Relapsing-Remitting Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, MS
Brief summary
The primary objectives for the initial treatment period of this study are to further evaluate the safety of natalizumab monotherapy by evaluating the risk of hypersensitivity reactions and immunogenicity following re-exposure to natalizumab and confirming the safety of switching from interferon (IFN), glatiramer acetate, or other multiple sclerosis (MS) therapies to natalizumab. The primary objective for the long-term treatment period of this study is to evaluate the long-term impact of natalizumab monotherapy on the progression of disability measured by Expanded Disability Status Scale (EDSS) changes over time.
Detailed description
Study 101-MS-322 (NCT00306592) was conducted to evaluate the safety of natalizumab monotherapy following re-exposure to natalizumab in former clinical trial participants in Studies C-1801 (NCT00027300), C-1802 (NCT00030966), and C-1803 (NCT00097760) and included subjects in North America. In parallel with the conduct of that study, this study (101-MS-321 \[NCT00297232\]) was initiated for participants in Europe and the rest of the world. In addition, after 48 weeks, participants from 101-MS-322 (NCT00306592) could enter study 101-MS-321 (NCT 00297232), which was considered the Long-Term Treatment Period of 101-MS-322 (NCT00306592). The primary purpose and primary outcome for both studies are identical; therefore, the combined long-term data from both studies are presented. (Combined Week 48 data from both studies are presented in the 101-MS-322 \[NCT00306592\] record.)
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 No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria * MS subjects who completed Study C-1801 (NCT00027300), C-1802 (NCT00030966), or C-1803 (NCT00097760) and a Dosing Suspension Safety Evaluation (neurological examination or a magnetic resonance imaging scan) or participated in the IMA 04001 (STARS) Study * Subjects who are considered by the Investigator to be free of signs and symptoms suggestive of progressive multifocal leukoencephalopathy and willing to discontinue and remain free from concomitant immunosuppressive or immunomodulatory treatment (including IFN-beta and glatiramer acetate) while being treated with natalizumab during the study. * In addition, subjects who completed 48 weeks of treatment in Study 101-MS-322 (NCT00306592) in Canada will be allowed to enter this study at the start of the long-term treatment period (Week 52 - 480). Key
Exclusion criteria
* Considered by the Investigator to be immunocompromised * History of persistent anti-natalizumab antibodies, based upon testing from prior natalizumab studies * History of any major disease or malignancy * Discontinued natalizumab in a previous study due to allergic reaction NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to 24-week Confirmed Expanded Disability Status Scale (EDSS) Progression | up to 480 weeks | Time to 24-week confirmed EDSS progression in participants with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 24-week EDSS progression was defined as ≥ 0.5 point increase from a baseline EDSS ≥ 6.0, or ≥ 1.0 point increase from a baseline EDSS ≥ 1.0 and \< 6.0, or ≥ 1.5 point increase from a baseline EDSS of 0, all sustained for 24 weeks. |
| Time to 48-week Confirmed EDSS Progression | up to 480 weeks | Time to 48-week confirmed EDSS progression in particpants with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 48-week EDSS progression was defined as ≥ 0.5 point increase from a baseline EDSS ≥ 6.0, or ≥ 1.0 point increase from a baseline EDSS ≥ 1.0 and \< 6.0, or ≥ 1.5 point increase from a baseline EDSS of 0, all sustained for 48 weeks. |
| Time to 24-week Confirmed EDSS Improvement Where Baseline ≥ 2.0 | Up to 480 weeks | Time to 24-week confirmed EDSS improvement in subjects with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 24-week EDSS improvement is defined as ≥ 1.0 point decrease from baseline sustained for 24 weeks. |
Countries
Australia, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Netherlands, New Zealand, Poland, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
Participants from studies 101-MS-321 (NCT00297232) and 101-MS-322 (NCT00306592) are included in this presentation of combined final data. Note: In the Participant Flow table, 'progressive multifocal leukoencephalopathy' is abbreviated to 'PML'. and John Cunningham virus is abbreviated to 'JCV'.
Participants by arm
| Arm | Count |
|---|---|
| Natalizumab 300 mg IV infusions once every 4 weeks for up to 480 weeks | 1,094 |
| Total | 1,094 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 63 |
| Overall Study | Anti-JCV Antibody Positive | 13 |
| Overall Study | Anti-natalizumab Positive | 8 |
| Overall Study | Death | 9 |
| Overall Study | Did Not Enroll to Week 264 | 34 |
| Overall Study | Did Not Enroll to Week 480 | 17 |
| Overall Study | Disease Progression | 8 |
| Overall Study | Fear of PML | 10 |
| Overall Study | Investigator Withdrew From Program | 19 |
| Overall Study | Lack of Efficacy | 7 |
| Overall Study | Lost to Follow-up | 10 |
| Overall Study | Miscellaneous | 5 |
| Overall Study | No data available after Week 264 | 161 |
| Overall Study | Other | 1 |
| Overall Study | Persistently Positive Antibodies | 11 |
| Overall Study | Sponsor Decision | 34 |
| Overall Study | Subject Relocated | 7 |
| Overall Study | Subject was Noncompliant | 9 |
| Overall Study | Subject Withdrew Consent | 37 |
| Overall Study | Switched to Commercial Tysabri | 22 |
| Overall Study | Voluntary Withdrawal | 120 |
Baseline characteristics
| Characteristic | Natalizumab |
|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 8.12 |
| Age, Customized 20 to 29 years | 98 years |
| Age, Customized 30 to 39 years | 347 years |
| Age, Customized 40 to 49 years | 454 years |
| Age, Customized 50 to 59 years | 195 years |
| Sex: Female, Male Female | 755 Participants |
| Sex: Female, Male Male | 339 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 752 / 1,094 |
| serious Total, serious adverse events | 231 / 1,094 |
Outcome results
Primary
Time to 24-week Confirmed EDSS Improvement Where Baseline ≥ 2.0
Time to 24-week confirmed EDSS improvement in subjects with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 24-week EDSS improvement is defined as ≥ 1.0 point decrease from baseline sustained for 24 weeks.
Time frame: Up to 480 weeks
Population: Participants with EDSS improvement (regardless of length of follow-up) sustained for 24 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Natalizumab | Time to 24-week Confirmed EDSS Improvement Where Baseline ≥ 2.0 | 48.1 weeks |
Primary
Time to 24-week Confirmed Expanded Disability Status Scale (EDSS) Progression
Time to 24-week confirmed EDSS progression in participants with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 24-week EDSS progression was defined as ≥ 0.5 point increase from a baseline EDSS ≥ 6.0, or ≥ 1.0 point increase from a baseline EDSS ≥ 1.0 and \< 6.0, or ≥ 1.5 point increase from a baseline EDSS of 0, all sustained for 24 weeks.
Time frame: up to 480 weeks
Population: Participants with EDSS progression (regardless of length of follow-up) sustained for 24 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Natalizumab | Time to 24-week Confirmed Expanded Disability Status Scale (EDSS) Progression | 121.9 weeks |
Primary
Time to 48-week Confirmed EDSS Progression
Time to 48-week confirmed EDSS progression in particpants with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 48-week EDSS progression was defined as ≥ 0.5 point increase from a baseline EDSS ≥ 6.0, or ≥ 1.0 point increase from a baseline EDSS ≥ 1.0 and \< 6.0, or ≥ 1.5 point increase from a baseline EDSS of 0, all sustained for 48 weeks.
Time frame: up to 480 weeks
Population: Participants with EDSS progression (regardless of length of follow-up) sustained for 48 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Natalizumab | Time to 48-week Confirmed EDSS Progression | 130.1 weeks |