Clinical trial NCT03737812
Conditions: Multiple Sclerosis (MS)
Keywords: Progressive multiple sclerosis Elezanumab ABT-555
Sponsor: AbbVie
Start date: 2019-02-27; Completion date: 2021-08-30
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of elezanumab in participants with progressive Multiple Sclerosis (PMS).

Detailed description:

Arms: arm 1: Participants randomized to receive placebo by intravenous infusion. arm 2: Participants randomized to receive 400mg of elezanumab by intravenous infusion. arm 3: Participants randomized to receive 1800mg of elezanumab by intravenous infusion.
Interventions: intervention 1: elezanumab intervention 2: placebo
Intervention descriptions: intervention 1: solution for infusion intervention 2: solution for infusion

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
6
2.1
BACKGROUND AND RATIONALE
6
2.2
BENEFITS AND RISKS TO SUBJECTS
6
3
STUDY OBJECTIVES AND ENDPOINTS
7
3.1
OBJECTIVE
7
3.2
PRIMARY ENDPOINT
7
3.3
SECONDARY ENDPOINTS
7
3.4
SAFETY ENDPOINTS
7
3.5
PHARMACOKINETIC ENDPOINTS
8
3.6
BIOMARKER RESEARCH ENDPOINTS FOR TARGET ENGAGEMENT AND NEURO-RESTORATION
8
3.7
EXPLORATORY ENDPOINTS
8
4
INVESTIGATIONAL PLAN
9
4.1
OVERALL STUDY DESIGN AND PLAN
9
4.2
DISCUSSION OF STUDY DESIGN
11
5
STUDY ACTIVITIES
12
5.1
ELIGIBILITY CRITERIA
12
5.2
CONTRACEPTION RECOMMENDATIONS
16
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
18
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
18
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
20
5.7
STUDY DRUG
20
5.8
RANDOMIZATION/DRUG ASSIGNMENT
24
5.9
PROTOCOL DEVIATIONS
24
6
SAFETY CONSIDERATIONS
25
6.1
COMPLAINTS AND ADVERSE EVENTS
25
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
28
7.1
STATISTICAL AND ANALYTICAL PLANS
28
7.2
DEFINITION FOR ANALYSIS SETS
28
7.3
STATISTICAL ANALYSES FOR EFFICACY
28
7.4
STATISTICAL ANALYSES FOR SAFETY
29
7.5
INTERIM ANALYSIS
29
7.6
SUBGROUP ANALYSIS
29
8
ETHICS
29
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
29
8.2
ETHICAL CONDUCT OF THE STUDY
30
8.3
SUBJECT CONFIDENTIALITY
30
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
30
10 DATA QUALITY ASSURANCE
30
11 COMPLETION OF THE STUDY
31
12 REFERENCES
31
LIST OF TABLES
TABLE 1.
STUDY DRUG IDENTIFICATION
21
TABLE 2.
STUDY DRUG ADMINISTRATION SCHEDULE
22
LIST OF FIGURES
FIGURE 1.
PERIOD 1 SCHEMATIC
10
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
32
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
35
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
36
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APPENDIX D.
ACTIVITY SCHEDULE
37
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
41
APPENDIX F.
OPERATIONS MANUAL
42
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Elezanumab is an investigational product under development for the treatment of multiple sclerosis 
(MS).  It is a monoclonal immunoglobulin (Ig) of the human immunoglobulin G1 (IgG1) isotype that binds 
specifically to the soluble and the membrane-bound forms of repulsive guidance molecule A (RGMa).
Neutralization of RGMa is a novel approach that may potentially provide neurorestoration/regeneration 
and functional recovery in a variety of degenerative central nervous system (CNS) diseases.  Repulsive 
guidance molecule A is a potent inhibitor of neurite outgrowth and is recognized as an important factor 
in inhibiting neuronal regeneration and functional recovery following CNS trauma or inflammation.  
Elezanumab binds to human repulsive guidance molecule A (hRGMa), but not to related family members 
RGMb and RGMc.
Elezanumab is being evaluated to determine whether this novel approach of neutralization of RGMa 
could lead to neural restoration and improvement in MS-related physical function.  This mechanism of 
action is distinct from those used by the immunomodulatory, anti-inflammatory drugs that are currently 
approved for the treatment of MS and, if successful, could serve to fulfill an unmet medical need in MS.
Clinical Hypothesis
Elezanumab will improve physical functioning in subjects with progressive forms of MS (Progressive 
forms of multiple sclerosis [PMS]) who have disability.
2.2 Benefits and Risks to Subjects
The safety and efficacy data from the elezanumab clinical program support development of elezanumab 
in Phase 2 in subjects with PMS.
For further details, please see findings from completed studies, including safety data in the elezanumab 
Investigator's Brochure.1
An internal safety review group will conduct reviews of safety data throughout the conduct of the study.
Considering the coronavirus disease - 2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  Management of these adverse events (AEs) will be 
made on a case-by-case basis with consideration of benefit/risk.  However, based on the limited 
information to date, the population and disease being studied, and the anticipation that 
COVID-19-related risks are not expected to differ substantially between study subjects and the broader 
population of subjects receiving treatment for MS, no change to the benefit/risk balance for subjects in 
this study is expected at this time.
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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objective
To evaluate the safety and efficacy of elezanumab in subjects with PMS.
3.2 Primary Endpoint
Primary endpoint:
Mean Overall Response Score (ORS) at Week 52.
Overall Response Score is a composite score derived from 4 components: 

Expanded Disability Status Scale (EDSS)

Timed 25-Foot Walk (T25FW)

9-Hole Peg Test in the dominant hand (9HPT-D)

9HPT in the non-dominant hand (9HPT-ND)
The ORS is scored with a range from –4 to +4 at each assessment.  Scores for each component are 
assessed relative to their baseline value:  –1 if there is clinically significant worsening, 0 if the change 
does not meet the clinically significant threshold criteria, or +1 if there is clinically significant 
improvement.  The scores for all components are summed at each assessment.
The clinically significant change thresholds for T25FW and 9HPT are defined by a 20% change from 
baseline (≥ 20% decrease from baseline for improvement and ≥ 20% increase from baseline for 
worsening).  For EDSS, improvement is defined as a 1-point decrease (baseline EDSS range of 1 to 5.5), 
or 0.5-point decrease if the baseline EDSS is 6.0 or greater (baseline EDSS range of 6.0 to 6.5).  
Corresponding increases in the designated ranges is defined as EDSS worsening.
3.3 Secondary Endpoints
1.
Disability improvement response rate on the Expanded Disability Status Scale Plus (EDSS +) 
(T25FW, 9-Hole Peg test [9HPT, either hand], EDSS) at Week 52 
2.
ORS at Weeks 12, 24, and 36
3.4 Safety Endpoints
Safety evaluations include AE monitoring, serious adverse event (SAE) monitoring, adverse events of 
special interest (AESI) monitoring, physical examinations, neurologic examinations, vital sign 
measurements, clinically significant magnetic resonance imaging (MRI) abnormalities, electrocardiogram 
(ECG) variables, Columbia-Suicide Severity Rating Scale (C-SSRS) assessments, and clinical laboratory 
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testing (hematology, chemistry, and urinalysis) as measures of safety and tolerability for the entire study 
duration.
3.5 Pharmacokinetic Endpoints
Samples will be collected for serum elezanumab concentrations, elezanumab anti-drug antibody (ADA) 
titers, and elezanumab neutralizing ADAs.  Samples will be obtained at the visits indicated in Figure 1
and Appendix D.  Descriptive summary statistics will be provided for all serum elezanumab 
concentrations.  Additional parameters may be estimated if useful in the interpretation of the data.
3.6 Biomarker Research Endpoints for Target Engagement and 
Neuro-restoration
Blood samples including serum and plasma will be collected at specified time points (Appendix D) 
throughout the study to evaluate known and/or novel disease-related and target engagement 
biomarkers and their response to treatment.  Types of biomarkers may include nucleic acids, proteins, 
lipids, and/or metabolites.  Biomarker endpoints may include, but are not restricted to RGMa, 
neurofilament light (NFL), glial fibrillary acidic protein (GFAP) and neuro-restoration markers 
[e.g., microRNA-338 (miR-338), myelin basic protein (MBP), proteolipid protein 1 (PLP1), growth 
associated protein-43 (GAP-43), brain-derived neurotrophic factor (BDNF), interleukin-10 (IL-10)] that 
may be measured as extravesicular protein and/or nucleic acid cargoes in the plasma.  Other biomarkers 
that may be examined in the blood include matrix metalloproteinase 9 (MMP-9) and chemokine (C-X-C 
motif) ligand 13 (CXCL13), which have been shown to be elevated in MS patients.  DNA and RNA samples 
(transcriptional profiling) will be collected and may be analyzed from all subjects, unless precluded by 
local regulations or restrictions.  This research may be exploratory in nature and the results may not be 
included with the clinical study report.
3.7 Exploratory Endpoints
1.
Disability improvement response rate on the T25FW, 9HPT, either hand, and EDSS at Weeks 12, 
24, 36, and 52, and the EDSS + at Weeks 12, 24, and 36.
2.
Change from Baseline on the T25FW and 9HPT, either hand, at Weeks 12, 24, 36, and 52 
3.
Disability progression response rate on the EDSS + (T25FW, 9HPT, either hand, EDSS) and for 
each EDSS + component
4.
12- and 24-week confirmed disability improvement response rate on the EDSS + (T25FW, 9HPT, 
either hand, EDSS) and for each EDSS + component
5.
Change from Baseline on the MS Impact Scale (MSIS-29) version 2 at Weeks 12, 24, 36, and 52 
6.
Change from Baseline on the Modified Fatigue Impact Scale (MFIS) at Weeks 12, 24, 36, and 52 
7.
Change from Baseline on cognition battery at Weeks 12, 24, 36, and 52: 

Symbol Digit Modalities Test (SDMT) – Oral Version

Brief Assessment of Cognition Verbal Memory - Immediate Recall – BAC App Version
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
Brief Assessment of Cognition Tower of London – BAC App Version
8.
Change from Baseline on the Low Contrast Visual Acuity (LCVA) assessments at Weeks 12, 24, 
36, and 52
9.
Change from Baseline in plasma biomarkers at Weeks 12, 24, 36, and 52
10. Change from Baseline on the MS Individualized Outcome Assessment (Multiple Sclerosis 
Individualized Outcome Assessment [MSIOA]) scale at Weeks 24 and 52
11. Change from Baseline in one week average daily step count and other activity measures (via 
home actigraphy with wearable biosensor) initiated at Weeks 24, 36, and 52
MRI Endpoints
The following imaging tests will be conducted.  Details will be provided in the Statistical Analysis Plan 
(SAP). 

Lesion counts and volumes

Brain and spinal cord atrophy measures 

Magnetization transfer ratio (MTR) 

Diffusion tensor imaging (DTI) 
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a 52-week, Phase 2a, proof-of concept, randomized, double-blinded, parallel-group, 
placebo-controlled multicenter study to evaluate the safety and efficacy of 2 doses of elezanumab in 
adult subjects with progressive forms of MS who have established disability.
This study will include an approximate 30-day Screening period.  The Treatment Period will include 
14 visits from Baseline (Week 0) every 4 weeks through Week 52.  Doses will be administered via 
Intravenous (IV) infusion at Week 0 (Baseline) and every 4 weeks thereafter through Week 48 for a total 
of 13 doses.  The follow-up period includes 6 follow-up telephone calls that will occur at Weeks 56 
through 76.  All visits during the Treatment Period and Follow-up Period will be allowed a window of ± 7 
days.  Safety parameters such as clinical laboratory test results, ECG, and vital signs will be monitored 
(see Operations Manual [Appendix F]).  Throughout the study and for a period of 39 weeks (5 half-lives) 
after the time of last study drug administration, females of childbearing potential will undergo monthly 
pregnancy testing; and for all subjects' AEs will be collected, whether solicited or spontaneously 
reported by the subject.
Eligible subjects will be randomized at the Week 0 - Baseline Visit to receive either elezanumab 
 
or 
 as an IV infusion or placebo in a 1:1:1 ratio (Section 5.8 and Section 7.3).  Blinded doses will 
be administered intravenously every 4 weeks for 48 weeks.  Subjects should remain on their current MS 
treatment regimen throughout the study.
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4.2 Discussion of Study Design
Choice of Control Group
The control group will be administered placebo infusion every 4 weeks.  Subjects will be maintained on 
their MS standard of care therapy without any adjustment in their treatment so that management of 
their underlying MS is not compromised.  In addition, no neurorestorative treatment is available to 
improve physical function.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  The EDSS scale, 
T25FW, and 9HPT are standard tools for assessing disability in patients with MS and are suitable for 
detecting change.
Suitability of Subject Population
Patients with PMS must have disability in order to enable detection of physical improvement.  Relapses 
occurring during study treatment will confound the ability to detect improvement.  Therefore, a study 
population with reduced risk of relapse is necessary.  Consequently, subjects receiving most approved 
immunomodulators for > 6 months will be included as will subjects not receiving immunomodulators for 
6 months.  Subjects with PMS must have been relapse-free (RF) for at least 24 months.
Selection of Doses in the Study
The dose levels of 
 and 
 monthly for this study were selected on the basis of safety and 
biomarker data from two Phase 1 clinical studies.
The safety and tolerability of elezanumab has been demonstrated in ~50 healthy volunteers and 
~20 patients with relapsing MS in Phase 1 studies.  In Study M14-141, single doses of up to 
 mg 
were administered to healthy volunteers.  All dose levels were safe and well tolerated.  With the 
possible exception of headache, no pattern was evident with regard to the nature or frequency of 
treatment-emergent AEs following IV infusion or SC injection of elezanumab compared with subjects 
who received placebo.  Adverse events were, in general, mild, sporadic, and self-limiting.  No 
dose-related effect was observed with respect to AEs.  No other safety findings were observed, including 
clinical labs, physical and neurological examination, MRI, and ECGs.
In Study M14-173, single doses of up to 
 (
 infusions on two consecutive days) and 
monthly doses of up to 
 were administered to MS patients for up to 4 months.  Similar to the 
single-dose study in healthy volunteers, no pattern was evident with regard to the nature or frequency 
of treatment-emergent AEs in subjects who received elezanumab compared with subjects who received 
placebo.  A possible transient, non–dose-related, non-clinically significant elevation in blood pressure 
immediately following IV infusion was observed in a few subjects who received elezanumab. There 
were no notable changes on physical or neurological exam, and no ECG, MRI, clinical laboratory, or 
other vital sign perturbations.  Adverse events, when reported, were mild, sporadic, and self-limiting 
with the exception of 2 MS relapses that occurred in 1 subject receiving placebo and another receiving 
 elezanumab.
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Two prespecified CSF biomarkers demonstrated a concentration-response relationship in the Phase 1 
studies.  Interleukin-10 has been associated with the promotion of remyelination, neuroregeneration, 
and neuroprotection as well as being able to mitigate inflammatory demyelination.  In Study M14-173, a 
statistically significant increase in CSF IL-10 was observed.  The increase was observed only in the high 
dose of 
 monthly.  Likewise, in the same study, a statistically significant decrease in CSF 
neurofilament light (NF-l), a marker of neurodegeneration, was observed at the 
 dose when 
compared with the 
 dose group.  These data suggest a clinically relevant, dose-related 
pharmacodynamic effect.  Reductions in CSF soluble RGMa were observed in both Studies M14-141 and 
M14-173.  The maximum reduction was approximately 50% from baseline, and the maximum reduction 
was seen at single doses equal to and exceeding 
 in healthy volunteers and repeat doses equal to 
or exceeding 
 monthly in MS patients.  It is noteworthy that the maximum CSF reduction in 
soluble RGMa was achieved in the 
 dose group, which was characterized by a range of CSF 
ABT-555 concentrations from 
  The relationship of sRGMa reduction and clinical 
efficacy is not understood.
The elezanumab doses selected for the current study are 
 Q28D and are expected to be 
safe and well tolerated based on previous exposures of these doses in healthy volunteers and MS 
patients.  In addition, to ensure patient safety, intense patient safety monitoring procedures have been 
implemented.  An unblinded internal Data Monitoring Committee (DMC), independent from the study 
team, will review and evaluate safety information including, but not limited to AEs, vital signs, and 
clinical laboratory assessments.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
A subject will be eligible for study participation if he/she meets all of the following inclusion and none of 
the exclusion criteria.
Inclusion Criteria
Consent
1. Subjects or their legally authorized representative must voluntarily sign and date an informed 
consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), 
before the initiation of any screening or study-specific procedures.
Demographic and Laboratory Assessments
2. Subject must be an adult male or female, between 18 and 65 years of age, inclusive.
3. Body mass index (BMI) is 18.0 to 45.0, inclusive at Screening.  Body mass index is calculated as 
weight in kg divided by the square of height measured in meters.
4. Laboratory values meeting the following criteria within the screening period before the 
first dose of study drug:

Serum alanine transaminase (ALT) < 2 × ULN;
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
Total white blood cell (WBC) count > 2,500/µL;

Absolute neutrophil count (ANC) > 1,300/µL;

Platelet count > 100,000/µL;

Absolute lymphocyte count > 700/µL;

Absolute lymphocyte count > 500/µL for subjects taking fingolimod (Gilenya), siponimod 
(Mayzent), dimethyl fumarate (Tecfidera) or teriflunomide (Aubagio).

Hemoglobin > 9 g/dL.
5. No positive screen for drugs of abuse, e.g., amphetamines, cocaine, opiates, barbiturates,
benzodiazepines as detected at Screening or Day –1.  A positive cannabinoid test is allowed if 
the responsible agent is taken for the management of MS symptoms (either concurrent or 
within the past 30 days).  Positive drug screen resulting from other prescribed medications is 
only allowed at the discretion of the AbbVie study-designated physician.
6. Willing and able to comply with procedures required in this protocol.
Disease Activity
7. Subject meets the diagnosis of primary-progressive MS (PPMS) or secondary-progressive MS 
(SPMS) according to the 2017 revised McDonald criteria and has a brain MRI demonstrating 
lesion(s) consistent with MS.
8. Not experiencing or recovering from a MS clinical relapse (reported by subject as diagnosed 
by a medical professional) within 24 months of Screening.
9. Baseline EDSS between 2 and 6.5, inclusive,
OR
Baseline T25FW ≥ 8 seconds (if EDSS < 2)
OR
Baseline 9HPT ≥ 33 seconds in either hand (if EDSS < 2)
10. Currently receiving one of the following MS medications for at least 6 months:  glatiramer 
acetate (Copaxone®, others), teriflunomide (Aubagio®), fingolimod (Gilenya®), dimethyl 
fumarate (Tecfidera®), rituximab (Rituxan®), siponimod (Mayzent®) or ocrelizumab (Ocrevus®) 
with no dose changes for at least 6 months before Screening and no anticipated change in MS 
medication or dose during the study.  Dalfampridine-ER (Ampyra®) or fampridine-SR (Fampyra®) 
is allowed if the subject has been on a stable dose for at least 3 months and plans to remain on 
this dose and regimen throughout the study.
OR
Has not been treated with an MS immunotherapy for the past 6 months (12 months if the 
subject previously received cyclophosphamide, alemtuzumab, rituximab, or ocrelizumab) before 
Screening.  Has not been treated with dalfampridine-ER (Ampyra®) or fampridine-SR (Fampyra®) 
for at least 3 months before screening.
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Subject History
11. Judged by the principal investigator to be in good general health based upon the results of a 
medical history, physical examination, laboratory profile, and a 12-lead ECG performed during 
the Screening period.
Contraception
12. For all females of child-bearing potential:  a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test before all doses of study drug.
13. Female subjects of childbearing potential practice at least 1 protocol-specified method of 
birth control that is effective from Study Week 0 through at least 39 weeks (5 half-lives) after 
the last dose of study drug.  Female subjects of non-childbearing potential do not need to use 
birth control.
14. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study and for at least 39 weeks (5 half-lives) after the last dose of study drug.
Exclusion criteria
Disease Activity
1. Prior treatment with any of the following:

Total lymphoid irradiation

Cladribine or mitoxantrone

T cell or T cell receptor vaccination

Stem cell therapy
2. Treatment with IV, oral, or intrathecal corticosteroids (or corticosteroid precursors such as 
adrenocorticotropic hormone) within the 6 months before Screening if used for the treatment 
of MS flare or disability progression (pre- or post-treatment with corticosteroids within 
6 months to prevent immunomodulatory infusion reactions is allowed).  Treatment with 
corticosteroids for non-MS conditions within the 6 months before Screening may be allowed at 
the discretion of the AbbVie study-designated physician. 
Subject History
3. History of known chronic or relevant acute infections including tuberculosis (TB).  Subjects 
with a positive QuantiFERON® TB/purified protein derivative (purified protein derivative 
(tuberculin)) test result may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the subject has no evidence of active TB.
4. History of, or positive screening test result for, human immunodeficiency virus (HIV).
5. History of, or positive screening test result for, hepatitis B virus (HBsAg), or a positive 
screening test for hepatitis C with virus titer > 0 following curative treatment.
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6. Onset of active varicella or herpes zoster virus infection or any severe viral infection requiring 
medical attention within 6 weeks before Screening.
7. Exposure to individuals with active varicella zoster virus infections within 21 days before 
Screening.
8. History of active systemic infection during the last 2 weeks before Week 0 - Baseline Visit 
(exception:  viral rhinitis), as assessed by the investigator.
9. Documented active or suspected malignancy or history of any malignancy within the last 
5 years except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma 
in situ of the cervix.
10. History of organ transplantation or plans for organ transplantation during the trial.
11. MRI is contraindicated, (i.e., aneurysm clip, metal fragments, internal electrical devices such 
as a cochlear implant, spinal cord stimulator, or pacemaker), contraindicated for or allergic to 
gadolinium (including renal impairment, previous diagnosis of nephrogenic systemic fibrosis and 
allergy), subject has claustrophobia that cannot be medically managed, or is not able to lie still 
for at least 1 hour for the imaging procedures.
12. Major surgery performed within 12 weeks before Screening or planned during the conduct 
of the study (e.g., hip replacement, aneurysm repair, stomach ligation), as assessed by the 
investigator.
13. History of clinically significant medical conditions or any other reason, including any physical, 
psychological, or psychiatric condition that in the investigator's opinion would compromise the 
safety or interfere with the subject's participation in this study or would make the subject an 
unsuitable candidate to receive study drug or would put the subject at risk by participating in 
the study, history of or abnormal screening lab or imaging results that, in the opinion of the 
investigator, are indicative of any significant cardiac, endocrinologic, hematologic, hepatic, 
immunologic, infectious, metabolic, urologic, pulmonary, gastrointestinal, dermatologic, 
psychiatric, renal, neurologic (other than MS), and/or other major disease that would preclude 
administration of elezanumab or MS immunomodulatory therapy, including any finding on brain 
MRI scan indicating clinically significant brain abnormalities other than MS.
14. History of drug abuse, misuse, or engagement in non-medical use of either prescribed or 
over-the-counter medication within 2 years before study drug administration or plans to do so 
during the study.
15. History of alcohol abuse within the last 2 years.
16. History of an allergic reaction or significant sensitivity to constituents of the study drug (and 
its excipients) and/or other products in the same class.
17. History of epilepsy or unexplained blackouts OR history of a seizure within 6 months of 
screening.  Subjects with febrile seizures before the age of 6 years are allowed.
18. History of treatment-refractory DSM-V defined major depressive disorder within 1 month of 
Screening.
19. History of suicidal ideation within 1 year before Screening, as evidenced by answering "yes" 
to questions 4 or 5 on the suicidal ideation portion of the C-SSRS completed at Screening, or any 
history of suicide attempts.
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20. Clinically relevant or significant ECG abnormalities, including ECG with QT interval corrected 
for heart rate (QTc) using Fridericia's formula (QTcF) > 450 msec (males) or > 470 msec 
(females).
Contraception
21. Female who is pregnant, breastfeeding, or considering becoming pregnant during the study 
or within 39 weeks (5 half-lives) after the last dose of study drug.
Concomitant Medications
22. Subject has received any investigational product within 30 days or 5 half-lives of the drug 
(whichever is longer) before the first dose of study drug or is currently enrolled in another 
clinical study.  Simultaneous enrollment in a non-interventional study is permitted so long as 
these studies do not assess the EDSS, T25FW, or 9HPT and are not overly burdensome and likely, 
in the investigator's opinion, to trigger subject discontinuation. 
23. Subject has any history of receipt of elezanumab before participation in this study.
24. Subject has received any live vaccine, including, but not limited to:  measles/mumps/rubella 
vaccine, varicella zoster virus within 4 weeks before randomization, or expected need of live 
vaccination during study participation including at least 4 weeks after the last dose of study 
drug.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)

Females of Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drug and for at least 
39 weeks (5 half-lives) after the last dose of study drug.  Females must commit to one of the 
following methods of birth control:
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
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 1 month 
before Screening.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month before Screening.

Bilateral tubal occlusion/ligation, i.e., Essure (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized sexual partner (provided the vasectomized partner has received medical 
confirmation of the surgical success of the vasectomy and is the sole sexual partner of the 
trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when this is 
in line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., 
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable).
5.3 Prohibited Medications and Therapy
In addition to the medications listed in the eligibility criteria, prior exposure to any of the following is 
NOT allowed:
1.
No prior treatment with the any of the following:

Total lymphoid irradiation

Cladribine or mitoxantrone

T cell or T cell receptor vaccination

Stem cell therapy
2.
No treatment with any of the following medications or procedures within the 6 months before 
Screening:

Natalizumab

Cyclosporine

Azathioprine

Methotrexate

Mycophenolate mofetil

Intravenous immunoglobulin (IVIg)

Any interferon product
3.
No treatment with cyclophosphamide or alemtuzumab within 1 year before Screening.
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4.
No treatment with IV, oral, or intrathecal corticosteroids (or corticosteroid precursors such as 
adrenocorticotropic hormone) for the purpose of treating an MS-flare within the 6 months 
before Screening.  Pre- or post-treatment with corticosteroids to prevent immunomodulatory 
infusion reactions for allowed concomitant medications is allowed.  Treatment with 
corticosteroids for non-MS conditions within the 6 months before Screening may be allowed at 
the discretion of the AbbVie study-designated physician.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject received since 30 days before Screening or receives during the 
study must be recorded through the post-treatment visit (Week 76).
Non-immunomodulatory therapies used for the treatment of MS symptoms may be allowed at the 
discretion of the AbbVie study-designated physician.
Subjects who experience a suspected MS relapse may be treated with IV methylprednisolone 
 for 1 to 5 consecutive days, or another corticosteroid regimen that is consistent with good 
neurological practice. 
For subjects who experience a sustained reduction in lymphocyte level to below 
 for at least 
6 months, or a level less than 
 on a single confirmed test, the investigator, or their treating 
neurologist if applicable, should consider the need to discontinue or switch their current 
immunomodulatory therapy. 
Any questions regarding concomitant or prior therapy should be raised to the sponsor/AbbVie medical 
contact.  Information regarding potential drug interactions with elezanumab can be located in the 
elezanumab Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications before initial study drug 
administration (immunomodulator discontinuation criteria listed above).  Subjects must be consented 
for the study before discontinuing any prohibited medications for the purpose of meeting study 
eligibility.
All allowable concomitant medications must be at a stable dose for at least 30 days before the subject's 
screening visit (6 months for immunomodulators), and it is anticipated that no change in dose will be 
required during the study treatment period.  All medications should remain at stable doses for the 
duration of the study unless a change in regimen is medically necessary.  All concomitant medications, 
including any change in dose must be recorded with the reason for use, dates of administration, dosages 
and frequency in the electronic case report form (eCRF).
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:
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
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie Therapeutic Area Medical Director.

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages along with continuation of the study drug 
would place the subject at risk.

The subject has a positive drug screen, including for cannabis, opioids, and benzodiazepines, 
unless they have been instructed to use the substance by a medical professional.

The subject becomes pregnant while on study drug.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.  Subjects who missed visits due to COVID-19 investigator 
site closures or opted to refrain from on-site visits during the COVID-19 pandemic will not be 
requested to prematurely discontinue by the sponsor.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure all acceptable mitigation steps have 
been explored.
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
During the Treatment Period, a subject with confirmed (viral test positive) or suspected COVID-19 
infection can only be dosed with study drug if the following COVID-19 viral clearance criteria are met:

Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since recovery, defined as resolution of fever without use of antipyretics 
and improvement in respiratory symptoms (e.g., cough, shortness of breath)
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
Asymptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since prior positive result (note:  subjects who develop symptoms will 
follow guidance above for symptomatic subjects)
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie medical contact, along with the possibility of premature discontinuation from the 
Treatment Period.  Follow subsequent protocol Section 5.6 for subjects who discontinued study drug.  
Frequency or timing of COVID-19 testing and intervals between testing for the above viral clearance 
criteria may be adjusted to account for epidemiologic trends, updated information regarding infectivity, 
and local/institutional guidelines.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
If a subject prematurely discontinues study participation (withdrawal of informed consent), the
procedures outlined for the Early-Discontinuation (ED) Visit should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after the last 
dose of study drug may be completed to ensure any treatment-emergent AEs/SAEs have been resolved.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that the subject 
has withdrawn and no longer wishes biomarker research to continue, samples will not be analyzed and
no new biomarker analysis data will be collected for the withdrawn subject or added to the existing data 
or database(s).
5.7 Study Drug
Elezanumab (ABT-555) is manufactured by AbbVie as shown in Table 1, below.  For subjects randomized 
to the treatment arms, the solution contained in the study vial(s) of ABT-555 will be diluted in the 0.9% 
Sodium Chloride Injection/Solution for Infusion.  
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Table 1.
Study Drug Identification
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
ABT-555 
Infusion
Solution for infusion 
in a vial
AbbVie Deutschland 
GmbH & Co. KG, 
Ludwigshafen, 
Germany
Placebo
Infusion
0.9% Sodium 
Chloride 
Injection/Solution 
for Infusion, 250 mL
N/A
Various* 
(See below)
N/A = Not applicable
*
Can be sourced from approved marketed products from various commercial manufacturers depending on availability.
0.9% Sodium Chloride Injection/Solution for Infusion will be administered to those subjects not receiving 
active elezanumab (ABT-555) and as a vehicle for administration of elezanumab (ABT-555).  0.9% 
Sodium Chloride Injection/Solution for Infusion will be supplied with commercially available material in 
either bags or bottles, locally sourced by sites.  However, if mandated by local regulation, or in the case 
of exceptional circumstances when sites are unable to procure on their own, AbbVie may supply 0.9% 
Sodium Chloride Injection/Solution for Infusion if necessary.
Treatment Administration
The study drug will be administered intravenously at the visits listed in the Operations Manual 
Section 2.0 (Appendix F).  AbbVie will provide study drug as liquid in a vial that requires sterile 
preparation.  The time from start of preparation to start of infusion must not exceed 21 hours.  The 
study drug can be administered without regard to food consumption and infusion time is 90 to 
120 minutes.  However, infusion time may be increased in subjects who have experienced possible 
infusion reactions during prior infusions in this study (Operations Manual [Appendix F] Appendix D 
Criteria for Monitoring Elezanumab Infusion Reactions).  Pre-medication with antihistamines or 
corticosteroids before investigational product infusion is not allowed without the consent of the AbbVie 
study-designated physician.    
The first dose of study drug will be administered after all other Week 0 – Baseline procedures are 
completed.  For this reason, it is recommended that the study drug is not prepared until eligibility is 
reconfirmed at the Week 0-Baseline visit.  Timing of the preparation of subsequent doses is at the 
discretion of the site.  
Study drug will be administered by IV infusion at each visit, as shown in Table 2, below.
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Table 2.
Study Drug Administration Schedule
Study Drug Treatment Group
Administration
Placebo (0.9% Sodium Chloride Injection/Solution 
for Infusion)
IV infusions at Week 0-Baseline visit, then every 4 weeks 
through Week 48
Elezanumab (ABT-555) 
Elezanumab (ABT-555) 
IV = Intravenous
The start and stop time of each study drug infusion will be recorded to the nearest minute.
Packaging and Labeling
Elezanumab (ABT-555) will be provided in a vial as a solution for infusion 
) packaged in a 
carton, with 1 vial per carton.  One carton is equivalent to 1 kit.  Each kit (vial and carton) will be labeled 
per local requirements and this label must remain affixed to the kit.  Upon receipt, study drug should be 
stored as specified on the label and kept in a secure location.  Each kit will contain a unique kit number. 
The commercially sourced 0.9% Sodium Chloride Injection/Solution for Infusion (250 ml) will not be 
labeled as an Investigational Medicinal Product (IMP) before the handling by the unblinded pharmacist 
or qualified designee.  However, after addition of elezanumab (ABT-555) to the 0.9% Sodium Chloride 
Injection/Solution for Infusion to be administered in the active arm, the unblinded pharmacist or 
qualified designee will add a blinded dispensing label.  Likewise, the unblinded pharmacist or qualified 
designee will add a blinded dispensing label to the 0.9% Sodium Chloride Injection/Solution for Infusion, 
to be administered in the placebo arm.  Labels must remain affixed to the material.
If an IMP label on the 0.9% Sodium Chloride Injection/Solution for Infusion is mandated by local 
agencies, labels may be applied on the overwrap and will be removed by the unblinded pharmacist 
before administration.
Storage and Disposition of Study Drug
Study drug, elezanumab (ABT-555) must be refrigerated (2° to 8°C), protected from light, and cannot be 
frozen.  The investigational product is for investigational use only and is to be used only within the 
context of this study.  The study drug supplied for this study must be maintained under adequate 
security and stored under the conditions specified on the label until dispensed for subject use or 
destroyed on site as appropriate.
A storage temperature log is to be maintained to document proper storage conditions.  Sites must 
record the refrigerator temperature daily on a temperature log.  Malfunctions or any temperature 
excursion must be reported to the sponsor immediately using the AbbVie Temperature Excursion 
Management System (ATEMS).  Study medication should be quarantined and not dispensed until ATEMS 
deems the medication as acceptable.
0.9% Sodium Chloride Injection/Solution for Infusion should be stored per the locally approved 
commercial label, Summary of Product Characteristics (SmPC), or clinical study label. 
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The investigational products are for investigational use only and are to be used only within the context 
of this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under conditions specified on the label until dispensed for subject use or returned to AbbVie.
Subject Identifier Assignment
An interactive response technology (IRT) system will assign a unique identification number to each 
subject at the Screening Visit.  For subjects who do not meet the study selection criteria, site personnel 
must register the subject as a screen failure in the IRT system.
Subjects who are enrolled will retain the subject number assigned to them at Screening Visit throughout 
the study.
Interactive response technology Vendor contact information and user guidelines will be provided to 
each site.
Timing of Dose for Each Subject
Eligible subjects will receive either elezanumab 
 or placebo as an IV infusion at a 
constant rate by gravity or pump over an interval of 90 to 120 minutes.  The start and stop time of each 
study drug infusion will be recorded to the nearest minute.  Interruptions of infusion administration will 
be recorded to the nearest minute as well.  Blinded doses will be administered intravenously every 
4 weeks for 48 weeks (13 total infusions).
Study Drug Accountability
The investigator or his representative will verify that study drug supplies are received intact and in the 
correct amounts.  This will be documented by signing and dating a proof of receipt or similar document.  
A current (running) and accurate inventory of study drug will be maintained in the IRT system.
Throughout the study and at the study site closeout visit, overall accountability will be performed and 
verified by the AbbVie unblinded clinical research associate (CRA) (Pharmacy CRA).  
The unblinded pharmacist or qualified designee will be responsible for maintaining study drug 
preparation records and drug accountability records for study drug as well as the saline IV solution 
dispensed by the site, including product description, manufacturer, and lot numbers.  Further details are 
provided in the Pharmacy Manual.
Study Blinding
Subjects in the placebo group will be administered 0.9% Sodium Chloride Injection/Solution for Infusion 
that is identical in appearance and volume to the elezanumab solution.  An unblinded pharmacist or 
qualified designee will receive assignments and prepare the blinded doses across the treatment groups.  
The investigator, study site personnel (except the unblinded pharmacist or qualified designee) and the 
subject will remain blinded to the treatment assignment throughout the course of the study.
Because of the blinding of this study, deliveries of elezanumab and 0.9% Sodium Chloride 
Injection/Solution, if applicable, will be shipped directly to the pharmacy.  The unblinded pharmacist or 
qualified designee will prepare the dosing of elezanumab (in a blinded manner) following the available 
preparation instructions in the Pharmacy Manual and based on the subject's assigned treatment group.  
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For blinding purposes, identical commercial 0.9% Sodium Chloride Injection/Solution for Infusion bag or 
bottle will be used in the placebo and elezanumab arms at each site.
For investigational product monitoring, there will be an unblinded AbbVie CRA (also referred to as a 
Pharmacy CRA) for verification of unblinded preparation documentation.  The unblinded Pharmacy CRA 
will be a separate individual than the blinded CRA to ensure blinding is maintained.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team, the unblinded CRA and the AbbVie safety review 
group), the investigator, study site personnel, and the subject will remain blinded to each subject's 
treatment throughout the study.
The IRT will provide access to unblinded subject treatment information in the case of a medical 
emergency.
AbbVie must be notified before breaking the blind, unless identification of the study drug is required for 
a medical emergency, i.e., situation in which the knowledge or the specific blinded treatment will affect 
the immediate management of the subject's conditions (e.g., antidote is available).  AbbVie must then 
be notified within 24 hours of the blind being broken.  The date and reason that the blind was broken 
must be recorded in the source documentation and on the eCRF, as applicable.
5.8 Randomization/Drug Assignment
Subjects will be randomized in a 1:1:1 ratio to one of two doses of elezanumab or placebo according to 
the randomization schedule generated by the Abbvie statistics department.  An IRT system will be used 
to assign subject numbers and drug kits in accordance with the subject's assigned treatment group.  The 
use of the IRT system is described in the Operations Manual Section 3.15 (Appendix F).
Randomization (Section 7.3) will be stratified between treatment and placebo arms based on the 
following factors:

Diagnosis of PPMS vs. SPMS

Presence or absence of background MS immunotherapy
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying IEC/independent review board (IRB), regulatory authorities 
(as applicable), and AbbVie.
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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Event
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.  The investigators will monitor each subject for clinical and laboratory evidence of AEs on a 
routine basis throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre planned before study entry.  However, if the pre-existing condition deteriorates unexpectedly during
the study (e.g., surgery performed earlier than planned), then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or contract research organization (CRO) (as appropriate) 
as an SAE within 24 hours of the site's being made aware of the SAE (refer to Section 4.2 of the 
Operations Manual [Appendix F] for reporting details and contact information):
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Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or visit to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration up to 39 weeks (5 half-lives) from the last 
dose of study drug (Week 48 visit) will be collected, whether solicited or spontaneously reported by the 
subject.  In addition, SAEs and protocol-related nonserious AEs will be collected from the time the 
subject signs the study-specific informed consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the IMP in accordance with global and local requirements.  Additional information about SUSAR 
reporting is presented in the Operations Manual (Appendix F) Section 5.2 SUSAR Reporting.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE as mild, moderate, or severe.  The investigator will use 
the following definitions to rate the severity of each AE:
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Mild:  The AE is transient and easily tolerated by the subject.
Moderate:  The AE causes the subject discomfort and interrupts the subject's usual activities.
Severe:  The AE causes considerable interference with the subject's usual activities and may be 
incapacitating or life-threatening.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
For AESIs, serious and nonserious, meeting predefined criteria, specific questionnaires will be used to 
standardize the collection of follow-up information.  The AESI questionnaires will be issued within the 
electronic data capture (EDC) system once applicable.  The investigator will enter the information into 
the EDC system once applicable.
The following AESI will be monitored during the study:

Infusion reactions
Further information about AESIs is provided in the Operations Manual (Appendix F) Section 4.1.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  If a pregnancy occurs in a study subject, information regarding the 
pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
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7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
statistical analysis plan (SAP).  The SAP will be finalized before the interim database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Sets
The Modified ITT (mITT) Set includes all randomized subjects who received at least 1 dose of study drug.  
Subjects will be grouped according to treatment as randomized. 
Multiple sclerosis expert(s) will confirm which subjects experienced a clinical relapse(s) through 
adjudication of study data, including the MS-relapse questionnaire.  The RF Set includes all subjects in 
the mITT data set without any MS-related relapse during the Treatment Period (from Week 0 to 
Week 52).  Subjects will be grouped according to treatment as randomized.
The Minimal Missed Infusion Analysis (MMIA) Set includes all randomized subjects who received at least 
6 infusions total and missed no consecutive infusions before the subject's final dose.  Subjects will be 
grouped according to treatment as randomized.
The Safety Analysis Set includes all subjects who received at least 1 dose of study drug.  Subjects will be 
grouped according to treatment received regardless of randomization.
7.3 Statistical Analyses for Efficacy
The ORS scores will be summarized descriptively (including n, mean, standard deviation, minimum, 
median, and maximum) along with the 95% confidence interval at each visit.  The frequency and 
percentage of ORS for –4 to +4 will also be provided by treatment group at each visit.  The ORS for each 
treatment group at scheduled visits and overall will also be estimated using a mixed-effect model for 
repeated measures (MMRM) including treatment group, visit, treatment-by-visit interaction, and 
stratification factors as fixed effects, with the baseline values for the ORS components as covariates.
For other continuous efficacy endpoints, the mean, standard deviation, median, minimum and 
maximum will be reported for each treatment group.  The treatment comparison will be conducted 
using MMRM model including treatment group, visit, treatment-by-visit interaction, and stratification 
factors as fixed effects and the baseline value associated with the endpoint as a covariate.
For binary efficacy endpoints, the frequency and percentage will be provided by treatment group.  The 
treatment comparison will be conducted using a logistic regression model adjusted for the stratification 
factors and baseline score associated with the endpoint.
All efficacy endpoints will be analyzed on mITT population.  The RF and MMIA Sets will be used for the 
primary and other efficacy analyses as specified in the SAP.
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Sample Size Estimation
Approximately 90 subjects will be equally randomized 1:1:1 to each treatment group (30 subjects in 
each treatment group, with a target of 20 PPMS subjects and approximately 10 SPMS subjects per 
treatment group).  There is limited prior data to estimate the magnitude of effect and variance for a 
neurorestorative therapy.  The sample size was therefore selected based on operational feasibility, 
variance seen in prior MS trials, and the likelihood of predicting success in subsequent phases of 
development. 
7.4 Statistical Analyses for Safety
Analysis of the following safety evaluations will be performed during the study:  Adverse events and 
SAEs; vital signs, laboratory tests, ECG, physical and neurologic examinations, and C-SSRS assessments.
Complete and specific details of the statistical analysis of safety evaluations will be described and fully 
documented in the SAP.
7.5 Interim Analysis
There are no interim efficacy or futility analyses.
7.6 Subgroup Analysis
The primary efficacy analyses will also be performed in the following subgroups to assess the 
consistency of the treatment effect:

Sex (male, female)

Age (≤ 40 years, > 40 years)

EDSS baseline (≤ median, > median)

Diagnosis of MS form (primary-progressive [PPMS], SPMS) 

Presence of background MS immunotherapy (yes, no)
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Independent Ethics Committee/Institutional Review Board (IEC/IRB) for review and 
approval.  Approval of both the protocol and the informed consent form(s) must be obtained before any 
subject is enrolled.  Any amendment to the protocol will require review and approval by the IEC/IRB 
before the changes are implemented to the study.  In addition, all changes to the consent form(s) will be 
IEC/IRB approved.
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8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations, and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties in performing 
protocol-specified procedures, AbbVie will engage with study site personnel in efforts to ensure the 
safety of subjects, maintain protocol compliance, and minimize risks to the integrity of the study while 
trying to best manage subject continuity of care.  This may include alternative methods for assessments 
(e.g., phone contacts, virtual site visits, or hybrid visits to minimize subject face-to-face time), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping of supplies via 
a direct-to-patient vendor to ensure continuity of treatment where allowed.  Refer to the Operations 
Manual in Appendix F for additional details.  In all cases, these alternative measures must be allowed by 
local regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent safety 
measures are taken to protect the subjects against any immediate hazard.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  Remote monitoring of data may be employed if allowed by the local regulatory 
authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
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STUDY M14-397  |  Version 5.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
12
REFERENCES
1.
AbbVie.  Elezanumab Investigator's Brochure.
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STUDY M14-397  |  Version 5.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
ANC
Absolute neutrophil count
ATEMS
AbbVie Temperature Excursion Management System
BDNF
Brain-derived neurotrophic factor
BMI
Body mass index
CNS
Central nervous system
COVID-19
Coronavirus Disease – 2019
CRA
Clinical research associate
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CXCL13
C-X-C motif ligand 13
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DTI
Diffusion tensor imaging
ECG
Electrocardiogram
eCRF
Electronic case report form
ED
Early discontinuation
EDC
Electronic data capture
EDSS
Expanded Disability Status Scale
EDSS+
Expanded Disability Status Scale Plus
FSH
Follicle-stimulating hormone
GAP-43
Growth associated protein-43
GCP
Good clinical practice
GFAP
Glial fibrillary acidic protein
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
hRGMa
Human repulsive guidance molecule A
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STUDY M14-397  |  Version 5.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent ethics committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
Ig
Immunoglobulin
IgG1
Immunoglobulin G1
IL-10
Interleukin-10
IMP
Investigational medicinal product
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-treat
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVIg
Intravenous immunoglobulin
LCVA
Low Contrast Visual Acuity
MBP
Myelin basic protein
MFIS
Modified Fatigue Impact Scale
MFIS-5
Modified Fatigue Impact Scale
miR-338
MicroRNA-338
mITT
Modified intent-to-treat
MMIA
Minimal Missed Infusion Analysis
MMP-9
Matrix metalloproteinase 9
MMRM
Mixed-effect model for repeated measures
MRI
Magnetic resonance imaging
MS
Multiple sclerosis
MSIOA
Multiple Sclerosis Individualized Outcome Assessment
MTR
Magnetization transfer ratio
N/A
Not applicable
NF-l
Neurofilament light
NFL
Neurofilament light
NMSC
Non-melanoma skin cancer
ORS
Overall Response Score
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STUDY M14-397  |  Version 5.0
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PK
Pharmacokinetic(s)
PLP1
proteolipid protein 1
PMS
Progressive forms of multiple sclerosis
PPD
Purified protein derivative (tuberculin)
PPMS
Primary-progressive MS
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RF
Relapse-free
RGMa
Repulsive guidance molecule A
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SDMT
Symbol Digit Modalities Test
SmPC
Summary of Product Characteristics
SPMS
Secondary-progressive MS
SUSAR
Suspected unexpected serious adverse reactions
T25FW
Timed 25-Foot Walk
TB
Tuberculosis
ULN
Upper limit of normal
vs.
Versus
WBC
White blood cell
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STUDY M14-397  |  Version 5.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M14-397:  A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Assess the 
Safety and Efficacy of Elezanumab when Added to Standard of Care in Progressive Forms of Multiple 
Sclerosis
Protocol Date:  19 March 2021
Clinical research studies sponsored by AbbVie are subject to the ICH GCP and local regulations and 
guidelines governing the study at the site location.  In signing the Investigator Agreement, the 
investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and Operations Manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate IRB/IEC, except when necessary to protect the subject from 
immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Program Development
Medical Writing
Neuroscience
Data and Statistical Sciences
Data and Statistical Sciences
Clinical Pharmacology
Bioanalytics
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STUDY M14-397  |  Version 5.0
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the study.  The individual activities are described 
in detail in Section 3 of the Operations Manual (Appendix F).  Allowed modifications due to COVID-19 
are detailed within the Operations Manual.
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STUDY M14-397  |  Version 5.0
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date
Version 1.0
30 August 2018
Version 2.0
01 February 2019
Version 3.0
07 August 2019
Version 4.0
03 November 2020
Protocol Summary of Changes
The purpose of this version is the removal of on-site assessments performed at Weeks 64 and 76 so that 
all visits in the Follow-up period can be conducted virtually.  Other administrative revisions were made 
throughout the protocol, including the synopsis, and to the Operations Manual, to ensure consistency 
with the changes below:
1.
Protocol Section 4.1, Overall Study Design and Plan, Figure 1. Study Schematic and Protocol 
Appendix D. Activity Schedule: Remove Weeks 64 and 76 as an on-site visit. 
2.
Update to Appendix F, Operations Manual: Section 2.1, Individual Treatment Period Visit 
Activities and Section 2.2, Individual Post-Treatment Period Visit Activities (Week 64 and 
Week 76) to remove vital signs, EDSS, T25FW, 9HPT, urine drug and alcohol test, PK and ADA 
sample collections; Section 3.6 Scales and Questionnaires table to remove EDSS T25FW, 9HPT 
from Follow-up at Weeks 64 and 76.
Rationale:
By January 2021, all study subjects had completed 52 weeks of therapy.  A recent, planned efficacy 
analysis revealed that elezanumab therapy provided no beneficial effects.  A lack of efficacy was 
observed on all endpoints.
The study initially had scheduled in person site visits at Week 64 and Week 76.  The purpose of these 
visits was to perform assessment of the primary endpoint to better understand the durability of 
improvement observed at Week 52.  Because there were no beneficial drug effects at Week 52, there is 
no scientific purpose to having the subjects return for in person visits.  The ongoing COVID-19 pandemic 
also provides a strong justification for NOT having subjects perform unneeded in person site visits.
The collection of safety-related information by phone every 4 weeks through Week 76, including AEs, 
C-SSRS assessments, and pregnancy testing results will continue.
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SAP_001.pdf: 
Elezanumab (ABT-555)
M14-397 – Statistical Analysis Plan
Version 2.0 – 06 Jan 2021
1
1.0
Title Page
Statistical Analysis Plan
Study M14-397
Randomized, Double-Blind, Placebo-Controlled, 
Multiple Dose Study to Assess the Safety and 
Efficacy of Elezanumab when Added to Standard of 
Care in Progressive Forms of Multiple Sclerosis
Date:  06 Jan 2021
Version 2.0
 
NCT03737812


Elezanumab (ABT-555)
M14-397 – Statistical Analysis Plan
Version 2.0 – 06 Jan 2021
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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Background...................................................................5
4.1
Objective....................................................................................................5
4.2
Study Design..............................................................................................5
4.2.1
Study Design and Design Diagram............................................................5
4.2.2
Variables used for Stratification at Randomization...................................6
4.3
Endpoint.....................................................................................................7
4.3.1
Primary Efficacy Endpoint ........................................................................7
4.3.2
Secondary Efficacy Endpoints...................................................................8
4.3.3
Exploratory Efficacy Endpoints.................................................................8
4.3.4
Safety Endpoints ......................................................................................10
4.4
Sample Size Justification .........................................................................11
4.5
Interim Analysis.......................................................................................11
4.6
Multiplicity Testing Procedures for Type-I Error Control ......................11
4.7
Missing Data Imputation..........................................................................11
5.0
Analysis Sets and Important Subgroups.............................12
5.1
Analysis Sets............................................................................................12
5.2
Subgroups ................................................................................................13
6.0
Subject Disposition................................................................14
7.0
Extent of Exposure and Compliance ...................................14
8.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................15
8.1
Demographics and Baseline Characteristics............................................15
8.2
Medical History .......................................................................................16
8.3
MS Disease History .................................................................................16
8.4
Prior and Concomitant Medications ........................................................16
8.5
Protocol Deviations and Visit Modifications...........................................17
9.0
Efficacy Analyses...................................................................17
9.1
General Considerations............................................................................17
 


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9.2
Primary Efficacy Analysis .......................................................................18
9.3
Secondary Efficacy Analyses...................................................................19
9.3.1
Sensitivity Analysis of the Primary and Secondary Endpoints ...............20
9.4
Other Efficacy Analyses ..........................................................................21
9.4.1
Confirmed Improvement on the EDSS + and its components.................21
9.4.2
Disability Progression..............................................................................22
9.4.3
T25FW .....................................................................................................23
9.4.4
9HPT........................................................................................................23
9.4.5
Exploratory Patient and Clinician Measured Scales................................23
9.4.6
SDMT ......................................................................................................23
9.4.7
MFIS-5.....................................................................................................24
9.4.8
Low Contrast Visual Acuity ....................................................................24
9.4.9
Actigraphy................................................................................................25
9.4.10
Biomarkers...............................................................................................26
9.4.11
MRI Parameters .......................................................................................26
9.5
Efficacy Subgroup Analyses....................................................................28
9.6
Figures Based on the EDSS + and Its Components.................................29
10.0
Safety Analyses ......................................................................29
10.1
General Considerations............................................................................29
10.2
Analysis of Adverse Events.....................................................................30
10.2.1
Treatment-Emergent Adverse Events ......................................................30
10.2.2
Adverse Event Overview .........................................................................30
10.2.3
Adverse Events by System Organ Class and Preferred Term..................30
10.2.4
Adverse Event Incidence .........................................................................31
10.2.5
Adverse Events by Maximum Severity ...................................................31
10.2.6
Adverse Events by Maximum Relationship ............................................32
10.2.7
Adverse Events of Special Interest ..........................................................32
10.2.8
Listings of Adverse Events ......................................................................33
10.2.9
Adverse Events by Preferred Term in Decreasing Frequency.................33
10.3
Analysis of Laboratory Data....................................................................33
10.3.1
Analysis of Laboratory Tests...................................................................34
10.3.2
Shifts Between Normal and Abnormal for Laboratory Tests ..................34
 


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10.3.3
Analysis for Potentially Clinically Significant (PCS) Laboratory 
Values ......................................................................................................34
10.4
Analysis of Vital Signs and Weight.........................................................35
10.4.1
Vital Sign and Weight..............................................................................35
10.4.2
Potentially Clinically Significant (PCS) Vital Signs ...............................36
10.5
Analysis of ECG Parameters....................................................................37
10.6
Analysis of Columbia-Suicide Severity Rating Scale (C-SSRS) ............37
10.7
MS Relapses.............................................................................................37
10.8
Pregnancy.................................................................................................37
11.0
Summary of Changes ............................................................38
11.1
Summary of Changes Between the Previous Version and the 
Current Version........................................................................................38
11.2
Summary of Changes in Previous Version ..............................................39
12.0
Appendix.................................................................................39
12.1
Adverse Events of Special Interest ..........................................................39
12.2
Criteria for Potentially Clinically Significant Laboratory Values ...........40
12.3
Criteria for Potentially Clinically Significant Vital Sign Values.............41
13.0
References...............................................................................42
List of Figures
Figure 1.
Study Schematic.........................................................................................6
 


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Clinical Statistics Department for the elezanumab Phase 2a Study M14-397.  
Pharmacokinetics/pharmacodynamics, pharmacogenetic, and selected biomarkers will be 
analyzed separately and are not included in this SAP.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.
The SAP will not be updated in case of future administrative or minor amendments to the 
protocol, unless the changes have an impact on the analysis of study data.
4.0
Study Background
4.1
Objective
The objective of this study is to evaluate the safety and efficacy of elezanumab in subjects 
with progressive forms of multiple sclerosis (PMS).  
4.2
Study Design
4.2.1
Study Design and Design Diagram
This is a 52-week, Phase 2a, proof-of concept, randomized, double-blinded, parallel-
group, placebo-controlled multicenter study to evaluate the safety and efficacy of 2 doses 
of elezanumab in adult subjects with progressive forms of MS who have established 
disability.
This study will include an approximate 30-day Screening period.  The Treatment Period 
will include fourteen (14) visits from Baseline (Week 0) every four weeks through 
Week 52.  Doses will be administered via intravenous (IV) infusion at Week 0 (Baseline) 
and every 4 weeks thereafter through Week 48 for a total of 13 doses.  The follow-up 
period includes two visits that will occur at Weeks 64 and 76.
 




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4.3
Endpoint
4.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the Overall Response Score (ORS) at Week 52.
ORS is a composite score derived from 4 components:
●
Expanded Disability Status Scale (EDSS)
●
Timed 25-Foot Walk (T25FW)
●
9-Hole Peg Test in the dominant hand (9HPT-D)
●
9HPT in the non-dominant hand (9HPT-ND)
The EDSS + is a composite derived from the EDSS, T25FW, 9HPT-D and 9HPT-ND 
where responder status is defined as a clinical meaningful improvement on one or more of 
these endpoints.  Hereafter, the EDSS, T25FW, 9HPT-D and 9HPT-ND will also be 
referred to as "components of the EDSS +" or "components of the ORS."
The ORS is scored with a range from –4 to +4 at each assessment for all post-baseline 
visits.  Scores for each component are assessed relative to their baseline value:  –1 if there 
is clinically significant worsening, 0 if the change does not meet the clinically significant 
threshold criteria, or +1 if there is clinically significant improvement.  The scores for all 
components are summed at each assessment. If any of the 4 components of the ORS are 
missing within a visit window, then the ORS will be considered missing for that visit.
The clinically significant change thresholds for EDSS, T25FW and 9HPT are provided in 
the following table.
 


Elezanumab (ABT-555)
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ORS Components
Score of ORS Components at Post-Baseline Visits
–1
(Clinically Significant 
Worsening)
0
(No Clinically 
Significant Change)
1
(Clinically 
Significant 
Improvement)
EDSS change 
from baseline
≥ 1 if baseline EDSS 
≤5.5;
≥ 0.5 if baseline EDSS 
≥ 6.0
–0.5, 0 or 0.5 if 
baseline EDSS 
≤5.5;
0 if baseline EDSS 
≥ 6.0
≤ –1 if baseline 
EDSS ≤ 5.5;
≤ –0.5 if baseline 
EDSS ≥ 6.0
T25FW change 
from baseline
≥ 20%
> –20% and < 20%
≤ –20%
9HPT-D change 
from baseline
≥ 20%
> –20% and < 20%
≤ –20%
9HPT-ND change 
from baseline
≥ 20%
> –20% and < 20%
≤ –20%
4.3.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints include:
●
Disability improvement responder status (Yes or No) on the EDSS+
●
ORS at Weeks 12, 24, and 36 
4.3.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints include:
●
Disability improvement response rate on the EDSS, T25FW, 9HPT-D, and 
9HPT-ND at Weeks 12, 24, 36, and 52, and the EDSS + at Weeks 12, 24, and 
36.
●
Change from Baseline on the T25FW, 9HPT-D, 9HPT-ND at Weeks 12, 24, 
36, and 52 
 


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●
Disability progression response rate on the Expanded Disability Status Scale 
Plus (EDSS +) (T25FW, 9-Hole Peg test [9HPT, either hand], EDSS) and for 
each EDSS + component
●
12- and 24-week confirmed disability improvement response rate on the EDSS 
+ and for each EDSS + component
●
Change from Baseline on the Multiple Sclerosis Impact Scale (MSIS-29) total 
score at Weeks 12, 24, 36, and 52 
●
Change from Baseline on the Modified Fatigue Impact Scale (MFIS) total 
score at Weeks 12, 24, 36, and 52
●
Change from Baseline on cognition battery at Weeks 12, 24, 36, and 52: 
○
Total score of the Symbol Digit Modalities Test (SDMT) – Oral Version
○
Total score and T-score of the Brief Assessment of Cognition Verbal 
Memory - Immediate Recall – BAC App Version
○
Total score and T-score of the Brief Assessment of Cognition Tower of 
London – BAC App Version
●
Change from Baseline on the Low Contrast Visual Acuity (LCVA) 
assessments at Weeks 12, 24, 36, and 52
●
Change from Baseline in select plasma biomarkers for monitoring target 
binding, neuroprotection and/or neurorestoration at Weeks 12, 24, 36, and 52
●
Change from Baseline on the MS Individualized Outcome Assessment 
(MSIOA) overall symptom score and most bothersome symptom score scale at 
Weeks 24, and 52
●
Change from Week 0 in average daily step count and other activity measures 
(as described in Section 9.4.3) via home actigraphy with wearable biosensor 
initiated at Weeks 24, 36, and 52
●
Summary of variables from brain MRI at Baseline, Weeks 24 and 52
○
Presence of active lesions T1 Gadolinium (GAD)-enhancing lesions
○
Presence of active new and enlarging T2 hyperintense lesions
○
Cumulative number of total T1 GAD-enhancing lesions
○
Cumulative number of total T2 hyperintense lesions 
○
Cumulative number of post-baseline T1 GAD-enhancing lesions 
 


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○
Cumulative number of post-baseline new and enlarging T2 lesions 
○
Number of T1 GAD-enhancing lesions at each visit
○
Change from Baseline in total volumes of (T1 GAD-enhancing lesions)
○
Change from Baseline in total volume of T2 hyperintense lesions
○
Change from Baseline in whole brain, gray matter (GM), thalamus, white 
matter (WM) and normal appearing white matter (NAWM) volumes 
○
Change from Baseline in regional magnetization transfer ratio (MTR) 
parameters for whole brain, and NAWM, and MTR for T2 lesions
○
Change from baseline in lesion MTR for T1 (GAD)-enhancing lesions and 
delta MTR
○
Change from Baseline in diffusion tensor imaging (DTI) parameters 
(fractional anisotropy and Apparent Diffusion Coefficient (ADC)) for 
whole brain, NAWM and T2 hyperintense lesions
●
Summary of variables from cervical spinal MRI at Weeks 24 and 52
○
Chang from Baseline in cervical spinal cord area, volume and number of 
lesions
○
Change from Baseline in regional MTR for cervical spinal cord lesions
○
Change from baseline in DTI parameters (fractional anisotropy and ADC) 
for cervical spinal cord
4.3.4
Safety Endpoints
Safety variables include adverse events (AEs), serious adverse events (SAEs), adverse 
events of special interest (AESI), vital sign measurements (including pre- and 
post-infusion blood pressure), MS relapses, electrocardiogram (ECG) variables, 
Columbia-Suicide Severity Rating Scale (C-SSRS) assessments, and clinical laboratory 
testing (hematology, chemistry, and urinalysis) as measures of safety and tolerability for 
the entire study duration.
 


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4.4
Sample Size Justification
Approximately 90 subjects will be equally randomized 1:1:1 to each treatment group 
(approximately 30 subjects in each treatment, with at least 20 PPMS subjects and 
approximately 10 nrSPMS subjects).  There is limited prior data to estimate the magnitude 
of effect and variance.  This sample size will have approximately 80% power to detect an 
effect size (ES) of 0.59 with significance level of 0.1 and overall dropout rate of 
approximately 10%, using a 1-sided t-test.
4.5
Interim Analysis
An interim futility analysis was planned to assess study and/or dose futility when 
approximately 40% of planned subjects completed the Week 24 assessment.  However, 
due to the pattern of enrollment and missed infusions and efficacy data collection as a 
result of the COVID-19 pandemic, the interim futility analysis was eliminated.
4.6
Multiplicity Testing Procedures for Type-I Error Control
No multiplicity adjustment will be performed for this Phase 2a proof of concept study.
4.7
Missing Data Imputation
For continuous efficacy variables, data will be summarized using a mixed-effect model 
for repeated measures (MMRM) model unless otherwise specified.  Missing data will not 
be imputed before applying an MMRM model. 
The MMRM model relies on a missing at random (MAR) assumption.
For sensitivity analyses of the primary and secondary efficacy variables, missing values 
will be imputed using multiple imputation (MI) and categorized as responder/non-
responder after imputation.  The MI model also relies on a MAR assumption. 
Justification for the MAR Assumption:
 


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The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impact on treatment duration and the collection, analysis and the interpretation 
of clinical trial data. Some protocol-specified visits in this clinical trial may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  These missed visits will be recorded in the 
database.  The probability of having missed visits and missing data due to COVID-19 
infection or logistical restrictions related to the COVID-19 pandemic can be reasonably 
assumed to be unrelated to the unobserved values conditional on the observed data.  
Therefore, for the purpose of statistical analysis, it is reasonable to assume that these 
missing data are missing at random (MAR) and the statistical models that require MAR 
assumption are appropriate.  In some cases, sensitivity analyses may be performed to 
assess the impact of missing data and the robustness of the conclusion.
Where noted, summaries as observed will not impute values for missing evaluations, and 
thus a subject who does not have an evaluation on a scheduled visit will be excluded from 
the as observed for that visit.
Safety variables will be summarized as observed.
5.0
Analysis Sets and Important Subgroups
5.1
Analysis Sets
The Modified Intent-to-Treat (mITT) Population includes all randomized subjects who 
receive at least 1 dose of study drug.  Subjects will be grouped according to treatment as 
randomized.  The mITT analysis set will be used for all demographic and efficacy 
analyses, unless otherwise noted.
MS expert(s) will confirm which subjects experienced a clinical relapse(s) through 
adjudication of study data, including the MS-relapse questionnaire.  The Relapse-Free 
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MS-related relapse during the Treatment Period (from Week 0 to Week 52).  Subjects will 
be grouped according to treatment as randomized.
Due to the COVID-19 pandemic, a subset of the study population missed one or more 
study drug infusions.  For the purposes of conducting a sensitivity analysis of the primary 
and secondary endpoints, the Minimal Missed Infusion Analysis (MMIA) Set includes all 
randomized subjects who received at least 6 infusions total and missed no consecutive 
infusions prior to the subject's final dose.  Subjects will be grouped according to treatment 
as randomized.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  
Subjects will be grouped according to treatment received regardless of randomization.
If a subject was randomized to treatment X, but received treatment Y during the entire 
study, this subject will be included in the Y treatment group for analysis purposes.  If a 
subject receives both treatments but one > 50% of the time, the subject will be included in 
that treatment group.  If a subject receives both treatments an equal percentage of the 
time, the subject will be analyzed in the treatment group to which they were randomized.
5.2
Subgroups
The primary efficacy and secondary variables will also be analyzed by the following 
subgroups to assess the consistency of the treatment effect:
●
Sex (male, female)
●
Age (≤ 40, > 40)
●
EDSS baseline (≤ Median, > Median)
●
Diagnosis of MS form (primary-progressive MS [PPMS] vs. non-relapsing 
secondary-progressive MS [nrSPMS]) if at least 20% of subjects are in each 
stratum
●
Presence of background MS immunotherapy (Yes vs. No) if at least 20% of 
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In addition, the SPMS subjects from Study M18-918 may be integrated with SPMS 
patients from Study M14-397.  There will be an additional statistical analysis plan for the 
integrated data for the SMPS subjects.  
6.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group and overall, 
for the whole study and by investigator based on all randomized subjects:
●
Subjects enrolled (randomized) in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug 
●
Subjects who discontinued the study 
●
Subjects in each of the following analysis sets:  Safety Analysis Set, mITT 
analysis set, RF analysis set, MMIA set
The reasons for study drug discontinuation and study discontinuation will be summarized 
with the number and percentage of subjects for all reasons and the primary reason for the 
mITT analysis set by treatment group.
A summary of subject disposition will include the number randomized, number that never 
received study drug, number that received study drug other than randomized, and the 
number in each of the analysis sets noted in Section 5.1 for all subjects randomized by 
treatment group.
7.0
Extent of Exposure and Compliance
For the mITT analysis set, extent of exposure will be summarized for each treatment 
group.  Extent of exposure will be summarized as duration of treatment and number of 
infusions.  Duration of treatment is defined for each subject as last dose date minus first 
dose date + 28.  A gap in treatment due to missed infusions will not be considered in the 
 


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calculation of study duration.  Duration of treatment will be summarized using the number 
of subjects treated, mean, standard deviation, median, minimum and maximum.  In 
addition, the number and percentage of subjects in each unique treatment duration interval 
(28, 29 to 56, 57 to 84, 85 to 112, 113 to 140, 141 to 168, 169 to 196, 197 to 224, 225 to 
252, 253 to 280, 281 to 308, 309 to 336, 337 to 364, > 364) will be summarized.
The number and percentage of subjects for each number of infusions from 1 to 13 will be 
summarized.
The number and percentage of completed and missed infusions by visit will be 
summarized at each visit from Day 1 to Week 48.  The reason for missed infusions will be 
summarized at each visit.
The number of missed infusions by subject prior to the subject's last dose or premature 
discontinuation from study drug will be summarized by treatment group.
Because the treatment is administered by the site, compliance will not be summarized.
8.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the mITT analysis set overall and by 
treatment group. Categorical variables will be summarized with the number and 
percentage of subjects; percentages will be calculated based on the number of non-
missing observations. Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean and standard deviation, median, minimum 
and maximum).
8.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, weight by sex, height, and body 
mass index (BMI).  Categorical demographic variables include sex, ethnicity, race, age 
(<40, 40 – < 65, ≥65 years), BMI (< 25 or ≥ 25 kg/m2), country (United States or 
 


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Canada), tobacco user (current, former, never, unknown), and alcohol user (current, 
former, never, unknown).  The variables used for stratification of randomization as 
described in Section 4.2.2 will be summarized with the number and percentage of 
subjects.
8.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group for the safety analysis set. The system organ 
class (SOC) will be presented in alphabetical order, and the preferred terms will be 
presented in alphabetical order within each SOC. Subjects reporting more than one
condition/diagnosis will be counted only once in each row (SOC or preferred term).
8.3
MS Disease History
The number and percentage of subjects with each type of MS and number of relapses in 
the past 5 years (0, 1, 2, 3, ≥ 4) will be summarized categorically.  The time in months 
since onset of first symptoms, and time in months since most recent relapse will be 
summarized continuously with descriptive statistics overall and by treatment group.
8.4
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug. A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug plus 24 weeks (168 days). The number and 
percentage of subjects taking medications will be summarized by generic drug name 
 


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based on the World Health Organization (WHO) Drug Dictionary for both prior and 
concomitant medications by treatment group and overall.
The number and percentage of subjects taking MS immunmodulators at Baseline, defined 
as those taking any MS immumodulator on the first dose date, will be summarized by 
generic drug name by treatment group and overall.
8.5
Protocol Deviations and Visit Modifications
The number and percentage of subjects who reported at least one protocol deviation will 
be summarized by treatment group and overall.
The number and percentage of subjects with in-person partial visits, virtual visits, and 
missed visits will be summarized by treatment group and overall for each visit.  The 
primary reason for an impact to a visit will be summarized by treatment group and overall 
for each visit.  The denominator will be the number of subjects in that treatment group for 
the by-treatment summary, or in the entire mITT analysis set for the overall summary.
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy endpoints will be analyzed on mITT analysis set.  The primary and secondary 
efficacy endpoints analyses will be repeated for the on the RF analysis set and the MMIA 
set as described in Section 5.1.  Additional exploratory analyses will be repeated based on 
a subset of the population with a pre-defined deficit at baseline where noted.
For all exploratory efficacy analyses other than those related to MRI variables, where a 
continuous summary by visit is noted, the descriptive statistics will be provided by 
treatment group.  The statistics include number of observations, mean, standard deviation, 
minimum, median, and maximum. The number and percentage will be summarized for 
categorical variables.
 


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For all efficacy endpoints where change from baseline will be analyzed with an MMRM, 
the mean at baseline and that visit will be presented, as well as the LS means standard 
error, and the between group difference, standard error, and 95% confidence interval.
Baseline for efficacy will be defined as the last non-missing observation that is on or 
before the first dose date.
9.2
Primary Efficacy Analysis
The primary efficacy variable is the ORS at Week 52 and secondary efficacy variables are 
the ORS at Weeks 12, 24, and 36.  The ORS will be summarized continuously as 
observed  (including n, mean, standard deviation, minimum, median and maximum) at 
each visit.
The frequency and percentage of subjects with each ORS score in the range of –4 to +4 
will also be provided by treatment group at each visit.  The data will be analyzed and 
summarized as observed, i.e., no imputations will be implemented.
The comparisons between the each elezanumab group and placebo for the primary 
efficacy endpoint ORS at each scheduled visit during the study will be performed using an 
MMRM.  The ORS for each treatment group at scheduled visits and overall will be 
estimated from the model.  The within group LS mean 95% confidence interval, pooled 
standard deviation, effect size, and 95% confidence interval for the effect size will also be 
presented by treatment group.  The model will include the fixed effects of treatment, visit, 
diagnosis of MS (PPMS or nrSPMS), and background MS immunotherapy (Yes or No), 
and the treatment-by-visit interaction with baseline scores (EDSS, T25FW, 9HPT-D, 
9HPT-ND) as covariates.  The REPEATED statement will be used for visit with blocks in 
the covariance matrix identified by subject nested within treatment group.  The 
unstructured covariance structure will be used to estimate the within subject variance-
covariance.  If the model fails to converge, the first order autoregressive (AR[1]) 
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symmetry (CS) covariance structure will be substituted.  Denominator degrees of freedom 
will be computed using the Kenward-Roger method.
This will be repeated for the RF and MMIA sets.  
The posterior probability that each elezanumab group's effect size is greater than 0.1, 0.3, 
and 0.5 will be presented for the mITT analysis set.  
The ORS and corresponding 95% confidence interval based on the MMRM for the mITT 
analysis set will be plotted at each time point during the treatment period by treatment 
group.
The post-treatment ORS scores will be summarized continuously as observed.
9.3
Secondary Efficacy Analyses
Disability improvement on the EDSS + indicates clinically significant improvement on at 
least 1 of the components of the EDSS + (EDSS, T25FW, 9HPT [either hand]) as defined 
by the clinically significant change thresholds in Section 4.3.1).
Improvement responder status on the EDSS + and each of its components will be 
analyzed by time point based on the criteria in Section 4.3.1. No confirmation will be 
required, i.e., improvement at the analysis time point only is required to be considered a 
responder.  
The analysis will be presented at each time point with the number and percentage of 
responders, and the 95% confidence interval for the proportion of subjects based on Wald 
confidence limits, and the odds ratio and corresponding 95% confidence interval based on 
the logistic regression model including baseline as a covariate and treatment as a main 
effect.  The model for the EDSS + will include the baseline EDSS, baseline T25FW, 
baseline 9HPT-D, baseline 9HPT-ND as covariates and treatment as a main effect.  This 
will be presented based on the mITT, RF and MMIA analysis sets using non-responder 
 


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imputation.  The logistic regression analysis will be repeated for the mITT analysis set 
based on the same multiple imputation as detailed in Section 9.3.1.
A summary of the improvement responder status on the EDSS + and each of its 
components will be presented for the mITT analysis set as observed.
9.3.1
Sensitivity Analysis of the Primary and Secondary 
Endpoints
The primary and secondary endpoint analyses will be repeated for the RF and MMIA
analysis sets as noted those respective sections.
Additionally, the analysis of ORS at Weeks 12, 24, 36, and 52, and the number and 
percentage of subjects with 12- and 24-week confirmed improvement for the EDSS+ and 
each of its components will be repeated based on multiple imputation (MI).  First, a full 
dataset will be imputed using full data imputation MCMC.  Data will be imputed for the 
EDSS, T25FW, 9HPT-D and 9HPT-ND in a continuous fashion for each endpoint 
separately.  Then, the definition of clinically significant improvement/no change/clinically 
significant worsening as seen in Section 4.3.1 will be applied to determine the 
components of the ORS or 12- or 24- week confirmed improvement status.  The 
imputation model will include treatment group, type of MS, baseline use of 
immunomodulator therapies, baseline variable for the respective endpoint being imputed, 
and the non-missing post-baseline values for the variable that will be imputed (value at 
Week 12, 24, 36, 52, 64 and 76).  The number of imputed datasets will be 30, and the 
random seed will be 123455.  The ORS at each visit noted above will be summarized for 
each treatment group and compared to placebo using ANCOVA, with baseline values for 
each component of the EDSS + included in the model.  The responder status with 12- and 
24-week confirmed improvement will be analyzed with a logistic regression as noted in 
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9.4
Other Efficacy Analyses 
Change from baseline treatment comparison at each visit will be conducted using an 
MMRM model including treatment group, visit, treatment-by-visit interaction, and 
stratification factors as fixed effects, the baseline values associated with the endpoint as 
covariates.  The REPEATED statement will be used for visit with blocks in the covariance 
matrix identified by subject nested within treatment group.  The unstructured covariance 
structure will be used to estimate the within subject variance-covariance.  If the model 
fails to converge, the first order autoregressive (AR[1]) covariance structure will be 
substituted.  If the model still fails to converge, the compound symmetry (CS) covariance 
structure will be substituted.  Denominator degrees of freedom will be computed using the 
Kenward-Roger method.
For binary efficacy endpoints, the frequency and percentage will be provided by treatment 
group unless otherwise noted.
9.4.1
Confirmed Improvement on the EDSS + and its components
Confirmed 12-week disability improvement on the EDSS + or components of the EDSS + 
indicates a subject has clinically significant improvement at a visit as well as the next visit
for one or more EDSS + components, or if the next visit is missing, the subsequent visit.  
Confirmation may include assessments collected in the post-treatment follow-up period.  
The improvement confirmation must be in the same component of the EDSS +.  If a 
subject has improvement in more than one component of the EDSS +, the subject must 
have confirmation in at least one of the same components to be considered as having 
confirmed disability improvement.  For example, if a subject has clinically significant 
improvement in the T25FW at Week 12, the subject must have clinically significant 
improvement in the same component of the EDSS + at Week 24 (or if Week 24 is 
missing, Week 36) to be considered to have confirmed improvement. 
Confirmed 24-week improvement on the EDSS + or components of the EDSS + indicates 
a subject has clinically significant improvement at 3 consecutive visits, or if one of the 
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improvement at two of the subsequent three visits.  Improvement status after confirmed 
improvement is not considered, i.e., if a subject has disability improvement in one 
component of the EDSS + at Week 12 and Week 24, then this subject is considered to 
have 12-week confirmed disability improvement regardless of a Week 36 status of 
clinically significant worsening, no clinically significant change, or clinically significant 
improvement.
The 12-week and 24-week confirmed disability improvement response rate will be 
summarized for the study for the EDSS +, as well as each of the individual components
for the mITT, RF, and MMIA analysis sets based on a non-responder imputation.  The 
frequency and percentage will be provided by treatment group.  The treatment comparison 
will be conducted using the logistic regression model adjusted for the stratification factors 
and baseline scores associated with the endpoint.  The proportion of responders, 
difference in responder rate, and 95% confidence interval for the responder rate based on 
Wald confidence limits will be presented based on the univariate summary.  The odds 
ratio, and 95% confidence interval will be derived from the logistic regression model. 
The analyses for confirmed disability improvement will be repeated for the RF and 
MMIA analysis sets as noted those respective sections.
9.4.2
Disability Progression
Disability progression on the EDSS + indicates clinically significant worsening on at least 
1 of the components of the EDSS + (EDSS, T25FW, 9HPT [either hand]) as defined by 
the clinically significant change thresholds in Section 4.3.1).  This will be based on the 
imputed dataset described in Section 9.3.1.
Progression on the EDSS + and each of its components will be analyzed by time point 
based on the criteria in Section 4.3.1. No confirmation will be required, i.e., progression
at the analysis time point only is required.  
The analysis will be presented at each time point with the number and percentage of 
subjects, and the 95% confidence interval for the proportion of subjects based on Wald 
 


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confidence limits, and the odds ratio and corresponding 95% confidence interval based on 
the logistic regression model including baseline as a covariate and treatment as a main 
effect.  
9.4.3
T25FW
The change from baseline in the T25FW during the Treatment Period will be analyzed 
using an MMRM.  In addition to the summaries noted in Section 9.1, the pooled standard 
deviation, effect size, and 95% confidence interval of the effect size will be noted.
9.4.4
9HPT
The change from baseline in the 9HPT-D and 9HPT-ND during the Treatment Period will 
be analyzed using an MMRM.  In addition to the summaries noted in Section 9.1, the 
pooled standard deviation, effect size, and 95% confidence interval of the effect size will 
be noted.
9.4.5
Exploratory Patient and Clinician Measured Scales
The change from baseline in the total score for the MSIS-29, the total score for the BAC -
Tower of London, the total score for the BAC – Verbal Memory, BAC - Tower of London 
T-score, BAC - Verbal Memory T-score, and the overall symptom score and most 
bothersome symptom score for the MSIOA will be analyzed at the collected time points 
using an MMRM.
9.4.6
SDMT
The change from baseline for the SDMT total score will be summarized based on the 
mITT analysis set using an MMRM.
The above analysis of change from baseline will be repeated for the subset of subjects 
with an SDMT total score < 50 at baseline using the same MMRM as described in the 
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greater than 1 based on the SDMT total score will be presented.  A non-informative prior 
will be used. 
The number and percentage of subjects with a change from baseline in the SDMT total 
score ≥ 4 will be analyzed as observed.  The analysis will be presented at each time point
with the number and percentage of subjects, difference from placebo in responder rate, 
and the 95% confidence interval for the difference in proportion of subjects based on 
Wald confidence limits, and the odds ratio and corresponding 95% confidence interval 
based on the logistic regression model including baseline as a covariate and treatment as a 
main effect.
9.4.7
MFIS-5
The change from baseline for the MFIS-5 total score will be summarized based on the 
mITT analysis set using an MMRM.
The above analysis of change from baseline will be repeated for the subset of subjects 
with an MFIS-5 total score of ≥ 9 at baseline using the same MMRM as described in the 
previous paragraph.  The posterior probability of the difference of the group means being 
greater than 1 based on the MFIS-5 total score will be presented.  A non-informative prior 
will be used.
9.4.8
Low Contrast Visual Acuity
The change from baseline in low contrast visual acuity variables will be summarized as 
observed at each time point for the following parameters:
●
Number of characters read, bilateral, 100% contrast level
●
Number of characters read, bilateral, 2.5% contrast level
●
Number of characters read, bilateral, 1.25% contrast level
●
Number of characters read, right eye, 100% contrast level
●
Number of characters read, right eye, 2.5% contrast level
●
Number of characters read, right eye, 1.25% contrast level
 


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●
Number of characters read, left eye, 100% contrast level
●
Number of characters read, left eye, 2.5% contrast level
●
Number of characters read, left eye, 1.25% contrast level
The number of observations, mean, standard deviation, median, min and max will be 
presented.
The change from baseline in the number of characters read, bilateral at the 1.25% contrast 
level, will be summarized using an MMRM based on the population of subjects with a 
baseline deficit, defined as ≤ 11 characters (bilateral at the 1.25% contrast level) at 
baseline.  The posterior probability that the mean difference between groups is > 2 using a 
non-informative prior will be calculated.
9.4.9
Actigraphy
Actigraphy was collected for 7 days starting at the visits at Week 0 (Baseline), 24, 36, and 
52.  The actigraphy parameters of movement including average gait cadence, moving 
duration, walking duration, number of steps and resting duration will be analyzed.
Moving duration, walking duration, number of steps, and resting duration will be 
normalized for the number of hours per day the subject is wearing the device, i.e., divided 
by the (device wear time duration [in seconds] ÷ 3600).
The analysis of change from Week 0 for each of the moving duration, walking duration, 
number of steps, and resting duration will be based on the average hourly value for that 
visit, i.e., the Week X value will be the sum of the daily average hourly values for that 
parameter divided by the number of days the subject wore a sensor within a window.  The 
analysis of change from Week 0 for average gait cadence will be based on the average 
daily value of gait cadence for that visit, i.e., the Week X value will be the sum of the 
daily mean gait cadence values divided by the number of days the subject wore a sensor 
within a window.  The pooled standard deviation, effect size, and 95% confidence interval 
of the effect size will also be noted.
 


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9.4.10
Biomarkers
The change from baseline in the serum/plasma biomarkers repulsive guidance molecule a 
(RGMa), neurofilament light (NFL), micro RNA miR-146a and miR-338, mRNAs for 
PLP1 (proteolipid protein 1), glial fibrillary acidic protein (GFAP), and BDNF (brain-
derived neurotrophic factor), will be summarized using an MMRM.  The model will 
include the fixed effects of treatment, visit, the stratification factors of diagnosis of MS 
(PPMS or nrSPMS) and background MS immunotherapy (Yes or No), and the treatment-
by-visit interaction, with baseline value for the respective parameter as a covariate.  The 
REPEATED statement will be used for visit with blocks in the covariance matrix 
identified by subject nested within treatment group.  The unstructured covariance 
structure will be used to estimate the within subject variance-covariance.
9.4.11
MRI Parameters
The MRI parameters of interest and analyses are listed in Section 4.3.3.  
The number and percentage of subjects with active lesions will be summarized for T1 
GAD-enhancing lesions and T2 hyperintense lesions (separately).  The difference in the 
proportion between elezanumab and placebo groups with the 95% confidence interval for 
the difference based on Wald confidence limits will be presented.  
The cumulative number of total T1 GAD-enhancing lesions, cumulative number of total 
T2 hyperintense lesions, cumulative number of post-baseline T1 GAD-enhancing lesions, 
cumulative number of post-baseline new and enlarging T2-lesions, will be summarized 
with continuously and analyzed using an analysis of covariance (ANCOVA).  The model 
for the analysis of the cumulative number of total lesions will include treatment, the 
stratification factors of diagnosis of MS (PPMS or nrSPMS) and background MS 
immunotherapy (Yes or No).  For the cumulative number of lesions during the treatment 
period, only subjects with Baseline, Week 24, and Week 52 MRIs will be included.  For 
the cumulative number of lesions post-baseline, only subjects with Week 24 and Week 52 
will be included. 
 


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The number of T1 GAD-enhancing lesions at each visit (Baseline, Week 24, Week 52) 
will be summarized categorically with the number and percent of subjects for the 
following categories:  0, 1, 2, 3, 4, 5, > 5.
The following endpoints will be analyzed using change or percent change from baseline 
using an ANCOVA model.
●
Change from Baseline in total volumes of T1 GAD-enhancing lesions
●
Change from Baseline in total volume of T2 hyperintense lesions 
●
Percent change from Baseline in whole brain, gray matter (GM), thalamus, 
white matter (WM) and normal appearing white matter (NAWM) volumes 
●
Change from Baseline in regional magnetization transfer ratio (MTR) 
parameters for whole brain, and NAWM, and MTR for T2 lesions
●
Change from Baseline in diffusion tensor imaging (DTI) parameters (fractional 
anisotropy and Apparent Diffusion Coefficient (ADC)) for whole brain, 
NAWM and T2 hyperintense lesions
●
Change from Baseline in cervical spinal cord area, volume and number of 
lesions 
●
Change from Baseline in regional MTR for cervical spinal cord lesions 
●
Change from baseline in DTI parameters (fractional anisotropy and ADC) for 
cervical spinal cord
The model for the change from baseline analysis will include treatment, the stratification 
factors of diagnosis of MS (PPMS or nrSPMS) and background MS immunotherapy (Yes 
or No), and the baseline value.  For each treatment group, the number of subjects, mean, 
standard deviation, minimum, and maximum, will be presented, as well as the LS means 
and standard error, and the between group difference, standard error, and 95% confidence 
interval.  
The change from baseline in lesion MTR for T1 GAD-enhancing lesions and delta MTR 
will be analyzed using an MMRM.  The change from baseline will be calculated for each 
unique lesion within a treatment group.  A dummy code will be created based on each 
 


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subject-lesion to describe each unique lesion.  The model will include the fixed effects of 
treatment, visit, the stratification factors of diagnosis of MS (PPMS or nrSPMS) and 
background MS immunotherapy (Yes or No), and the treatment-by-visit interaction, with 
baseline MTR value as a covariate.  The RANDOM statement will be used for each 
subject.  The REPEATED statement will be used for visit with blocks in the covariance 
matrix identified by unique lesion nested within subject nested within treatment group.  
The unstructured covariance structure will be used to estimate the within subject variance-
covariance.  If the model fails to converge, the first order autoregressive (AR[1]) 
covariance structure will be substituted.  If the model still fails to converge, the compound 
symmetry (CS) covariance structure will be substituted.  Denominator degrees of freedom 
will be computed using the Kenward-Roger method.
9.5
Efficacy Subgroup Analyses
Subgroup analysis for the primary endpoint (ORS) based on the mITT analysis set will be 
conducted by the subgroups specified in Section 5.2.  This will be based on the MMRM 
analysis and the analysis will be presented for Week 12, 24, 36, and 52.  The model will 
include the fixed effects of treatment, visit, the stratification factors of diagnosis of MS 
(PPMS or nrSPMS) and background MS immunotherapy (Yes or No), subgroup, 
treatment-by-visit interaction, treatment by subgroup interaction, and treatment by 
subgroup by visit interaction with baseline EDSS, T25FW, 9HPT-D and 9HPT-ND values 
as covariates.  The REPEATED statement will be used for visit with blocks in the 
covariance matrix identified by subject nested within treatment group.  The unstructured 
covariance structure will be used to estimate the within subject variance-covariance.  If 
the model fails to converge, the first order autoregressive (AR[1]) covariance structure 
will be substituted.  If the model still fails to converge, the compound symmetry (CS) 
covariance structure will be substituted.  Denominator degrees of freedom will be 
computed using the Kenward-Roger method.
 


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9.6
Figures Based on the EDSS + and Its Components
A line plot of the LS mean and 95% confidence intervals of the ORS during the Treatment 
Period by treatment group based on the mITT analysis set and MMIA set will be 
produced.
A stacked bar plot displaying the proportion of subjects within each bucket of clinically 
significant change (see Section 4.3.1) in EDSS, T25FW, 9HPT-D, and 9HPT-ND by 
treatment will be produced for Week 12, 24, 36, and 52 based on the mITT analysis set 
and MMIA set as observed.
A bar plot displaying the proportion of subjects with each value of the ORS {-4, -3, -2, -1, 
0, 1, 2, 3, 4} by treatment group will be produced for Week 12, 24, 36, and 52 based on 
the mITT analysis set and MMIA set as observed.
A forest plot of the ORS by subgroups at Week 52 will be produced for the mITT analysis 
set.
10.0
Safety Analyses
10.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  Safety will be assessed 
by AEs, lab values, vital sign measurements (including change from pre- to post-infusion 
vital signs), ECG, and Columbia-Suicide Severity Rating Scale (C-SSRS).  Frequency 
tables and lists of subjects with treatment emergent AEs by preferred term as in the 
Medical Dictionary for Regulatory Activities (MedDRA), by system organ class and 
preferred term, by severity, and by relationship to the study treatment as assessed by the 
Investigator will be provided.  For continuous safety outcomes, the change from Baseline 
will be analyzed in a descriptive manner by treatment group and by visit.  For each 
variable in which change from baseline is analyzed, the raw visit values will be 
summarized for all time points (starting with Baseline) with the number of non-missing 
observations, mean and standard deviation, median, minimum and maximum.  For 
 


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categorical safety outcomes, the number and percentage of each category will be 
summarized by treatment group and by visit.  Shift of laboratory values from Baseline to 
defined time points will be tabulated. Shift to final visit will include data collected during 
the follow-up period.  Hypothesis testing will not be performed for safety parameters.
10.2
Analysis of Adverse Events
10.2.1
Treatment-Emergent Adverse Events
Treatment emergent adverse events (TEAE) will be defined as all events that begin or 
worsen on or after first dose of the study drug.
10.2.2
Adverse Event Overview
The number and percentage of subjects experiencing one or more TEAEs in the following 
adverse event categories will be summarized for each treatment group, combined 
elezanumab group and all subjects overall:
●
Any TEAE
●
Any TEAE that are considered related to study treatment
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE leading to discontinuation of study treatment
●
Any AE of Special Interest
●
Any TEAE leading to death
●
Death 
10.2.3
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing TEAEs will be tabulated using 
primary Medical Dictionary for Regulatory Activities (MedDRA) system organ classes 
(SOCs) and preferred terms (PTs) for each treatment group and combined elezanumab 
 


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group.  The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
A subject who reports more than 1 AE in different SOCs will be counted only once in the 
overall total.  A subject who reports 2 or more different PTs, which are in the same SOC, 
will be counted only once in the SOC total.  Subjects reporting more than 1 AE for a 
given PT will be counted only once for that term (most severe incident for the severity 
tables and most related incident for the relationship tables).
10.2.4
Adverse Event Incidence
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories will be summarized by primary SOC and PT for each 
treatment group, combined elezanumab total group and all subjects overall.
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that was moderate or severe
●
Any TEAE that led to discontinuation of study treatment
●
Any TEAE that have reasonable possibility being related to study treatment  
A list of subject numbers associated with each PT will also be presented for all TEAEs.
10.2.5
Adverse Events by Maximum Severity
The number and percentage of subjects experiencing one or more TEAEs will also be 
summarized by maximum severity category (mild, moderate, severe, or unknown) and 
primary SOC for each treatment group, combined elezanumab group and all subjects 
overall.  Subjects reporting more than one TEAE for a given PT will be counted only once 
for that term in the most severe category reported.  If a subject has an adverse event with 
unknown severity, then the subject will be counted in the severity category of "unknown," 
even if the subject has another occurrence of the same event with a severity present.  The 
only exception is if the subject has another occurrence of the same adverse event with the 
 


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most extreme severity – "Severe."  In this case, the subject will be counted under the 
"Severe" category.
10.2.6
Adverse Events by Maximum Relationship
The number and percentage of subjects experiencing one or more TEAEs will also be 
summarized by maximum relationship category (reasonable possibility, no reasonable 
possibility, or unknown), as assessed by the investigator, and primary SOC and PT for 
each treatment group, combined elezanumab group and all subjects overall.  Subjects 
reporting more than one TEAE for a given PT will be counted only once for that term in 
the most related category reported.  If a subject has an adverse event with unknown 
relationship, then the subject will be counted in the relationship category of "unknown," 
even if the subject has another occurrence of the same event with a relationship present.  
The only exception is if the subject has another occurrence of the same adverse event with 
a relationship assessment of "reasonable possibility."  In this case, the subject will be 
counted under the "reasonable possibility" category.
10.2.7
Adverse Events of Special Interest
For adverse events of special interest (AESIs), serious and non-serious, meeting 
predefined criteria, specific questionnaires will be used to standardize the collection of 
follow-up information.  The AESI questionnaires will be issued within the electronic data 
capture (EDC) system once applicable.  The investigator will enter the information into 
the EDC system once applicable.  Further information about AESIs is provided in the 
protocol operations manual. 
Adverse events of special interest (AESIs) include: 
●
Infusion reactions.
The number and percentage of subjects reporting AEs in each AESI category will be 
summarized by primary SOC and PT for each treatment group, combined elezanumab 
group and all subjects overall.
 


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10.2.8
Listings of Adverse Events
The following additional summaries of adverse events will be prepared.
●
Listing of all deaths for all subjects screened
●
Listing of all serious TEAEs
●
Listing of all pre-treatment serious AEs for all subjects screened
●
Listing of all TEAEs that led to discontinuation of study treatment
●
Listing of subjects with treatment-emergent adverse event of special interest
10.2.9
Adverse Events by Preferred Term in Decreasing Frequency
TEAEs occurring in any of the treatment arms will be summarized by MedDRA PT in 
decreasing frequency in combined elezanumab group.
10.3
Analysis of Laboratory Data
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, bands, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, Partial thromboplastin time (PTT) and Activated partial 
thromboplastin time (aPTT). 
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin
(TBL), albumin, glutamic pyruvic transaminase/Alanine transaminase (SGPT/ALT), 
glutamic-oxaloacetic transaminase/Aspartate transaminase (SGOT/AST), alkaline 
phosphatase, sodium, potassium, calcium, inorganic phosphorus, uric acid, cholesterol, 
total protein, glucose, triglycerides, bicarbonate/CO2, chloride and CPK. 
Urinalysis variables include:  blood, glucose, ketones, pH, protein and specific gravity.
The baseline value of lab is defined as the last non-missing lab measurement recorded 
before the first dose of study drug and final value will be defined as the last non-missing 
lab measurement post-baseline during the entire study.
 


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10.3.1
Analysis of Laboratory Tests
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum. Changes from Baseline in laboratory parameters for WBC 
count, CPK, and lymphocytes will be summarized by n, mean, standard deviation, 
minimum value, median, and maximum value for each treatment group. The baseline and 
visit means will be calculated for each visit for subjects who have both a baseline and visit 
value.
10.3.2
Shifts Between Normal and Abnormal for Laboratory Tests
Laboratory observations will be categorized as normal, low, or high relative to the 
reference (normal) range associated with the laboratory that performed the assay.  For 
each hematology, chemistry and urinalysis with a reference range, shift tables will be 
prepared for shifts from baseline to lowest, highest and final value during the entire study 
for each treatment group and all subjects overall.  The tables will present: 
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at any post-baseline visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at any post-baseline visit
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at the final visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at the final visit
10.3.3
Analysis for Potentially Clinically Significant (PCS) 
Laboratory Values
Criteria for potentially clinically significant (PCS) values have been predefined for 
selected laboratory variables as outlined in Appendix 12.2.  For each variable, a summary 
of the number and percentage of subjects who have at least one post-baseline observation 
 


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that meets the PCS criteria and is more extreme than their baseline value will be provided 
for each treatment group and all subjects overall.  A listing will also be prepared that will 
include, for each variable, all observations for each subject that met the PCS criteria for 
that variable at any time during the study.
The following criteria will be used to assess for potential hepatotoxicity.  The number and 
percentage of subjects meeting each of the following criteria will be summarized by 
treatment group, and a listing of ALT, AST, TBL, and alkaline phosphatase at each time 
for all subjects that met any of the criteria below at any time will be produced.
●
ALT > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
AST > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
TBL > 1.5 x ULN, > 2 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN
●
ALT > 3 × ULN and TBL > 1.5 × ULN
●
ALT > 3 × ULN and TBL > 2 × ULN
●
Alkaline phosphatase > 1.5 × ULN
10.4
Analysis of Vital Signs and Weight
Vital sign variables include:  body temperature, pulse and pre and post-infusion systolic 
and diastolic blood pressures (including retesting due to post-infusion elevations seen).
Weight variables include:  weight and BMI.
BMI will be calculated using height as measured during screening.
10.4.1
Vital Sign and Weight 
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum. Change from baseline to each planned visit and to the 
 


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minimum, maximum and final value during the Treatment Period will be summarized in a 
descriptive manner for each treatment group and all subjects overall for each vital sign 
and weight variable During the Treatment Period, this will be based on the pre-infusion 
value.
For each change from baseline analysis, the following summary statistics will be 
presented:  sample size, baseline mean, visit (time point) mean, and the mean, standard 
deviation, and median of the change from baseline.  The baseline and visit (time point) 
means will be calculated for each visit (time point) for subjects who have both a baseline 
and visit (time point) value.
The change from pre-infusion to post-infusion in systolic blood pressure, diastolic blood 
pressure, and pulse at each infusion visit will be summarized in a descriptive manner for 
each treatment group and all subjects overall through Week 48.  The following summary 
statistics will be presented:  sample size, pre-infusion mean, post-infusion mean, and the 
mean, standard deviation, and median of the change from pre-infusion to post-infusion.  
The pre-infusion and post-infusion means will be calculated for each infusion visit (time 
point) for subjects who have both values.
10.4.2
Potentially Clinically Significant (PCS) Vital Signs
Criteria for PCS values have been predefined for selected vital sign variables as outlined 
in Appendix 12.3.  For each variable including both pre- and post-infusion variables, a 
summary of the number and percentage of subjects who have at least one post-baseline 
observation that meets the PCS criteria and is more extreme than their baseline value will 
be provided for each treatment group and all subjects overall.  A listing will also be 
prepared that will include, for each variable, all observations for each subject that met the 
PCS criteria for that variable at any time during the study.
 


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10.5
Analysis of ECG Parameters
The proportion of subjects with Normal, Abnormal – not clinically significant and 
Abnormal – clinically significant electrocardiogram (ECG) readings will be summarized 
at each visit ECG is performed for each treatment group and all subjects overall. 
10.6
Analysis of Columbia-Suicide Severity Rating Scale
(C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a systematically administered 
instrument developed to track suicidal adverse events across a treatment study.  At 
Screening Visit 1 the C-SSRS will be administered to collect lifetime history as well as 
experience during the past year.  At all other visits, the C-SSRS will collect experience 
since the last visit.  Affirmative responses on the C-SSRS will be summarized for the 
initial screening and each subsequent visit for each treatment group and all subjects 
overall.
Each summary will include the number and percentage of subjects with one or more 
affirmative responses to each of the 5 suicidal ideation questions, each of the 6 suicidal 
behavior questions, any of the 5 suicidal ideation questions, any of the 6 suicidal behavior 
questions, any suicidal ideation or behavior question, and the self-injurious behavior 
without suicidal intent.  A listing will also be prepared that includes all subjects with 1 or 
more affirmative responses.
10.7
MS Relapses
The number and percentage of subjects with confirmed MS relapses will be summarized.
10.8
Pregnancy
Pregnancy information will be presented in listings only.
 


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11.0
Summary of Changes
11.1
Summary of Changes Between the Previous Version and the 
Current Version
Minor typographical corrections and text clarifications were made throughout.
An interim futility analysis previously planned was eliminated.  Sample size calculations 
have been corrected.
Due to an update to the format corresponding document to further define programming, 
the statistical programming plan, the following sections were added:
●
Subject Disposition
●
Extent of Exposure and Compliance
●
Demographics, Baseline Characteristics, Medical History and 
Prior/Concomitant Medications
●
Protocol Deviations and Visit Modifications
Due to the COVID-19 pandemic, significant modifications were made to the secondary 
and exploratory endpoints in the protocol.  These changes are reflected in the SAP.  
Additionally, due to increased missing data, an additional analysis set (MMIA set) was 
added, and missing data handling rules were updated.
Details of the analyses of exploratory endpoints and MRI were added.
Additional efficacy analyses were added to further characterize the treatment effect, 
including:
●
Improvement by visit on the EDSS + and its components
●
Disability progression
●
Continuous analyses of the change from baseline in T25FW and 9HPT
●
Analyses of the SDMT, MFIS-5, and LCVA based on a subset of the 
population with a deficit at baseline
 


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●
Exploratory analyses related to biomarkers and actigraphy
●
Figures specified in Section 9.6
Minor clarifications and updates were made to the safety analyses.  The adverse events of 
special interest were updated in the protocol and is reflected in this SAP.  A change from 
baseline summary is planned for specified laboratory values only.  A summary of liver 
function tests including possible Hy's Law cases is specified.  The PCS laboratory table 
was updated to reflect only the parameters which were collected in this study.  A 
summary of the number MS relapses is planned.  Details of the vital signs summaries 
were added.
11.2
Summary of Changes in Previous Version
This is the second version.  All changes from the initial version are summarized in the 
previous section.
12.0
Appendix 
12.1
Adverse Events of Special Interest
See the statistical programming plan for further description of AESIs.
 


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12.2
Criteria for Potentially Clinically Significant Laboratory 
Values
Variable Measured
Potentially Clinically Significant (PCS) Criteria
Very Low
Very High
Hematology
Activated partial thromboplastin time 
prolonged (aPTT)
NA
> ULN
Hemoglobin
< 10.0 g/dL
(6.2 mmol/L, 100 g/L)
> 4 gm/dL above ULN
Lymphocyte count
< 500/mm3 (0.5 × 109/L)
> 20, 000/mm3
Neutrophil count
< 1000/mm3 (1.0× 109/L)
NA
Platelet count
< 75,000/mm3 (75.0 × 109/L)
NA
White blood cell (WBC) 
< 2000/mm3 (2.0 × 109/L)
> 100,000/mm3
Chemistry
Blood bilirubin 
NA
> 1.5 × ULN
Cholesterol 
NA
> 500 mg/dL (12.92 mmol/L)
Creatinine 
NA
> 1.5 × ULN
Corrected Serum Calcium
< 7.0 mg/dL (1.75 mmol/L)
> 12.5 mg/dL (3.1 mmol/L)
Fasting Glucose 
< 40 mg/dL (2.2 mmol/L)
> 250 mg/dL (13.9 mmol/L)
Potassium
< 3.0 mmol/L
> 6.0 mmol/L
Sodium
< 130 mmol/L
> 155 mmol/L
Triglycerides
NA
> 500 mg/dL (5.7 mmol/L)
Uric acid 
NA
> 10 mg/dL (0.59 mmol/L)
Albumin
< 2 g/dL (20 g/L)
NA
phosphate
< 2.0 mg/dL (0.6 mmol/L)
NA
Enzymes
Alanine aminotransferase (ALT) 
NA
> 3.0 × ULN
Alkaline phosphatase 
NA
> 2.5 × ULN
Aspartate aminotransferase (AST) 
NA
> 3.0 × ULN
CPK
NA
> 5.0 × ULN
 


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12.3
Criteria for Potentially Clinically Significant Vital Sign 
Values
Vital Signs Variables
Criterion
Potentially Clinically Significant (PCS) Value
Systolic blood pressure 
(mmHg)
Low
≤ 90 mm Hg and decrease ≥ 20 mmHg from Baseline
High
≥ 180 mm Hg and increase ≥ 20 mmHg from Baseline
Diastolic blood 
pressure (mmHg)
Low
≤ 50 mm Hg and decrease ≥ 15 mmHg from Baseline
High
≥ 105 mm Hg and increase ≥ 15 mmHg from Baseline
Heart rate (bpm)
Low
≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
≥ 120 bpm and increase ≥ 15 bpm from Baseline
Temperature
High
≥ 38.3°C and ≥ 1.1°C above baseline value
Post-infusion systolic 
blood pressure
High
> 160 mmHg systolic and > 20 mm Hg above pre-infusion 
value
Post-infusion diastolic 
blood pressure
High
> 105 mm Hg diastolic and > 15 mm Hg above pre-infusion 
value
 


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13.0
References
1.
Protocol for Study M14-397, A Randomized, Double-Blind, Placebo-Controlled, 
Multiple Dose Study to Assess the Safety and Efficacy of Elezanumab when 
Added to Standard of Care in Progressive Forms of Multiple Sclerosis. 
2.
Operations manual for Clinical Study Protocol M14-397.