ASCEND in SPMS: A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis
Sponsor
Biogen (Industry)
Overall Status
Terminated
CT.gov ID
NCT01416181
Collaborator
(none)
889
161
2
55
5.5
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
889 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis, With Optional Open-Label Extension
Actual Study Start Date
:
Sep 13, 2011
Actual Primary Completion Date
:
Jul 28, 2015
Actual Study Completion Date
:
Apr 13, 2016
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: natalizumab In Part 1 participants were randomized to receive 300 mg of natalizumab intravenously (IV) every 4 weeks for 96 weeks. In Part 2 participants transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks. |
Drug: natalizumab
Administered as specified in the treatment arm
Other Names:
|
| Experimental: Placebo In Part 1 participants were randomized to receive placebo IV every 4 weeks for 96 weeks. In Part 2 participants transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks. |
Drug: natalizumab
Administered as specified in the treatment arm
Other Names:
Drug: Placebo
Matched placebo in part 1
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- 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 Change From Week 24 in Whole Brain Volume at Week 96 [Week 24 and Week 96]
Whole brain volume as measured by MRI.
- 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 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 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 58 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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 Exclusion Criteria (Part 2):
-
Subjects with any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in this extension study. The Investigator must re-review the subject's medical fitness for participation and consider any diseases that would preclude treatment.
-
Subjects who discontinued study treatment in Part 1 OR had fewer than 20 infusions in Part 1 OR missed 2 or more consecutive infusions in Part 1.
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Phoenix | Arizona | United States | 85013 |
| 2 | Research Site | Tucson | Arizona | United States | 85741 |
| 3 | Research Site | Fullerton | California | United States | 92835 |
| 4 | Research Site | Los Angeles | California | United States | 90027 |
| 5 | Research Site | Aurora | Colorado | United States | 80045 |
| 6 | Research Site | Tampa | Florida | United States | 33612 |
| 7 | Research Site | Chicago | Illinois | United States | 60637 |
| 8 | Research Site | Lake Barrington | Illinois | United States | 60010 |
| 9 | Research Site | Peoria | Illinois | United States | 61606 |
| 10 | Research Site | Indianapolis | Indiana | United States | 46202 |
| 11 | Research Site | Indianapolis | Indiana | United States | 46256 |
| 12 | Research Site | Kansas City | Kansas | United States | 66160 |
| 13 | Research Site | Lexington | Kentucky | United States | 40513 |
| 14 | Research Site | Lexington | Kentucky | United States | 40536 |
| 15 | Research Site | Baltimore | Maryland | United States | 21287 |
| 16 | Research Site | Burlington | Massachusetts | United States | 01805 |
| 17 | Research Site | Omaha | Nebraska | United States | 68198 |
| 18 | Research Site | Lebanon | New Hampshire | United States | 03756 |
| 19 | Research Site | Teaneck | New Jersey | United States | 07666 |
| 20 | Research Site | Latham | New York | United States | 12110 |
| 21 | Research Site | New York | New York | United States | 10029 |
| 22 | Research Site | Advance | North Carolina | United States | 27006 |
| 23 | Research Site | Charlotte | North Carolina | United States | 28207 |
| 24 | Research Site | Raleigh | North Carolina | United States | 27607 |
| 25 | Research Site | Akron | Ohio | United States | 44320 |
| 26 | Research Site | Uniontown | Ohio | United States | 44685 |
| 27 | Research Site | Oklahoma City | Oklahoma | United States | 73104 |
| 28 | Research Site | Clackamas | Oregon | United States | 97015 |
| 29 | Research Site | Portland | Oregon | United States | 97225 |
| 30 | Research Site | Portland | Oregon | United States | 97239 |
| 31 | Research Site | Nashville | Tennessee | United States | 37215 |
| 32 | Research Site | Charlottesville | Virginia | United States | 22903 |
| 33 | Research Site | Seattle | Washington | United States | 98101 |
| 34 | Research Site | Green Bay | Wisconsin | United States | 54311 |
| 35 | Research Site | Milwaukee | Wisconsin | United States | 53215 |
| 36 | Research Site | La Louviere | Belgium | 7100 | |
| 37 | Research Site | Melsbroek | Belgium | 1820 | |
| 38 | Research Site | Overpelt | Belgium | 3900 | |
| 39 | Research Site | Calgary | Alberta | Canada | T2N 2T9 |
| 40 | Research Site | Edmonton | Alberta | Canada | T6G 2G3 |
| 41 | Research Site | Vancouver | British Columbia | Canada | V6T 1Z3 |
| 42 | Research Site | Halifax | Nova Scotia | Canada | B3H 4K4 |
| 43 | Research Site | Kingston | Ontario | Canada | K7L 2V7 |
| 44 | Research Site | London | Ontario | Canada | N6A 5A5 |
| 45 | Research Site | Ottawa | Ontario | Canada | K1H 8L6 |
| 46 | Research Site | Toronto | Ontario | Canada | M4N 3M5 |
| 47 | Research Site | Gatineau | Quebec | Canada | J9J 0A5 |
| 48 | Research Site | Greenfield Park | Quebec | Canada | J4V 2J2 |
| 49 | Research Site | Montreal | Quebec | Canada | H2L 4M1 |
| 50 | Research Site | Montreal | Quebec | Canada | H3A 2B4 |
| 51 | Research Site | Hradec Kralove | Bohemia | Czechia | 50005 |
| 52 | Research Site | Brno | Czechia | 65691 | |
| 53 | Research Site | Olomouc | Czechia | 77520 | |
| 54 | Research Site | Praha | Czechia | 12111 | |
| 55 | Research Site | Arthus C | Denmark | 8000 | |
| 56 | Research Site | Esbjerg | Denmark | 6700 | |
| 57 | Research Site | Glostrup | Denmark | 2600 | |
| 58 | Research Site | København Ø | Denmark | 2100 | |
| 59 | Research Site | Odense | Denmark | 5000 | |
| 60 | Research Site | Jyväskylä | Finland | 40620 | |
| 61 | Research Site | Tampere | Finland | 33520 | |
| 62 | Research Site | Turku | Finland | 20520 | |
| 63 | Research Site | Nice | Alpes Maritimes | France | 06002 |
| 64 | Research Site | Marseille cedex 5 | Bouches-du-Rhône | France | 13385 |
| 65 | Research Site | Nantes | Loire Atlantique | France | 44093 |
| 66 | Research Site | Nancy | Meurthe et Moselle | France | 54035 |
| 67 | Research Site | Lille Cedex | Nord | France | 59000 |
| 68 | Research Site | Bron cedex | Rhone | France | 69677 |
| 69 | Research Site | Salouel | Somme | France | 80054 |
| 70 | Research Site | Bordeaux | France | 33076 | |
| 71 | Research Site | Bad Wilbad | Baden Wuerttemberg | Germany | 75323 |
| 72 | Research Site | Tuebingen | Baden Wuerttemberg | Germany | 72076 |
| 73 | Research Site | Bad Mergentheim | Baden-Wuerttemberg | Germany | 97980 |
| 74 | Research Site | Muenchen | Bayern | Germany | 81377 |
| 75 | Research Site | Muenchen | Bayern | Germany | 81675 |
| 76 | Research Site | Hennigsdorf | Brandenburg | Germany | 16761 |
| 77 | Research Site | Teupitz | Brandenburg | Germany | 15755 |
| 78 | Research Site | Kassel | Hessen | Germany | 34121 |
| 79 | Research Site | Duesseldorf | Nordrhein Westfalen | Germany | 40225 |
| 80 | Research Site | Muenster | Nordrhein Westfalen | Germany | 48149 |
| 81 | Research Site | Dresden | Sachsen | Germany | 01307 |
| 82 | Research Site | Dublin | Ireland | D4 | |
| 83 | Research Site | Dublin | Ireland | D9 | |
| 84 | Research Site | Jerusalem | Israel | 91120 | |
| 85 | Research Site | Ramat Gan | Israel | 52621 | |
| 86 | Research Site | Baggiovara | Modena | Italy | 41100 |
| 87 | Research Site | Cefalu | Palermo | Italy | 90015 |
| 88 | Research Site | Gallarate | Varese | Italy | 21013 |
| 89 | Research Site | Bari | Italy | 70124 | |
| 90 | Research Site | Florence | Italy | 50134 | |
| 91 | Research Site | Genova | Italy | 16132 | |
| 92 | Research Site | Milano | Italy | 20122 | |
| 93 | Research Site | Milano | Italy | 20132 | |
| 94 | Research Site | Naples | Italy | 80138 | |
| 95 | Research Site | Napoli | Italy | 80131 | |
| 96 | Research Site | Palermo | Italy | 90146 | |
| 97 | Research Site | Pavia | Italy | 27100 | |
| 98 | Research Site | Rome | Italy | 00176 | |
| 99 | Research Site | Rome | Italy | 00189 | |
| 100 | Research Site | Amsterdam | Netherlands | 1081 HV | |
| 101 | Research Site | Breda | Netherlands | 4800 RK | |
| 102 | Research Site | Hertogenbosch | Netherlands | 5223 GZ | |
| 103 | Research Site | Hoorn | Netherlands | 1624 NP | |
| 104 | Research Site | Nieuwegein | Netherlands | 3430 EM | |
| 105 | Research Site | Sittard-Geleen | Netherlands | 6130 MB | |
| 106 | Research Site | Bialystok | Poland | 15-276 | |
| 107 | Research Site | Gdansk | Poland | 80-803 | |
| 108 | Research Site | Katowice | Poland | 40-595 | |
| 109 | Research Site | Katowice | Poland | 40-635 | |
| 110 | Research Site | Katowice | Poland | 40-749 | |
| 111 | Research Site | Krakow | Poland | 31-505 | |
| 112 | Research Site | Lodz | Poland | 90-324 | |
| 113 | Research Site | Lublin | Poland | 20-954 | |
| 114 | Research Site | Olsztyn | Poland | 10-561 | |
| 115 | Research Site | Plewiska | Poland | 62-064 | |
| 116 | Research Site | Poznan | Poland | 61-853 | |
| 117 | Research Site | Szczecin | Poland | 70-111 | |
| 118 | Research Site | Warszawa-Miedzylesie | Poland | 04-749 | |
| 119 | Research Site | Warszawa | Poland | 01-697 | |
| 120 | Research Site | Warszawa | Poland | 02-097 | |
| 121 | Research Site | Warszawa | Poland | 04-141 | |
| 122 | Research Site | Wroclaw | Poland | 50-556 | |
| 123 | Research Site | Belgorod | Russian Federation | 308007 | |
| 124 | Research Site | Kazan | Russian Federation | 420021 | |
| 125 | Research Site | Kazan | Russian Federation | 420097 | |
| 126 | Research Site | Moscow | Russian Federation | 127015 | |
| 127 | Research Site | St. Petersburg | Russian Federation | 197110 | |
| 128 | Research Site | Tyumen | Russian Federation | 625000 | |
| 129 | Research Site | Barcelona | Spain | 08035 | |
| 130 | Research Site | Barcelona | Spain | 08036 | |
| 131 | Research Site | Barcelona | Spain | 08041 | |
| 132 | Research Site | El Palmar | Spain | 30120 | |
| 133 | Research Site | Madrid | Spain | 28034 | |
| 134 | Research Site | Madrid | Spain | 28040 | |
| 135 | Research Site | Majadahonda | Spain | 28222 | |
| 136 | Research Site | Málaga | Spain | 29010 | |
| 137 | Research Site | Santa Cruz de Tenerife | Spain | 38010 | |
| 138 | Research Site | Sevilla | Spain | 41009 | |
| 139 | Research Site | Göteborg | Sweden | 41345 | |
| 140 | Research Site | Stockholm | Sweden | 14186 | |
| 141 | Research Site | Stockholm | Sweden | 17176 | |
| 142 | Research Site | Stockholm | Sweden | 18288 | |
| 143 | Research Site | Umeå | Sweden | 90185 | |
| 144 | Research Site | Örebro | Sweden | 70185 | |
| 145 | Research Site | Irvine | Ayrshire | United Kingdom | KA12 8SS |
| 146 | Research Site | Edgbaston | Birmingham | United Kingdom | B15 2TH |
| 147 | Research Site | Exeter | Devon | United Kingdom | EX2 5DW |
| 148 | Research Site | Plymouth | Devon | United Kingdom | PL6 8BX |
| 149 | Research Site | London | Greater London | United Kingdom | E1 2AT |
| 150 | Research Site | London | Greater London | United Kingdom | SE5 9RS |
| 151 | Research Site | Hammersmith | London | United Kingdom | W6 8RF |
| 152 | Research Site | Edinburgh | Lothian Region | United Kingdom | EH4 2XU |
| 153 | Research Site | Salford | Manchester | United Kingdom | M6 8HD |
| 154 | Research Site | Liverpool | Merseyside | United Kingdom | L9 7LJ |
| 155 | Research Site | Norwich | Norfolk | United Kingdom | NR4 7UY |
| 156 | Research Site | Nottingham | Nottinghamshire | United Kingdom | NG7 2UH |
| 157 | Research Site | Morriston | Swansea | United Kingdom | SA6 6NL |
| 158 | Research Site | Newcastle | Tyne | United Kingdom | NE1 4LP |
| 159 | Research Site | Brighton | United Kingdom | BN2 5BE | |
| 160 | Research Site | London | United Kingdom | WC1N 3BG | |
| 161 | Research Site | Sheffield | United Kingdom | S10 2JF |
Sponsors and Collaborators
- Biogen
Investigators
- Study Director: Medical Director, Biogen
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Biogen
ClinicalTrials.gov Identifier:
NCT01416181
Other Study ID Numbers:
- 101MS326
- 2010-021978-11
First Posted:
Aug 12, 2011
Last Update Posted:
Sep 11, 2017
Last Verified:
Aug 1, 2017
Keywords provided by Biogen
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | Part 1: participants were randomized to receive placebo intravenously (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. | 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. |
| Period Title: Part 1 | ||
| STARTED | 449 | 440 |
| Withdrew Prior to Dosing | 0 | 1 |
| COMPLETED | 312 | 326 |
| NOT COMPLETED | 137 | 114 |
| Period Title: Part 1 | ||
| STARTED | 274 | 292 |
| Completed Treatment for 48 Weeks | 98 | 111 |
| Completed Treatment for 96 Weeks | 1 | 0 |
| Completed Treatment for > 96 Weeks | 1 | 0 |
| COMPLETED | 3 | 6 |
| NOT COMPLETED | 271 | 286 |
Baseline Characteristics
| Arm/Group Title | Placebo | Natalizumab 300 mg | Total |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Total of all reporting groups |
| Overall Participants | 449 | 439 | 888 |
| Age, Customized (participants) [Number] | |||
| 20 - 29 years |
10
2.2%
|
10
2.3%
|
20
2.3%
|
| 30 - 39 years |
73
16.3%
|
50
11.4%
|
123
13.9%
|
| 40 - 49 years |
162
36.1%
|
194
44.2%
|
356
40.1%
|
| ≥ 50 years |
204
45.4%
|
185
42.1%
|
389
43.8%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
280
62.4%
|
270
61.5%
|
550
61.9%
|
| Male |
169
37.6%
|
169
38.5%
|
338
38.1%
|
Outcome Measures
| Title | 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) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 448 | 439 |
| Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years |
48
10.7%
|
44
10%
|
| Confirmed on EDSS at 2 years |
15
3.3%
|
16
3.6%
|
| Confirmed on T25FW at 2 years |
35
7.8%
|
35
8%
|
| Confirmed on 9HPT (either hand) at 2 years |
23
5.1%
|
15
3.4%
|
| Confirmed on 9HPT (dominant hand) at 2 years |
13
2.9%
|
10
2.3%
|
| Confirmed on 9HPT (non-dominant hand) at 2 years |
16
3.6%
|
10
2.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 2 years | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2866 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.86 | |
| Confidence Interval |
(2-Sided) 95% 0.66 to 1.13 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on EDSS | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7530 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.06 | |
| Confidence Interval |
(2-Sided) 95% 0.74 to 1.53 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on T25FW | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9137 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.98 | |
| Confidence Interval |
(2-Sided) 95% 0.74 to 1.30 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on 9HPT (either hand) | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0012 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.56 | |
| Confidence Interval |
(2-Sided) 95% 0.40 to 0.80 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on 9HPT (dominant hand) | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1251 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.48 to 1.09 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on 9HPT (non-dominant hand) | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0091 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.58 | |
| Confidence Interval |
(2-Sided) 95% 0.39 to 0.87 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population: all participants who were randomized in Part 1 and received at least 1 infusion of study treatment in Part 2. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| Any event |
250
55.7%
|
245
55.8%
|
| Moderate or severe event |
157
35%
|
158
36%
|
| Severe event |
28
6.2%
|
27
6.2%
|
| Related event |
63
14%
|
56
12.8%
|
| Serious event |
24
5.3%
|
39
8.9%
|
| Discontinuation of treatment due to event |
12
2.7%
|
5
1.1%
|
| Withdrawal from study due to an event |
11
2.4%
|
3
0.7%
|
| Title | Part 1: Percentage of Participants With a T25FW Response |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 363 | 383 |
| Number (95% Confidence Interval) [percentage of participants] |
17
3.8%
|
19
4.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4369 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for baseline EDSS (<=5.5 or >=6) and T25FW. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.16 | |
| Confidence Interval |
(2-Sided) 95% 0.80 to 1.70 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
| Title | Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 436 | 431 |
| Mean (Standard Deviation) [units on a scale] |
4.04
(21.061)
|
2.70
(22.110)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5409 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between the active and placebo groups at Week 96 is based on ANCOVA model, adjusted for BL EDSS (<=5.5 or >=6) and BL MSWS-12. | |
| Title | Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 437 | 431 |
| Mean (Standard Deviation) [units on a scale] |
-3.45
(14.739)
|
-2.44
(13.023)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2586 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo groups at Week 96 is based on ANCOVA model, adjusted for BL EDSS (<=5.5 or >=6) and BL ABILHAND. | |
| Title | Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 428 | 430 |
| Mean (Standard Deviation) [units on a scale] |
3.34
(20.947)
|
0.61
(19.885)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1529 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Wk 96 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL MSIS-29 physical score. | |
| Title | Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96 |
|---|---|
| Description | Whole brain volume as measured by MRI. |
| Time Frame | Week 24 and Week 96 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 265 | 287 |
| Mean (Standard Deviation) [percentage change] |
-0.72
(0.656)
|
-0.66
(0.596)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Only participants with BL brain volume are included in the p-value calculation. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2424 |
| Comments | natalizumab participants had a baseline after 6 months of treatment and the placebo-to-natalizumab group had a baseline of initiation of treatment | |
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo groups at Week 96 is based on ANCOVA model, adjusted for BL EDSS (<=5.5 or >=6) and BL brain volume. | |
| Title | Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 448 | 439 |
| Number (95% Confidence Interval) [percentage of participants] |
29
6.5%
|
25
5.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1052 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for baseline EDSS (<=5.5 or >=6). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.78 | |
| Confidence Interval |
(2-Sided) 95% 0.58 to 1.05 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Part 2: Percentage of Participants With Disability Worsening at 156 Weeks |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2). |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| Confirmed on ≥1 of EDSS, T25FW, 9HPT at 156 weeks |
61
13.6%
|
52
11.8%
|
| Confirmed on EDSS at 156 weeks |
23
5.1%
|
18
4.1%
|
| Confirmed on T25FW at 156 weeks |
46
10.2%
|
41
9.3%
|
| Confirmed on 9HPT (either hand) at 156 weeks |
28
6.2%
|
19
4.3%
|
| Confirmed on 9HPT (dominant hand) at 156 weeks |
18
4%
|
12
2.7%
|
| Confirmed on 9HPT (non-dominant hand) at 156 weeks |
18
4%
|
13
3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 156 weeks | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0205 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.67 | |
| Confidence Interval |
(2-Sided) 95% 0.47 to 0.94 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on EDSS at 156 weeks | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1305 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.73 | |
| Confidence Interval |
(2-Sided) 95% 0.48 to 1.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on T25FW at 156 weeks | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1988 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.80 | |
| Confidence Interval |
(2-Sided) 95% 0.57 to 1.12 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on 9HPT (either hand) at 156 weeks | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0093 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.59 | |
| Confidence Interval |
(2-Sided) 95% 0.39 to 0.88 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors onm 9HPT (dominant hand) at 156 weeks | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0540 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.63 | |
| Confidence Interval |
(2-Sided) 95% 0.39 to 1.01 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Confirmed progressors on 9HPT (non-dominant hand) at 156 weeks | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1410 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand). | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.70 | |
| Confidence Interval |
(2-Sided) 95% 0.44 to 1.12 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | active/placebo | |
| Title | Part 2: Absolute Change From Baseline (Part 1) in T25FW |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 255 | 264 |
| Overall: Change from BL to Week 156; n=255, 264 |
12.80
(35.111)
|
7.78
(21.251)
|
| Overall: Change from BL to Week 204; n=39, 38 |
25.01
(56.582)
|
9.01
(22.507)
|
| CP Group: Change from BL to Week 156; n=156, 135 |
21.67
(42.510)
|
16.26
(26.943)
|
| CP Group: Change from BL to Week 204; n=25, 18 |
40.06
(66.275)
|
20.89
(28.200)
|
| NP Group: Change from BL to Week 156; n=99, 129 |
-1.17
(3.804)
|
-1.09
(3.593)
|
| NP Group: Change from BL to Week 204; n=14, 20 |
-1.88
(5.917)
|
-1.67
(4.613)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0273 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1974 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2506 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW. | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in T25FW |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 255 | 264 |
| Overall: Change from BL at Week 156; n=255, 264 |
75.52
(166.191)
|
55.91
(130.286)
|
| Overall: Change from BL at Week 204; n=39, 38 |
130.72
(272.117)
|
71.09
(177.668)
|
| CP Group: Change from BL at Week 156; n=156, 135 |
127.05
(195.138)
|
113.51
(160.857)
|
| CP Group: Change from BL at Week 204; n=25, 18 |
206.78
(316.344)
|
158.91
(228.458)
|
| NP Group: Change from BL at Week 156; n=99, 129 |
-5.68
(21.708)
|
-4.37
(25.050)
|
| NP Group: Change from BL at Week 204; n=14, 20 |
-5.09
(26.591)
|
-7.94
(29.856)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0960 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4957 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2916 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW. | |
| Title | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 257 | 271 |
| Overall: Change from BL to Week 156; n= 257, 271 |
5.22
(27.728)
|
2.12
(16.719)
|
| Overall: Change from BL to Week 204; n=39, 38 |
0.56
(7.923)
|
2.65
(16.001)
|
| CP Group: Change from BL to Week 156; n=158, 138 |
10.12
(33.675)
|
5.01
(20.625)
|
| CP Group: Change from BL to Week 204; n=24, 19 |
2.36
(9.187)
|
6.03
(21.994)
|
| NP Group: Change from BL to Week 156; n=99, 133 |
-2.60
(9.543)
|
-0.89
(10.602)
|
| NP Group: Change from BL to Week 204; n=15, 19 |
-2.32
(4.153)
|
-0.73
(4.292)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall, Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1119 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1129 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2351 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand). | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 257 | 271 |
| Overall: Change from BL to Week 156; n=257, 271 |
14.32
(59.727)
|
5.25
(32.649)
|
| Overall: Change from BL to Week 204; n=39, 38 |
2.27
(19.193)
|
6.87
(32.333)
|
| CP Group: Change from BL to Week 156; n=158, 138 |
25.87
(72.621)
|
12.84
(40.232)
|
| CP Group: Change from BL to Week 204; n=24, 19 |
8.43
(20.247)
|
16.25
(41.317)
|
| NP Group: Change from BL to Week 156; n=99, 133 |
-4.10
(17.661)
|
-2.63
(19.436)
|
| NP Group: Change from BL to Week 204; n=15, 19 |
-7.57
(12.560)
|
-2.52
(15.998)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0261 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0585 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6095 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand). | |
| Title | Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 254 | 269 |
| Overall: Change from BL to Week 156; n=254, 269 |
5.24
(32.910)
|
4.62
(30.333)
|
| Overall: Change from BL to Week 204; n=40, 40 |
1.41
(16.952)
|
4.91
(33.808)
|
| CP Group: Change from BL to Week 156; n=155, 137 |
11.25
(39.513)
|
11.25
(38.296)
|
| CP Group: Change from BL to Week 204; n=25, 20 |
5.87
(17.474)
|
17.20
(34.632)
|
| NP Group: Change from BL to Week 156; n=99, 132 |
-4.17
(13.999)
|
-2.26
(16.311)
|
| NP Group: Change from BL to Week 204; n=15, 20 |
-6.04
(13.491)
|
-7.39
(28.780)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7230 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8781 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2751 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand). | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 254 | 269 |
| Overall: Change from BL to Week 156; n=254, 269 |
13.87
(64.959)
|
11.04
(47.942)
|
| Overall: Change from BL to Week 204; n=40, 40 |
3.67
(28.755)
|
18.57
(62.537)
|
| CP Group: Change from BL to Week 156; n=155, 137 |
26.33
(79.957)
|
23.51
(60.074)
|
| CP Group: Change from BL to Week 204; n=25, 20 |
11.87
(31.050)
|
43.12
(80.639)
|
| NP Group: Change from BL to Week 156; n=99, 132 |
-5.63
(14.765)
|
-1.89
(24.987)
|
| NP Group: Change from BL to Week 204; n=15, 20 |
-9.98
(18.188)
|
-5.98
(16.005)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5051 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7283 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1666 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand). | |
| Title | Part 2: Absolute Change From Baseline (Part 1) in EDSS |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 260 | 275 |
| Overall: Change from BL to Week 156; n=260, 275 |
0.11
(0.746)
|
0.06
(0.797)
|
| Overall: Change from BL to Week 204; n=40, 40 |
-0.01
(0.895)
|
0.15
(0.928)
|
| CP Group: Change from BL to Week 156; n=162, 141 |
0.38
(0.631)
|
0.36
(0.703)
|
| CP Group: Change from BL to Week 204; n=25, 20 |
0.28
(0.542)
|
0.68
(0.634)
|
| NP Group: Change from BL to Week 156; n=98, 134 |
-0.33
(0.718)
|
-0.25
(0.775)
|
| NP Group: Change from BL to Week 204; n=15, 20 |
-0.50
(1.150)
|
-0.38
(0.887)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4330 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7122 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3861 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6). | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in EDSS |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 260 | 275 |
| Overall: Change from BL to Week 156; n=260, 275 |
2.07
(15.188)
|
1.65
(16.530)
|
| Overall: Change from BL to Week 204; n=40, 40 |
-0.63
(17.889)
|
2.91
(18.656)
|
| CP Group Change from BL to Week 156; n=162, 141 |
7.23
(13.513)
|
7.30
(15.728)
|
| CP Group Change from BL to Week 204; n=25, 20 |
5.31
(10.711)
|
13.18
(13.957)
|
| NP Group Change from BL to Week 156; n=98, 134 |
-6.47
(13.951)
|
-4.29
(15.266)
|
| NP Group Change from BL to Week 204; n=15, 20 |
-10.53
(22.953)
|
-7.35
(17.260)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Overall: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7225 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | CP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9121 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | NP Group: Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2594 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6). | |
| Title | Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 272 | 290 |
| Change from BL to Week 156; n=272, 289 |
-32.1
(117.55)
|
-40.4
(219.60)
|
| Change from BL to Week 204; n=272, 290 |
-33.3
(119.40)
|
-40.7
(219.58)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8066 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 6MWT. | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in the 6MWT |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 0 | 0 |
| Title | Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| Change from BL to Week 156 |
0.32
(20.943)
|
0.05
(20.843)
|
| Change to from BL Week 204 |
0.91
(21.018)
|
-0.28
(20.596)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7084 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL MSIS-29 physical score. | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 0 | 0 |
| Title | Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 273 | 291 |
| Change from BL to Week 108 |
13.6
(14.19)
|
15.5
(13.82)
|
| Change from BL to Week 112 |
14.4
(13.72)
|
15.1
(13.50)
|
| Change from BL to Week 116 |
14.1
(13.84)
|
15.3
(13.51)
|
| Change from BL to Week 120 |
14.3
(14.23)
|
15.3
(13.68)
|
| Change from BL to Week 124 |
14.4
(14.02)
|
15.7
(13.69)
|
| Change from BL to Week 128 |
15.1
(14.49)
|
15.7
(13.72)
|
| Change from BL to Week 132 |
15.1
(14.52)
|
15.6
(13.63)
|
| Change from BL to Week 136 |
14.8
(14.56)
|
16.3
(13.75)
|
| Change from BL to Week 140 |
15.4
(14.98)
|
16.4
(14.29)
|
| Change from BL to Week 144 |
15.7
(15.23)
|
16.2
(14.22)
|
| Change from BL to Week 148 |
15.5
(15.34)
|
16.3
(14.35)
|
| Change from BL to Week 152 |
15.5
(14.98)
|
16.3
(14.25)
|
| Change from BL to Week 156 |
11.2
(13.10)
|
12.3
(14.59)
|
| Change from BL to Week 160 |
15.2
(14.92)
|
16.2
(14.61)
|
| Change from BL to Week 164 |
15.6
(15.21)
|
16.3
(14.64)
|
| Change from BL to Week 168 |
15.8
(15.52)
|
16.4
(14.78)
|
| Change from BL to Week 172 |
15.6
(15.40)
|
16.3
(14.64)
|
| Change from BL to Week 176 |
15.5
(15.58)
|
16.3
(14.91)
|
| Change from BL to Week 180 |
15.5
(15.23)
|
16.4
(14.89)
|
| Change from BL to Week 184 |
15.6
(15.34)
|
16.3
(14.81)
|
| Change from BL to Week 188 |
15.6
(15.38)
|
16.4
(14.77)
|
| Change from BL to Week 192 |
15.6
(15.46)
|
16.3
(14.79)
|
| Change from BL to Week 196 |
15.7
(15.45)
|
16.3
(14.69)
|
| Change from BL to Week 200 |
15.7
(15.47)
|
16.3
(14.69)
|
| Change from BL to Week 204 |
15.7
(15.43)
|
16.3
(14.69)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3465 |
| Comments | ||
| Method | ANCOVA | |
| Comments | p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL SDMT. | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in the SDMT |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 0 | 0 |
| Title | Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 272 | 291 |
| Absenteeism: Week 108 |
2.6
(12.80)
|
1.4
(8.24)
|
| Absenteeism: Week 156 |
3.0
(14.61)
|
4.1
(17.36)
|
| Absenteeism: Week 204 |
3.0
(14.61)
|
4.2
(16.89)
|
| Presenteeism: Week 108 |
30.6
(12.10)
|
30.9
(11.71)
|
| Presenteeism: Week 156 |
30.8
(12.17)
|
33.0
(14.23)
|
| Presenteeism: Week 204 |
31.0
(12.29)
|
32.2
(13.78)
|
| Work Productivity Loss: Week 108 |
30.9
(12.36)
|
31.2
(11.70)
|
| Work Productivity Loss: Week 156 |
31.6
(13.54)
|
33.9
(15.75)
|
| Work Productivity Loss: Week 204 |
31.9
(13.66)
|
33.3
(15.61)
|
| Activity Impairment: Week 108 |
56.1
(24.78)
|
58.0
(24.84)
|
| Activity Impairment: Week 156 |
56.8
(26.49)
|
58.5
(24.08)
|
| Activity Impairment: Week 204 |
57.2
(25.15)
|
59.8
(23.60)
|
| Title | Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| Absenteeism: Change at Week 156; n=18,17 |
-10.3
(116.81)
|
-7.4
(95.77)
|
| Absenteeism: Change at Week 204; n=18, 17 |
-6.6
(116.90)
|
151.5
(457.29)
|
| Presenteeism: Change at Week 156; n=264, 285 |
4.0
(50.08)
|
14.4
(90.39)
|
| Presenteeism: Change at Week 204; n=264, 285 |
5.3
(51.23)
|
7.4
(58.95)
|
| WPL: Change at Week 156; n=264,286 |
4.7
(51.73)
|
16.8
(95.43)
|
| WPL: Change at Week 204; n=264, 286 |
5.9
(53.44)
|
10.6
(69.34)
|
| AI: Change at Week 156; n=264, 284 |
16.0
(95.68)
|
15.7
(83.70)
|
| AI: Change at Week 204; n=264, 284 |
16.1
(88.56)
|
20.4
(99.54)
|
| Title | Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume |
|---|---|
| Description | Whole brain volume as measured by MRI. |
| Time Frame | Week 24 (Part 1) and Weeks 156 and 204 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| Change from Week 24 to Week 156; n=155, 175 |
-1.164
(0.8228)
|
-0.948
(0.7193)
|
| Change from Week 24 to Week 204; n=28, 24 |
-1.687
(1.2872)
|
-1.517
(0.8412)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Percentage change from Week 24 to Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0070 |
| Comments | natalizumab participants had a baseline after 6 months of treatment and the placebo-to-natalizumab group had a baseline of initiation of treatment | |
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL normalized brain volume. | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume |
|---|---|
| Description | Whole grey matter brain volume as measured by MRI. |
| Time Frame | Baseline (Part 1) and Weeks 156 and 204 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| Change from Baseline to Week 156; n=149, 170 |
-1.566
(0.9303)
|
-1.514
(0.8969)
|
| Change from Baseline to Week 204; n=26, 20 |
-1.883
(1.4222)
|
-2.086
(0.9068)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Percentage hange from Baseline to Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5034 |
| Comments | natalizumab participants had a baseline after 6 months of treatment and the placebo-to-natalizumab group had a baseline of initiation of treatment | |
| Method | ANCOVA | |
| Comments | p-value for comparison between active & placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL WGM brain volume | |
| Title | Part 2: Summary of New/Enlarging T2 Lesion Counts |
|---|---|
| Description | New or enlarging T2 lesions as measured by MRI. |
| Time Frame | Baseline (Part 1) up to Week 204 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 274 | 291 |
| At Week 24 compared to BL; n=272, 287 |
2.1
(4.24)
|
0.6
(3.27)
|
| At Week 48 compared to Week 24; n=272, 289 |
1.8
(4.47)
|
0.0
(0.37)
|
| At Week 72 compared to Week 48; n=271, 287 |
1.6
(3.76)
|
0.0
(0.19)
|
| At Week 96 compared to Week 72; n=269, 284 |
1.8
(4.33)
|
0.0
(0.00)
|
| At Week 108 compared to Week 96; n=269, 288 |
1.2
(3.38)
|
0.0
(0.13)
|
| At Week 156 compared to Week 108; n=245, 258 |
0.2
(0.79)
|
0.0
(0.20)
|
| At Week 204 compared to Week 156; n=50, 47 |
0.0
(0.20)
|
0.0
(0.15)
|
| Cumulative count from BL to Week 204; n=274, 291 |
8.6
(16.04)
|
0.7
(3.53)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Natalizumab 300 mg |
|---|---|---|
| Comments | Week 156 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | < 0.0001 |
| Comments | p-value for comparison between the active and placebo groups at Week 156 compared to Week 108 is based on negative binomial regression model, adjusted for baseline EDSS (<=5.5 or >=6) and baseline volume of T2 lesions. | |
| Method | negative binomial regression model | |
| Comments | natalizumab participants had a baseline after 6 months of treatment and the placebo-to-natalizumab group had a baseline of initiation of treatment | |
| Title | Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions |
|---|---|
| Description | New or enlarging T2 lesions as measured by MRI. |
| Time Frame | Baseline (Part 1) and Weeks 156 and 204 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Placebo | Natalizumab 300 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | Adverse events are captured through the last study visit; participants were followed through Week 228, or 24 weeks following last dose of study treatment, or premature withdrawal. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Treatment-emergent adverse events only are presented. | |||
| Arm/Group Title | Placebo | Natalizumab 300 mg | ||
| Arm/Group Description | 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. | 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. | ||
All Cause Mortality |
||||
| Placebo | Natalizumab 300 mg | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Placebo | Natalizumab 300 mg | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 100/449 (22.3%) | 90/439 (20.5%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 0/449 (0%) | 1/439 (0.2%) | ||
| Cardiac disorders | ||||
| Acute myocardial infarction | 2/449 (0.4%) | 1/439 (0.2%) | ||
| Atrial fibrillation | 2/449 (0.4%) | 0/439 (0%) | ||
| Coronary artery disease | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Tachycardia | 0/449 (0%) | 1/439 (0.2%) | ||
| Congenital, familial and genetic disorders | ||||
| Pelvic kidney | 1/449 (0.2%) | 0/439 (0%) | ||
| Ear and labyrinth disorders | ||||
| Vertigo positional | 1/449 (0.2%) | 0/439 (0%) | ||
| Endocrine disorders | ||||
| Toxic nodular goitre | 0/449 (0%) | 1/439 (0.2%) | ||
| Eye disorders | ||||
| Uveitis | 1/449 (0.2%) | 0/439 (0%) | ||
| Gastrointestinal disorders | ||||
| Abdominal hernia | 1/449 (0.2%) | 0/439 (0%) | ||
| Colitis | 0/449 (0%) | 1/439 (0.2%) | ||
| Constipation | 1/449 (0.2%) | 0/439 (0%) | ||
| Duodenal ulcer | 1/449 (0.2%) | 0/439 (0%) | ||
| Enteritis | 1/449 (0.2%) | 0/439 (0%) | ||
| Gastritis | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Haematemesis | 0/449 (0%) | 1/439 (0.2%) | ||
| Hiatus hernia | 0/449 (0%) | 1/439 (0.2%) | ||
| Inguinal hernia | 1/449 (0.2%) | 0/439 (0%) | ||
| Oesophageal food impaction | 1/449 (0.2%) | 0/439 (0%) | ||
| Small intestinal stenosis | 1/449 (0.2%) | 0/439 (0%) | ||
| Upper gastrointestinal haemorrhage | 0/449 (0%) | 1/439 (0.2%) | ||
| Vomiting | 1/449 (0.2%) | 0/439 (0%) | ||
| General disorders | ||||
| Asthenia | 0/449 (0%) | 2/439 (0.5%) | ||
| Catheter site haemorrhage | 1/449 (0.2%) | 0/439 (0%) | ||
| Gait disturbance | 1/449 (0.2%) | 2/439 (0.5%) | ||
| Influenza like illness | 1/449 (0.2%) | 0/439 (0%) | ||
| Pyrexia | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Hepatobiliary disorders | ||||
| Cholecystitis acute | 1/449 (0.2%) | 0/439 (0%) | ||
| Cholelithiasis | 0/449 (0%) | 1/439 (0.2%) | ||
| Drug-induced liver injury | 0/449 (0%) | 1/439 (0.2%) | ||
| Immune system disorders | ||||
| Anaphylactic reaction | 0/449 (0%) | 3/439 (0.7%) | ||
| Anaphylactic shock | 2/449 (0.4%) | 0/439 (0%) | ||
| Hypersensitivity | 0/449 (0%) | 1/439 (0.2%) | ||
| Infections and infestations | ||||
| Bacterial sepsis | 1/449 (0.2%) | 0/439 (0%) | ||
| Brain abscess | 1/449 (0.2%) | 0/439 (0%) | ||
| Bronchitis | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Cellulitis | 2/449 (0.4%) | 3/439 (0.7%) | ||
| Clostridium difficile colitis | 0/449 (0%) | 1/439 (0.2%) | ||
| Cystitis | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Enteritis infectious | 1/449 (0.2%) | 0/439 (0%) | ||
| Gastroenteritis | 0/449 (0%) | 3/439 (0.7%) | ||
| H1n1 influenza | 1/449 (0.2%) | 0/439 (0%) | ||
| Herpes virus infection | 0/449 (0%) | 1/439 (0.2%) | ||
| Infected dermal cyst | 0/449 (0%) | 1/439 (0.2%) | ||
| Infected skin ulcer | 1/449 (0.2%) | 0/439 (0%) | ||
| Influenza | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Localised infection | 1/449 (0.2%) | 0/439 (0%) | ||
| Lower respiratory tract infection | 2/449 (0.4%) | 0/439 (0%) | ||
| Pneumonia | 5/449 (1.1%) | 2/439 (0.5%) | ||
| Prostatic abscess | 0/449 (0%) | 1/439 (0.2%) | ||
| Pyelonephritis | 1/449 (0.2%) | 0/439 (0%) | ||
| Pyelonephritis acute | 1/449 (0.2%) | 0/439 (0%) | ||
| Sepsis | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Sinusitis | 0/449 (0%) | 1/439 (0.2%) | ||
| Urinary tract infection | 12/449 (2.7%) | 5/439 (1.1%) | ||
| Urinary tract infection enterococcal | 1/449 (0.2%) | 0/439 (0%) | ||
| Urosepsis | 1/449 (0.2%) | 3/439 (0.7%) | ||
| Injury, poisoning and procedural complications | ||||
| Ankle fracture | 2/449 (0.4%) | 0/439 (0%) | ||
| Brain contusion | 0/449 (0%) | 1/439 (0.2%) | ||
| Comminuted fracture | 1/449 (0.2%) | 0/439 (0%) | ||
| Concussion | 0/449 (0%) | 1/439 (0.2%) | ||
| Contusion | 1/449 (0.2%) | 0/439 (0%) | ||
| Ear injury | 0/449 (0%) | 1/439 (0.2%) | ||
| Extradural haematoma | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Fall | 3/449 (0.7%) | 6/439 (1.4%) | ||
| Femoral neck fracture | 0/449 (0%) | 1/439 (0.2%) | ||
| Femur fracture | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Fibula fracture | 2/449 (0.4%) | 0/439 (0%) | ||
| Foot fracture | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Fractured sacrum | 0/449 (0%) | 1/439 (0.2%) | ||
| Head injury | 0/449 (0%) | 1/439 (0.2%) | ||
| Hip fracture | 0/449 (0%) | 1/439 (0.2%) | ||
| Infusion related reaction | 0/449 (0%) | 1/439 (0.2%) | ||
| Ligament sprain | 1/449 (0.2%) | 0/439 (0%) | ||
| Multiple fractures | 0/449 (0%) | 1/439 (0.2%) | ||
| Overdose | 0/449 (0%) | 1/439 (0.2%) | ||
| Postoperative ileus | 0/449 (0%) | 1/439 (0.2%) | ||
| Radius fracture | 1/449 (0.2%) | 0/439 (0%) | ||
| Road traffic accident | 0/449 (0%) | 1/439 (0.2%) | ||
| Soft tissue injury | 0/449 (0%) | 1/439 (0.2%) | ||
| Stab wound | 1/449 (0.2%) | 0/439 (0%) | ||
| Subdural haematoma | 1/449 (0.2%) | 0/439 (0%) | ||
| Thermal burn | 1/449 (0.2%) | 0/439 (0%) | ||
| Wrist fracture | 0/449 (0%) | 1/439 (0.2%) | ||
| Investigations | ||||
| Weight decreased | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Metabolism and nutrition disorders | ||||
| Diabetic ketoacidosis | 0/449 (0%) | 1/439 (0.2%) | ||
| Insulin-requiring type 2 diabetes mellitus | 0/449 (0%) | 1/439 (0.2%) | ||
| Obesity | 1/449 (0.2%) | 0/439 (0%) | ||
| Type 1 diabetes mellitus | 0/449 (0%) | 1/439 (0.2%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 1/449 (0.2%) | 1/439 (0.2%) | ||
| Foot deformity | 1/449 (0.2%) | 0/439 (0%) | ||
| Fracture nonunion | 1/449 (0.2%) | 0/439 (0%) | ||
| Intervertebral disc protrusion | 0/449 (0%) | 1/439 (0.2%) | ||
| Myalgia | 0/449 (0%) | 1/439 (0.2%) | ||
| Osteoarthritis | 0/449 (0%) | 1/439 (0.2%) | ||
| Rotator cuff syndrome | 1/449 (0.2%) | 0/439 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Basal cell carcinoma | 1/449 (0.2%) | 0/439 (0%) | ||
| Breast cancer | 1/449 (0.2%) | 0/439 (0%) | ||
| Cholesteatoma | 0/449 (0%) | 1/439 (0.2%) | ||
| Colon adenoma | 1/449 (0.2%) | 0/439 (0%) | ||
| Lipoma | 1/449 (0.2%) | 0/439 (0%) | ||
| Lung neoplasm malignant | 0/449 (0%) | 1/439 (0.2%) | ||
| Pancreatic carcinoma | 0/449 (0%) | 1/439 (0.2%) | ||
| Papillary cystadenoma lymphomatosum | 0/449 (0%) | 1/439 (0.2%) | ||
| Renal cell carcinoma | 0/449 (0%) | 1/439 (0.2%) | ||
| Signet-ring cell carcinoma | 0/449 (0%) | 1/439 (0.2%) | ||
| Tonsil cancer | 0/449 (0%) | 1/439 (0.2%) | ||
| Uterine leiomyoma | 1/449 (0.2%) | 0/439 (0%) | ||
| Nervous system disorders | ||||
| Cerebral venous thrombosis | 0/449 (0%) | 1/439 (0.2%) | ||
| Cervical myelopathy | 0/449 (0%) | 1/439 (0.2%) | ||
| Epilepsy | 0/449 (0%) | 1/439 (0.2%) | ||
| Generalised tonic-clonic seizure | 0/449 (0%) | 1/439 (0.2%) | ||
| Multiple sclerosis | 5/449 (1.1%) | 0/439 (0%) | ||
| Multiple sclerosis relapse | 28/449 (6.2%) | 21/439 (4.8%) | ||
| Muscle spasticity | 0/449 (0%) | 2/439 (0.5%) | ||
| Optic neuritis | 2/449 (0.4%) | 0/439 (0%) | ||
| Quadriparesis | 1/449 (0.2%) | 0/439 (0%) | ||
| Secondary progressive multiple sclerosis | 1/449 (0.2%) | 0/439 (0%) | ||
| Seizure | 1/449 (0.2%) | 0/439 (0%) | ||
| Syncope | 1/449 (0.2%) | 0/439 (0%) | ||
| Tonic convulsion | 0/449 (0%) | 1/439 (0.2%) | ||
| Transient global amnesia | 1/449 (0.2%) | 0/439 (0%) | ||
| Transient ischaemic attack | 1/449 (0.2%) | 0/439 (0%) | ||
| Uhthoff's phenomenon | 3/449 (0.7%) | 1/439 (0.2%) | ||
| Psychiatric disorders | ||||
| Abnormal behaviour | 0/449 (0%) | 1/439 (0.2%) | ||
| Acute psychosis | 1/449 (0.2%) | 0/439 (0%) | ||
| Mood disorder due to a general medical condition | 0/449 (0%) | 1/439 (0.2%) | ||
| Substance-induced psychotic disorder | 1/449 (0.2%) | 0/439 (0%) | ||
| Renal and urinary disorders | ||||
| Acute kidney injury | 1/449 (0.2%) | 0/439 (0%) | ||
| Calculus ureteric | 1/449 (0.2%) | 0/439 (0%) | ||
| Nephrolithiasis | 0/449 (0%) | 1/439 (0.2%) | ||
| Neurogenic bladder | 0/449 (0%) | 1/439 (0.2%) | ||
| Tubulointerstitial nephritis | 1/449 (0.2%) | 0/439 (0%) | ||
| Urge incontinence | 0/449 (0%) | 1/439 (0.2%) | ||
| Urinary incontinence | 1/449 (0.2%) | 0/439 (0%) | ||
| Urinary retention | 0/449 (0%) | 1/439 (0.2%) | ||
| Reproductive system and breast disorders | ||||
| Cervical dysplasia | 0/449 (0%) | 1/439 (0.2%) | ||
| Metrorrhagia | 0/449 (0%) | 1/439 (0.2%) | ||
| Ovarian cyst | 1/449 (0.2%) | 0/439 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Asthma | 1/449 (0.2%) | 0/439 (0%) | ||
| Pulmonary oedema | 1/449 (0.2%) | 0/439 (0%) | ||
| Sinus polyp | 1/449 (0.2%) | 0/439 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Erythema multiforme | 0/449 (0%) | 1/439 (0.2%) | ||
| Rash | 1/449 (0.2%) | 0/439 (0%) | ||
| Surgical and medical procedures | ||||
| Joint surgery | 0/449 (0%) | 1/439 (0.2%) | ||
| Limb operation | 0/449 (0%) | 1/439 (0.2%) | ||
| Meniscus operation | 0/449 (0%) | 1/439 (0.2%) | ||
| Nephrectomy | 0/449 (0%) | 1/439 (0.2%) | ||
| Vascular disorders | ||||
| Deep vein thrombosis | 0/449 (0%) | 2/439 (0.5%) | ||
| Hypotension | 0/449 (0%) | 1/439 (0.2%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Placebo | Natalizumab 300 mg | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 347/449 (77.3%) | 325/439 (74%) | ||
| Gastrointestinal disorders | ||||
| Constipation | 26/449 (5.8%) | 21/439 (4.8%) | ||
| Diarrhoea | 31/449 (6.9%) | 33/439 (7.5%) | ||
| Nausea | 23/449 (5.1%) | 34/439 (7.7%) | ||
| General disorders | ||||
| Fatigue | 53/449 (11.8%) | 59/439 (13.4%) | ||
| Infections and infestations | ||||
| Cystitis | 16/449 (3.6%) | 22/439 (5%) | ||
| Influenza | 33/449 (7.3%) | 32/439 (7.3%) | ||
| Nasopharyngitis | 73/449 (16.3%) | 98/439 (22.3%) | ||
| Upper respiratory tract infection | 30/449 (6.7%) | 48/439 (10.9%) | ||
| Urinary tract infection | 103/449 (22.9%) | 100/439 (22.8%) | ||
| Injury, poisoning and procedural complications | ||||
| Contusion | 17/449 (3.8%) | 26/439 (5.9%) | ||
| Fall | 85/449 (18.9%) | 82/439 (18.7%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 40/449 (8.9%) | 43/439 (9.8%) | ||
| Back pain | 50/449 (11.1%) | 45/439 (10.3%) | ||
| Muscle spasms | 21/449 (4.7%) | 23/439 (5.2%) | ||
| Muscular weakness | 39/449 (8.7%) | 28/439 (6.4%) | ||
| Pain in extremity | 42/449 (9.4%) | 42/439 (9.6%) | ||
| Nervous system disorders | ||||
| Dizziness | 35/449 (7.8%) | 22/439 (5%) | ||
| Headache | 50/449 (11.1%) | 66/439 (15%) | ||
| Multiple sclerosis relapse | 116/449 (25.8%) | 68/439 (15.5%) | ||
| Muscle spasticity | 27/449 (6%) | 17/439 (3.9%) | ||
| Paraesthesia | 13/449 (2.9%) | 22/439 (5%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 20/449 (4.5%) | 24/439 (5.5%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Results Point of Contact
| Name/Title | Biogen Study Medical Director |
|---|---|
| Organization | Biogen |
| Phone | |
| clinicaltrials@biogen.com |
Responsible Party:
Biogen
ClinicalTrials.gov Identifier:
NCT01416181
Other Study ID Numbers:
- 101MS326
- 2010-021978-11
First Posted:
Aug 12, 2011
Last Update Posted:
Sep 11, 2017
Last Verified:
Aug 1, 2017