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Natalizumab

Immunologic Factors

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.

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.

Administered as specified in the treatment arm

natalizumab

Placebo

Medical Director

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

Whole grey matter brain volume as measured by MRI.

New or enlarging T2 lesions as measured by MRI.

Biogen

Treatment-emergent adverse events only are presented.

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.

Natalizumab 300 mg

Total

20 - 29 years

30 - 39 years

40 - 49 years

≥ 50 years

Age, Customized

Sex: Female, Male

Safety population: all participants who were randomized and received at least 1 infusion of study treatment in Part 1.

Biogen Study Medical Director

Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 2 years

Confirmed progressors on 9HPT (either hand)

Confirmed progressors on 9HPT (dominant hand)

Confirmed progressors on 9HPT (non-dominant hand)

Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years

Confirmed on EDSS at 2 years

Confirmed on T25FW at 2 years

Confirmed on 9HPT (either hand) at 2 years

Confirmed on 9HPT (dominant hand) at 2 years

Confirmed on 9HPT (non-dominant hand) at 2 years

Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment.

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)

Any event

Moderate or severe event

Severe event

Related event

Serious event

Discontinuation of treatment due to event

Withdrawal from study due to an event

Safety population: all participants who were randomized in Part 1 and received at least 1 infusion of study treatment in Part 2.

Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Part 1: Percentage of Participants With a T25FW Response

Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12)

Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire

Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score

Only participants with BL brain volume are included in the p-value calculation.

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.

Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96

Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores

Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 156 weeks

Confirmed progressors on EDSS at 156 weeks

Confirmed progressors on T25FW at 156 weeks

Confirmed progressors on 9HPT (either hand) at 156 weeks

Confirmed progressors onm 9HPT (dominant hand) at 156 weeks

Confirmed progressors on 9HPT (non-dominant hand) at 156 weeks

Confirmed on ≥1 of EDSS, T25FW, 9HPT at 156 weeks

Confirmed on EDSS at 156 weeks

Confirmed on T25FW at 156 weeks

Confirmed on 9HPT (either hand) at 156 weeks

Confirmed on 9HPT (dominant hand) at 156 weeks

Confirmed on 9HPT (non-dominant hand) at 156 weeks

Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2).

Part 2: Percentage of Participants With Disability Worsening at 156 Weeks

Overall: Change from BL to Week 156; n=255, 264

Overall: Change from BL to Week 204; n=39, 38

CP Group: Change from BL to Week 156; n=156, 135

CP Group: Change from BL to Week 204; n=25, 18

NP Group: Change from BL to Week 156; n=99, 129

NP Group: Change from BL to Week 204; n=14, 20

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.

Part 2: Absolute Change From Baseline (Part 1) in T25FW

Overall: Change from BL at Week 156; n=255, 264

Overall: Change from BL at Week 204; n=39, 38

CP Group: Change from BL at Week 156; n=156, 135

CP Group: Change from BL at Week 204; n=25, 18

NP Group: Change from BL at Week 156; n=99, 129

NP Group: Change from BL at Week 204; n=14, 20

Part 2: Percentage Change From Baseline (Part 1) in T25FW

Overall: Change from BL to Week 156; n= 257, 271

CP Group: Change from BL to Week 156; n=158, 138

CP Group: Change from BL to Week 204; n=24, 19

NP Group: Change from BL to Week 156; n=99, 133

NP Group: Change from BL to Week 204; n=15, 19

Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand)

Overall: Change from BL to Week 156; n=257, 271

Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand)

Overall: Change from BL to Week 156; n=254, 269

Overall: Change from BL to Week 204; n=40, 40

CP Group: Change from BL to Week 156; n=155, 137

CP Group: Change from BL to Week 204; n=25, 20

NP Group: Change from BL to Week 156; n=99, 132

NP Group: Change from BL to Week 204; n=15, 20

Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)

Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)

Overall: Change from BL to Week 156; n=260, 275

CP Group: Change from BL to Week 156; n=162, 141

NP Group: Change from BL to Week 156; n=98, 134

Part 2: Absolute Change From Baseline (Part 1) in EDSS

CP Group Change from BL to Week 156; n=162, 141

CP Group Change from BL to Week 204; n=25, 20

NP Group Change from BL to Week 156; n=98, 134

NP Group Change from BL to Week 204; n=15, 20

Part 2: Percentage Change From Baseline (Part 1) in EDSS

Change from BL to Week 156; n=272, 289

Change from BL to Week 204; n=272, 290

Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT)

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.

Part 2: Percentage Change From Baseline (Part 1) in the 6MWT

Change from BL to Week 156

Change to from BL Week 204

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.

Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score

Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score

Change from BL to Week 108

Change from BL to Week 112

Change from BL to Week 116

Change from BL to Week 120

Change from BL to Week 124

Change from BL to Week 128

Change from BL to Week 132

Change from BL to Week 136

Change from BL to Week 140

Change from BL to Week 144

Change from BL to Week 148

Change from BL to Week 152

Change from BL to Week 160

Change from BL to Week 164

Change from BL to Week 168

Change from BL to Week 172

Change from BL to Week 176

Change from BL to Week 180

Change from BL to Week 184

Change from BL to Week 188

Change from BL to Week 192

Change from BL to Week 196

Change from BL to Week 200

Change from BL to Week 204

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.

Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT)

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis	NCT01416181	Secondary Progr...	natalizumab Placebo	18 Years - 58 Years	Biogen
A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis	NCT01416181	Secondary Progr...	natalizumab Placebo	18 Years - 58 Years	Biogen

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Spots Global Cancer Trial Database for tysabri

Every month we try and update this database with for tysabri cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for tysabri cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.