase 2/3
Study type
Interventional
Enrollment
106
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Multiple Sclerosis
03

In context

Multiple Sclerosis

3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.

This study's enrollment of 106 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.

Browse Multiple Sclerosis studies →

Lead sponsor

Biogen is the lead sponsor of 494 studies on the registry; 22 are open to participants now.

Of its 98 completed or terminated interventional studies of FDA-regulated products, 49 (50%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility 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.

05

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
106 participants (actual)

Study arms

  • Experimental
    Double-blind Natalizumab 300 mg

    300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks

    Drug: Natalizumab (BG00002)

  • 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)

Interventions

  • DrugNatalizumab (BG00002)

    Also known as: Tysabri

  • DrugPlacebo
06

What researchers measure

Primary outcomes

  1. 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

  2. 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

Secondary outcomes

  1. Part B: Cumulative Number of New Active Lesions Over 24 Weeks

    Time frame: Baseline (Week 0) to Week 24

  2. 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

  3. Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks

    Time frame: Baseline (Week 0) to Week 24

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Part A: Summary of Lymphocyte Counts Over Time

    Time frame: Baseline [Week 0]); 28 days post-dose; Weeks 12, 24, and 32 (follow-up)

07

Results

Posted Oct 21, 2014

Participant flow

Participant flow — Overall Study
MilestoneOpen Label NatalizumabDouble-Blind PlaceboDouble-Blind Natalizumab
Started124747
Completed104346
Not completed241
Withdrew: Adverse event200
Withdrew: Withdrawal by subject031
Withdrew: Other010

Outcome measures

PrimaryPart 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
Reported as:
Number · participants
Part A: Number of Participants With Adverse Events (AEs)
participantsOpen Label Natalizumab
Participants with an adverse event (AE)8
Participants with a moderate or severe event4
Participants with a severe event1
Participants with an AE related to study drug3
Participants with a serious event (SAE)2
Participants with an SAE related to study drug1
Participants discontinuing treatment due to an AE1
Participants withdrawing from study due to an AE2
PrimaryPart 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
Reported as:
Mean · lesions per week over 24 weeks
Part B: Rate of Development of New Active Lesions Over 24 Weeks
lesions per week over 24 weeksDouble-Blind PlaceboDouble-Blind Natalizumab
Part B: Rate of Development of New Active Lesions Over 24 Weeks0.352 ± 0.56480.058 ± 0.0748
Statistical analysis
  • Double-Blind Placebo vs Double-Blind Natalizumab · Wilcoxon (Mann-Whitney) · p = <0.001 (P-value obtained from the Mann-Whitney U test stratified by the presence or absence of Gd+ lesions at baseline.)
SecondaryPart B: Cumulative Number of New Active Lesions Over 24 Weeks
Time frame:
Baseline (Week 0) to Week 24
Reported as:
Mean · lesions
Part B: Cumulative Number of New Active Lesions Over 24 Weeks
lesionsDouble-Blind PlaceboDouble-Blind Natalizumab
Part B: Cumulative Number of New Active Lesions Over 24 Weeks8.5 ± 13.351.5 ± 2.06
SecondaryPart 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
Reported as:
Number · relapses per year
Part B: Adjusted Annualized Relapse Rate Over 24 Weeks
relapses per yearDouble-Blind PlaceboDouble-Blind Natalizumab
Part B: Adjusted Annualized Relapse Rate Over 24 Weeks1.727 (1.218 to 2.448)0.532 (0.286 to 0.992)
SecondaryPart B: Cumulative Number of Gd+ Lesions Over 24 Weeks
Time frame:
Baseline (Week 0) to Week 24
Reported as:
Mean · lesions
Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks
lesionsDouble-Blind PlaceboDouble-Blind Natalizumab
Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks7.4 ± 12.151.2 ± 1.68
Statistical analysis
  • Double-Blind Placebo vs Double-Blind Natalizumab · Van Elteren test · p = <0.001 (P-value obtained from the Van Elteren test stratified by the presence or absence of Gd+ lesions at baseline.)
SecondaryPart B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks
Time frame:
Baseline (Week 0) to Week 24
Reported as:
Mean · lesions
Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks
lesionsDouble-Blind PlaceboDouble-Blind Natalizumab
Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks1.1 ± 1.840.3 ± 0.91
Statistical analysis
  • Double-Blind Placebo vs Double-Blind Natalizumab · Wilcoxon rank sum test · p = 0.006
SecondaryPart 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
Reported as:
Number · participants
Part B: Number of Participants Who Were Relapse Free Over 24 Weeks
participantsDouble-Blind PlaceboDouble-Blind Natalizumab
Relapse free = yes1837
Relapse free = no279
Relapse free = unknown21
Statistical analysis
  • Double-Blind Placebo vs Double-Blind Natalizumab · Fisher Exact · p = <0.001 · Difference in proportions: 0.404 · 95% CI 0.223 to 0.586
SecondaryPart 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
Reported as:
Mean · units on a scale
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)
units on a scaleDouble-Blind PlaceboDouble-Blind Natalizumab
Baseline; n=47, 4763.5 ± 23.6669.6 ± 20.70
Change from Baseline at Week 12; n=47, 47-4.9 ± 24.89-5.3 ± 21.49
Change from Baseline at Week 24; n=44, 46-2.9 ± 25.20-4.8 ± 17.40
Statistical analysis
  • Double-Blind Placebo vs Double-Blind Natalizumab · ANCOVA · p = 0.729 (P-value for comparison between the treated and placebo groups was based on analysis of covariance, adjusted for the baseline VAS score.)
  • Double-Blind Placebo vs Double-Blind Natalizumab · ANCOVA · p = 0.942 (P-value for comparison between the treated and placebo groups was based on analysis of covariance, adjusted for the baseline VAS score.)
SecondaryPart 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
Reported as:
Mean · µg/mL
Part A: Concentration of Natalizumab in Serum
µg/mLOpen Label Natalizumab
Week 0: pre-dose; n=12NA ± NA
Week 0: post-dose; n=12119.4550 ± 18.86145
Week 0: 4 hours post-dose; n=12111.8159 ± 18.35129
Week 0: 24 hours post-dose; n=12100.5707 ± 26.17036
Week 0: 48 hours post-dose; n=1292.5144 ± 18.26611
Week 0: 96 hours post-dose; n=1273.2038 ± 17.02067
7 days post-dose; n=1262.3874 ± 16.49046
14 days post-dose; n=1241.2363 ± 12.02968
21 days post-dose; n=1230.9994 ± 11.45474
Week 4: pre-dose; n=1222.5702 ± 9.55131
Week 8: pre-dose; n=1124.7048 ± 15.50352
Week 12: pre-dose; n=1027.9105 ± 16.06085
Week 16: pre-dose; n=1032.9645 ± 16.41578
Week 20: pre-dose; n=1036.2724 ± 14.51395
Week 20: post-dose; n=10145.5353 ± 38.26877
Week 20: 4 hours post-dose; n=10137.6666 ± 30.47429
Week 20: 24 hours post-dose; n=10130.8829 ± 30.17375
Week 20: 48 hours post-dose; n=10120.0772 ± 28.68860
Week 20: 96 hours post-dose; n=10103.3549 ± 26.94133
Week 20: 7 days post-dose; n=1086.2563 ± 24.70785
Week 20: 14 days post-dose; n=1065.7307 ± 24.60531
Week 20: 21 days post-dose; n=1052.4002 ± 21.41919
Week 20: 28 days post-dose; n=1035.8368 ± 16.33283
SecondaryPart 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
Reported as:
Mean · µg/mL
Part B: Concentration of Natalizumab in Serum
µg/mLDouble-Blind Natalizumab
Baseline; n=47NA ± NA
Week 12; n=4532.6475 ± 14.68246
Week 24; n=4544.4830 ± 22.53573
SecondaryPart 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
Reported as:
Geometric mean · µg/mL
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Cmax
µg/mLOpen Label Natalizumab
Dose 1/Week 0; n=12119.58 (89.4 to 166.0)
Dose 6/Week 20; n=10144.36 (92.6 to 221.0)
SecondaryPart 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
Reported as:
Geometric mean · µg*h/mL
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: AUC(0-last) and (0-AUC∞)
µg*h/mLOpen Label Natalizumab
AUC(0-last), Dose 1/Week 0; n=1231574.6 (24462 to 49818)
AUC(0-last), Dose 6/Week 20; n=1046094.8 (30407 to 71319)
AUC(0-∞), Dose 1/Week 0; n=1243172.6 (25631 to 68072)
SecondaryPart 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
Reported as:
Geometric mean · hours
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Tmax and T1/2
hoursOpen Label Natalizumab
Tmax, Dose 1/Week 0; n=121.49 (1.0 to 22.0)
Tmax, Dose 6/Week 20; n=102.27 (1.0 to 6.0)
T1/2, Dose 1/Week 0; n=12344.9 (158 to 697)
T1/2, Dose 6/Week 20; n=10381.2 (181 to 533)
SecondaryPart 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
Reported as:
Geometric mean · L
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: Vd
LOpen Label Natalizumab
Dose 1/Week 0; n=123.422 (2.30 to 5.05)
Dose 6/Week 20; n=103.561 (2.19 to 6.05)
SecondaryPart 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
Reported as:
Geometric mean · mL/h
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL
mL/hOpen Label Natalizumab
Part A: Pharmacokinetic (PK) Profile of Natalizumab in Serum: CL6.9497 (4.410 to 11.700)
SecondaryPart 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
Reported as:
Number · participants
Part B: Status of Serum Antibodies to Natalizumab
participantsDouble-Blind PlaceboDouble-Blind Natalizumab
Negative at all post-dose results4745
Positive at any time02
Positive at final evaluation01
Persistently positive01
SecondaryPart 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
Reported as:
Number · participants
Part B: Number of Participants With Adverse Events (AEs)
participantsDouble-Blind PlaceboDouble-Blind Natalizumab
Participants with an adverse event (AE)4134
Participants with a moderate or severe AE3014
Participants with a severe AE50
Participants with an AE related to study drug77
Participants with a serious event (SAE)117
Participants with an SAE related to study drug11
Participants discontinuing treatment due to an AE10
Participants withdrawing from study due to an AE10
SecondaryPart 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
Reported as:
Mean · percent saturation
Part A: Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC)
percent saturationOpen Label Natalizumab
Pre-dose (n=12)6.282 ± 1.6450
4 hours post-dose (n=12)88.371 ± 4.6811
7 days post-dose (n=12)85.491 ± 7.1019
14 days post-dose (n=12)77.929 ± 6.8396
21 days post-dose (n=12)71.362 ± 6.8992
28 days post-dose (n=12)69.742 ± 7.3283
Week 8: pre-dose (n=11)64.057 ± 20.2412
Week 12: pre-dose (n=11)60.615 ± 22.0351
Week 16: pre-dose (n=10)75.485 ± 4.4088
Week 20: pre-dose (n=10)75.314 ± 7.1022
Week 20: 4 hours post-dose (n=10)88.859 ± 5.0230
Week 20: 7 days post-dose (n=10)83.575 ± 5.9416
Week 20: 14 days post-dose (n=10)80.376 ± 5.4459
Week 20: 21 days post-dose (n=10)80.842 ± 5.5828
Week 20: 28 days post-dose (n=10)70.897 ± 4.5757
SecondaryPart A: Summary of Lymphocyte Counts Over Time
Time frame:
Baseline [Week 0]); 28 days post-dose; Weeks 12, 24, and 32 (follow-up)
Reported as:
Mean · cells/microliter
Part A: Summary of Lymphocyte Counts Over Time
cells/microliterOpen Label Natalizumab
Screening; n=121708.3 ± 556.71
Pre-dose; n=121775.0 ± 534.49
28 days Post-dose; n=123016.7 ± 845.13
Week 12; n=113018.2 ± 1112.49
Week 24; n=103340.0 ± 939.50
Week 32 Follow-up; n=21550.0 ± 70.71

Adverse events

Collected over AEs were collected from Baseline (Week 0) through Week 24 (treatment period) + 20 Weeks (or 24 weeks after last infusion). Serious adverse events (SAEs) were collected from the time of informed consent.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Open Label Natalizumab—2/12 (16.7%)8/12 (66.7%)
Double-Blind Placebo—11/47 (23.4%)32/47 (68.1%)
Double-Blind Natalizumab—7/47 (14.9%)21/47 (44.7%)
Most frequent serious events
Most frequent serious events
EventOpen Label NatalizumabDouble-Blind PlaceboDouble-Blind Natalizumab
Multiple Sclerosis RelapseNervous system disorders1/1210/474/47
Retinal DetachmentEye disorders1/120/470/47
PyelonephritisInfections and infestations0/121/470/47
Basal Cell CarcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/120/471/47
Asperger's DisorderPsychiatric disorders0/120/471/47
Somatoform DisorderPsychiatric disorders0/121/470/47
DiarrhoeaGastrointestinal disorders0/120/471/47
Most frequent other events
Showing 10 of 28
Most frequent other events
EventOpen Label NatalizumabDouble-Blind PlaceboDouble-Blind Natalizumab
Multiple Sclerosis RelapseNervous system disorders2/1217/478/47
NasopharyngitisInfections and infestations3/1214/479/47
HeadacheNervous system disorders3/120/470/47
CystitisInfections and infestations2/120/470/47
PharyngitisInfections and infestations2/122/473/47
Acute SinusitisInfections and infestations1/120/470/47
Bacterial InfectionInfections and infestations1/120/470/47
Depressed MoodPsychiatric disorders1/120/470/47
InsomniaPsychiatric disorders1/121/473/47
Central Nervous System LesionNervous system disorders1/120/470/47

Baseline characteristics

This was a 2-part, multicenter study, each part (open-label, double-blind) comprising discrete cohorts of BG00002-naïve participants.

Age, Customized
Age, Customized(participants)Open Label NatalizumabDouble-Blind PlaceboDouble-Blind NatalizumabTotal
18 to < 20 years0202
20 to < 30 years18918
30 to < 40 years6241848
40 to < 50 years3101629
50 to < 60 years1337
>/= 60 years1012
Sex: Female, Male
Sex: Female, Male(Participants)Open Label NatalizumabDouble-Blind PlaceboDouble-Blind NatalizumabTotal
Female7323473
Male5151333
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Study locations

17 sites
  • 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
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References and documents

Publications

  • Saida T, Kira JI, Kishida S, Yamamura T, Sudo Y, Ogiwara K, Tibung JT, Lucas N, Subramanyam M; Natalizumab Trial Principal Investigators. Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study. Mult Scler Relat Disord. 2017 Jan;11:25-31. doi: 10.1016/j.msard.2016.11.002. Epub 2016 Nov 11. PubMed 28104251 ↗
  • Saida T, Kira JI, Kishida S, Yamamura T, Ohtsuka N, Dong Q, Tibung JT. Natalizumab for Achieving Relapse-Free, T1 Gadolinium-Enhancing-Lesion-Free, and T2 Lesion-Free Status in Japanese Multiple Sclerosis Patients: A Phase 2 Trial Subanalysis. Neurol Ther. 2017 Jun;6(1):153-159. doi: 10.1007/s40120-016-0062-4. Epub 2017 Jan 11. PubMed 28078634 ↗
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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Oct 21, 2014, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01440101
Lead sponsor
Biogen
Responsible party
Sponsor
First posted
Sep 26, 2011
Start date
Nov 2010
Primary completion
Aug 2012
Completion
Aug 2012
Results posted
Oct 21, 2014
Last update
Oct 21, 2014

Study contacts

Medical Director
study director · Biogen

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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