Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis
Conditions
Brief summary
The primary objective of the study is to further evaluate the long-term safety and tolerability profiles of BG00002 (natalizumab) in Japanese participants with relapsing-remitting multiple sclerosis (RRMS). The secondary objective of this study is to further evaluate the long-term efficacy profile of BG00002 in Japanese participants with RRMS.
Detailed description
This is a multicenter, long-term, open-label, extension study in participants who have successfully completed Study 101MS203 (NCT01440101).
Interventions
DRUGnatalizumab
Sponsors
Biogen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and any authorizations required by local law. * Subjects who participated in and completed all protocol-related evaluations through Week 24 of Study 101MS203 (NCT01440101). * Subjects participating in study 101MS204 (NCT01416155) participated either in the open label pharmacokinetics-pharmacodynamics study or placebo-controlled study of natalizumab 300 mg q4wks (parts A and B of study 101MS203, respectively). * Subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 12 weeks after their last dose of study treatment. * Must be willing to remain free from concomitant immunosuppressive or immunomodulatory treatment (including interferon beta \[IFNβ\] and long-term systemic corticosteroids) for the duration of the study. Key
Exclusion criteria
Medical History * Any significant change in medical history since Study 101MS203 (NCT01440101), including laboratory tests, or current clinically important condition that in the opinion of the Investigator would have excluded the subject's participation in the previous study. The Investigator must re-review the subject's medical fitness for participation and consider diseases that would preclude treatment. * Subjects from Study 101MS203 (NCT01440101) who discontinued study treatment due to an adverse event. * Subjects who are determined to be persistently positive for anti-BG0002 antibodies based on prior testing. Treatment History * Treatment with any of the following medications between last dose of study treatment in Study 101MS203 (NCT01440101) and the start of this study: intravenous immunoglobulin (IVIg), plasmapheresis, cytapheresis, immunosuppressant medications (e.g., mitoxantrone, azathioprine, cyclophosphamide, methotrexate, cyclosporine, FTY720), immunomodulatory medications (including IFNβ and glatiramer acetate \[GA\]) total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any murine protein, any other therapeutic monoclonal antibody, or any 4-aminopyridine or related products. Miscellaneous * For female subjects, unless postmenopausal for at least 1 year or surgically sterile (does not include tubal ligation), unwillingness to practice effective contraception, as defined by the Investigator, during the study. Women considering becoming pregnant while on study are to be excluded. * Female subjects who are currently pregnant or breast feeding, including subjects whose pregnancy test is positive at Week 0. * Unwillingness or inability to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the study protocol. * Subjects with any other condition, clinical finding, or reason that in the opinion of the Investigator and/or the Sponsor makes the subject unsuitable for enrollment into the study. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Day 1 through First Follow-Up (12 Weeks After Last Infusion) +/- 7 days. Approximately 62 months | An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the subject at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the subject or may have required intervention to prevent one of the other outcomes listed in the definition above. |
| Number of Participants With Serum Antibodies to Natalizumab | Day 1 up to approximately 50 months | Negative is defined as negative for antibodies at all post-baseline results. Transient positivity is defined as only 1 positive result. Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Annualized Relapse Rate | Day 1 up to approximately 50 months | Clinical relapses are defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurological findings upon examination by the neurologist. The annualized relapse rate is calculated overall as the total number of relapses experienced in the study divided by the number of days followed in the study, and the ratio multiplied by 365. Obtained from a Poisson regression model, adjusted for the baseline relapse rate from study 101MS203 (NCT01440101). |
| Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Day 1 up to Week 192 | The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. |
Countries
Japan
Participant flow
Recruitment details
Subjects who participated in and completed all protocol-related evaluations through Week 24 in Study 101MS203 (NCT01440101) were eligible for this study.
Participants by arm
| Arm | Count |
|---|---|
| Natalizumab 300 mg IV infusions of natalizumab open label every 4 weeks | 97 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Investigator decision | 8 |
| Overall Study | Other | 7 |
| Overall Study | Positive for anti-BG00002 antibodies | 2 |
| Overall Study | Withdrawal by Subject | 33 |
Baseline characteristics
| Characteristic | Natalizumab |
|---|---|
| Age, Continuous | 37.2 years STANDARD_DEVIATION 8.67 |
| Age, Customized 18 to 19 years | 1 participants |
| Age, Customized 20 to 29 years | 16 participants |
| Age, Customized 30 to 39 years | 44 participants |
| Age, Customized 40 to 49 years | 28 participants |
| Age, Customized 50 to 59 years | 7 participants |
| Age, Customized >= 60 years | 1 participants |
| Sex: Female, Male Female | 66 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 78 / 97 |
| serious Total, serious adverse events | 29 / 97 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs
An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the subject at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the subject or may have required intervention to prevent one of the other outcomes listed in the definition above.
Time frame: Day 1 through First Follow-Up (12 Weeks After Last Infusion) +/- 7 days. Approximately 62 months
Population: Safety population: all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants with an event | 92 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants with a moderate or severe event | 52 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants with a severe event | 10 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants with an event related to study drug | 33 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants with an SAE | 29 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants with an SAE related to study drug | 7 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants discontinuing treatment due to event | 10 participants |
| Natalizumab | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Participants withdrawing from study due to event | 10 participants |
Primary
Number of Participants With Serum Antibodies to Natalizumab
Negative is defined as negative for antibodies at all post-baseline results. Transient positivity is defined as only 1 positive result. Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks.
Time frame: Day 1 up to approximately 50 months
Population: Immunogenicity population: all participants who had received at least 1 infusion of BG00002, were negative for BG00002 antibodies at baseline and had at least 1 nonmissing post-baseline assessment of antibody status.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Natalizumab | Number of Participants With Serum Antibodies to Natalizumab | Participants negative | 91 participants |
| Natalizumab | Number of Participants With Serum Antibodies to Natalizumab | Participants positive at any time | 5 participants |
| Natalizumab | Number of Participants With Serum Antibodies to Natalizumab | Participants transiently positive | 3 participants |
| Natalizumab | Number of Participants With Serum Antibodies to Natalizumab | Participants positive at final evaluation only | 2 participants |
| Natalizumab | Number of Participants With Serum Antibodies to Natalizumab | Participants persistently positive | 2 participants |
Secondary
Adjusted Annualized Relapse Rate
Clinical relapses are defined as new or recurrent neurologic symptoms, not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurological findings upon examination by the neurologist. The annualized relapse rate is calculated overall as the total number of relapses experienced in the study divided by the number of days followed in the study, and the ratio multiplied by 365. Obtained from a Poisson regression model, adjusted for the baseline relapse rate from study 101MS203 (NCT01440101).
Time frame: Day 1 up to approximately 50 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Natalizumab | Adjusted Annualized Relapse Rate | 0.243 relapses per subject-years |
Secondary
Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192
The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist.
Time frame: Day 1 up to Week 192
Population: n=number of participants with an assessment at given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 12; n=92 | -0.05 units on a scale | Standard Deviation 0.486 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 24; n=86 | -0.15 units on a scale | Standard Deviation 0.49 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 36; n=84 | -0.08 units on a scale | Standard Deviation 0.647 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 48; n=78 | -0.09 units on a scale | Standard Deviation 0.585 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 60; n=76 | -0.09 units on a scale | Standard Deviation 0.534 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 72; n=72 | -0.04 units on a scale | Standard Deviation 0.804 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 84; n=60 | -0.08 units on a scale | Standard Deviation 0.764 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 96; n=53 | -0.10 units on a scale | Standard Deviation 0.743 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 108; n=46 | -0.18 units on a scale | Standard Deviation 0.791 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 120; n=38 | -0.12 units on a scale | Standard Deviation 0.842 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 132; n=31 | -0.11 units on a scale | Standard Deviation 0.854 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 144; n=22 | -0.07 units on a scale | Standard Deviation 0.877 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 156; n=11 | 0.14 units on a scale | Standard Deviation 0.778 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 168; n=8 | 0.31 units on a scale | Standard Deviation 0.961 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 180; n=8 | 0.25 units on a scale | Standard Deviation 0.926 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Week 192; n=2 | 0.50 units on a scale | Standard Deviation 0 |
| Natalizumab | Mean Change From Baseline in the Assessment of Expanded Disability Status Scale (EDSS) up to Week 192 | Change from Baseline to Final Treatment Visit;n=36 | -0.17 units on a scale | Standard Deviation 0.862 |