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
Phase: PHASE2
Conditions: Multiple Sclerosis (MS)
Sponsor: AbbVie



STUDY M14-397  |  Version 5.0
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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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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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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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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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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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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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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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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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