Trial Outcomes & Findings for A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis (NCT NCT01416181)

Last Updated: 2017-09-11

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

889 participants

Primary outcome timeframe

Up to 96 weeks (2 years)

Results posted on

2017-09-11

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo 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.	Natalizumab 300 mg Part 1: participants were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: participants transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
Part 1 STARTED	449	440
Part 1 Withdrew Prior to Dosing	0	1
Part 1 COMPLETED	312	326
Part 1 NOT COMPLETED	137	114
Part 2 STARTED	274	292
Part 2 Completed Treatment for 48 Weeks	98	111
Part 2 Completed Treatment for 96 Weeks	1	0
Part 2 Completed Treatment for > 96 Weeks	1	0
Part 2 COMPLETED	3	6
Part 2 NOT COMPLETED	271	286

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 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.	Natalizumab 300 mg Part 1: participants were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: participants transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
Part 1 Other	10	24
Part 1 Death	0	1
Part 1 Investigator Decision	7	6
Part 1 Withdrawal by Subject	74	48
Part 1 Lack of Efficacy	16	8
Part 1 Lost to Follow-up	1	1
Part 1 Adverse Event	15	18
Part 1 Ongoing in Follow-Up	14	8
Part 2 Adverse Event	11	4
Part 2 Other	234	267
Part 2 Investigator Decision	6	7
Part 2 Withdrawal by Subject	14	5
Part 2 Lack of Efficacy	4	1
Part 2 Lost to Follow-up	2	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=449 Participants 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.	Natalizumab 300 mg n=439 Participants 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 n=888 Participants Total of all reporting groups
Age, Customized 20 - 29 years	10 participants n=93 Participants	10 participants n=4 Participants	20 participants n=27 Participants
Age, Customized 30 - 39 years	73 participants n=93 Participants	50 participants n=4 Participants	123 participants n=27 Participants
Age, Customized 40 - 49 years	162 participants n=93 Participants	194 participants n=4 Participants	356 participants n=27 Participants
Age, Customized ≥ 50 years	204 participants n=93 Participants	185 participants n=4 Participants	389 participants n=27 Participants
Sex: Female, Male Female	280 Participants n=93 Participants	270 Participants n=4 Participants	550 Participants n=27 Participants
Sex: Female, Male Male	169 Participants n=93 Participants	169 Participants n=4 Participants	338 Participants n=27 Participants

PRIMARY outcome

Timeframe: Up to 96 weeks (2 years)

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

Outcome measures

Outcome measures
Measure	Placebo n=448 Participants 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.	Natalizumab 300 mg n=439 Participants 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.
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years	48 percentage of participants Interval 43.1 to 52.4	44 percentage of participants Interval 39.8 to 49.1
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) Confirmed on EDSS at 2 years	15 percentage of participants Interval 11.7 to 18.3	16 percentage of participants Interval 12.3 to 19.1
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) Confirmed on 9HPT (either hand) at 2 years	23 percentage of participants Interval 19.3 to 27.1	15 percentage of participants Interval 11.3 to 17.9
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) Confirmed on T25FW at 2 years	35 percentage of participants Interval 30.8 to 39.7	35 percentage of participants Interval 30.4 to 39.3
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) Confirmed on 9HPT (dominant hand) at 2 years	13 percentage of participants Interval 10.2 to 16.5	10 percentage of participants Interval 7.2 to 12.8
Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) Confirmed on 9HPT (non-dominant hand) at 2 years	16 percentage of participants Interval 12.5 to 19.2	10 percentage of participants Interval 7.2 to 12.8

PRIMARY outcome

Timeframe: 218 weeks

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Discontinuation of treatment due to event	12 participants	5 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Any event	250 participants	245 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Severe event	28 participants	27 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Moderate or severe event	157 participants	158 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Related event	63 participants	56 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Serious event	24 participants	39 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Withdrawal from study due to an event	11 participants	3 participants

SECONDARY outcome

Timeframe: Up to 96 weeks

Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Excludes participants who withdrew prior to 1 year (defined as stopping treatment prior to Week 48) of participation in the study.

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.

Outcome measures

Outcome measures
Measure	Placebo n=363 Participants 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.	Natalizumab 300 mg n=383 Participants 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.
Part 1: Percentage of Participants With a T25FW Response	17 percentage of participants Interval 12.7 to 20.3	19 percentage of participants Interval 14.6 to 22.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=436 Participants 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.	Natalizumab 300 mg n=431 Participants 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.
Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12)	4.04 units on a scale Standard Deviation 21.061	2.70 units on a scale Standard Deviation 22.110

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=437 Participants 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.	Natalizumab 300 mg n=431 Participants 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.
Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire	-3.45 units on a scale Standard Deviation 14.739	-2.44 units on a scale Standard Deviation 13.023

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=428 Participants 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.	Natalizumab 300 mg n=430 Participants 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.
Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score	3.34 units on a scale Standard Deviation 20.947	0.61 units on a scale Standard Deviation 19.885

SECONDARY outcome

Timeframe: Week 24 and Week 96

Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment. Includes those participants with an assessment at Weeks 24 and 96.

Whole brain volume as measured by MRI.

Outcome measures

Outcome measures
Measure	Placebo n=265 Participants 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.	Natalizumab 300 mg n=287 Participants 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.
Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96	-0.72 percentage change Standard Deviation 0.656	-0.66 percentage change Standard Deviation 0.596

SECONDARY outcome

Timeframe: Up to 96 weeks

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=448 Participants 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.	Natalizumab 300 mg n=439 Participants 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.
Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores	29 percentage of participants Interval 25.2 to 33.7	25 percentage of participants Interval 20.6 to 28.6

SECONDARY outcome

Timeframe: Week 156

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks Confirmed on ≥1 of EDSS, T25FW, 9HPT at 156 weeks	61 percentage of participants Interval 55.2 to 66.7	52 percentage of participants Interval 45.8 to 57.3
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks Confirmed on EDSS at 156 weeks	23 percentage of participants Interval 18.3 to 28.4	18 percentage of participants Interval 13.8 to 22.6
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks Confirmed on T25FW at 156 weeks	46 percentage of participants Interval 40.1 to 51.9	41 percentage of participants Interval 35.2 to 46.5
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks Confirmed on 9HPT (either hand) at 156 weeks	28 percentage of participants Interval 23.1 to 33.8	19 percentage of participants Interval 14.4 to 23.4
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks Confirmed on 9HPT (dominant hand) at 156 weeks	18 percentage of participants Interval 13.0 to 22.0	12 percentage of participants Interval 8.0 to 15.4
Part 2: Percentage of Participants With Disability Worsening at 156 Weeks Confirmed on 9HPT (non-dominant hand) at 156 weeks	18 percentage of participants Interval 13.0 to 22.0	13 percentage of participants Interval 9.2 to 16.9

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156, 204

Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2); n=participants who had an assessment at Baseline and given time point.

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.

Outcome measures

Outcome measures
Measure	Placebo n=255 Participants 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.	Natalizumab 300 mg n=264 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in T25FW NP Group: Change from BL to Week 204; n=14, 20	-1.88 seconds Standard Deviation 5.917	-1.67 seconds Standard Deviation 4.613
Part 2: Absolute Change From Baseline (Part 1) in T25FW Overall: Change from BL to Week 156; n=255, 264	12.80 seconds Standard Deviation 35.111	7.78 seconds Standard Deviation 21.251
Part 2: Absolute Change From Baseline (Part 1) in T25FW Overall: Change from BL to Week 204; n=39, 38	25.01 seconds Standard Deviation 56.582	9.01 seconds Standard Deviation 22.507
Part 2: Absolute Change From Baseline (Part 1) in T25FW CP Group: Change from BL to Week 156; n=156, 135	21.67 seconds Standard Deviation 42.510	16.26 seconds Standard Deviation 26.943
Part 2: Absolute Change From Baseline (Part 1) in T25FW CP Group: Change from BL to Week 204; n=25, 18	40.06 seconds Standard Deviation 66.275	20.89 seconds Standard Deviation 28.200
Part 2: Absolute Change From Baseline (Part 1) in T25FW NP Group: Change from BL to Week 156; n=99, 129	-1.17 seconds Standard Deviation 3.804	-1.09 seconds Standard Deviation 3.593

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=255 Participants 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.	Natalizumab 300 mg n=264 Participants 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.
Part 2: Percentage Change From Baseline (Part 1) in T25FW Overall: Change from BL at Week 156; n=255, 264	75.52 percentage change Standard Deviation 166.191	55.91 percentage change Standard Deviation 130.286
Part 2: Percentage Change From Baseline (Part 1) in T25FW Overall: Change from BL at Week 204; n=39, 38	130.72 percentage change Standard Deviation 272.117	71.09 percentage change Standard Deviation 177.668
Part 2: Percentage Change From Baseline (Part 1) in T25FW CP Group: Change from BL at Week 156; n=156, 135	127.05 percentage change Standard Deviation 195.138	113.51 percentage change Standard Deviation 160.857
Part 2: Percentage Change From Baseline (Part 1) in T25FW CP Group: Change from BL at Week 204; n=25, 18	206.78 percentage change Standard Deviation 316.344	158.91 percentage change Standard Deviation 228.458
Part 2: Percentage Change From Baseline (Part 1) in T25FW NP Group: Change from BL at Week 156; n=99, 129	-5.68 percentage change Standard Deviation 21.708	-4.37 percentage change Standard Deviation 25.050
Part 2: Percentage Change From Baseline (Part 1) in T25FW NP Group: Change from BL at Week 204; n=14, 20	-5.09 percentage change Standard Deviation 26.591	-7.94 percentage change Standard Deviation 29.856

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=257 Participants 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.	Natalizumab 300 mg n=271 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) Overall: Change from BL to Week 156; n= 257, 271	5.22 seconds Standard Deviation 27.728	2.12 seconds Standard Deviation 16.719
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) Overall: Change from BL to Week 204; n=39, 38	0.56 seconds Standard Deviation 7.923	2.65 seconds Standard Deviation 16.001
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) CP Group: Change from BL to Week 156; n=158, 138	10.12 seconds Standard Deviation 33.675	5.01 seconds Standard Deviation 20.625
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) CP Group: Change from BL to Week 204; n=24, 19	2.36 seconds Standard Deviation 9.187	6.03 seconds Standard Deviation 21.994
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) NP Group: Change from BL to Week 156; n=99, 133	-2.60 seconds Standard Deviation 9.543	-0.89 seconds Standard Deviation 10.602
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand) NP Group: Change from BL to Week 204; n=15, 19	-2.32 seconds Standard Deviation 4.153	-0.73 seconds Standard Deviation 4.292

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156, 204

Outcome measures

Outcome measures
Measure	Placebo n=257 Participants 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.	Natalizumab 300 mg n=271 Participants 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.
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) Overall: Change from BL to Week 156; n=257, 271	14.32 percentage change Standard Deviation 59.727	5.25 percentage change Standard Deviation 32.649
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) Overall: Change from BL to Week 204; n=39, 38	2.27 percentage change Standard Deviation 19.193	6.87 percentage change Standard Deviation 32.333
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) CP Group: Change from BL to Week 156; n=158, 138	25.87 percentage change Standard Deviation 72.621	12.84 percentage change Standard Deviation 40.232
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) CP Group: Change from BL to Week 204; n=24, 19	8.43 percentage change Standard Deviation 20.247	16.25 percentage change Standard Deviation 41.317
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) NP Group: Change from BL to Week 156; n=99, 133	-4.10 percentage change Standard Deviation 17.661	-2.63 percentage change Standard Deviation 19.436
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand) NP Group: Change from BL to Week 204; n=15, 19	-7.57 percentage change Standard Deviation 12.560	-2.52 percentage change Standard Deviation 15.998

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156, 204

Outcome measures

Outcome measures
Measure	Placebo n=254 Participants 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.	Natalizumab 300 mg n=269 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) Overall: Change from BL to Week 156; n=254, 269	5.24 seconds Standard Deviation 32.910	4.62 seconds Standard Deviation 30.333
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) Overall: Change from BL to Week 204; n=40, 40	1.41 seconds Standard Deviation 16.952	4.91 seconds Standard Deviation 33.808
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) CP Group: Change from BL to Week 156; n=155, 137	11.25 seconds Standard Deviation 39.513	11.25 seconds Standard Deviation 38.296
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) CP Group: Change from BL to Week 204; n=25, 20	5.87 seconds Standard Deviation 17.474	17.20 seconds Standard Deviation 34.632
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) NP Group: Change from BL to Week 156; n=99, 132	-4.17 seconds Standard Deviation 13.999	-2.26 seconds Standard Deviation 16.311
Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) NP Group: Change from BL to Week 204; n=15, 20	-6.04 seconds Standard Deviation 13.491	-7.39 seconds Standard Deviation 28.780

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156, 204

Outcome measures

Outcome measures
Measure	Placebo n=254 Participants 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.	Natalizumab 300 mg n=269 Participants 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.
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) Overall: Change from BL to Week 156; n=254, 269	13.87 percentage change Standard Deviation 64.959	11.04 percentage change Standard Deviation 47.942
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) Overall: Change from BL to Week 204; n=40, 40	3.67 percentage change Standard Deviation 28.755	18.57 percentage change Standard Deviation 62.537
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) CP Group: Change from BL to Week 156; n=155, 137	26.33 percentage change Standard Deviation 79.957	23.51 percentage change Standard Deviation 60.074
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) CP Group: Change from BL to Week 204; n=25, 20	11.87 percentage change Standard Deviation 31.050	43.12 percentage change Standard Deviation 80.639
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) NP Group: Change from BL to Week 156; n=99, 132	-5.63 percentage change Standard Deviation 14.765	-1.89 percentage change Standard Deviation 24.987
Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand) NP Group: Change from BL to Week 204; n=15, 20	-9.98 percentage change Standard Deviation 18.188	-5.98 percentage change Standard Deviation 16.005

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=260 Participants 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.	Natalizumab 300 mg n=275 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in EDSS NP Group: Change from BL to Week 204; n=15, 20	-0.50 units on a scale Standard Deviation 1.150	-0.38 units on a scale Standard Deviation 0.887
Part 2: Absolute Change From Baseline (Part 1) in EDSS Overall: Change from BL to Week 156; n=260, 275	0.11 units on a scale Standard Deviation 0.746	0.06 units on a scale Standard Deviation 0.797
Part 2: Absolute Change From Baseline (Part 1) in EDSS Overall: Change from BL to Week 204; n=40, 40	-0.01 units on a scale Standard Deviation 0.895	0.15 units on a scale Standard Deviation 0.928
Part 2: Absolute Change From Baseline (Part 1) in EDSS CP Group: Change from BL to Week 156; n=162, 141	0.38 units on a scale Standard Deviation 0.631	0.36 units on a scale Standard Deviation 0.703
Part 2: Absolute Change From Baseline (Part 1) in EDSS CP Group: Change from BL to Week 204; n=25, 20	0.28 units on a scale Standard Deviation 0.542	0.68 units on a scale Standard Deviation 0.634
Part 2: Absolute Change From Baseline (Part 1) in EDSS NP Group: Change from BL to Week 156; n=98, 134	-0.33 units on a scale Standard Deviation 0.718	-0.25 units on a scale Standard Deviation 0.775

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=260 Participants 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.	Natalizumab 300 mg n=275 Participants 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.
Part 2: Percentage Change From Baseline (Part 1) in EDSS Overall: Change from BL to Week 156; n=260, 275	2.07 percentage change Standard Deviation 15.188	1.65 percentage change Standard Deviation 16.530
Part 2: Percentage Change From Baseline (Part 1) in EDSS Overall: Change from BL to Week 204; n=40, 40	-0.63 percentage change Standard Deviation 17.889	2.91 percentage change Standard Deviation 18.656
Part 2: Percentage Change From Baseline (Part 1) in EDSS CP Group Change from BL to Week 156; n=162, 141	7.23 percentage change Standard Deviation 13.513	7.30 percentage change Standard Deviation 15.728
Part 2: Percentage Change From Baseline (Part 1) in EDSS CP Group Change from BL to Week 204; n=25, 20	5.31 percentage change Standard Deviation 10.711	13.18 percentage change Standard Deviation 13.957
Part 2: Percentage Change From Baseline (Part 1) in EDSS NP Group Change from BL to Week 156; n=98, 134	-6.47 percentage change Standard Deviation 13.951	-4.29 percentage change Standard Deviation 15.266
Part 2: Percentage Change From Baseline (Part 1) in EDSS NP Group Change from BL to Week 204; n=15, 20	-10.53 percentage change Standard Deviation 22.953	-7.35 percentage change Standard Deviation 17.260

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=272 Participants 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.	Natalizumab 300 mg n=290 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) Change from BL to Week 156; n=272, 289	-32.1 meters Standard Deviation 117.55	-40.4 meters Standard Deviation 219.60
Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT) Change from BL to Week 204; n=272, 290	-33.3 meters Standard Deviation 119.40	-40.7 meters Standard Deviation 219.58

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156, 204

Population: Actual change from baseline tables are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data on Weeks 204 and 252, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156 and 204

Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2) who had an assessment at Baseline and given time point.

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.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score Change from BL to Week 156	0.32 units on a scale Standard Deviation 20.943	0.05 units on a scale Standard Deviation 20.843
Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score Change to from BL Week 204	0.91 units on a scale Standard Deviation 21.018	-0.28 units on a scale Standard Deviation 20.596

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156, 204

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Part 1) and every 4 weeks from Week 108 to Week 204

Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2). Missing values were imputed using last observation carried forward.

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).

Outcome measures

Outcome measures
Measure	Placebo n=273 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 168	15.8 units on a scale Standard Deviation 15.52	16.4 units on a scale Standard Deviation 14.78
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 172	15.6 units on a scale Standard Deviation 15.40	16.3 units on a scale Standard Deviation 14.64
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 184	15.6 units on a scale Standard Deviation 15.34	16.3 units on a scale Standard Deviation 14.81
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 188	15.6 units on a scale Standard Deviation 15.38	16.4 units on a scale Standard Deviation 14.77
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 192	15.6 units on a scale Standard Deviation 15.46	16.3 units on a scale Standard Deviation 14.79
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 200	15.7 units on a scale Standard Deviation 15.47	16.3 units on a scale Standard Deviation 14.69
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 204	15.7 units on a scale Standard Deviation 15.43	16.3 units on a scale Standard Deviation 14.69
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 108	13.6 units on a scale Standard Deviation 14.19	15.5 units on a scale Standard Deviation 13.82
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 112	14.4 units on a scale Standard Deviation 13.72	15.1 units on a scale Standard Deviation 13.50
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 116	14.1 units on a scale Standard Deviation 13.84	15.3 units on a scale Standard Deviation 13.51
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 120	14.3 units on a scale Standard Deviation 14.23	15.3 units on a scale Standard Deviation 13.68
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 124	14.4 units on a scale Standard Deviation 14.02	15.7 units on a scale Standard Deviation 13.69
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 128	15.1 units on a scale Standard Deviation 14.49	15.7 units on a scale Standard Deviation 13.72
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 132	15.1 units on a scale Standard Deviation 14.52	15.6 units on a scale Standard Deviation 13.63
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 136	14.8 units on a scale Standard Deviation 14.56	16.3 units on a scale Standard Deviation 13.75
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 140	15.4 units on a scale Standard Deviation 14.98	16.4 units on a scale Standard Deviation 14.29
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 144	15.7 units on a scale Standard Deviation 15.23	16.2 units on a scale Standard Deviation 14.22
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 148	15.5 units on a scale Standard Deviation 15.34	16.3 units on a scale Standard Deviation 14.35
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 152	15.5 units on a scale Standard Deviation 14.98	16.3 units on a scale Standard Deviation 14.25
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 156	11.2 units on a scale Standard Deviation 13.10	12.3 units on a scale Standard Deviation 14.59
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 160	15.2 units on a scale Standard Deviation 14.92	16.2 units on a scale Standard Deviation 14.61
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 164	15.6 units on a scale Standard Deviation 15.21	16.3 units on a scale Standard Deviation 14.64
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 176	15.5 units on a scale Standard Deviation 15.58	16.3 units on a scale Standard Deviation 14.91
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 180	15.5 units on a scale Standard Deviation 15.23	16.4 units on a scale Standard Deviation 14.89
Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT) Change from BL to Week 196	15.7 units on a scale Standard Deviation 15.45	16.3 units on a scale Standard Deviation 14.69

SECONDARY outcome

Timeframe: Baseline (Part 1) and every 4 weeks from Week 108 to Week 204

Population: Actual change from baseline tables are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data up to Weeks 204 and 252, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary, and the analysis was not done.

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).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Part 2 Baseline (Week 108) and Weeks 156 and 204

Population: Intent to treat population: all participants who were randomized and received at least 1 infusion of study treatment (Part 2) who had an assessment at Baseline and given time point.

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.

Outcome measures

Outcome measures
Measure	Placebo n=272 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Absenteeism: Week 204	3.0 percentage of impairment Standard Deviation 14.61	4.2 percentage of impairment Standard Deviation 16.89
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Presenteeism: Week 108	30.6 percentage of impairment Standard Deviation 12.10	30.9 percentage of impairment Standard Deviation 11.71
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Absenteeism: Week 108	2.6 percentage of impairment Standard Deviation 12.80	1.4 percentage of impairment Standard Deviation 8.24
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Absenteeism: Week 156	3.0 percentage of impairment Standard Deviation 14.61	4.1 percentage of impairment Standard Deviation 17.36
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Presenteeism: Week 156	30.8 percentage of impairment Standard Deviation 12.17	33.0 percentage of impairment Standard Deviation 14.23
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Presenteeism: Week 204	31.0 percentage of impairment Standard Deviation 12.29	32.2 percentage of impairment Standard Deviation 13.78
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Work Productivity Loss: Week 108	30.9 percentage of impairment Standard Deviation 12.36	31.2 percentage of impairment Standard Deviation 11.70
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Work Productivity Loss: Week 156	31.6 percentage of impairment Standard Deviation 13.54	33.9 percentage of impairment Standard Deviation 15.75
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Work Productivity Loss: Week 204	31.9 percentage of impairment Standard Deviation 13.66	33.3 percentage of impairment Standard Deviation 15.61
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Activity Impairment: Week 108	56.1 percentage of impairment Standard Deviation 24.78	58.0 percentage of impairment Standard Deviation 24.84
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Activity Impairment: Week 156	56.8 percentage of impairment Standard Deviation 26.49	58.5 percentage of impairment Standard Deviation 24.08
Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire Activity Impairment: Week 204	57.2 percentage of impairment Standard Deviation 25.15	59.8 percentage of impairment Standard Deviation 23.60

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire Absenteeism: Change at Week 156; n=18,17	-10.3 percentage change Standard Deviation 116.81	-7.4 percentage change Standard Deviation 95.77
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire Absenteeism: Change at Week 204; n=18, 17	-6.6 percentage change Standard Deviation 116.90	151.5 percentage change Standard Deviation 457.29
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire Presenteeism: Change at Week 156; n=264, 285	4.0 percentage change Standard Deviation 50.08	14.4 percentage change Standard Deviation 90.39
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire Presenteeism: Change at Week 204; n=264, 285	5.3 percentage change Standard Deviation 51.23	7.4 percentage change Standard Deviation 58.95
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire WPL: Change at Week 156; n=264,286	4.7 percentage change Standard Deviation 51.73	16.8 percentage change Standard Deviation 95.43
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire WPL: Change at Week 204; n=264, 286	5.9 percentage change Standard Deviation 53.44	10.6 percentage change Standard Deviation 69.34
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire AI: Change at Week 156; n=264, 284	16.0 percentage change Standard Deviation 95.68	15.7 percentage change Standard Deviation 83.70
Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire AI: Change at Week 204; n=264, 284	16.1 percentage change Standard Deviation 88.56	20.4 percentage change Standard Deviation 99.54

SECONDARY outcome

Timeframe: Week 24 (Part 1) and Weeks 156 and 204

Whole brain volume as measured by MRI.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume Change from Week 24 to Week 156; n=155, 175	-1.164 percentage change Standard Deviation 0.8228	-0.948 percentage change Standard Deviation 0.7193
Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume Change from Week 24 to Week 204; n=28, 24	-1.687 percentage change Standard Deviation 1.2872	-1.517 percentage change Standard Deviation 0.8412

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156 and 204

Whole grey matter brain volume as measured by MRI.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume Change from Baseline to Week 156; n=149, 170	-1.566 percentage change Standard Deviation 0.9303	-1.514 percentage change Standard Deviation 0.8969
Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume Change from Baseline to Week 204; n=26, 20	-1.883 percentage change Standard Deviation 1.4222	-2.086 percentage change Standard Deviation 0.9068

SECONDARY outcome

Timeframe: Baseline (Part 1) up to Week 204

New or enlarging T2 lesions as measured by MRI.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 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.	Natalizumab 300 mg n=291 Participants 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.
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 24 compared to BL; n=272, 287	2.1 lesions Standard Deviation 4.24	0.6 lesions Standard Deviation 3.27
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 48 compared to Week 24; n=272, 289	1.8 lesions Standard Deviation 4.47	0.0 lesions Standard Deviation 0.37
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 72 compared to Week 48; n=271, 287	1.6 lesions Standard Deviation 3.76	0.0 lesions Standard Deviation 0.19
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 96 compared to Week 72; n=269, 284	1.8 lesions Standard Deviation 4.33	0.0 lesions Standard Deviation 0.00
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 108 compared to Week 96; n=269, 288	1.2 lesions Standard Deviation 3.38	0.0 lesions Standard Deviation 0.13
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 156 compared to Week 108; n=245, 258	0.2 lesions Standard Deviation 0.79	0.0 lesions Standard Deviation 0.20
Part 2: Summary of New/Enlarging T2 Lesion Counts At Week 204 compared to Week 156; n=50, 47	0.0 lesions Standard Deviation 0.20	0.0 lesions Standard Deviation 0.15
Part 2: Summary of New/Enlarging T2 Lesion Counts Cumulative count from BL to Week 204; n=274, 291	8.6 lesions Standard Deviation 16.04	0.7 lesions Standard Deviation 3.53

SECONDARY outcome

Timeframe: Baseline (Part 1) and Weeks 156 and 204

Population: Summary new/enlarging T2 lesion values are provided in previous Outcome Measure. Due to the nature of self-selected population in an extension trial and sparse data up to Week 204, further tabulations on percentage changes on these endpoints were deemed less meaningful and unnecessary, and the analysis was not done.

New or enlarging T2 lesions as measured by MRI.

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 100 serious events

Other events: 347 other events

Deaths: 0 deaths

Natalizumab 300 mg

Serious events: 90 serious events

Other events: 325 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Biogen Study Medical Director

Biogen

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=449 participants at risk 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.	Natalizumab 300 mg n=439 participants at risk 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.
Gastrointestinal disorders Constipation	5.8% 26/449 • 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. Treatment-emergent adverse events only are presented.	4.8% 21/439 • 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. Treatment-emergent adverse events only are presented.
Gastrointestinal disorders Diarrhoea	6.9% 31/449 • 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. Treatment-emergent adverse events only are presented.	7.5% 33/439 • 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. Treatment-emergent adverse events only are presented.
Gastrointestinal disorders Nausea	5.1% 23/449 • 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. Treatment-emergent adverse events only are presented.	7.7% 34/439 • 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. Treatment-emergent adverse events only are presented.
General disorders Fatigue	11.8% 53/449 • 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. Treatment-emergent adverse events only are presented.	13.4% 59/439 • 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. Treatment-emergent adverse events only are presented.
Infections and infestations Cystitis	3.6% 16/449 • 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. Treatment-emergent adverse events only are presented.	5.0% 22/439 • 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. Treatment-emergent adverse events only are presented.
Infections and infestations Influenza	7.3% 33/449 • 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. Treatment-emergent adverse events only are presented.	7.3% 32/439 • 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. Treatment-emergent adverse events only are presented.
Infections and infestations Nasopharyngitis	16.3% 73/449 • 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. Treatment-emergent adverse events only are presented.	22.3% 98/439 • 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. Treatment-emergent adverse events only are presented.
Infections and infestations Upper respiratory tract infection	6.7% 30/449 • 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. Treatment-emergent adverse events only are presented.	10.9% 48/439 • 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. Treatment-emergent adverse events only are presented.
Infections and infestations Urinary tract infection	22.9% 103/449 • 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. Treatment-emergent adverse events only are presented.	22.8% 100/439 • 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. Treatment-emergent adverse events only are presented.
Injury, poisoning and procedural complications Contusion	3.8% 17/449 • 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. Treatment-emergent adverse events only are presented.	5.9% 26/439 • 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. Treatment-emergent adverse events only are presented.
Injury, poisoning and procedural complications Fall	18.9% 85/449 • 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. Treatment-emergent adverse events only are presented.	18.7% 82/439 • 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. Treatment-emergent adverse events only are presented.
Musculoskeletal and connective tissue disorders Arthralgia	8.9% 40/449 • 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. Treatment-emergent adverse events only are presented.	9.8% 43/439 • 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. Treatment-emergent adverse events only are presented.
Musculoskeletal and connective tissue disorders Back pain	11.1% 50/449 • 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. Treatment-emergent adverse events only are presented.	10.3% 45/439 • 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. Treatment-emergent adverse events only are presented.
Musculoskeletal and connective tissue disorders Muscle spasms	4.7% 21/449 • 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. Treatment-emergent adverse events only are presented.	5.2% 23/439 • 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. Treatment-emergent adverse events only are presented.
Musculoskeletal and connective tissue disorders Muscular weakness	8.7% 39/449 • 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. Treatment-emergent adverse events only are presented.	6.4% 28/439 • 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. Treatment-emergent adverse events only are presented.
Musculoskeletal and connective tissue disorders Pain in extremity	9.4% 42/449 • 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. Treatment-emergent adverse events only are presented.	9.6% 42/439 • 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. Treatment-emergent adverse events only are presented.
Nervous system disorders Dizziness	7.8% 35/449 • 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. Treatment-emergent adverse events only are presented.	5.0% 22/439 • 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. Treatment-emergent adverse events only are presented.
Nervous system disorders Headache	11.1% 50/449 • 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. Treatment-emergent adverse events only are presented.	15.0% 66/439 • 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. Treatment-emergent adverse events only are presented.
Nervous system disorders Multiple sclerosis relapse	25.8% 116/449 • 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. Treatment-emergent adverse events only are presented.	15.5% 68/439 • 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. Treatment-emergent adverse events only are presented.
Nervous system disorders Muscle spasticity	6.0% 27/449 • 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. Treatment-emergent adverse events only are presented.	3.9% 17/439 • 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. Treatment-emergent adverse events only are presented.
Nervous system disorders Paraesthesia	2.9% 13/449 • 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. Treatment-emergent adverse events only are presented.	5.0% 22/439 • 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. Treatment-emergent adverse events only are presented.
Respiratory, thoracic and mediastinal disorders Cough	4.5% 20/449 • 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. Treatment-emergent adverse events only are presented.	5.5% 24/439 • 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. Treatment-emergent adverse events only are presented.