Primary Outcomes

Description: Physiological fall risk will be determined by the physiological profile assessment which assesses physiological function related to fall risk by combining measures of vision, proprioception, lower-limb strength, postural sway, and cognitive function.

Measure: Physiological Fall risk

Time: 3 months

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Secondary Outcomes

Description: Mobility will be quantified with performance on timed 25 foot walk (T25W), timed up and go (TUG), Six spot step test, 6 minute walk and the MS walking scale-12.

Measure: Mobility

Time: 3 months

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Description: Balance will be quantified with the Berg Balance scale; self-report of balance impairment (ABC); and force platform metrics (sway range and velocity).

Measure: Balance

Time: 3 Months

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Description: Spasticity will be assessed with the modified ashworth scale.

Measure: Spasticity

Time: 3 Months

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Primary Outcomes

Measure: Fall incidence

Time: 3 months

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Secondary Outcomes

Description: Physiological fall risk will be determined by the short form of the Physiological Profile Assessment (PPA)(Lord, 2003). The PPA is a standardized test battery which assesses vision (edge contrast sensitivity), lower limb proprioception, strength (knee extension), postural sway, and cognitive function (simple hand reaction time). The outcome of each test will be combined to generate an overall fall risk score

Measure: Physiological Fall Risk

Time: 3 Months

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Description: Specific measures of walking speed, endurance, coordination and self-reported walking function scale will be employed to assess overall mobility of each person. Walking speed was quantified with the Timed 25-Foot Walk (T25W), walking endurance was assessed with the 6-Minute Walk (6MW), and functional mobility was quantified with the Timed Up and Go (TUG) . The Multiple Sclerosis Walking Scale-12 (MSWS-12) will be used as a self-reported measure of walking impairment.

Measure: Mobility

Time: 3 months

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Description: To assess balance (e.g. postural control), we conducted a clinical assessment To measure balance the Berg Balance Scale (BBS) and self-reports of balance confidence will be used. The BBS is a clinical assessment of balance. Scores on the BBS range from 0-56 with higher scores indicating greater balance. The Activities-Specific Balance Confidence (ABC) scale was used as a measure of balance confidence.

Measure: Balance

Time: 3 Months

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Primary Outcomes

Measure: Time to First Protocol-Defined Relapse in the Double-Blind Period

Time: From the date of randomization until the first occurrence of a protocol-defined relapse throughout the double-blind period (up to approximately 50 months)

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Secondary Outcomes

Description: The VAS for pain is a subjective measure and it consists of a 100 millimeter (mm) line with two end points representing 'no pain' to 'pain as bad as it could be'. Participants are asked to rate their pain by placing a mark on the line corresponding to their current level of pain. The distance along the line from the 'no pain' marker is then measured with a ruler giving a pain score out of 10.

Measure: Change from Baseline to Week 24 in the Visual Analogue Scale (VAS) Score for Pain

Time: Baseline, Week 24

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Description: FACIT fatigue scale includes 13 statements, which measures fatigue/asthenia for participants with chronic, life-threatening illnesses. For each question, a participant rates his/her condition for the past week on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). A score is calculated by averaging the individual question scores, with lower scores indicative of less fatigue.

Measure: Change from Baseline to Week 24 in the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score

Time: Baseline, Week 24

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the Short Form Generic Health Survey (SF-36) Bodily Pain Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 General Health Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Mental Health Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Physical Functioning Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Role-Emotional Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Role-Physical Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Social Role Functioning Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Vitality Domain Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Mental Component Summary Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The SF-36 domain scores range from 0-100. Higher scores indicate better quality of life.

Measure: Change from Baseline Over Time in the SF-36 Physical Component Summary Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The EQ-5D is a participant-answered questionnaire measuring 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression with 3 possible response categories: 1) no problems; 2) some problems; 3) severe problems. The EQ-5D index score is scored on a scale of -0.2 to 1. A higher score reflects a better health state.

Measure: Change from Baseline Over Time in the EuroQoL-5 Dimensions (EQ-5D) Index Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The T25W is the measurement to assess walking ability. The time (in seconds) that it takes the participant to walk 25 feet is measured.

Measure: Change from Baseline Over Time in the Timed 25-Foot Walk (T25W)

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Percentage of Participants Who Are Relapse-Free Over Time

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Annualized Relapse Rate

Time: From Baseline until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The mRS is a 7-point disability scale that assesses the degree of disability in patients with neurological impairment. Possible scores range from 0 (no symptoms at all) up to 6 (death). Higher scores reflect increased disability.

Measure: Change from Baseline Over Time in Modified Rankin Scale (mRS) Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain caregivers perceive. Responses range from 0 (never) to 4 (nearly always). The overall ZBI score ranges from 0 to 88. The higher the total score, the heavier the perceived burden.

Measure: Change from Baseline Over Time in Zarit Burden Interview (ZBI) Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Description: The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability.

Measure: Change from Baseline Over Time in Expanded Disability Status Scale (EDSS) Score

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Change from Baseline Over Time in Visual Acuity (Snellen Chart)

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Change from Baseline Over Time in Low-Contrast Visual Acuity, as Assessed Using the Low-Contrast Sloan Letter Chart (LCSLC)

Time: Baseline and every 24 weeks thereafter until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Number of Participants with at Least One Adverse Event by Severity

Time: From Baseline until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Number of Participants with at Least One Serious Adverse Event by Severity

Time: From Baseline until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Number of Participants with Non-Serious Adverse Events of Special Interest by Severity

Time: From Baseline until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Number of Participants with Selected Adverse Events by Severity

Time: From Baseline until 12 weeks after last dose of satralizumab (up to approximately 7.25 years)

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Measure: Number of Participants by Columbia-Suicide Severity Rating Scale (C-SSRS) Scores

Time: Baseline, Weeks 2, 4, 8, and every 4 weeks thereafter of double-blind period; every 4 weeks for first 48 weeks and every 12 weeks thereafter of open-label extension period (up to approximately 7.25 years)

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Measure: Serum Satralizumab Concentration Over Time

Time: Baseline, Weeks 2, 4, 5, 6, 8, and every 4 weeks thereafter of double-blind period; every 4 weeks for first 48 weeks and every 24 weeks thereafter of open-label extension period (up to approximately 7.25 years)

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Measure: Serum Interleukin-6 (IL-6) Concentration Over Time

Time: Baseline, Weeks 2, 4, 8, and every 4 weeks thereafter of double-blind period; every 4 weeks for first 48 weeks of open-label extension period (up to approximately 7.25 years)

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Measure: Serum Soluble IL-6 Receptor (sIL-6R) Concentration Over Time

Time: Baseline, Weeks 2, 4, 8, and every 4 weeks thereafter of double-blind period; every 4 weeks for first 48 weeks of open-label extension period (up to approximately 7.25 years)

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Measure: Serum High Sensitivity C-Reactive Protein (hsCRP) Concentration Over Time

Time: Baseline, Weeks 2, 4, 8, and every 4 weeks thereafter of double-blind period; every 4 weeks for first 48 weeks of open-label extension period (up to approximately 7.25 years)

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Measure: Blood Anti-Aquaporin-4 (AQP4) Antibody Concentration Over Time

Time: Baseline, Weeks 2, 4, 8, 12, 24, 48, and every 24 weeks thereafter of double-blind period; every 24 weeks for first 48 weeks of open-label extension period (up to approximately 7.25 years)

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Measure: Blood Plasmablast Concentration Over Time

Time: Baseline, Weeks 2, 4, 8, 12, 24, 48, and every 24 weeks thereafter of double-blind period (up to approximately 50 months)

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Measure: Number of Participants with Anti-Drug Antibodies to Satralizumab

Time: Baseline and every 4 weeks thereafter of double-blind period; every 4 weeks for first 48 weeks and every 24 weeks thereafter of open-label extension period (up to approximately 7.25 years)

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Primary Outcomes

Description: quantitative ambulation performance test

Measure: Timed 25-Foot Walk (T25W)

Time: up to 12 months

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Secondary Outcomes

Description: brief, standardized, quantitative test of upper extremity

Measure: 9-Hole Peg Test

Time: administered at baseline, one month, 6 months, and 12 months

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Description: measures cognitive processing speed and working memory

Measure: Symbol Digit Modalities Test

Time: administered at baseline, one month, 6 months, and 12 months

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Description: EDSS is the standard measure of neurologic impairment that is used to describe disability in MS. The neurological assessment comprises seven functional systems.

Measure: Functional Systems and Expanded Disability Status Scale (EDSS)

Time: administered at baseline, one month, 6 months, and 12 months

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Description: structured, self-report questionnaire with 21 itmes concerning how fatigue impacts patient's life

Measure: Modified Fatigue Impact Scale (MFIS)

Time: administered at baseline, one month, 6 months, and 12 months

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Description: 54-item multidimensional health-related quality of life measure that combines both generic and MS-specific items

Measure: Multiple Sclerosis Quality of Life Scale 54 item version

Time: administered at baseline, one month, 6 months, and 12 months

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Primary Outcomes

Description: Safety and tolerability

Measure: Part 1 and Part 2: Incidence of adverse events

Time: At 12 months after the first dose of study drug

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Measure: Part 1: Incidence of clinically significant changes in laboratory tests, electrocardiograms (ECGs), and vital signs

Time: At 12 months after the first dose of study drug

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Description: Dose assessment

Measure: Part 1: Recommended Part 2 dose of ATA188 monotherapy

Time: Day 1 to Day 35 of Cycle 1 for each participant in dose escalation part (approximately 1 year)

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Description: Antibody assessment and quantification

Measure: Part 2: Change from baseline in immunoglobulin G (IgG) index, including quantification of IgG production

Time: At 12 months after the first dose of study drug

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Secondary Outcomes

Description: Changes in disability score

Measure: Part 1: Change from baseline in expanded disability status scale (EDSS) score

Time: At 12 months after the first dose of study drug

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Description: Changes in disability score

Measure: Part 2: Change from baseline in clinical disability as assessed by the EDSS score and/or Timed 25 foot Walk (T25W) and/or 9-hole Peg Test (9HPT)

Time: At 12 months after the first dose of study drug

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Description: Change in MRI activity

Measure: Part 2: Change from baseline in cervical spinal cord volume and whole brain volume on MRI scans

Time: At 12 months after the first dose of study drug

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Description: Change in MRI activity

Measure: Part 2: Change from baseline in the number of Gadolinium-enhancing and new or enlarging T2 lesions on brain MRI scans

Time: At 12 months after the first dose of study drug

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Primary Outcomes

Description: PET outcome measure change at 18 months from baseline

Measure: PET Uptake/Standardized uptake value ratio (SUVR) change

Time: baseline and 18 months

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Secondary Outcomes

Description: PET outcome measure change at 6 months from baseline

Measure: PET Uptake/Standardized uptake value ratio (SUVR) change

Time: baseline and 6 months

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Description: MRI outcome measure change at 18 months from baseline

Measure: T2/FLAIR lesion load change

Time: baseline and 18 months

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Description: MRI outcome measure change at 18 months from baseline

Measure: Whole brain/deep gray matter atrophy change

Time: baseline and 18 months

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Description: Clinical outcome measure change at 18 months from baseline; Scale Range: 0-10; Higher values represent worse outcomes

Measure: Expanded Disability Status Scale (EDSS) change

Time: baseline and 18 months

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Description: Clinical outcome measure change at 18 months from baseline

Measure: Timed 25-foot walk (T25FW) change

Time: baseline and 18 months

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Description: Clinical outcome measure change at 18 months from baseline; Physical subscale range: 0-36; Cognitive subscale range: 0-40; Psychosocial subscale range: 0-8; Total MFIS Score scale range (Subscales Summed): 0-84; Higher values represent worse outcomes

Measure: Modified Fatigue Impact Scale (MIFS) change

Time: baseline and 18 months

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Description: Clinical outcome measure change at 18 months from baseline

Measure: Minimal Assessment of Cognitive Function in MS (MACFIMS) change

Time: baseline and 18 months

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Primary Outcomes

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with an increase in raw score of ≥ 4 points or 10% from baseline (improved)

Time: Up to approximately 3 years

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Secondary Outcomes

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with a decrease in raw score of ≥ 4 points or 10% from baseline (worsened)

Time: Up to approximately 3 years

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Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with a raw score change from baseline who do not meet the improved or worsened definition (stable)

Time: Up to approximately 3 years

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Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with an increase in raw score of ≥ 3 points from baseline

Time: Up to approximately 3 years

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Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with a decrease in raw score of ≥ 3 points from baseline

Time: Up to approximately 3 years

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Description: The SDMT is a measure of cognitive processing speed

Measure: Change from baseline in Symbol Digit Modalities Test (SMDT)

Time: Up to approximately 3 years

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Description: Magnetic resonance imaging (MRI) brain volume

Measure: Percent change from baseline in thalamic, cortical grey matter, whole brain, lateral ventricular, and MOV volumes

Time: Up to approximately 3 years

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Description: Magnetic Resonance Imaging

Measure: Proportion of subjects free of gadolinium enhancing (GdE) lesions over 3 years

Time: Up to approximately 3 years

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Description: Magnetic Resonance Imaging

Measure: GdE lesion volume over 3 years

Time: Up to approximately 3 years

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Description: Magnetic Resonance Imaging

Measure: Number of unique new or enlarging hyperintense T2-weighted lesions and their volume from baseline to Year 3

Time: Up to approximately 3 years

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Description: Magnetic Resonance Imaging

Measure: Number of unique new or enlarging hypointense T1 weighted lesions and their volume from baseline to Year 3

Time: Up to approximately 3 years

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Description: Change is TSQM score over 3 years

Measure: Treatment Satisfaction Questionnaire for Medication (TSQM v1.4)

Time: Up to approximately 3 years

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Description: Change in WPAI score over 3 years

Measure: Work Productivity and Activity Impairment-Multiple Sclerosis (WPAI-MS)

Time: Up to approximately 3 years

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Description: The Fatigue Severity Scale (FSS) questionnaire contains nine statements that attempt to explore severity of fatigue symptoms.

Measure: Fatigue Severity Scale (FSS)

Time: Up to approximately 3 years

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Description: The MSQOL-54 is a multidimensional health-related QOL measure that combines both generic and MS-specific items into a single instrument

Measure: Multiple Sclerosis Quality of Life-54 (MSQOL-54)

Time: Up to approximately 3 years

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Description: The HADS was developed to identify anxiety disorders and depression among subjects in nonpsychiatric hospital clinics

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: Up to approximately 3 years

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Description: Change in relapse rate over 3 years

Measure: Annualized relapse rate (ARR)

Time: Up to approximately 3 years

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Description: Disability progression assessed by 20% worsening from baseline over 3 years on T25W

Measure: Timed 25-foot Walk (T25W)

Time: Up to approximately 3 years

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Description: Change from baseline in the time in seconds needed to complete test activity

Measure: Nine-hole Peg Test (9-HPT)

Time: Up to approximately 3 years

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Description: Change from baseline in EDSS score (0-10) yearly and at 3 years

Measure: Expanded Disability Status Scale (EDSS)

Time: Up to approximately 3 years

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Description: An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE.

Measure: Adverse Events (AEs)

Time: Up to approximately 3 years

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Primary Outcomes

Description: PET outcome measure

Measure: Standardized Uptake Value (SUV)/Standardized Uptake Value Ratio (SUVR)

Time: Baseline

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Secondary Outcomes

Description: Clinical outcome measure; Physical subscale range: 0-36; Cognitive subscale range: 0-40; Psychosocial subscale range: 0-8; Total MFIS Score scale range (Subscales Summed): 0-84; Higher values represent worse outcomes.

Measure: Modified Fatigue Impact Scale (MFIS)

Time: Baseline

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Description: PET outcome measure

Measure: Binding Potential (BPnd)

Time: Baseline

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Description: MRI outcome measure

Measure: MRI grey matter lesional load/brain atrophy

Time: Baseline

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Description: PET outcome measure

Measure: Tissue Volume of distribution (Vt)/Distribution Volume Ratios (DVR)

Time: Baseline

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Description: MRI outcome measure

Measure: MRI global/regional volumetrics

Time: Baseline

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Primary Outcomes

Description: The primary endpoint of the study will be the change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements at early and late time-points (5, 28, 90 and 273 days) as compared to baseline.

Measure: Effect of Ofatumumab on microglial activity

Time: Baseline to 9 months

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Secondary Outcomes

Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in the peripheral CD19 counts at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and CD19 counts

Time: Baseline to 9 months

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Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in the serum glial fibrillary acid protein (GFAP) level measurements at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and glial fibrillary acid protein (GFAP)

Time: Baseline to 9 months

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Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in the serum neurofilament light chain levels at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and neurofilament light chain

Time: Baseline to 9 months

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Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in MRI -based brain volume (in ml) measurements at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and MRI-based brain atrophy changes

Time: Baseline to 9 months

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Description: Association of changes in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in disease severity (measured using expanded disability status scale or EDSS) at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and physical disability

Time: Baseline to 9 months

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Description: Association of changes in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in severity of cognitive impairment (measured using symbol digit modality test or SDMT) at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and cognitive disability

Time: Baseline to 9 months

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