A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Secondary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: natalizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 58 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: natalizumab<br>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<br>* Administered as specified in the treatment arm<br>* Other names: BG00002;|
| Experimental: Placebo<br>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<br>* Administered as specified in the treatment arm<br>* Other names: BG00002;Drug: Placebo<br>* Matched placebo in part 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) | Confirmed disability progression, defined as ≥1 of the following criteria (confirmed at a second visit ≥6 months later and at Week 96): Confirmed progression in EDSS (EDSS score increased from baseline [BL] by ≥1 point if BL EDSS ≤5.5 or by ≥0.5 points if BL EDSS ≥6); Confirmed progression in T25FW (T25FW increased by ≥20% of the BL walk); Confirmed progression in 9HPT (9HPT increased by ≥20% of the time taken at BL on either hand and confirmed on the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. The 95% confidence interval (CI) of the percentage is based on normal approximation. | Up to 96 weeks (2 years) | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE: any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, placed the participant at immediate risk of death (a life-threatening event); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect. An SAE may have also been any other medically important event in the opinion of the Investigator. | 218 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Percentage of Participants With a T25FW Response | T25FW response is defined as any improvement from the best pre-dose T25FW in at least 75% of the scheduled on-treatment visits through Week 96. The T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. The score for the T25FW is the average of the 2 completed trials. The 95% CI of the percentage is based on normal approximation. | Up to 96 weeks | 
| Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12) | MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A negative number on change from BL value indicates an improvement in MSWS-12. | Baseline and Week 96 | 
| Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire | The ABILHAND Questionnaire measures the participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability. A positive number on change from baseline value indicates an improvement in ABILHAND. | Baseline and Week 96 | 
| Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score | The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29. | Baseline and Week 96 | 
| Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96 | Whole brain volume as measured by MRI. | Week 24 and Week 96 | 
| Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores | The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. Participants with confirmed progression of disability in EDSS physical functional system scores will be defined as those who met one of the following criteria: an increase of ≥ 1 point from baseline system score of ≥ 1 or an increase of ≥ 2 points from baseline system score of 0 in at least 2 physical functional systems, or an increase of ≥ 2 points from baseline system score of ≥ 1 or an increase of ≥ 3 points from baseline system score of 0 in any 1 physical functional system. A confirmed progressor was defined as a participant who met the criteria for disability progression at any given visit and at the 6-Month Confirmation Visit. The 95% CIs are based on normal approximation. | Up to 96 weeks | 
| Part 2: Percentage of Participants With Disability Worsening at 156 Weeks | Percentage of participants with disability worsening at each scheduled efficacy visit in Part 2, defined as one or more of the following: • ≥ 20% worsening from Part 1 baseline in T25FW; • ≥ 20% worsening from Part 1 baseline in 9HPT; • Worsening from Part 1 baseline in EDSS (≥ 1 point increase if Part 1 baseline EDSS ≤ 5.5 or ≥ 0.5 point increase if Part 1 baseline EDSS > 5.5). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. 95% CIs of percentages are based on normal approximation. | Week 156 | 
| Part 2: Absolute Change From Baseline (Part 1) in T25FW | The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Lower scores on time taken to reach 25 foot mark reflect a better outcome. Values are presented for the overall group, as well as the Confirmed Progressor (CP, defined in the primary outcome measure description above) and Non-Progressor (NP) subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in T25FW | The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Absolute Change From Baseline (Part 1) in EDSS | The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in EDSS | The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. Values are presented for the overall group, as well as the CP (defined in the primary outcome measure description above) and NP subgroups. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) | The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. | Baseline (Part 1) and Weeks 156 and 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in the 6MWT | The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score | The 29-item MSIS-29 is a patient-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a patient's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29. | Baseline (Part 1) and Weeks 156 and 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score | The 29-item MSIS-29 is a patient-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a patient's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29. | Baseline (Part 1) and Weeks 156, 204 | 
| Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) | SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). | Baseline (Part 1) and every 4 weeks from Week 108 to Week 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in the SDMT | SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). | Baseline (Part 1) and every 4 weeks from Week 108 to Week 204 | 
| Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire | The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (percentage of overall work impairment [absenteeism plus presenteeism]) 4. Activity Impairment (percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. | Part 2 Baseline (Week 108) and Weeks 156 and 204 | 
| Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire | The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (WPL; percentage of overall work impairment [absenteeism plus presenteeism]) 4. Activity Impairment (AI; percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. | Part 2 Baseline (Week 108) and Weeks 156 and 204 | 
| Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume | Whole brain volume as measured by MRI. | Week 24 (Part 1) and Weeks 156 and 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume | Whole grey matter brain volume as measured by MRI. | Baseline (Part 1) and Weeks 156 and 204 | 
| Part 2: Summary of New/Enlarging T2 Lesion Counts | New or enlarging T2 lesions as measured by MRI. | Baseline (Part 1) up to Week 204 | 
| Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions | New or enlarging T2 lesions as measured by MRI. | Baseline (Part 1) and Weeks 156 and 204 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, Natalizumab, secondary, multiple sclerosis, SPMS, Tysabri