Secondary Progressive Multiple Sclerosis
Conditions
Keywords
Natalizumab, secondary, multiple sclerosis, MS, SPMS, Tysabri
Brief summary
This is a Phase 3b, multicenter, international study conducted in 2 parts. Upon completion of the placebo-controlled period (Part 1), participants will have the option of enrolling in a 2-year open-label extension (Part 2). Part 1: The primary objective of the study is to investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in participants with secondary progressive multiple sclerosis (SPMS). The secondary objectives of Part 1 of this study are to determine the proportion of participants with consistent improvement in Timed 25-Foot Walk (T25FW), the change in participant-reported ambulatory status as measured by the 12-item MS Walking Scale (MSWS-12), the change in manual ability based on the ABILHAND Questionnaire, the impact of natalizumab on participant-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical), the change in whole brain volume between the end of study and Week 24 using magnetic resonance imaging (MRI) and the proportion of participants experiencing progression of disability as measured by individual physical Expanded Disability Status Scale (EDSS) system scores. Part 2: The primary objective of Part 2 of the study is to evaluate the safety profile of natalizumab in participants with SPMS. The secondary objectives of Part 2 of the study are to investigate long-term disability (based on clinical or participant-reported assessments) in participants with SPMS receiving natalizumab treatment for approximately 4 years and to assess change in brain volume and T2 lesion volume.
Interventions
DRUGnatalizumab
Administered as specified in the treatment arm
DRUGPlacebo
Matched placebo in part 1
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 58 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria (Part 1): * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local subject privacy regulations. * SPMS defined as relapsing-remitting disease followed by progression of disability independent of or not explained by multiple sclerosis (MS) relapses for at least 2 years. * EDSS score of 3.0 to 6.5, inclusive. * Multiple Sclerosis Severity Score of 4 or higher. * Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide. Key
Exclusion criteria
(Part 1): * Relapsing remitting multiple sclerosis (RRMS) or primary progressive MS as defined by the revised McDonald Committee criteria. * Clinical relapse (within 3 months) prior to randomization. * T25FW test of \>30 seconds during the screening period. * Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils. * Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment. * Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed). * History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study. * History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured). * Known history of or positive test result for human immunodeficiency virus. * Positive test result for hepatitis C virus (test for hepatitis C virus antibody or hepatitis B virus (test for hepatitis B surface antigen and/or hepatitis B core antibody). * History of transplantation or any anti-rejection therapy. * Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening. * History of progressive multifocal leukoencephalopathy or other opportunistic infections. Treatment History (Part 1) * Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation. * Any prior treatment with natalizumab. * Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization. * Treatment with intravenous or oral corticosteroids, intravenous immunoglobulin, or plasmapheresis for treatment of MS within the 3 months prior to randomization. * Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization. * Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study. Key Inclusion Criteria (Part 2): * Subjects must have participated in and completed Part 1 per protocol, and have documented assessment attempts for EDSS, T25FW, and 9HPT prior to first open-label dosing. Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Up to 96 weeks (2 years) | Confirmed disability progression, defined as ≥1 of the following criteria (confirmed at a second visit ≥6 months later and at Week 96): * Confirmed progression in EDSS (EDSS score increased from baseline \[BL\] by ≥1 point if BL EDSS ≤5.5 or by ≥0.5 points if BL EDSS ≥6); * Confirmed progression in T25FW (T25FW increased by ≥20% of the BL walk); * Confirmed progression in 9HPT (9HPT increased by ≥20% of the time taken at BL on either hand and confirmed on the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. The 95% confidence interval (CI) of the percentage is based on normal approximation. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 218 weeks | AE: any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, placed the participant at immediate risk of death (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. An SAE may have also been any other medically important event in the opinion of the Investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12) | Baseline and Week 96 | MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A negative number on change from BL value indicates an improvement in MSWS-12. |
| Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire | Baseline and Week 96 | The ABILHAND Questionnaire measures the participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability. A positive number on change from baseline value indicates an improvement in ABILHAND. |
| Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score | Baseline and Week 96 | The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29. |
| Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores | Up to 96 weeks | 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. Participants with confirmed progression of disability in EDSS physical functional system scores will be defined as those who met one of the following criteria: * an increase of ≥ 1 point from baseline system score of ≥ 1 or an increase of ≥ 2 points from baseline system score of 0 in at least 2 physical functional systems, or * an increase of ≥ 2 points from baseline system score of ≥ 1 or an increase of ≥ 3 points from baseline system score of 0 in any 1 physical functional system. A confirmed progressor was defined as a participant who met the criteria for disability progression at any given visit and at the 6-Month Confirmation Visit. The 95% CIs are based on normal approximation. |
| Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Week 156 | Percentage of participants with disability worsening at each scheduled efficacy visit in Part 2, defined as one or more of the following: • ≥ 20% worsening from Part 1 baseline in T25FW; • ≥ 20% worsening from Part 1 baseline in 9HPT; • Worsening from Part 1 baseline in EDSS (≥ 1 point increase if Part 1 baseline EDSS ≤ 5.5 or ≥ 0.5 point increase if Part 1 baseline EDSS \> 5.5). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. 95% CIs of percentages are based on normal approximation. |
| Part 2: Absolute Change From Baseline (Part 1) in T25FW | Baseline (Part 1) and Weeks 156, 204 | The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Lower scores on time taken to reach 25 foot mark reflect a better outcome. Values are presented for the overall group, as well as the Confirmed Progressor (CP, defined in the primary outcome measure description above) and Non-Progressor (NP) subgroups. |
| Part 2: Percentage Change From Baseline (Part 1) in T25FW | Baseline (Part 1) and Weeks 156, 204 | The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Baseline (Part 1) and Weeks 156, 204 | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Baseline (Part 1) and Weeks 156, 204 | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Baseline (Part 1) and Weeks 156, 204 | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Baseline (Part 1) and Weeks 156, 204 | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 2: Absolute Change From Baseline (Part 1) in EDSS | Baseline (Part 1) and Weeks 156, 204 | 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. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96 | Week 24 and Week 96 | Whole brain volume as measured by MRI. |
| Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) | Baseline (Part 1) and Weeks 156 and 204 | The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. |
| Part 2: Percentage Change From Baseline (Part 1) in the 6MWT | Baseline (Part 1) and Weeks 156, 204 | The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. |
| Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score | Baseline (Part 1) and Weeks 156 and 204 | The 29-item MSIS-29 is a patient-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a patient's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29. |
| Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score | Baseline (Part 1) and Weeks 156, 204 | The 29-item MSIS-29 is a patient-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a patient's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29. |
| Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Baseline (Part 1) and every 4 weeks from Week 108 to Week 204 | SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). |
| Part 2: Percentage Change From Baseline (Part 1) in the SDMT | Baseline (Part 1) and every 4 weeks from Week 108 to Week 204 | SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). |
| Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Part 2 Baseline (Week 108) and Weeks 156 and 204 | The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (percentage of overall work impairment \[absenteeism plus presenteeism\]) 4. Activity Impairment (percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. |
| Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Part 2 Baseline (Week 108) and Weeks 156 and 204 | The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (WPL; percentage of overall work impairment \[absenteeism plus presenteeism\]) 4. Activity Impairment (AI; percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. |
| Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume | Week 24 (Part 1) and Weeks 156 and 204 | Whole brain volume as measured by MRI. |
| Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume | Baseline (Part 1) and Weeks 156 and 204 | Whole grey matter brain volume as measured by MRI. |
| Part 2: Summary of New/Enlarging T2 Lesion Counts | Baseline (Part 1) up to Week 204 | New or enlarging T2 lesions as measured by MRI. |
| Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions | Baseline (Part 1) and Weeks 156 and 204 | New or enlarging T2 lesions as measured by MRI. |
| Part 2: Percentage Change From Baseline (Part 1) in EDSS | Baseline (Part 1) and Weeks 156, 204 | 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. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. |
| Part 1: Percentage of Participants With a T25FW Response | Up to 96 weeks | T25FW response is defined as any improvement from the best pre-dose T25FW in at least 75% of the scheduled on-treatment visits through Week 96. The T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. The score for the T25FW is the average of the 2 completed trials. The 95% CI of the percentage is based on normal approximation. |
Countries
Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, Poland, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Part 1: participants were randomized to receive placebo IV every 4 weeks for 96 weeks. Part 2: participants transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks. | 449 |
| Natalizumab 300 mg Part 1: participants were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: participants transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks. | 439 |
| Total | 888 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1 | Adverse Event | 15 | 18 |
| Part 1 | Death | 0 | 1 |
| Part 1 | Investigator Decision | 7 | 6 |
| Part 1 | Lack of Efficacy | 16 | 8 |
| Part 1 | Lost to Follow-up | 1 | 1 |
| Part 1 | Ongoing in Follow-Up | 14 | 8 |
| Part 1 | Other | 10 | 24 |
| Part 1 | Withdrawal by Subject | 74 | 48 |
| Part 2 | Adverse Event | 11 | 4 |
| Part 2 | Investigator Decision | 6 | 7 |
| Part 2 | Lack of Efficacy | 4 | 1 |
| Part 2 | Lost to Follow-up | 2 | 2 |
| Part 2 | Other | 234 | 267 |
| Part 2 | Withdrawal by Subject | 14 | 5 |
Baseline characteristics
| Characteristic | Placebo | Natalizumab 300 mg | Total |
|---|---|---|---|
| Age, Customized 20 - 29 years | 10 participants | 10 participants | 20 participants |
| Age, Customized 30 - 39 years | 73 participants | 50 participants | 123 participants |
| Age, Customized 40 - 49 years | 162 participants | 194 participants | 356 participants |
| Age, Customized ≥ 50 years | 204 participants | 185 participants | 389 participants |
| Sex: Female, Male Female | 280 Participants | 270 Participants | 550 Participants |
| Sex: Female, Male Male | 169 Participants | 169 Participants | 338 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 347 / 449 | 325 / 439 |
| serious Total, serious adverse events | 100 / 449 | 90 / 439 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE: any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, placed the participant at immediate risk of death (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. An SAE may have also been any other medically important event in the opinion of the Investigator.
Time frame: 218 weeks
Population: Safety population: all participants who were randomized in Part 1 and received at least 1 infusion of study treatment in Part 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Withdrawal from study due to an event | 11 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any event | 250 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Moderate or severe event | 157 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Severe event | 28 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related event | 63 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious event | 24 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Discontinuation of treatment due to event | 12 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Withdrawal from study due to an event | 3 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related event | 56 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any event | 245 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Discontinuation of treatment due to event | 5 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Moderate or severe event | 158 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious event | 39 participants |
| Natalizumab 300 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Severe event | 27 participants |
Primary
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT)
Confirmed disability progression, defined as ≥1 of the following criteria (confirmed at a second visit ≥6 months later and at Week 96): * Confirmed progression in EDSS (EDSS score increased from baseline \[BL\] by ≥1 point if BL EDSS ≤5.5 or by ≥0.5 points if BL EDSS ≥6); * Confirmed progression in T25FW (T25FW increased by ≥20% of the BL walk); * Confirmed progression in 9HPT (9HPT increased by ≥20% of the time taken at BL on either hand and confirmed on the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. The 95% confidence interval (CI) of the percentage is based on normal approximation.
Time frame: Up to 96 weeks (2 years)
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on 9HPT (either hand) at 2 years | 23 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on EDSS at 2 years | 15 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on 9HPT (dominant hand) at 2 years | 13 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on T25FW at 2 years | 35 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on 9HPT (non-dominant hand) at 2 years | 16 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years | 48 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on 9HPT (non-dominant hand) at 2 years | 10 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years | 44 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on T25FW at 2 years | 35 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on 9HPT (either hand) at 2 years | 15 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on 9HPT (dominant hand) at 2 years | 10 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed on EDSS at 2 years | 16 percentage of participants |
Comparison: Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 2 yearsp-value: 0.286695% CI: [0.66, 1.13]Regression, Logistic
Comparison: Confirmed progressors on EDSSp-value: 0.75395% CI: [0.74, 1.53]Regression, Logistic
Comparison: Confirmed progressors on T25FWp-value: 0.913795% CI: [0.74, 1.3]Regression, Logistic
Comparison: Confirmed progressors on 9HPT (either hand)p-value: 0.001295% CI: [0.4, 0.8]Regression, Logistic
Comparison: Confirmed progressors on 9HPT (dominant hand)p-value: 0.125195% CI: [0.48, 1.09]Regression, Logistic
Comparison: Confirmed progressors on 9HPT (non-dominant hand)p-value: 0.009195% CI: [0.39, 0.87]Regression, Logistic
Secondary
Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire
The ABILHAND Questionnaire measures the participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability. A positive number on change from baseline value indicates an improvement in ABILHAND.
Time frame: Baseline and Week 96
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Excludes participants who withdrew prior to 1 year (defined as stopping treatment prior to Week 48) of participation in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire | -3.45 units on a scale | Standard Deviation 14.739 |
| Natalizumab 300 mg | Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire | -2.44 units on a scale | Standard Deviation 13.023 |
p-value: 0.2586ANCOVA
Secondary
Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12)
MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A negative number on change from BL value indicates an improvement in MSWS-12.
Time frame: Baseline and Week 96
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Excludes participants who withdrew prior to 1 year (defined as stopping treatment prior to Week 48) of participation in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12) | 4.04 units on a scale | Standard Deviation 21.061 |
| Natalizumab 300 mg | Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12) | 2.70 units on a scale | Standard Deviation 22.11 |
p-value: 0.5409ANCOVA
Secondary
Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score
The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29.
Time frame: Baseline and Week 96
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Excludes participants who withdrew prior to 1 year (defined as stopping treatment prior to Week 48) of participation in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score | 3.34 units on a scale | Standard Deviation 20.947 |
| Natalizumab 300 mg | Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score | 0.61 units on a scale | Standard Deviation 19.885 |
p-value: 0.1529ANCOVA
Secondary
Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96
Whole brain volume as measured by MRI.
Time frame: Week 24 and Week 96
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Includes those participants with an assessment at Weeks 24 and 96.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96 | -0.72 percentage change | Standard Deviation 0.656 |
| Natalizumab 300 mg | Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96 | -0.66 percentage change | Standard Deviation 0.596 |
Comparison: Only participants with BL brain volume are included in the p-value calculation.p-value: 0.2424ANCOVA
Secondary
Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores
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. Participants with confirmed progression of disability in EDSS physical functional system scores will be defined as those who met one of the following criteria: * an increase of ≥ 1 point from baseline system score of ≥ 1 or an increase of ≥ 2 points from baseline system score of 0 in at least 2 physical functional systems, or * an increase of ≥ 2 points from baseline system score of ≥ 1 or an increase of ≥ 3 points from baseline system score of 0 in any 1 physical functional system. A confirmed progressor was defined as a participant who met the criteria for disability progression at any given visit and at the 6-Month Confirmation Visit. The 95% CIs are based on normal approximation.
Time frame: Up to 96 weeks
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores | 29 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores | 25 percentage of participants |
p-value: 0.105295% CI: [0.58, 1.05]Regression, Logistic
Secondary
Part 1: Percentage of Participants With a T25FW Response
T25FW response is defined as any improvement from the best pre-dose T25FW in at least 75% of the scheduled on-treatment visits through Week 96. The T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. The score for the T25FW is the average of the 2 completed trials. The 95% CI of the percentage is based on normal approximation.
Time frame: Up to 96 weeks
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Excludes participants who withdrew prior to 1 year (defined as stopping treatment prior to Week 48) of participation in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Part 1: Percentage of Participants With a T25FW Response | 17 percentage of participants |
| Natalizumab 300 mg | Part 1: Percentage of Participants With a T25FW Response | 19 percentage of participants |
p-value: 0.436995% CI: [0.8, 1.7]Regression, Logistic
Secondary
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand)
The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 156; n= 257, 271 | 5.22 seconds | Standard Deviation 27.728 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 204; n=39, 38 | 0.56 seconds | Standard Deviation 7.923 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 156; n=158, 138 | 10.12 seconds | Standard Deviation 33.675 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 204; n=24, 19 | 2.36 seconds | Standard Deviation 9.187 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 133 | -2.60 seconds | Standard Deviation 9.543 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 19 | -2.32 seconds | Standard Deviation 4.153 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 133 | -0.89 seconds | Standard Deviation 10.602 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 156; n= 257, 271 | 2.12 seconds | Standard Deviation 16.719 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 204; n=24, 19 | 6.03 seconds | Standard Deviation 21.994 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 204; n=39, 38 | 2.65 seconds | Standard Deviation 16.001 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 19 | -0.73 seconds | Standard Deviation 4.292 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 156; n=158, 138 | 5.01 seconds | Standard Deviation 20.625 |
Comparison: Overall, Week 156p-value: 0.1119ANCOVA
Comparison: CP Group: Week 156p-value: 0.1129ANCOVA
Comparison: NP Group: Week 156p-value: 0.2351ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)
The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 156; n=254, 269 | 5.24 seconds | Standard Deviation 32.91 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 204; n=40, 40 | 1.41 seconds | Standard Deviation 16.952 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 156; n=155, 137 | 11.25 seconds | Standard Deviation 39.513 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 204; n=25, 20 | 5.87 seconds | Standard Deviation 17.474 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 132 | -4.17 seconds | Standard Deviation 13.999 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 20 | -6.04 seconds | Standard Deviation 13.491 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 132 | -2.26 seconds | Standard Deviation 16.311 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 156; n=254, 269 | 4.62 seconds | Standard Deviation 30.333 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 204; n=25, 20 | 17.20 seconds | Standard Deviation 34.632 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 204; n=40, 40 | 4.91 seconds | Standard Deviation 33.808 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 20 | -7.39 seconds | Standard Deviation 28.78 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 156; n=155, 137 | 11.25 seconds | Standard Deviation 38.296 |
Comparison: Overall: Week 156p-value: 0.723ANCOVA
Comparison: CP Group: Week 156p-value: 0.8781ANCOVA
Comparison: NP Group: Week 156p-value: 0.2751ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 1) in EDSS
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. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 156; n=260, 275 | 0.11 units on a scale | Standard Deviation 0.746 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 204; n=40, 40 | -0.01 units on a scale | Standard Deviation 0.895 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in EDSS | CP Group: Change from BL to Week 156; n=162, 141 | 0.38 units on a scale | Standard Deviation 0.631 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in EDSS | CP Group: Change from BL to Week 204; n=25, 20 | 0.28 units on a scale | Standard Deviation 0.542 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in EDSS | NP Group: Change from BL to Week 156; n=98, 134 | -0.33 units on a scale | Standard Deviation 0.718 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in EDSS | NP Group: Change from BL to Week 204; n=15, 20 | -0.50 units on a scale | Standard Deviation 1.15 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in EDSS | NP Group: Change from BL to Week 156; n=98, 134 | -0.25 units on a scale | Standard Deviation 0.775 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 156; n=260, 275 | 0.06 units on a scale | Standard Deviation 0.797 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in EDSS | CP Group: Change from BL to Week 204; n=25, 20 | 0.68 units on a scale | Standard Deviation 0.634 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 204; n=40, 40 | 0.15 units on a scale | Standard Deviation 0.928 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in EDSS | NP Group: Change from BL to Week 204; n=15, 20 | -0.38 units on a scale | Standard Deviation 0.887 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in EDSS | CP Group: Change from BL to Week 156; n=162, 141 | 0.36 units on a scale | Standard Deviation 0.703 |
Comparison: Overall: Week 156p-value: 0.433ANCOVA
Comparison: CP Group: Week 156p-value: 0.7122ANCOVA
Comparison: NP Group: Week 156p-value: 0.3861ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 1) in T25FW
The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Lower scores on time taken to reach 25 foot mark reflect a better outcome. Values are presented for the overall group, as well as the Confirmed Progressor (CP, defined in the primary outcome measure description above) and Non-Progressor (NP) subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in T25FW | Overall: Change from BL to Week 156; n=255, 264 | 12.80 seconds | Standard Deviation 35.111 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in T25FW | Overall: Change from BL to Week 204; n=39, 38 | 25.01 seconds | Standard Deviation 56.582 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in T25FW | CP Group: Change from BL to Week 156; n=156, 135 | 21.67 seconds | Standard Deviation 42.51 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in T25FW | CP Group: Change from BL to Week 204; n=25, 18 | 40.06 seconds | Standard Deviation 66.275 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in T25FW | NP Group: Change from BL to Week 156; n=99, 129 | -1.17 seconds | Standard Deviation 3.804 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in T25FW | NP Group: Change from BL to Week 204; n=14, 20 | -1.88 seconds | Standard Deviation 5.917 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in T25FW | NP Group: Change from BL to Week 156; n=99, 129 | -1.09 seconds | Standard Deviation 3.593 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in T25FW | Overall: Change from BL to Week 156; n=255, 264 | 7.78 seconds | Standard Deviation 21.251 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in T25FW | CP Group: Change from BL to Week 204; n=25, 18 | 20.89 seconds | Standard Deviation 28.2 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in T25FW | Overall: Change from BL to Week 204; n=39, 38 | 9.01 seconds | Standard Deviation 22.507 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in T25FW | NP Group: Change from BL to Week 204; n=14, 20 | -1.67 seconds | Standard Deviation 4.613 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in T25FW | CP Group: Change from BL to Week 156; n=156, 135 | 16.26 seconds | Standard Deviation 26.943 |
Comparison: Week 156p-value: 0.0273ANCOVA
Comparison: CP Group: Week 156p-value: 0.1974ANCOVA
Comparison: NP Group: Week 156p-value: 0.2506ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT)
The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
Time frame: Baseline (Part 1) and Weeks 156 and 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) | Change from BL to Week 156; n=272, 289 | -32.1 meters | Standard Deviation 117.55 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) | Change from BL to Week 204; n=272, 290 | -33.3 meters | Standard Deviation 119.4 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) | Change from BL to Week 156; n=272, 289 | -40.4 meters | Standard Deviation 219.6 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) | Change from BL to Week 204; n=272, 290 | -40.7 meters | Standard Deviation 219.58 |
Comparison: Week 156p-value: 0.8066ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score
The 29-item MSIS-29 is a patient-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a patient's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29.
Time frame: Baseline (Part 1) and Weeks 156 and 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2) who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score | Change from BL to Week 156 | 0.32 units on a scale | Standard Deviation 20.943 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score | Change to from BL Week 204 | 0.91 units on a scale | Standard Deviation 21.018 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score | Change from BL to Week 156 | 0.05 units on a scale | Standard Deviation 20.843 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score | Change to from BL Week 204 | -0.28 units on a scale | Standard Deviation 20.596 |
p-value: 0.7084ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT)
SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best).
Time frame: Baseline (Part 1) and every 4 weeks from Week 108 to Week 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2). Missing values were imputed using last observation carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 180 | 15.5 units on a scale | Standard Deviation 15.23 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 108 | 13.6 units on a scale | Standard Deviation 14.19 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 112 | 14.4 units on a scale | Standard Deviation 13.72 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 116 | 14.1 units on a scale | Standard Deviation 13.84 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 120 | 14.3 units on a scale | Standard Deviation 14.23 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 124 | 14.4 units on a scale | Standard Deviation 14.02 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 128 | 15.1 units on a scale | Standard Deviation 14.49 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 132 | 15.1 units on a scale | Standard Deviation 14.52 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 136 | 14.8 units on a scale | Standard Deviation 14.56 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 140 | 15.4 units on a scale | Standard Deviation 14.98 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 144 | 15.7 units on a scale | Standard Deviation 15.23 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 148 | 15.5 units on a scale | Standard Deviation 15.34 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 152 | 15.5 units on a scale | Standard Deviation 14.98 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 156 | 11.2 units on a scale | Standard Deviation 13.1 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 160 | 15.2 units on a scale | Standard Deviation 14.92 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 164 | 15.6 units on a scale | Standard Deviation 15.21 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 168 | 15.8 units on a scale | Standard Deviation 15.52 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 172 | 15.6 units on a scale | Standard Deviation 15.4 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 176 | 15.5 units on a scale | Standard Deviation 15.58 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 200 | 15.7 units on a scale | Standard Deviation 15.47 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 184 | 15.6 units on a scale | Standard Deviation 15.34 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 188 | 15.6 units on a scale | Standard Deviation 15.38 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 192 | 15.6 units on a scale | Standard Deviation 15.46 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 196 | 15.7 units on a scale | Standard Deviation 15.45 |
| Placebo | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 204 | 15.7 units on a scale | Standard Deviation 15.43 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 180 | 16.4 units on a scale | Standard Deviation 14.89 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 156 | 12.3 units on a scale | Standard Deviation 14.59 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 108 | 15.5 units on a scale | Standard Deviation 13.82 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 204 | 16.3 units on a scale | Standard Deviation 14.69 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 112 | 15.1 units on a scale | Standard Deviation 13.5 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 160 | 16.2 units on a scale | Standard Deviation 14.61 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 116 | 15.3 units on a scale | Standard Deviation 13.51 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 184 | 16.3 units on a scale | Standard Deviation 14.81 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 120 | 15.3 units on a scale | Standard Deviation 13.68 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 164 | 16.3 units on a scale | Standard Deviation 14.64 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 124 | 15.7 units on a scale | Standard Deviation 13.69 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 196 | 16.3 units on a scale | Standard Deviation 14.69 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 128 | 15.7 units on a scale | Standard Deviation 13.72 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 168 | 16.4 units on a scale | Standard Deviation 14.78 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 132 | 15.6 units on a scale | Standard Deviation 13.63 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 188 | 16.4 units on a scale | Standard Deviation 14.77 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 136 | 16.3 units on a scale | Standard Deviation 13.75 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 172 | 16.3 units on a scale | Standard Deviation 14.64 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 140 | 16.4 units on a scale | Standard Deviation 14.29 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 200 | 16.3 units on a scale | Standard Deviation 14.69 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 144 | 16.2 units on a scale | Standard Deviation 14.22 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 176 | 16.3 units on a scale | Standard Deviation 14.91 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 148 | 16.3 units on a scale | Standard Deviation 14.35 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 192 | 16.3 units on a scale | Standard Deviation 14.79 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | Change from BL to Week 152 | 16.3 units on a scale | Standard Deviation 14.25 |
Comparison: Week 156p-value: 0.3465ANCOVA
Secondary
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire
The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (percentage of overall work impairment \[absenteeism plus presenteeism\]) 4. Activity Impairment (percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
Time frame: Part 2 Baseline (Week 108) and Weeks 156 and 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2) who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Absenteeism: Week 108 | 2.6 percentage of impairment | Standard Deviation 12.8 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Absenteeism: Week 156 | 3.0 percentage of impairment | Standard Deviation 14.61 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Absenteeism: Week 204 | 3.0 percentage of impairment | Standard Deviation 14.61 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Presenteeism: Week 108 | 30.6 percentage of impairment | Standard Deviation 12.1 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Presenteeism: Week 156 | 30.8 percentage of impairment | Standard Deviation 12.17 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Presenteeism: Week 204 | 31.0 percentage of impairment | Standard Deviation 12.29 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Work Productivity Loss: Week 108 | 30.9 percentage of impairment | Standard Deviation 12.36 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Work Productivity Loss: Week 156 | 31.6 percentage of impairment | Standard Deviation 13.54 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Work Productivity Loss: Week 204 | 31.9 percentage of impairment | Standard Deviation 13.66 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Activity Impairment: Week 108 | 56.1 percentage of impairment | Standard Deviation 24.78 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Activity Impairment: Week 156 | 56.8 percentage of impairment | Standard Deviation 26.49 |
| Placebo | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Activity Impairment: Week 204 | 57.2 percentage of impairment | Standard Deviation 25.15 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Activity Impairment: Week 156 | 58.5 percentage of impairment | Standard Deviation 24.08 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Absenteeism: Week 108 | 1.4 percentage of impairment | Standard Deviation 8.24 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Work Productivity Loss: Week 108 | 31.2 percentage of impairment | Standard Deviation 11.7 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Absenteeism: Week 156 | 4.1 percentage of impairment | Standard Deviation 17.36 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Activity Impairment: Week 108 | 58.0 percentage of impairment | Standard Deviation 24.84 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Absenteeism: Week 204 | 4.2 percentage of impairment | Standard Deviation 16.89 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Work Productivity Loss: Week 156 | 33.9 percentage of impairment | Standard Deviation 15.75 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Presenteeism: Week 108 | 30.9 percentage of impairment | Standard Deviation 11.71 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Activity Impairment: Week 204 | 59.8 percentage of impairment | Standard Deviation 23.6 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Presenteeism: Week 156 | 33.0 percentage of impairment | Standard Deviation 14.23 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Work Productivity Loss: Week 204 | 33.3 percentage of impairment | Standard Deviation 15.61 |
| Natalizumab 300 mg | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | Presenteeism: Week 204 | 32.2 percentage of impairment | Standard Deviation 13.78 |
Secondary
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand)
The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 156; n=257, 271 | 14.32 percentage change | Standard Deviation 59.727 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 204; n=39, 38 | 2.27 percentage change | Standard Deviation 19.193 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 156; n=158, 138 | 25.87 percentage change | Standard Deviation 72.621 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 204; n=24, 19 | 8.43 percentage change | Standard Deviation 20.247 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 133 | -4.10 percentage change | Standard Deviation 17.661 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 19 | -7.57 percentage change | Standard Deviation 12.56 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 133 | -2.63 percentage change | Standard Deviation 19.436 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 156; n=257, 271 | 5.25 percentage change | Standard Deviation 32.649 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 204; n=24, 19 | 16.25 percentage change | Standard Deviation 41.317 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | Overall: Change from BL to Week 204; n=39, 38 | 6.87 percentage change | Standard Deviation 32.333 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 19 | -2.52 percentage change | Standard Deviation 15.998 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | CP Group: Change from BL to Week 156; n=158, 138 | 12.84 percentage change | Standard Deviation 40.232 |
Comparison: Overall: Week 156p-value: 0.0261ANCOVA
Comparison: CP Group: Week 156p-value: 0.0585ANCOVA
Comparison: NP Group: Week 156p-value: 0.6095ANCOVA
Secondary
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)
The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 156; n=254, 269 | 13.87 percentage change | Standard Deviation 64.959 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 204; n=40, 40 | 3.67 percentage change | Standard Deviation 28.755 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 156; n=155, 137 | 26.33 percentage change | Standard Deviation 79.957 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 204; n=25, 20 | 11.87 percentage change | Standard Deviation 31.05 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 132 | -5.63 percentage change | Standard Deviation 14.765 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 20 | -9.98 percentage change | Standard Deviation 18.188 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 156; n=99, 132 | -1.89 percentage change | Standard Deviation 24.987 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 156; n=254, 269 | 11.04 percentage change | Standard Deviation 47.942 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 204; n=25, 20 | 43.12 percentage change | Standard Deviation 80.639 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | Overall: Change from BL to Week 204; n=40, 40 | 18.57 percentage change | Standard Deviation 62.537 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | NP Group: Change from BL to Week 204; n=15, 20 | -5.98 percentage change | Standard Deviation 16.005 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | CP Group: Change from BL to Week 156; n=155, 137 | 23.51 percentage change | Standard Deviation 60.074 |
Comparison: Overall: Week 156p-value: 0.5051ANCOVA
Comparison: CP Group: Week 156p-value: 0.7283ANCOVA
Comparison: NP Group: Week 156p-value: 0.1666ANCOVA
Secondary
Part 2: Percentage Change From Baseline (Part 1) in EDSS
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. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in EDSS | CP Group Change from BL to Week 204; n=25, 20 | 5.31 percentage change | Standard Deviation 10.711 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 204; n=40, 40 | -0.63 percentage change | Standard Deviation 17.889 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in EDSS | NP Group Change from BL to Week 156; n=98, 134 | -6.47 percentage change | Standard Deviation 13.951 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 156; n=260, 275 | 2.07 percentage change | Standard Deviation 15.188 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in EDSS | NP Group Change from BL to Week 204; n=15, 20 | -10.53 percentage change | Standard Deviation 22.953 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in EDSS | CP Group Change from BL to Week 156; n=162, 141 | 7.23 percentage change | Standard Deviation 13.513 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in EDSS | NP Group Change from BL to Week 204; n=15, 20 | -7.35 percentage change | Standard Deviation 17.26 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 156; n=260, 275 | 1.65 percentage change | Standard Deviation 16.53 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in EDSS | Overall: Change from BL to Week 204; n=40, 40 | 2.91 percentage change | Standard Deviation 18.656 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in EDSS | CP Group Change from BL to Week 204; n=25, 20 | 13.18 percentage change | Standard Deviation 13.957 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in EDSS | NP Group Change from BL to Week 156; n=98, 134 | -4.29 percentage change | Standard Deviation 15.266 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in EDSS | CP Group Change from BL to Week 156; n=162, 141 | 7.30 percentage change | Standard Deviation 15.728 |
Comparison: Overall: Week 156p-value: 0.7225ANCOVA
Comparison: CP Group: Week 156p-value: 0.9121ANCOVA
Comparison: NP Group: Week 156p-value: 0.2594ANCOVA
Secondary
Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions
New or enlarging T2 lesions as measured by MRI.
Time frame: Baseline (Part 1) and Weeks 156 and 204
Population: Summary new/enlarging T2 lesion values are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data up to Week 204, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary, and the analysis was not done.
Secondary
Part 2: Percentage Change From Baseline (Part 1) in T25FW
The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in T25FW | Overall: Change from BL at Week 156; n=255, 264 | 75.52 percentage change | Standard Deviation 166.191 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in T25FW | Overall: Change from BL at Week 204; n=39, 38 | 130.72 percentage change | Standard Deviation 272.117 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in T25FW | CP Group: Change from BL at Week 156; n=156, 135 | 127.05 percentage change | Standard Deviation 195.138 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in T25FW | CP Group: Change from BL at Week 204; n=25, 18 | 206.78 percentage change | Standard Deviation 316.344 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in T25FW | NP Group: Change from BL at Week 156; n=99, 129 | -5.68 percentage change | Standard Deviation 21.708 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in T25FW | NP Group: Change from BL at Week 204; n=14, 20 | -5.09 percentage change | Standard Deviation 26.591 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in T25FW | NP Group: Change from BL at Week 156; n=99, 129 | -4.37 percentage change | Standard Deviation 25.05 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in T25FW | Overall: Change from BL at Week 156; n=255, 264 | 55.91 percentage change | Standard Deviation 130.286 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in T25FW | CP Group: Change from BL at Week 204; n=25, 18 | 158.91 percentage change | Standard Deviation 228.458 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in T25FW | Overall: Change from BL at Week 204; n=39, 38 | 71.09 percentage change | Standard Deviation 177.668 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in T25FW | NP Group: Change from BL at Week 204; n=14, 20 | -7.94 percentage change | Standard Deviation 29.856 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in T25FW | CP Group: Change from BL at Week 156; n=156, 135 | 113.51 percentage change | Standard Deviation 160.857 |
Comparison: Overall: Week 156p-value: 0.096ANCOVA
Comparison: CP Group: Week 156p-value: 0.4957ANCOVA
Comparison: NP Group: Week 156p-value: 0.2916ANCOVA
Secondary
Part 2: Percentage Change From Baseline (Part 1) in the 6MWT
The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Actual change from baseline tables are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data on Weeks 204 and 252, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary.
Secondary
Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score
The 29-item MSIS-29 is a patient-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a patient's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29.
Time frame: Baseline (Part 1) and Weeks 156, 204
Population: Actual change from baseline tables are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data on Weeks 204 and 252, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary.
Secondary
Part 2: Percentage Change From Baseline (Part 1) in the SDMT
SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best).
Time frame: Baseline (Part 1) and every 4 weeks from Week 108 to Week 204
Population: Actual change from baseline tables are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data up to Weeks 204 and 252, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary, and the analysis was not done.
Secondary
Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume
Whole grey matter brain volume as measured by MRI.
Time frame: Baseline (Part 1) and Weeks 156 and 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume | Change from Baseline to Week 156; n=149, 170 | -1.566 percentage change | Standard Deviation 0.9303 |
| Placebo | Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume | Change from Baseline to Week 204; n=26, 20 | -1.883 percentage change | Standard Deviation 1.4222 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume | Change from Baseline to Week 156; n=149, 170 | -1.514 percentage change | Standard Deviation 0.8969 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume | Change from Baseline to Week 204; n=26, 20 | -2.086 percentage change | Standard Deviation 0.9068 |
Comparison: Percentage hange from Baseline to Week 156p-value: 0.5034ANCOVA
Secondary
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire
The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (WPL; percentage of overall work impairment \[absenteeism plus presenteeism\]) 4. Activity Impairment (AI; percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
Time frame: Part 2 Baseline (Week 108) and Weeks 156 and 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Absenteeism: Change at Week 156; n=18,17 | -10.3 percentage change | Standard Deviation 116.81 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Absenteeism: Change at Week 204; n=18, 17 | -6.6 percentage change | Standard Deviation 116.9 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Presenteeism: Change at Week 156; n=264, 285 | 4.0 percentage change | Standard Deviation 50.08 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Presenteeism: Change at Week 204; n=264, 285 | 5.3 percentage change | Standard Deviation 51.23 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | WPL: Change at Week 156; n=264,286 | 4.7 percentage change | Standard Deviation 51.73 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | WPL: Change at Week 204; n=264, 286 | 5.9 percentage change | Standard Deviation 53.44 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | AI: Change at Week 156; n=264, 284 | 16.0 percentage change | Standard Deviation 95.68 |
| Placebo | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | AI: Change at Week 204; n=264, 284 | 16.1 percentage change | Standard Deviation 88.56 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | AI: Change at Week 204; n=264, 284 | 20.4 percentage change | Standard Deviation 99.54 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Absenteeism: Change at Week 156; n=18,17 | -7.4 percentage change | Standard Deviation 95.77 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | WPL: Change at Week 156; n=264,286 | 16.8 percentage change | Standard Deviation 95.43 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Absenteeism: Change at Week 204; n=18, 17 | 151.5 percentage change | Standard Deviation 457.29 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | AI: Change at Week 156; n=264, 284 | 15.7 percentage change | Standard Deviation 83.7 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Presenteeism: Change at Week 156; n=264, 285 | 14.4 percentage change | Standard Deviation 90.39 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | WPL: Change at Week 204; n=264, 286 | 10.6 percentage change | Standard Deviation 69.34 |
| Natalizumab 300 mg | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | Presenteeism: Change at Week 204; n=264, 285 | 7.4 percentage change | Standard Deviation 58.95 |
Secondary
Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume
Whole brain volume as measured by MRI.
Time frame: Week 24 (Part 1) and Weeks 156 and 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume | Change from Week 24 to Week 156; n=155, 175 | -1.164 percentage change | Standard Deviation 0.8228 |
| Placebo | Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume | Change from Week 24 to Week 204; n=28, 24 | -1.687 percentage change | Standard Deviation 1.2872 |
| Natalizumab 300 mg | Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume | Change from Week 24 to Week 156; n=155, 175 | -0.948 percentage change | Standard Deviation 0.7193 |
| Natalizumab 300 mg | Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume | Change from Week 24 to Week 204; n=28, 24 | -1.517 percentage change | Standard Deviation 0.8412 |
Comparison: Percentage change from Week 24 to Week 156p-value: 0.007ANCOVA
Secondary
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks
Percentage of participants with disability worsening at each scheduled efficacy visit in Part 2, defined as one or more of the following: • ≥ 20% worsening from Part 1 baseline in T25FW; • ≥ 20% worsening from Part 1 baseline in 9HPT; • Worsening from Part 1 baseline in EDSS (≥ 1 point increase if Part 1 baseline EDSS ≤ 5.5 or ≥ 0.5 point increase if Part 1 baseline EDSS \> 5.5). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. 95% CIs of percentages are based on normal approximation.
Time frame: Week 156
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on ≥1 of EDSS, T25FW, 9HPT at 156 weeks | 61 percentage of participants |
| Placebo | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on EDSS at 156 weeks | 23 percentage of participants |
| Placebo | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on T25FW at 156 weeks | 46 percentage of participants |
| Placebo | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on 9HPT (either hand) at 156 weeks | 28 percentage of participants |
| Placebo | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on 9HPT (dominant hand) at 156 weeks | 18 percentage of participants |
| Placebo | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on 9HPT (non-dominant hand) at 156 weeks | 18 percentage of participants |
| Natalizumab 300 mg | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on 9HPT (dominant hand) at 156 weeks | 12 percentage of participants |
| Natalizumab 300 mg | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on ≥1 of EDSS, T25FW, 9HPT at 156 weeks | 52 percentage of participants |
| Natalizumab 300 mg | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on 9HPT (either hand) at 156 weeks | 19 percentage of participants |
| Natalizumab 300 mg | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on EDSS at 156 weeks | 18 percentage of participants |
| Natalizumab 300 mg | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on 9HPT (non-dominant hand) at 156 weeks | 13 percentage of participants |
| Natalizumab 300 mg | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Confirmed on T25FW at 156 weeks | 41 percentage of participants |
Comparison: Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 156 weeksp-value: 0.020595% CI: [0.47, 0.94]Regression, Logistic
Comparison: Confirmed progressors on EDSS at 156 weeksp-value: 0.130595% CI: [0.48, 1.1]Regression, Logistic
Comparison: Confirmed progressors on T25FW at 156 weeksp-value: 0.198895% CI: [0.57, 1.12]Regression, Logistic
Comparison: Confirmed progressors on 9HPT (either hand) at 156 weeksp-value: 0.009395% CI: [0.39, 0.88]Regression, Logistic
Comparison: Confirmed progressors onm 9HPT (dominant hand) at 156 weeksp-value: 0.05495% CI: [0.39, 1.01]Regression, Logistic
Comparison: Confirmed progressors on 9HPT (non-dominant hand) at 156 weeksp-value: 0.14195% CI: [0.44, 1.12]Regression, Logistic
Secondary
Part 2: Summary of New/Enlarging T2 Lesion Counts
New or enlarging T2 lesions as measured by MRI.
Time frame: Baseline (Part 1) up to Week 204
Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 24 compared to BL; n=272, 287 | 2.1 lesions | Standard Deviation 4.24 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 48 compared to Week 24; n=272, 289 | 1.8 lesions | Standard Deviation 4.47 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 72 compared to Week 48; n=271, 287 | 1.6 lesions | Standard Deviation 3.76 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 96 compared to Week 72; n=269, 284 | 1.8 lesions | Standard Deviation 4.33 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 108 compared to Week 96; n=269, 288 | 1.2 lesions | Standard Deviation 3.38 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 156 compared to Week 108; n=245, 258 | 0.2 lesions | Standard Deviation 0.79 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 204 compared to Week 156; n=50, 47 | 0.0 lesions | Standard Deviation 0.2 |
| Placebo | Part 2: Summary of New/Enlarging T2 Lesion Counts | Cumulative count from BL to Week 204; n=274, 291 | 8.6 lesions | Standard Deviation 16.04 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | Cumulative count from BL to Week 204; n=274, 291 | 0.7 lesions | Standard Deviation 3.53 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 24 compared to BL; n=272, 287 | 0.6 lesions | Standard Deviation 3.27 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 108 compared to Week 96; n=269, 288 | 0.0 lesions | Standard Deviation 0.13 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 48 compared to Week 24; n=272, 289 | 0.0 lesions | Standard Deviation 0.37 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 204 compared to Week 156; n=50, 47 | 0.0 lesions | Standard Deviation 0.15 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 72 compared to Week 48; n=271, 287 | 0.0 lesions | Standard Deviation 0.19 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 156 compared to Week 108; n=245, 258 | 0.0 lesions | Standard Deviation 0.2 |
| Natalizumab 300 mg | Part 2: Summary of New/Enlarging T2 Lesion Counts | At Week 96 compared to Week 72; n=269, 284 | 0.0 lesions | Standard Deviation 0 |
Comparison: Week 156p-value: <0.0001negative binomial regression model