Conditions: Multiple Sclerosis
Keywords: MS Relapsing Remitting Multiple Sclerosis RRMS dimethyl fumarate DMF
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1057
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the long-term safety and tolerability of ALKS 8700 for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS). The secondary objective of this study is to evaluate treatment effect over time in adult participants with RRMS treated with ALKS 8700.

Detailed description:

Arms:
arm 1: Oral capsules taken twice daily.

Interventions: intervention 1: ALKS 8700
Intervention descriptions: intervention 1: Administered as specified in the treatment arm.

Protocol document:
Prot_000.pdf: 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
SPONSOR INFORMATION
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
For urgent medical issues in which the study Medical Director should be contacted, please refer 
to the Study Reference Manual’s Official Study Contact List for complete contact information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities.




Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
TABLE OF CONTENTS
SPONSOR INFORMATION ..........................................................................................................2
1.
KEY STUDY ELEMENTS..........................................................................................9
1.1.
Synopsis........................................................................................................................9
1.2.
Study Design Schematic.............................................................................................13
1.3.
Schedule of Activities.................................................................................................14
2.
LIST OF ABBREVIATIONS.....................................................................................19
3.
INTRODUCTION......................................................................................................21
3.1.
Study Rationale...........................................................................................................21
3.1.1.
Rationale for Study Population...................................................................................21
3.1.2.
Rationale for Dosing Regimen ...................................................................................21
3.2.
Background.................................................................................................................22
3.2.1.
Overview of Multiple Sclerosis..................................................................................22
3.2.2.
Current Therapies for Multiple Sclerosis ...................................................................22
3.2.3.
Profile of Previous Experience With ALKS 8700......................................................23
3.2.3.1.
Clinical Studies...........................................................................................................23
3.2.3.2.
Nonclinical Studies.....................................................................................................24
3.3.
Benefit-Risk Assessment............................................................................................25
4.
STUDY OBJECTIVES AND ENDPOINTS..............................................................26
5.
STUDY DESIGN .......................................................................................................27
5.1.
Study Overview ..........................................................................................................27
5.2.
Study Duration for Subjects........................................................................................27
5.3.
Study treatment Dose Adjustment and Stopping Rules..............................................28
5.4.
Unscheduled Visits .....................................................................................................28
5.5.
Follow-up....................................................................................................................29
5.6.
End of Study ...............................................................................................................29
6.
STUDY POPULATION.............................................................................................30
6.1.
Inclusion Criteria ........................................................................................................30
6.1.1.
Rollover Subjects........................................................................................................30
6.1.2.
De Novo Subjects .......................................................................................................30
6.2.
Exclusion Criteria.......................................................................................................31
6.2.1.
Rollover Subjects........................................................................................................31


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
5
6.2.2.
De Novo Subjects .......................................................................................................31
6.3.
Screening, Retesting, and Screen Failures..................................................................33
6.3.1.
Screening ....................................................................................................................33
6.3.2.
Retesting .....................................................................................................................33
6.3.3.
Screen Failures............................................................................................................34
7.
STUDY TREATMENT..............................................................................................35
7.1.
Regimen......................................................................................................................35
7.2.
Modification of Dose and/or Treatment Schedule......................................................35
7.2.1.
Rescue.........................................................................................................................36
7.2.2.
Relapse........................................................................................................................36
7.3.
Study Treatment Management....................................................................................37
7.3.1.
ALKS 8700.................................................................................................................38
7.3.1.1.
Packaging and Labeling..............................................................................................38
7.3.1.2.
Storage ........................................................................................................................38
7.3.1.3.
Handling and Disposal................................................................................................38
7.3.1.4.
Accountability.............................................................................................................38
7.4.
Blinding Procedures....................................................................................................38
7.5.
Precautions..................................................................................................................39
7.6.
Compliance.................................................................................................................39
7.7.
Concomitant Therapy and Procedures........................................................................39
7.7.1.
Concomitant Therapy .................................................................................................39
7.7.1.1.
Allowed Concomitant Therapy...................................................................................39
7.7.1.2.
Disallowed Concomitant Therapy..............................................................................39
7.7.2.
Concomitant Procedures.............................................................................................40
7.8.
Continuation of Treatment..........................................................................................40
8.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................41
8.1.
Discontinuation of Study Treatment...........................................................................41
8.2.
Lost to Follow-Up.......................................................................................................41
8.3.
Withdrawal of Subjects From the Study.....................................................................42
9.
EFFICACY AND PHARMACOKINETIC ASSESSMENTS...................................44
9.1.
Clinical Efficacy Assessments....................................................................................44


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
6
44
9.1.2.
Structured Interviews and Questionnaires..................................................................45
9.1.2.1.
Expanded Disability Status Scale...............................................................................45
9.1.2.2.
EuroQol Group Health Outcome Measure (5 level; EQ-5D-5L) ...............................46
9.1.3.
Timed 25-Foot Walk...................................................................................................46
9.1.3.1.
Short Form 12 Health Survey.....................................................................................46
9.1.3.2.
Columbia-Suicide Severity Rating Scale....................................................................46
9.2.
Pharmacokinetic Assessments....................................................................................46
10.
SAFETY ASSESSMENTS ........................................................................................48
10.1.
Clinical Safety Assessments.......................................................................................48
10.2.
Laboratory Safety Assessments..................................................................................48
10.2.1.
Pregnancy Testing ......................................................................................................49
10.2.2.
Serology Testing.........................................................................................................50
11.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................51
11.1.
Definitions ..................................................................................................................51
11.1.1.
Adverse Event.............................................................................................................51
11.1.2.
Serious Adverse Event................................................................................................51
11.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................52
11.2.
Safety Classifications..................................................................................................52
11.2.1.
Investigator Assessment of Events.............................................................................52
11.2.2.
Relationship of Events to Study Treatment................................................................52
11.2.3.
Severity of Events.......................................................................................................54
11.2.4.
Expectedness of Events ..............................................................................................54
11.3.
Monitoring and Recording Events..............................................................................54
11.3.1.
Adverse Events ...........................................................................................................54
11.3.2.
Serious Adverse Events..............................................................................................55
11.3.3.
Immediate Reporting of Serious Adverse Events.......................................................55
11.3.3.1.
Deaths .........................................................................................................................56
11.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................56
11.4.
Procedures for Handling Special Situations ...............................................................56
11.4.1.
Pregnancy ...................................................................................................................56


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
7
11.4.2.
Overdose.....................................................................................................................57
11.4.3.
Medical Emergency....................................................................................................57
11.5.
Contraception Requirements ......................................................................................57
11.6.
Safety Responsibilities................................................................................................58
11.6.1.
The Investigator..........................................................................................................58
11.6.2.
The Sponsor................................................................................................................59
12.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........60
12.1.
General Considerations...............................................................................................60
12.2.
Analysis Sets...............................................................................................................60
12.2.1.
Safety Population........................................................................................................60
12.2.2.
Efficacy Population ....................................................................................................60
12.3.
Demographics and Baseline Characteristics...............................................................60
12.4.
Methods of Analysis for Efficacy Endpoints..............................................................60
12.5.
Methods of Analysis for Pharmacokinetic Endpoints ................................................61
12.6.
Methods of Analysis for Safety Endpoints.................................................................62
12.7.
Interim Analyses.........................................................................................................62
12.8.
Sample Size Considerations .......................................................................................62
13.
ETHICAL AND REGULATORY REQUIREMENTS..............................................63
13.1.
Declaration of Helsinki...............................................................................................63
13.2.
Ethics Committee........................................................................................................63
13.3.
Changes to Final Protocol...........................................................................................64
13.4.
Informed Consent .......................................................................................................64
13.5.
Confirmation of Willingness to Continue in the Study ..............................................64
13.6.
Subject Data Protection ..............................................................................................65
13.7.
Compensation for Injury.............................................................................................65
13.8.
Conflict of Interest......................................................................................................66
13.9.
Study Report Signatory...............................................................................................66
13.10.
Registration of Study and Disclosure of Study Results..............................................66
13.11.
Retention of Study Data..............................................................................................66
14.
KEY ROLES AND STUDY GOVERNANCE COMMITTEES...............................67
14.1.
Vendors.......................................................................................................................67
14.1.1.
Contract Research Organization.................................................................................67


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8
14.1.2.
Interactive Response Technology...............................................................................67
14.1.3.
Electronic Data Capture..............................................................................................67
14.1.4.
Central Laboratories for Laboratory Assessments .....................................................67
14.2.
Study Committees.......................................................................................................67
15.
ADMINISTRATIVE PROCEDURES.......................................................................68
15.1.
Study Site Initiation....................................................................................................68
15.2.
Quality Control and Quality Assurance......................................................................68
15.3.
Case Report Forms .....................................................................................................68
15.4.
Confidentiality of Data ...............................................................................................68
15.5.
Monitoring of the Study..............................................................................................69
15.6.
Audits and Inspections................................................................................................69
15.7.
Study Funding.............................................................................................................69
15.8.
Publications.................................................................................................................70
16.
REFERENCES ...........................................................................................................71
17.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................74
LIST OF TABLES
Table 1:
Schedule of Assessments............................................................................................14
Table 2:
Additional Follow-Up for Subjects With Lymphopenia ............................................18
Table 3:
Clinical Laboratory Assessments ...............................................................................49
LIST OF FIGURES
Figure 1:
Study Design Schematic.............................................................................................13


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
9
1.
KEY STUDY ELEMENTS
1.1.
Synopsis
Protocol Title:
A Phase 3 Open Label Study to Evaluate the Long-Term Safety 
and Tolerability of ALKS 8700 in Adults With Relapsing 
Remitting Multiple Sclerosis
Protocol Number:
ALK8700-A301
Version Number:
5.0
Name of Study Treatment:
ALKS 8700 (also known as BIIB098 and diroximel fumarate)
Study Phase:
3
Study Indication:
Multiple sclerosis (MS)
Study Rationale:
Disease-modifying therapies are widely used for the treatment of 
relapsing forms of MS and have been demonstrated to delay 
disease progression, prevent disability, and improve quality of 
life. The ALKS 8700 drug product is a modified-release oral 
dosage form that provides a monomethyl fumarate (MMF) 
exposure profile that may limit gastrointestinal (GI) effects 
associated with dimethyl fumarate (DMF) treatment while 
maintaining efficacy comparable to that demonstrated with 
DMF. Accordingly, ALKS 8700 has the potential to address an 
unmet medical need for patients with relapsing forms of MS who 
are unable to tolerate DMF, particularly due to GI effects.
Rationale for Dose and 
Schedule Selection:
Unless otherwise specified all doses referred to are administered 
twice daily (BID). The selected dose level of ALKS 8700 
delayed release (DR; 462 mg) is supported by clinical safety, 
tolerability, and pharmacokinetic (PK) data from prior clinical 
studies. The doses of ALKS 8700 to be used for initial dose 
titration (231 mg) and for treatment maintenance (462 mg) in this 
study are within the range of doses evaluated in a completed 
single ascending dose study and in a completed repeat dose 
clinical study. Safety data from both studies indicate that doses 
of 210 mg, 420 mg, and 630 mg (231 mg and 462 mg doses to be 
used in this study), administered either as a single dose or BID
for 5 days in healthy volunteers were generally well tolerated 
with no relevant differences in safety or tolerability between 
single or repeat dosing at each dose level. In addition, it was 




Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
11
This study will be conducted in De Novo Subjects who meet the 
following criteria:

Male and female adults aged 18 to 65 years, inclusive, 
at Screening

Has a confirmed diagnosis of RRMS according to the 
revised 2010 McDonald criteria

EDSS score of 0.0-6.0 at screening and Visit 2

Neurologically stable with no evidence of relapse 
within 30 days prior to Visit 2
This study will be conducted in Rollover Subjects who meet the 
following criterion:

Completed the full treatment period of any eligible 
study of ALKS 8700 within 7 days of Visit 2
Detailed criteria are described in Section 6.
Number of Planned
Subjects:
Approximately 1000 subjects will be dosed.
Treatment Groups:
Study treatment includes ALKS 8700 231 mg administered as 
one capsule and ALKS 8700 462 mg administered as two 
231 mg capsules.
This study will enroll both De Novo and Rollover Subjects. Any 
subject not currently receiving ALKS 8700 or DMF will titrate 
from ALKS 8700 231 mg BID for the first week on treatment 
followed by 462 mg BID from Day 8 onwards. For those 
subjects already receiving ALKS 8700 or DMF, the initial ALKS 
8700 dose will be 462 mg BID starting from Day 1.
Capsules will be administered orally BID. Study staff will 
administer the first dose of ALKS 8700 at Visit 2 (Day 1). From 
that point on during the treatment period, the staff will dispense 
ALKS 8700 for participations’ self-administration. Subjects will 
be instructed to take study treatment with or without food. 
However, subjects will be instructed to avoid taking study 
treatment with a high-fat, high-calorie meal.
Sample Size 
Determination:
No formal sample size calculation is performed for this study. A 
sample size of approximately 1000 subjects will contribute to the 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
12
long-term safety experience of ALKS 8700 in subjects with 
RRMS, taking into account International Council for 
Harmonisation guidance on the extent of patient exposures 
required to assess clinical safety for a new drug.
Visit Schedule:
Subjects will have up to 16 visits during the study. 
Study assessments conducted at each visit are listed in the
Schedule of Activities (Table 1).
Duration of Study 
Participation:
Study duration for each subject will be approximately 
102 weeks:

4-week screening period (De Novo Subjects only)

96-week treatment period

2-week follow-up period
Benefit-Risk Analysis:
The potential risks related to participation in this study are 
justified by the anticipated benefit to subjects.
The modified-release oral dosage form may provide an MMF 
exposure profile that may limit GI effects associated with DMF 
treatment while maintaining efficacy. Accordingly, ALKS 8700 
has the potential to address an unmet medical need for patients 
with relapsing forms of MS who are unable to tolerate DMF.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
13
1.2.
Study Design Schematic
Figure 1:
Study Design Schematic
*Dosing is twice daily.
De Novo Subjects and Rollover Subjects defined in Section 5.1.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
14
1.3.
Schedule of Activities
Table 1:
Schedule of Assessments
Screening
96-Week-Open-Label Treatment1
Visit
12
23
TC4
3
TC4
4
5
6
7
8
9
10
11
12
13
14
15/E
T
16 
Follow-
Up
Day
-28 to -1
1
8
(±2)
15
(±3)
22
(±2)
29
(±3)
57
(±5)
85
(±5)
113
(±5)
141
(±5)
169
(±5)
253
(±5)
337
(±5)
421
(±5)
505
(±5)
589
(±5)
673
(±5)
687
(±5)
Week
-4 to -1
1
2
4
8
12
16
20
24
36
48
60
72
84
96
98
Informed 
consent5
X
Eligibility 
Criteria 
Review
X
X6
Demographics 
and Medical 
History
X
Physical 
Examination7
X
X7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height8
X
Weight
X
X6
X
X
X
X
X
X
X
X
X
X
X
Urine 
Pregnancy 
Test
X
X6
X
X
X
X
X
X
X
X
X
X
X
X
Serology 
Testing8
X


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
15
Screening
96-Week-Open-Label Treatment1
Visit
12
23
TC4
3
TC4
4
5
6
7
8
9
10
11
12
13
14
15/E
T
16 
Follow-
Up
Day
-28 to -1
1
8
(±2)
15
(±3)
22
(±2)
29
(±3)
57
(±5)
85
(±5)
113
(±5)
141
(±5)
169
(±5)
253
(±5)
337
(±5)
421
(±5)
505
(±5)
589
(±5)
673
(±5)
687
(±5)
Week
-4 to -1
1
2
4
8
12
16
20
24
36
48
60
72
84
96
98
Biochemistry, 
Urinalysis9, 
and 
Hematology
X
X6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs10
X
X6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standard 
12-Lead ECG
X
X6
X
X
X
X
X
X
X
X
X
X
PK sampling11
X6
X
X
X
Timed 25-Foot 
Walk
X
X6
X
X
X
X
X
X
X
X
EDSS
X
X6
X
X
X
X
X
X
X
X
SF-12
X6
X
X
X
X
EQ-5D-5L
X6
X
X
X
X
C-SSRS15
X
X6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication 
Review
X
X
X4
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
AE 
Monitoring 
X
X
X4
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
16
Screening
96-Week-Open-Label Treatment1
Visit
12
23
TC4
3
TC4
4
5
6
7
8
9
10
11
12
13
14
15/E
T
16 
Follow-
Up
Day
-28 to -1
1
8
(±2)
15
(±3)
22
(±2)
29
(±3)
57
(±5)
85
(±5)
113
(±5)
141
(±5)
169
(±5)
253
(±5)
337
(±5)
421
(±5)
505
(±5)
589
(±5)
673
(±5)
687
(±5)
Week
-4 to -1
1
2
4
8
12
16
20
24
36
48
60
72
84
96
98
Study 
treatment
Dispensation
X
X
X
X
X
X
X
X
X
X
X
X
X
Study 
treatment
Accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Emergency 
Treatment 
Card16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; 
EQ-5D-5L = EuroQoL Group health outcome measure 5-level version; ET = early termination; 
 
; PK = pharmacokinetic; SF-12 = 12-item Short Form Health Survey; TC = telephone call.
Unscheduled visit may occur at any time as per protocol requirements.
2 Only De Novo Subjects will participate in the Screening Visit.
3 For Rollover Subjects, identical assessments taken at the last treatment visit in the antecedent study do not need to be repeated at Visit 2 in the current study.
4 Safety and tolerability assessments (including AEs and concomitant medications) will be conducted by telephone on these days.
5 Eligible, consenting De Novo Subjects will give written consent at screening. Eligible, consenting Rollover Subjects will give written consent prior to 
participating in any study-specific procedures at Visit 2. Written confirmation of a subject's willingness to continue in the study will be required if one or more of 
the following occur during the study: MS relapse, disability progression, 
 
6 To be conducted predose at Visit 2.
7 Full physical examination at screening. Brief physical examination, symptom-directed, at all other visits.
8 For Rollover Subjects, height will be carried over from information recorded in the antecedent ALKS 8700 study in which they participated.
8 Serology testing includes hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody.
9 Urinalysis includes urine dipstick, urine microscopy (as applicable), urine beta-2-microglobulin, urine albumin, and urine creatinine.
10Vital signs measurements include temperature, respiratory rate, blood pressure, and heart rate. Blood pressure, respiratory rate, and heart rate will be measured 
after the subject has been in a seated or supine position for at least 5 minutes.




Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
18
Table 2:
Additional Follow-Up for Subjects With Lymphopenia
Assessments
LM Visits1
LM Visit 1
(2 months after Safety 
Follow-Up Visit ± 7 days)
LM Visit 2
(4 months after Safety 
Follow-Up Visit ± 7 days)
LM Visit 3
(6 months after Safety 
Follow-Up Visit ± 7 days)
Lymphocyte Count
X
X
X
Concomitant Medication
X
X
X
LM = lymphocyte monitoring.
1 Subjects who complete the study or who terminate the study early and have a last measured lymphocyte count < 0.8 x 103/μL will return to the clinic for 
additional LM visits every 2 months starting from Visit 16 for a period of 6 months (i.e., a maximum of 3 visits) or until lymphocyte counts reach normal limits 
(≥0.91 x 103/μL), whichever occurs first. All assessments required for the Safety Follow-Up Visit (Visit 16, Table 1) should be completed for these subjects 
prior to initiation of the lymphocyte monitoring visits. 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
19
2.
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ARR
annualized relapse rate
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUClast
area under the plasma concentration versus time curve calculated 
using the trapezoidal method from time zero to the last observed 
concentration above the lower limit of quantification
BID
twice daily
Cmax
maximum observed concentration
CRO
contract research organization
CSA
Clinical Study Agreement
C-SSRS
Columbia-Suicide Severity Rating Scale
DMF
dimethyl fumarate
DMT
disease-modifying therapy
DR
delayed release
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EDSS
Expanded Disability Status Scale
EQ-5D-5L
EuroQol Group health outcome measure (5-level)
ET
early termination
FAS
full analysis set
FS
functional system
GCP
Good Clinical Practice
GdE
gadolinium-enhancing
GI
gastrointestinal
GMP
Good Manufacturing Practice
HDPE
high density polyethylene
hERG
human ether-à-go-go-related gene
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation 
IRB
institutional review board
IFN
interferon
IRT
interactive response technology
IV
intravenous
LM
lymphocyte monitoring
MMF
monomethyl fumarate


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
20
MS
multiple sclerosis
NEDA
No Evidence of Disease Activity
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
RRMS
relapsing-remitting multiple sclerosis
SAE
serious adverse event
SF-12
Short Form-12 Health Survey
SF-12v2
Short Form-12 Health Survey Version 2
T25-FW
Timed 25-Foot Walk
TEAE
treatment-emergent adverse event
TSH
thyroid-stimulating hormone
Tmax
time to reach Cmax
ULN
upper limit of normal
VAS
Visual Analog Scale


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
21
3.
INTRODUCTION
3.1.
Study Rationale
3.1.1.
Rationale for Study Population
The majority of patients with multiple sclerosis (MS) initially have a form known as 
relapsing-remitting MS (RRMS). Early and effective treatment is necessary to improve quality of 
life and to reduce the risk of patients developing more progressive forms of the disease leading to 
severe physical disability.
3.1.2.
Rationale for Dosing Regimen
The selected dose level of ALKS 8700 DR (462 mg) is supported by clinical safety, tolerability, 
and PK data from prior clinical studies (Study ALK8700-001, ALK8700-A102, 
ALK8700-A103, and ALK8700-A104). All doses referred to in this section are twice daily 
(BID).
The doses of ALKS 8700 to be used for initial dose titration (231 mg) and for treatment 
maintenance (462 mg) in this study are within the range of doses evaluated in a completed single 
ascending dose study (Study ALK8700-001) and in a completed repeat dose clinical study 
(Study ALK8700-A102). Safety data from both studies (Study ALK8700-001 and 
ALK8700-A102) indicate that doses of 210 mg, 420 mg, and 630 mg (231 mg and 462 mg doses 
to be used in this study), administered either as a single dose or BID for 5 days in healthy 
subjects were generally well tolerated with no relevant differences in safety or tolerability 
between single or repeat dosing at each dose level. In addition, from Study ALK8700-A102, it 
was demonstrated that the incidence of flushing with ALKS 8700 DR was lower in the fed 
condition (37.5% of subjects) compared to the fasted condition (50.0% of subjects).
The appropriateness of a maintenance 462 mg dose of ALKS 8700 DR was confirmed by 
2 relative bioavailability studies (Study ALK8700-A103 and ALK8700-A104) in which PK 
results showed that ALKS 8700 462 mg results in comparable monomethyl fumarate (MMF)
exposure to dimethyl fumarate (DMF) 240 mg under fasted conditions, as well as in the presence 
of a high-fat, high-calorie meal. MMF exposure following administration of ALKS 8700 
provides comparable exposure to DMF in the fasted condition (Study ALK8700-A103) and met 
the PK criteria for bioequivalence to DMF for area under the concentration-time curve (AUC)
and maximum observed concentration (Cmax). While total systemic exposure to MMF was 
comparable between ALKS 8700 and DMF in the presence of a high-fat, high-calorie meal, Cmax
was 26% lower (ALK8700-A104). In a subsequent study (ALK8700-A109), it was found that 
medium-fat, medium-calorie and low-fat, low-calorie meals resulted in reductions in Cmax that 
were no greater than that observed with DMF when co-administered with a high-fat, high-calorie 
meal. Therefore, ALKS 8700 can be taken with or without food. However, subjects will be 
instructed to avoid taking study treatment with a high-fat, high-calorie meal. Administration with 
food may reduce the incidence of flushing (as observed in Study ALK8700-A102).


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
22
3.2.
Background
3.2.1.
Overview of Multiple Sclerosis
MS is a chronic, debilitating disease of the central nervous system that currently affects 
approximately 2.5 million people worldwide with 5 to 10 new cases per 100,000 people each 
year [Ropper 2012; Tremlett 2010].
3.2.2.
Current Therapies for Multiple Sclerosis
Recent therapeutic advancements have led to significant improvement in the management of the 
disease. Disease-modifying therapies (DMTs) are widely used for the treatment of relapsing 
forms of MS [Costello 2014] and have been demonstrated to delay disease progression, prevent 
disability and improve quality of life.
The most commonly used first-line MS therapies are interferons (IFNs) and glatiramer acetate 
[Waldman 2011]. Relative to placebo, IFNs have been shown to reduce relapse rate by 
approximately 27% to 36% [Calabresi 2014; Jacobs 1996; PRISMS Study Group 1998; The 
IFNB Multiple Sclerosis Study Group 1993], and glatiramer acetate by approximately 30% 
[Johnson 1995]. The IFN beta-1a products have also been shown to delay disability progression 
[Jacobs 1996; PRISMS Study Group 1998].
Other currently approved therapies for MS include the following:

Natalizumab: a humanized monoclonal antibody directed against α4 integrins 
[Polman 2006]

Fingolimod: a selective oral immunosuppressant that is metabolized to a functional 
antagonist of sphingosine 1-phosphate receptors on lymphocytes [Kappos 2010]

Mitoxantrone: a synthetic antineoplastic anthracenedione that intercalates into 
deoxyribonucleic acid and interferes with ribonucleic acid [Chitnis 2012]

Teriflunomide: an immunomodulatory drug inhibiting pyrimidine synthesis by 
blocking dihydroorotate dehydrogenase [O'Connor 2011]

Alemtuzumab: a humanized monoclonal antibody targeting CD-52 antigen expressed 
on the surface of most leukocytes [Coles 2012]


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
23
3.2.3.
Profile of Previous Experience With ALKS 8700
3.2.3.1.
Clinical Studies
Five Phase I studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of 
ALKS 8700 in healthy adults (ALK8700-001, ALK8700-A102, ALK8700-A103 and 
ALK8700-A104, ALK8700-A105) have been completed. Three Phase 1 studies (ALK8700-106, 
ALK8700-107, and ALK8700-A109) have been clinically completed and the data analyses are 
ongoing.
The general PK characteristics for ALKS 8700 have been evaluated in the abovementioned 
completed Phase 1 studies. ALKS 8700 undergoes rapid presystemic hydrolysis to MMF with a 
dose proportionate increase in MMF exposure over the ALKS 8700 dose range tested (49 to 
980 mg; ALK8700-001). Administration of ALKS 8700 420 mg with a high-fat, high-calorie 
meal delayed absorption of MMF, resulting in a significant decrease in Cmax (44%) and a modest 
reduction in area under the plasma concentration versus time curve calculated using the 
trapezoidal method from time zero to the last observed concentration above the lower limit of 
quantification (AUClast 11%, ALK8700-A102). Minimal accumulation of MMF was observed in 
plasma following repeated administration of 210 to 630 mg BID for 5 days (ALK8700-A102). In 
addition, RDC-6567 has been identified as a major human metabolite of ALKS 8700 that is 
primarily eliminated in urine (ALK8700-A105).
The relative bioavailability of ALKS 8700 462 mg compared with DMF 240 mg was initially
evaluated in a fasted condition (ALK8700-A103) as well as in the presence of a high-fat, 
high-calorie meal (ALK8700-A104). ALKS 8700 462 mg resulted in similar MMF exposure to 
DMF 240 mg under fasted conditions and met the PK criteria for bioequivalence to DMF based 
on Cmax and AUC (ALK8700-A103). ALKS 8700 462 mg resulted in similar MMF exposure to 
DMF 240 mg with a high-fat, high-calorie meal and met the PK criteria for bioequivalence to 
DMF for AUC, but Cmax was 26% lower for ALKS 8700 as compared to DMF 
(ALK8700-A104).
Given the reduction in Cmax with a high-fat, high-calorie meal, an additional study was conducted 
evaluating meal compositions with lower fat and caloric content. In this study (ALK8700-A109), 
MMF AUC for ALKS 8700 when administered with medium-fat, medium-calorie and low-fat, 
low-calorie meals was comparable to DMF under fasted conditions. Administration of 
ALKS 8700 with medium-fat, medium-calorie and low-fat, low-calorie meals resulted in 
reductions in Cmax that were less than that observed for DMF when administered with a high-fat, 
high-calorie meal (ALK8700-A109). Therefore, when co-administered with medium-fat, 
medium-calorie and low-fat, low-calorie meals, ALKS 8700 resulted in MMF exposure within 
the accepted therapeutic exposure range for DMF. Accordingly, ALKS 8700 can be administered 
with or without food but should be avoided with high-fat, high-calorie meals as described in
Section 7.1.
Overall safety analyses from the abovementioned completed Phase 1 clinical studies have 
demonstrated that ALKS 8700 has been generally well tolerated at all doses tested 
(49 mg-980 mg) with no reported serious adverse events (SAEs) and no unanticipated or 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
24
unforeseen clinical safety issues after single or repeat dosing in healthy subjects. All reported 
treatment-emergent adverse events (TEAEs) have been mild or moderate in severity 
(predominantly mild), and there have been no relevant differences in tolerability between single 
and repeat dosing at the same dose levels. The most commonly reported TEAEs have been 
flushing followed by gastrointestinal (GI)-related TEAEs which have both occurred in a 
dose-dependent manner. GI-related TEAEs have been observed with ALKS 8700 at consistently 
low rates throughout the studies at dose levels comparable (in terms of MMF exposure) to the 
therapeutic maintenance dose of DMF (240 mg). Results from Phase 1 clinical investigations 
available to date on the PK, safety, and tolerability of ALKS 8700 are summarized in the 
Investigator’s Brochure.
3.2.3.2.
Nonclinical Studies
A comprehensive series of nonclinical studies were conducted to support the clinical 
development of ALKS 8700 and are described in more detail in the ALKS 8700 Investigator’s 
Brochure.
Results from genetic toxicity assays showed that ALKS 8700 was non-mutagenic in bacteria 
in vitro and was associated with chromosomal aberrations in vitro in human peripheral blood 
lymphocytes but not in vivo in rats. ALKS 8700 had limited capacity to inhibit human ether-à-
go-go-related gene (hERG) potassium channel activity in a human cell line (i.e., concentration 
resulting in 50% inhibition of response [IC50] > 300 µM). Inhibition of hERG current has been 
associated with increased duration of the cardiac action potential and prolongation of the QT 
interval.
General toxicology findings were generally similar to those described for DMF and consisted of 
target organ effects in kidney (tubular degeneration/necrosis with regeneration, tubular 
hypertrophy, and interstitial fibrosis in rats, mice, and/or monkeys), GI tract (mucosal 
hyperplasia of the nonglandular stomach and duodenum of rats and/or mice), bone (physeal 
dysplasia of proximal and distal femur and proximal tibia in monkeys), heart 
(inflammation/necrosis in rats), and testes (minimal degeneration in mice).
ALKS 8700 was evaluated for developmental and reproductive toxicity in rats and rabbits. In 
fertility studies in male and female rats, no notable fertility or embryonic developmental findings 
occurred. In embryo-fetal development studies in rats and rabbits, noteworthy findings of fetal 
vertebral malformations were observed in rabbits but not in rats.
The safety evaluation of ALKS 8700 and its metabolites (i.e., MMF, RDC-6567, and RDC-8439) 
was adequate as systemic exposures of these analytes in nonclinical studies were similar to or 
exceeded those in humans at the Phase 3 clinical dose of 924 mg/day (462 mg BID) of 
ALKS 8700. For the major human metabolites, MMF and RDC-6567, the exposures associated 
with adverse findings in nonclinical safety studies are detailed in the ALKS 8700 Investigator’s 
Brochure.
Data generated through additional nonclinical studies will continue to be evaluated as they 
become available, including any potential influence on the risk-benefit profile of ALKS 8700.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
25
See the Investigator’s Brochure for further detailed information on relevant nonclinical and 
clinical studies
3.3.
Benefit-Risk Assessment
The potential risks related to participation in this study are justified by the anticipated benefit to 
subjects.
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events (AEs) of ALKS 800 is provided in the Investigator’s Brochure and informed 
consent form (ICF). A high-level summary of those benefits and risks known during study 
design is provided here.
ALKS 8700 is being developed as a modified-release oral treatment for relapsing forms of MS. 
ALKS 8700 is an aminoethyl ester of MMF that undergoes hydrolysis through esterases to 
produce MMF. MMF is also the active metabolite of the approved drug product, DMF. An oral 
form of DMF has been approved by the US Food and Drug Administration since 2013 under the 
trade name Tecfidera® for the treatment of patients with relapsing forms of MS [Tecfidera®
Prescribing Information 2017/SmPC 2017].
In clinical trials, DMF and, by extrapolation, its metabolite, MMF, have demonstrated robust 
efficacy in modulating the course of disease in patients with RRMS. Compared with placebo, 
DMF treatment resulted in significant reductions in annualized relapse rate (ARR), disability 
progression, as well as the number of new gadolinium-enhancing (GdE) lesions and new or 
enlarging T2 lesions [Fox 2012; Gold 2012; Kappos 2008].
The safety profile of DMF is well understood and GI-related tolerability is a recognized 
tolerability concern. As noted in the Summary Review of the Drug Approval Package for 
Tecfidera, in placebo-controlled trials of Tecfidera, 40% of DMF-treated subjects experienced 
one or more GI AEs. Reviewers described “a panoply of uncomfortable and fairly common GI 
AEs” that are an “obstacle to tolerability,” including nausea, vomiting, diarrhea, and abdominal 
pain [FDA 2013]. In addition, GI AEs were the leading cause of discontinuations due to AEs 
[FDA 2013]. The frequency and severity of the GI-related side effects are an important issue for 
patients taking DMF and is a barrier to treatment adherence and can lead to drug discontinuation 
which increases risk of relapse [Phillips 2014; Utz 2014]. This underscores the need for an 
efficacious agent with improved tolerability to optimize patient satisfaction and treatment 
outcomes [Phillips and Fox 2013].
The ALKS 8700 drug product is a modified-release oral dosage form that provides an MMF 
exposure profile that may limit GI effects associated with DMF treatment while maintaining 
efficacy comparable to that demonstrated with DMF. Accordingly, ALKS 8700 has the potential 
to address an unmet medical need for patients with relapsing forms of MS who are unable to 
tolerate DMF, particularly due to GI effects.




Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
27
5.
STUDY DESIGN
5.1.
Study Overview
This multicenter, open-label study will evaluate the long-term safety and tolerability of 
ALKS 8700 up to 96 weeks in approximately 1000 subjects. The target population for this study 
will be adults, aged 18 to 65 years, diagnosed with RRMS. The study will be conducted at 
approximately 125 sites in North America and Europe.
See Figure 1 for a schematic of the study design.
5.2.
Study Duration for Subjects
Subjects will enter into the study in one of two ways:
De Novo Subjects: Those who have not participated in any prior eligible study of ALKS 8700.
Rollover Subjects: Those who have completed the treatment period for any prior eligible study of 
ALKS 8700.
For De Novo Subjects, the study duration is expected to be up to 102 weeks, which includes up 
to 4 weeks for screening, a 96-week open-label treatment period, and a 2-week follow-up period. 
De Novo Subjects will be initially evaluated for eligibility at screening (Visit 1) that may last up 
to 28 days (4 weeks) prior to Visit 2. For Rollover Subjects, Visit 2 will be the first visit of the 
study and there will not be a separate screening visit. For these subjects, Visit 2 of this study will 
occur at the time of or within 7 days of the subject’s end of treatment visit in the antecedent 
study. Completed assessments taken at the end of treatment visit of the antecedent study will be 
carried forward and do not need to be repeated at Visit 2 of this study unless otherwise specified 
in the schedule of assessments. At Visit 2, all eligible, consenting subjects will begin open-label 
treatment. Any subject not currently receiving ALKS 8700 or DMF will initiate treatment with 
ALKS 8700 231 mg BID on Day 1 through Day 7 followed by 462 mg BID from Day 8 
onwards. For those subjects already receiving ALKS 8700 or DMF prior to Day 1, the initial 
ALKS 8700 dose will be 462 mg BID starting from Day 1.
Dosing is described in detail in Section 7.1. From Day 8 onwards, all participating subjects will 
take ALKS 8700 462 mg BID, with allowable dose reduction for tolerability as described in
Section 7.2.
Study staff will administer the first dose of ALKS 8700 at Visit 2 (Day 1). From that point on 
during the treatment period, according to the schedule of assessments as shown in Table 1, the 
staff will dispense ALKS 8700 for subjects’ self-administration. Subjects will be instructed to 
take study treatment with or without food. However, subjects will be instructed to avoid taking 
study treatment with a high-fat, high-calorie meal.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
28
During the 96-week treatment period (Visits 2-15), subjects will return to the clinic for periodic 
scheduled visits for the assessment of safety, tolerability, PK (in a subset of de novo subjects in 
selected sites), and clinical status. Two safety and tolerability assessments by phone will be 
scheduled (one between Visits 2 and 3 and one between Visits 3 and 4). See Figure 1 for a study 
schematic.
Subjects will return to the clinic for a safety follow-up visit (Visit 16) 2 weeks after the end of 
treatment visit (Visit 15). Any subject who prematurely discontinues from either study treatment 
or the study will be asked to return to the clinic for an early termination (ET) visit (Visit 15) as 
well as a safety follow-up visit 2 weeks later (Visit 16).
Subjects who complete the study or who terminate the study early and have a last measured 
lymphocyte count < 0.8 × 103/µL will return to the clinic for additional lymphocyte count 
monitoring visits every 2 months starting from Visit 16 for a period of 6 months (i.e., a 
maximum of 3 visits) or until lymphocyte counts reach normal limits (≥0.91 × 103/µL), 
whichever occurs first.
A treatment completer will be a subject who completes the 96-week treatment period (i.e., 
through Visit 15). Subjects completing the follow-up visit will be categorized as completing the 
study.
The end of study date for a subject may be the last study visit, last follow-up telephone 
conversation, or last protocol-specified assessment, or if the subject has ongoing AEs that are 
being followed, the date may be the date of AE resolution.
5.3.
Study treatment Dose Adjustment and Stopping Rules
Starting on Day 8 of treatment, dose reduction to ALKS 8700 231 mg BID is permitted at the 
Investigator’s discretion for subjects who are unable to tolerate ALKS 8700 462 mg BID. Once a 
subject has stabilized after dose reduction, attempts should again be made to achieve and 
maintain the target maintenance dose of ALKS 8700 462 mg BID. If a subject remains unable to 
tolerate ALKS 8700 462 mg BID after 1 month on treatment (i.e., by Visit 4), further dose 
reduction will not be permitted, and the subject will be discontinued from the study.
The Sponsor may terminate this study at any time, after informing Investigators. The Sponsor 
will notify Investigators when the study is to be placed on hold, completed, or terminated.
5.4.
Unscheduled Visits
Data collected during unscheduled visits should be recorded in electronic case report forms 
(eCRFs) only if the data support protocol objectives and/or are required for safety monitoring.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
29
An Unscheduled Relapse Visit will be conducted in the event of a suspected relapse
(Section 7.2.2). This visit should occur as early as possible but within 7 days of the onset of the 
potential relapse. The following assessments will be made:

Physical examination

Concomitant medication review

AE monitoring

Urine pregnancy test

Vital signs

Safety laboratory assessments

Relapse assessment

EDSS
5.5.
Follow-up
Subjects will return to the clinic for a safety follow-up visit (Visit 16) 2 weeks after the end of 
treatment visit (Visit 15) for the required assessments (Table 1). Any subject who prematurely 
discontinues from the study will be asked to return to the clinic for an ET visit (Visit 15) as well 
as a safety follow-up visit 2 weeks later (Visit 16) for the required assessments (Table 1).
Subjects who complete the study or who terminate the study early and have a last measured 
lymphocyte count < 0.8 × 103/µL at the last study visit (Visit 16) will be required to return to the 
clinic for additional lymphocyte count monitoring visits every 2 months (± 7 days) starting from 
the last study visit for a period of 6 months (i.e., a maximum of 3 visits) or until lymphocyte 
counts reach normal limits (≥0.91 × 103/µL), whichever occurs first (Table 2).
During the lymphocyte count monitoring visits, blood samples will be collected to measure 
lymphocyte count and any concomitant medications the subjects are taking will be recorded 
(Section 7.7).
5.6.
End of Study
The end of study is last subject, last visit for final collection of data.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
30
6.
STUDY POPULATION
6.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria
as listed in Table 1 or at the timepoint specified in the individual eligibility criterion listed.
6.1.1.
Rollover Subjects
In order to qualify for participation in this study, Rollover Subjects must meet all of the 
following criteria:
1. Is willing and able to provide informed consent.
2. Capable of understanding and complying with the protocol.
3. Agrees to use an acceptable method of contraception for the duration of the study and for 
30 days after any study treatment administration or is surgically sterile or postmenopausal 
(see Section 11.5).
4. Completed the full treatment period of any eligible study of ALKS 8700 within 7 days of 
Visit 2.
6.1.2.
De Novo Subjects
In order to qualify for participation in this study, De Novo Subjects must meet all of the 
following criteria:
1. Is willing and able to provide informed consent.
2. Capable of understanding and complying with the protocol.
3. Agrees to use an acceptable method of contraception for the duration of the study and for 
30 days after any study treatment administration or is surgically sterile or postmenopausal 
(see Section 11.5).
4. Male and female adults aged 18 to 65 years, inclusive, at screening.
5. Has a confirmed diagnosis of RRMS according to the revised 2010 McDonald criteria 
[Polman 2011].
6. EDSS score of 0.0-6.0 at screening and Visit 2.
7. Neurologically stable with no evidence of relapse within 30 days prior to Visit 2.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
31
6.2.
Exclusion Criteria
6.2.1.
Rollover Subjects
Rollover Subjects will be excluded from participation in this trial if they meet any of the 
following criteria:
1. Have any finding(s) that in the view of the Investigator or Medical Monitor would 
compromise the safety of the subject, affect their ability to adhere to the protocol visit 
schedule, or to fulfill visit requirements or make the subject unsuitable for participation in 
the study (including overall clinical assessment).
2. Subject is pregnant or breastfeeding or plans to become pregnant or begin breastfeeding 
at any point during the study and for 30 days after any study treatment administration.
3. Is employed by Biogen, contract research organization (CRO), or study site (permanent, 
temporary contract worker, or designee responsible for the conduct of the study) or is 
immediate family of a Biogen, CRO, or study site employee. Immediate family is defined 
as a spouse, parent, sibling, or child, whether biological or legally adopted.
6.2.2.
De Novo Subjects
De Novo Subjects will be excluded from participation in this trial if they meet any of the 
following criteria:
1. Have any finding that in the view of the Investigator or the Medical Monitor would 
compromise the safety of the subject or affect their ability to adhere to the protocol visit 
schedule or fulfill visit requirements or make the subject unsuitable for participation in 
the study (including overall clinical assessment).
2. Diagnosis of primary progressive, secondary progressive, or progressive relapsing MS as 
defined by Lublin and Reingold [Lublin and Reingold 1996].
3. History of clinically significant cardiovascular, pulmonary, GI (e.g., inflammatory bowel 
disease, peptic ulcer disease), dermatologic, psychiatric, neurologic (other than MS), 
endocrine, renal and/or other major disease that would preclude participation in a clinical 
trial.
4. History of clinically significant recurring or active GI symptoms (e.g., nausea, diarrhea, 
dyspepsia, constipation) within 3 months of screening, including symptoms that require 
the initiation of symptomatic medical treatment (e.g., initiation of a medication to treat 
gastroesophageal reflux disease) or a change in symptomatic medical treatment (e.g., an 
increase in dose) within 3 months of screening.
5. History of malignancy, unless an exception is granted by the Medical Monitor 
(e.g., subjects with basal cell carcinoma that has been completely excised prior to study 
entry remain eligible).


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
32
6. Has a clinically significant medical condition or observed abnormality at screening 
(e.g., clinically significant physical examination finding, vital sign result, ECG result, or 
laboratory test result).
7. History of a myocardial infarction, including a silent myocardial infarction identified on 
ECG, or unstable angina.
8. History of clinically significant drug or alcohol abuse within the past year 
(per Investigator judgment).
9. Has a positive serology test for hepatitis B surface antigen, hepatitis C antibody, or 
human immunodeficiency virus (HIV) antibody at screening.
10. Has any of the following abnormal blood tests at screening:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 times the 
upper limit of normal (ULN)

Thyroid-stimulating hormone (TSH) level >10% of the ULN at screening

Estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 (using the Chronic 
Kidney Disease Epidemiology Collaboration equation) [Levey 2009]

Lymphocyte count < 0.9 × 103/μL
11. Has any of the following abnormal urine tests at screening:

Beta-2 microglobulin > 0.3 μg/mL

Albumin to creatinine ratio > 200 mg/g
12. Has a clinically significant history of suicidal ideation or suicidal behavior occurring in 
the past 12 months as assessed by the C-SSRS at screening.
13. Has previously discontinued treatment with Tecfidera due to tolerability issues and/or 
lack of efficacy.
14. Has a history of treatment with or has received the following:

Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, total 
body irradiation, or total lymphoid irradiation at any time

Stem cell transplantation at any time

Mitoxantrone or other immunosuppressant agents (e.g., cyclosporine, 
cyclophosphamide, methotrexate, mycophenolate) within 2 years prior to Visit 2


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
33

Teriflunomide within 2 years of Visit 2, unless the serum/plasma concentration of 
teriflunomide is < 0.020 μg/mL (< 20 ng/mL) prior to Visit 2 (an accelerated 
elimination procedure for teriflunomide with cholestyramine is permitted during 
screening)

Natalizumab within 2 months prior to Visit 2 or any prior use of alemtuzumab

Fingolimod within 90 days prior to Visit 2

Daclizumab within 6 months prior to Visit 2

B-cell targeted therapies for the treatment of MS (e.g., ocrelizumab, rituximab) within 
12 months of screening; greater than 12 months of screening is permissible with 
evidence that the CD19 cells have returned to within normal range (per local 
laboratory reference range)

Eligibility related to prior treatment with an investigational drug and/or a 
commercially available drug for the treatment of MS not listed above within the past 
24 months will be determined on a case-by-case basis by the Medical Monitor

Steroids, with the exception of topical or inhaled steroids, or intravenous (IV)
immunoglobulin within 30 days prior to Visit 2
15. Current or prior participation in a clinical trial within 3 months of screening.
16. Subject is pregnant or breastfeeding or plans to become pregnant or begin breastfeeding 
at any point during the study and for 30 days after any study treatment administration.
17. Is employed by Biogen, CRO, or study site (permanent, temporary contract worker, or 
designee responsible for the conduct of the study) or is immediate family of a Biogen, 
CRO, or study site employee. Immediate family is defined as a spouse, parent, sibling, or 
child, whether biological or legally adopted.
6.3.
Screening, Retesting, and Screen Failures
6.3.1.
Screening
Once informed consent is obtained, screening assessments can occur. At this time, a unique 
identification number is assigned that will be used on study-related documents pertaining to the 
subject. Any identification numbers that are assigned will not be reused even if the subject does 
not receive treatment or continue in the study. Study sites are required to document all screened 
subjects initially considered for inclusion in the study.
6.3.2.
Retesting
Not applicable.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
34
6.3.3.
Screen Failures
Not applicable.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
35
7.
STUDY TREATMENT
7.1.
Regimen
Study treatment includes ALKS 8700 231 mg administered as one capsule and ALKS 8700 462 
mg administered as two 231 mg capsules.
This study will enroll both De Novo and Rollover Subjects. Any subject not currently receiving 
ALKS 8700 or DMF will titrate from ALKS 8700 231 mg BID for the first week on treatment 
followed by 462 mg BID from Day 8 onwards. For those subjects already receiving ALKS 8700 
or DMF, the initial ALKS 8700 dose will be 462 mg BID starting from Day 1.
Capsules will be administered orally BID. Study staff will administer the first dose of 
ALKS 8700 at Visit 2 (Day 1). From that point on during the treatment period, the staff will 
dispense ALKS 8700 for subjects’ self-administration. Subjects will be instructed to take study 
treatment with or without food. However, subjects will be instructed to avoid taking study 
treatment with a high-fat, high-calorie meal. Detailed dosing instructions will be provided to the 
patients by the site personnel.
7.2.
Modification of Dose and/or Treatment Schedule
Starting on Day 8 of treatment, dose reduction to ALKS 8700 231 mg BID is permitted at the 
Investigator’s discretion for subjects who are unable to tolerate ALKS 8700 462 mg BID. Once a 
subject has stabilized after dose reduction, attempts should again be made to achieve and 
maintain the target maintenance dose of ALKS 8700 462 mg BID. If a subject remains unable to 
tolerate ALKS 8700 462 mg BID after 1 month on treatment (i.e., by Visit 4), further dose 
reduction will not be permitted, and the subject will be discontinued from the study.
In the event of a suspected relapse (new symptoms or worsening symptoms), subjects will be 
asked to call the treating neurologist within 48 to 72 hours of the onset of the symptoms to 
determine the necessity of an Unscheduled Relapse Visit. An Unscheduled Relapse Visit will be 
conducted as described in Section 5.4. Further instruction is also provided in Section 7.2.2.
Should progressive multifocal leukoencephalopathy (PML) be suspected by the treating 
neurologist based on symptoms or signs during the relapse visit, study treatment will be withheld 
and an appropriate diagnostic work-up should be performed as soon as possible (within 14 days 
of the relapse visit). If PML is excluded based on the diagnostic work-up, the subject may 
resume taking study treatment if approved by the Medical Monitor. If the diagnostic work-up 
exceeds 14 days, the subject will be discontinued from the study. Should a diagnosis of PML be 
confirmed, the subject will be discontinued from the study and provided with appropriate 
medical care.
If serious infection occurs, study treatment should be withheld until it has resolved.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
36
Study treatment must also be temporarily withheld if any of the following laboratory parameters 
meet the following threshold limits:

AST or ALT > 3 × ULN; confirmed by repeat testing as soon as possible. If the value 
remains > 3 × ULN for ≥4 weeks after discontinuation of study treatment, the subject
must permanently discontinue study treatment.

Lymphocyte count < 0.5 × 109/L; confirmed by repeat testing as soon as possible. If 
the value remains < 0.5 × 109/L for ≥4 weeks after discontinuation of study 
treatment, the subject must permanently discontinue study treatment. (Subjects who 
permanently discontinue the study with a last measured lymphocyte count 
< 0.8 × 103/µL will require additional follow-up to monitor their lymphocyte counts.)

eGFR < 60 mL/min/1.73 m2; confirmed by repeat testing as soon as possible. If the 
eGFR remains < 60 mL/min/1.73 m2 for ≥4 weeks after discontinuation of study 
treatment, the subject must permanently discontinue study treatment.

Urine albumin to urine creatinine ratio > 200 mg/g; confirmed by repeat testing as 
soon as possible. If the urine albumin to urine creatinine ratio remains > 200 mg/g for 
≥4 weeks after discontinuation of study treatment, the subject must permanently 
discontinue study treatment.
Resuming study treatment after it has been withheld is to be considered on a case by case basis 
and must be discussed with the Medical Monitor.
The study may be stopped at any time or study sites may be closed at the Sponsor’s discretion.
7.2.1.
Rescue
Subjects will be eligible to remain on assigned study treatment for 96 weeks, even if they 
experience a relapse (see Section 7.2.2). In the event of a confirmed acute event (relapse), the 
treating neurologist may opt to prescribe 1000 mg of oral or IV methylprednisolone treatment 
(administered once daily or in divided doses) for 3-5 days with no taper. Treatment with oral or 
IV methylprednisolone will not affect the subject’s eligibility to continue in the study. The 
subject will continue on study treatment while being treated with methylprednisolone. Subjects 
may also refuse relapse treatment. Any deviations from this recommended treatment must first 
be discussed with the Medical Monitor.
7.2.2.
Relapse
Efficacy analyses related to MS relapse include only events of protocol-defined relapse. 
Protocol-defined relapse consists of the following:

New or recurrent neurologic symptoms, not associated with fever or infection, lasting 
for at least 24 hours, accompanied by one or more of the following:


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
37

New objective neurological findings upon examination by the treating neurologist 
that are functionally consistent with findings on the EDSS (performed within 
7 days of onset of symptoms) with an increase over the prior visit of ≥0.5 for the 
total score,

An increase of ≥2 in 1 functional system (FS), except bladder/cognitive changes, 
and/or,

An increase of ≥1 in 2 FS, except bladder/cognitive changes.
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse, and should not be treated with corticosteroids. New 
or recurrent neurologic symptoms that occur less than 30 days following the onset of a protocol 
defined relapse should be considered part of the same relapse and would not be treated with oral 
or IV methylprednisolone within the protocol.

Subjects who experience new neurologic symptoms must contact the treating nurse or 
neurologist within 48-72 hours of the onset of symptoms to determine the necessity of 
an Unscheduled Relapse Visit (see Section 5.4).

If required, the subject will then be evaluated in person by the neurologist as early as 
possible but within 7 days of the onset of the potential relapse.

The neurologist is to perform a relapse assessment and obtain an EDSS score. New 
objective findings on neurological examination performed by the neurologist in 
conjunction with the EDSS changes described above will confirm whether the 
suspected protocol-defined relapse has occurred.

Treatment of the acute event may then proceed at the discretion of the neurologist
(according to the methylprednisolone regimen described in Section 7.2.1) only after 
the neurologist has completed his/her examination. Treatment of an acute event of 
relapse with oral or IV methylprednisolone will not affect the subject’s eligibility to 
continue in the study.

Subjects must provide written confirmation of their willingness to continue 
participation in the study upon any determined event of MS relapse as described in
Section 13.5.
7.3.
Study Treatment Management
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice (GMP).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff. Study 
treatment is to be dispensed only to subjects enrolled in this study. Once study treatment is 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
38
prepared for a subject, it can be administered only to that subject. Study treatment is for one-time 
use only; do not use any study treatment remaining in the vial for another subject.
7.3.1.
ALKS 8700
ALKS 8700 DR capsules consist of enteric-coated, pH sensitive, DR minitablets contained 
within a hydroxypropyl methylcellulose capsule for oral administration.
The doses of ALKS 8700 DR to be used in this study are 231 mg (administered as one capsule) 
and 462 mg (administered as two 231 mg capsules). Capsules will be administered orally, BID.
7.3.1.1.
Packaging and Labeling
ALKS 8700 DR capsules are supplied in both 20-count, 100 cc, induction sealed, high density 
polyethylene (HDPE) bottle and 64 count, 150 cc, induction sealed, HDPE bottle configuration.
Labeling will meet all applicable local and regulatory requirements.
7.3.1.2.
Storage
All study materials are to be stored at room temperature not to exceed 25°C in a secure location.
7.3.1.3.
Handling and Disposal
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. Packages may be destroyed on site according to Good Clinical Practice (GCP) and 
site practice. Alternatively, the Sponsor may arrange for destruction with a third party vendor 
operating in accordance with GCP and/or GMP, as applicable.
7.3.1.4.
Accountability
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed, amount returned by the subject, and accounts of any study treatment accidentally or 
deliberately destroyed or lost. 
Unless otherwise notified, all packaging both used and unused, must be saved for study treatment 
accountability. By the end of the study, reconciliation must be made between the amount of
ALKS 8700 supplied, dispensed, and subsequently destroyed, lost, or returned to the Sponsor. A 
written explanation must be provided for any discrepancies.
7.4.
Blinding Procedures
Not applicable. The study is open-label.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
39
7.5.
Precautions
In the event of a confirmed acute event (relapse), the treating neurologist may opt to prescribe 
1000 mg of oral or IV methylprednisolone treatment (administered once daily or in divided 
doses) for 3 to 5 days with no taper. Treatment with oral or IV methylprednisolone will not affect 
the subject’s eligibility to continue in the study. The subject will continue on study treatment 
while being treated with methylprednisolone. Subjects may also refuse relapse treatment. Any 
deviations from this recommended treatment must first be discussed with the Medical Monitor.
7.6.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.
According to the schedule in Table 1, at each specified dispensing visit, subjects will receive a 
supply of ALKS 8700 to last until the following visit. Subjects will be instructed to bring any 
unused drug and the bottle(s) with them to each subsequent visit. Drug adherence will be 
reviewed with subjects at each visit.
7.7.
Concomitant Therapy and Procedures
7.7.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the time the subject is 
enrolled in the study and until the completion of the safety follow-up visit (Visit 16).
Subjects should be instructed to contact their Investigators before taking any new medications, 
including nonprescription drugs and herbal preparations.
7.7.1.1.
Allowed Concomitant Therapy
At screening all De Novo Subjects will be asked about the medications they have taken in the 
last 30 days. For a potential subject to qualify for the study, those exclusions outlined in 
Section 7.7.1.2 must be ruled out. At each subsequent study visit, review of concomitant 
medications will be repeated for all subjects. Concomitant medications to be reviewed at each 
study visit include prescription and nonprescription medications, vitamins, and supplements.
The Investigator will record the following data on all medications used by the subjects: name, 
dose, regimen, route of administration, start and stop dates, and the indication for use.
7.7.1.2.
Disallowed Concomitant Therapy
Immunomodulatory treatments for RRMS (besides study treatment) are prohibited during 
treatment with study treatment unless approved by the Medical Monitor. Prohibited 
immunomodulatory therapies include, but are not restricted to the following:

Any alternative drug treatments directed toward the treatment of MS such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
40
not limited to: IFN-beta, IFN-alpha, glatiramer acetate, DMF, natalizumab, 
cyclophosphamide, methotrexate, azathioprine, teriflunomide, and fingolimod)

Of note, the timing of discontinuing IFN-beta, IFN-alpha, glatiramer acetate, or 
DMF prior to initiating treatment with study treatment (Visit 2) is at the 
Investigator’s discretion

The initiation of a DMT for the treatment of RRMS is permitted if initiated after 
the last dose of study treatment (it is also preferable that it be initiated at least 1 
day after Visit 15 and not on Visit 15)

Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications

Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, mitoxantrone, cyclosporine, IV immunoglobulin, 
plasmapheresis, or cytapheresis
The use of corticosteroids for the treatment of clinical relapses and steroids that are administered 
by nonsystemic routes (e.g., inhaled or topical) are permitted. 
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not prohibited but 
should be optimized as early as possible after screening in an attempt to maintain consistent 
treatment during the study.
Immunization using inactivated, killed, or viral particle vaccines (e.g., influenza vaccine) is 
permitted and can be administered according to Investigator judgment. Vaccines using live or 
attenuated viruses should not be administered unless approved by the Medical Monitor.
Subjects should be instructed not to start taking any new medications, including nonprescribed 
drugs, unless they have received permission from the Investigator.
See Section 7.7.1.1 for details regarding the concomitant medication review.
7.7.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and until the completion of the safety follow-up visit 
(Visit 16).
7.8.
Continuation of Treatment
No further provisions are made for access to the study treatment following trial completion.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
41
8.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
8.1.
Discontinuation of Study Treatment
A subject must permanently discontinue ALKS 8700 for any of the following reasons:

The subject becomes pregnant. Study treatment must be discontinued immediately. 
Report the pregnancy according to the instructions in Section 11.4.1.

The subject withdraws consent to continue study treatment. 

The subject experiences an AE that necessitates permanent discontinuation of study 
treatment.

At the discretion of the Investigator for medical reasons.
The primary reason for discontinuation of study treatment must be recorded in the subject’s 
eCRF.
Any subject who prematurely discontinues from either study treatment or the study will be asked 
to return to the clinic for an ET visit (Visit 15) as well as a safety follow-up visit 2 weeks later 
(Visit 16) for the required assessments. Please see Section 5.5 for the follow-up of subjects with 
lymphopenia.
8.2.
Lost to Follow-Up
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the study site for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the study.

In cases in which the subject is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the subject. These contact attempts should 
be documented in the subject’s medical record.

Should the subject continue to be unreachable, that subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
42
8.3.
Withdrawal of Subjects From the Study
A treatment completer will be a subject who completes the 96-week treatment period (i.e., 
through Visit 15). Subjects completing the follow-up visit will be categorized as completing the 
study.
A subject may be withdrawn from the study at any time if the subject, Investigator, or Sponsor 
determines that it is not in the best interest of the subject to continue participation. Reasons for 
discontinuation include:

AE

Lack of efficacy

Lost to follow-up

Withdrawal by subject

Protocol deviation (noncompliance with study treatment or study procedures)

Physician decision

Pregnancy

Study terminated by Sponsor

Other
If a subject withdraws from the study for any reason, any ongoing AEs will be followed until 
resolution, until deemed stable by the Investigator, or until the subject is deemed by the 
Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is necessary to 
monitor a subject beyond the safety follow-up visit, the follow-up period may be extended as 
necessary. In such instances, the Sponsor and the Investigator will agree to an acceptable 
follow-up schedule. If a subject withdraws from the study and has a last lymphocyte count which 
is < 0.8 × 103/µL, the subject will return to the clinic for additional lymphocyte count monitoring 
visits every 2 months starting from the safety follow-up for up to 6 months (i.e., a maximum of 
3 visits) or until the lymphocyte count reaches normal limits (≥0.91 × 103/µL), whichever occurs 
first.
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 
rights. Subjects discontinuing study treatment and withdrawing from the study are to be asked to 
return to the clinic for an ET visit. The ET visit should be scheduled as close as possible to the 
subject’s last dose and will mimic the assessments scheduled to be conducted at Visit 15.
Following the ET visit, subjects will be asked to participate in the safety follow-up period. If the 
subject fails or refuses to return to the study site, an attempt must be made to contact the subject


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
43
by telephone in order to assess as many safety and efficacy parameters as possible. All data 
collected over the telephone must be documented and kept in the subject’s record.
The Investigator must maintain a record of all subjects who fail to complete the study. The 
reason for study discontinuation will be documented and made on the appropriate eCRF. If a 
subject is lost to follow-up, a reasonable attempt to contact the subjects must be made and 
documented.
Subjects who withdraw from the study after receiving the first dose of study treatment may not
be replaced.






Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
46
9.1.2.2.
EuroQol Group Health Outcome Measure (5 level; EQ-5D-5L)
The EQ-5D-5L™is a trademark of the EuroQol Group© and is an instrument designed to assess 
decrements in health. The EQ-5D-5L includes a Visual Analog Scale (VAS) and a descriptive 
system that defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response categories 
corresponding to the level of severity (i.e., no problems, slight problems, moderate problems, 
severe problems, and unable to/extreme problems). Subjects will complete the questionnaire 
according to the schedule in Table 1. A sample of the EQ-5D-5L will be provided to study sites 
outside of this protocol.
9.1.3.
Timed 25-Foot Walk
The T25-FW [Kaufman 2000] is a reliable quantitative mobility and leg function performance 
test based on a timed 25-foot walk. The subject is directed to one end of a clearly marked 25-foot 
course and is instructed to walk 25 feet as quickly as possible, but safely. Subjects are allowed to 
use assistive devices (canes, crutches, walkers) as needed. The time is calculated from when the 
lead foot crosses the start point to when the subject has reached the 25-foot mark. The task is 
immediately administered again by having the subject walk back the same distance. The score 
for the T25-FW is the average of the 2 completed trials.
9.1.3.1.
Short Form 12 Health Survey
Quality of life will be assessed using the 12-item Short-Form health survey Version 2 (SF-12v2)
[Maruish 2012]. Subjects will complete the questionnaire according to the schedule in Table 1. A 
sample of the SF-12 will be provided to the study sites outside of this protocol.
9.1.3.2.
Columbia-Suicide Severity Rating Scale
The C-SSRS is a clinician-administered instrument that assesses suicidal ideation and behavior 
[Posner 2011]. The “Screening” version of the instrument will be administered to De Novo 
Subjects at the screening visit. The “Since Last Visit” version will be administered to all 
participating subjects at all other visits specified in Table 1. A sample of the C-SSRS will be 
provided to the study sites outside of this protocol.
9.2.
Pharmacokinetic Assessments
PK samples will be collected from a subset of de novo subjects (approximately 50) enrolled at 
selected sites. 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
47
The following parameters, but are not limited to, will be calculated to assess the PK of 
ALKS 8700:

Maximum observed concentration (Cmax)

Time to reach Cmax (Tmax)

AUClast
Concentrations of analytes considered appropriate for further evaluation (e.g., MMF, RDC-6567, 
and RDC-8439) will be quantified in plasma samples collected for PK evaluation. See 
Section 12.5 for further details.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
48
10.
SAFETY ASSESSMENTS
See Section 1.3 for the timing of all safety assessments.
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, subjects will be asked to return to the study 
site to have the evaluations repeated.
10.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of ALK 8700:

AEs and SAEs will be monitored continuously from the time a subject signs the ICF 
until the completion of the final study visit (Table 1) and additional follow-up, if 
required.

Medical history.

Physical examinations: A full physical examination and measurement of body height 
and weight will be performed at screening. For Rollover Subjects, height will be 
carried over from information recorded in the antecedent study in which they 
participated. All subjects will have brief, symptom-directed physical examinations 
and will be weighed at timepoints specified in Table 1.

Vital sign measurements (temperature, heart rate, systolic and diastolic blood 
pressure, and respiratory rate): Blood pressure, heart rate, and respiratory rate will be 
measured after the subject has been resting in a seated or supine position for at least 
5 minutes. Consistent measurements and procedures should be used for all 
assessments (Table 1).

12-Lead ECGs will be performed after the subject has rested quietly for at least 
5 minutes in the supine position. ECGs will be conducted using calibrated equipment 
and assessed by a qualified clinician (Table 1).

C-SSRS administered by the clinician: The “Screening” version of the instrument will 
be administered to De Novo subjects at the Screening Visit. The “Since Last Visit” 
version will be administered to all subjects at all other visits specified in Table 1.

Concomitant therapy and procedure recording.
10.2.
Laboratory Safety Assessments
Blood and urine samples for laboratory assessments will be collected at the timepoints specified 
in Table 1. Specific hematology, biochemistry, and urinalysis assessments to evaluate the safety 


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
49
profile of ALKS 8700 are listed in Table 3. Samples will be collected in accordance with the 
site’s usual procedures and analyzed by a central laboratory.
Samples will be analyzed using Good Laboratory Practice-validated assays. 
Table 3:
Clinical Laboratory Assessments
Hematology1
Biochemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell count
Total and differential (absolute) 
white blood cell count
Platelets
Sodium
Potassium
Chloride
Bicarbonate
Glucose
Thyroid-stimulating hormone 
(TSH)2
Calcium
Uric Acid
Creatinine
Total protein
Blood urea nitrogen
Albumin
Total bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase 
(AST)
Lactic dehydrogenase (LDH)
Alkaline phosphatase
Creatine phosphokinase
Lipid profile: blood cholesterol, 
high-density lipoprotein, 
low density lipoprotein, and 
triglycerides
Color
pH
Specific gravity
Ketones
Protein
Glucose
Bilirubin
Nitrite
Urobilinogen
Occult blood
Microscopic examination of 
sediment only if urinalysis 
dipstick results are abnormal
Urine albumin
Urine beta-2-microglobulin
Urine creatinine
1 Additional hematology assessments will be collected for subjects requiring follow-up for lymphopenia at the time 
of study completion or early termination.
2 To be assessed at screening only.
10.2.1.
Pregnancy Testing
A urine pregnancy test will be administered to all women regardless of childbearing potential at 
the timepoints specified in Table 1. Results must be negative for initial study eligibility and
continued participation.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
50
10.2.2.
Serology Testing
A blood sample for a serology panel testing for hepatitis B surface antigen, hepatitis C antibody, 
and HIV antibody will be performed at screening only (Table 1).


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
51
11.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the subject. If necessary, appropriate 
medical intervention should be provided.
At the signing of the ICF, each subject and/or his/her legally authorized representative and/or 
main caregiver must be given the names and telephone numbers of site staff for reporting SAEs, 
pregnancies, overdoses, and medical emergencies. Throughout the protocol, the Sponsor is 
named, but reporting may be done through a CRO.
11.1.
Definitions
11.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject (subject)
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
Determination of whether an abnormal assessment (e.g., laboratory value, vital sign, and ECG)
result meets the definition of an AE will be made by the Investigator. Abnormal results are not 
considered AEs unless one or more of the following criteria are met:

The result meets the criteria for an SAE.

The result requires the subject to receive specific corrective therapy.

The result is considered by the Investigator to be clinically significant.
11.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death.

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death.

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
52

Results in a congenital anomaly/birth defect.

Is a medically important event.
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above. (Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization.)
11.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The study site must document all the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to be in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to be in the study and the time of the 
procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
o
If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 11.1.2 is met.
11.2.
Safety Classifications
11.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 11.1.2.

The relationship of the event to study treatment as defined in Section 11.2.2.

The severity of the event as defined in Section 11.2.3.
11.2.2.
Relationship of Events to Study Treatment
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment.






Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
55
The Investigator will assess all AEs regarding any causal relationship to the study treatment (see
Section 11.2.2), the severity of the event, action taken, and subject outcome.
The criteria set out in Section 11.2.3 should be used to guide the assessment of severity.
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up.
For clinical study safety reporting purposes, the version of the Investigator’s Brochure at the 
time of the event occurrence will be used as the reference document to designate event 
expectedness.
Withdrawal from the study as a result of an AE and any therapeutic measures that are taken shall 
be at the discretion of the Investigator. If a subject withdraws from the study for any reason, any 
ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or until 
the subject is deemed by the Investigator to be lost to follow-up.
11.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and until the 
completion of the safety follow-up visit (Visit 16) is to be recorded on an SAE form, regardless 
of the severity of the event or its relationship to study treatment. SAEs must be reported to the 
Sponsor within 24 hours as described in Section 11.3.3. Follow-up information regarding an 
SAE also must be reported within 24 hours.
Subjects will be followed for all SAEs until the completion of the safety follow-up visit 
(Visit 16). Thereafter, the event should be reported to the Sponsor only if the Investigator
considers the SAE to be related to study treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
11.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the Sponsor within 24 hours of the site staff becoming aware of the SAE. It is the 
Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately.




Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
57
11.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol. Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed or emailed to the Sponsor within 24 hours of the site becoming 
aware of the overdose. An overdose must be reported to the Sponsor even if the overdose does 
not result in an AE. If an overdose results in an AE, the AE must be recorded. If an overdose 
results in an SAE, both the SAE and Overdose forms must be completed and faxed or emailed to 
the Sponsor. All study treatment-related dosing information must be recorded on the dosing 
eCRF.
11.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, site staff will apply appropriate medical 
intervention, according to current standards of care. The Investigator (or designee) should 
contact the study’s Medical Director. Refer to the Study Reference Manual’s Official Study 
Contact List for complete contact information.
11.5.
Contraception Requirements
All male and female subjects must agree to the use of 2 methods of contraception for the 
duration of the study and 30 days after the final dose of study treatment. This includes at least 1 
form of highly effective method of contraception and 1 acceptable method of contraception (and 
additional restrictions, if required, will be clarified in the locally approved ICF). Subjects who 
are abstinent are eligible, provided they agree to the use of 2 contraceptive methods (at least 
1 being a highly effective method) should they become sexually active.
Highly effective methods may include:

Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation (oral contraceptives 
must have been initiated at least 30 days prior to screening)

Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral contraceptives must have been initiated at least 
30 days prior to screening)

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomized partner (provided that partner is sole sexual partner of subject and 
partner has received medical assessment of surgical success)


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
58

Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire study period through at least 30 days after the final dose of study treatment)
Acceptable methods may include:

Double-barrier protection (e.g., male condom, female condom, cervical cap or 
contraceptive sponge with spermicide, or a diaphragm with spermicide)
Subjects who are surgically sterile are exempt from the requirement to use contraception. 
Women who have undergone a documented complete hysterectomy, bilateral tubal ligation, or 
bilateral salpingo-oophorectomy at least 6 months prior to screening are considered surgically 
sterile. Men who have undergone a vasectomy are considered surgically sterile as long as 
medical confirmation of azoospermia is provided. Women who are postmenopausal are also 
exempt from the requirement to use contraception. For the purpose of this study, postmenopausal 
is defined as the permanent cessation of menstruation for at least 12 months prior to screening in 
women who are 45 years of age or older.
If any female subjects become or is found to be pregnant while participating in the study, she 
will be discontinued from study treatment immediately. Pregnancies in female subjects and 
female partners of male subjects should be handled in the same manner. The Investigator must 
fill out a Pregnancy Report Form and submit the information to the Sponsor within 24 hours of 
awareness of the pregnancy, irrespective of whether an AE has occurred. The ET and safety 
follow-up visits will be scheduled.
The Investigator will follow the pregnancy until completion or until pregnancy termination and 
notify the outcome to the Sponsor. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE the Investigator should follow the procedure of reporting 
SAEs (see Section 11.3.3). Additional follow-up may be required.
Pregnancy reporting is described in Section 11.4.1.
11.6.
Safety Responsibilities
11.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the eCRF regardless of the severity 
or relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow up on the outcome of all pregnancies.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
59

Complete an SAE form for each SAE and fax or email it to the Sponsor within 
24 hours of the site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently. Follow-up information 
must be reported to the Sponsor within 24 hours of the site staff becoming aware of 
new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. Record AE follow-up information, including resolution, on the eCRF, as 
applicable.

Report SAEs to local ethics committees, as required by local law.
11.6.2.
The Sponsor
The Sponsor’s responsibilities include the following:

Before a site can enroll any subjects, the Clinical Monitor (or designee) is responsible 
for reviewing with site staff the definitions of AE and SAE, as well as the instructions 
for monitoring, recording, and reporting AEs and SAEs.

The Sponsor is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
60
12.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 4.
12.1.
General Considerations
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan.
In general, summary statistics (number of subjects, mean, standard deviation, median, minimum,
and maximum values for continuous variables, and number and percentage of subjects in each 
category for categorical variables) will be provided for all parameters. All statistical results will 
be presented based on observed values. All individual subject level data will be presented as data 
listings.
12.2.
Analysis Sets
12.2.1.
Safety Population
The safety population, defined as all enrolled subjects who receive at least 1 dose of ALKS 8700, 
will be used in the safety analyses.
12.2.2.
Efficacy Population
The exploratory efficacy endpoints to assess treatment effect over time will be analyzed using 
data from the full analysis set (FAS), defined as all subjects who receive at least 1 dose of 
ALKS 8700 and receive 1 postbaseline efficacy assessment.
12.3.
Demographics and Baseline Characteristics
For De Novo Subjects, baseline is defined as Visit 2. For Rollover Subjects, baseline is defined 
as the baseline visit in the antecedent study.
Summary statistics will be provided for all demographic variables and baseline characteristics. 
Medical history will be summarized for the safety population using the number of observations 
and percentage of subjects reporting each category.
12.4.
Methods of Analysis for Efficacy Endpoints
Efficacy analyses of treatment effect over time will be based on data from the FAS population.
All endpoints listed below will be summarized by study timepoint and by change from baseline 
using descriptive statistics as appropriate.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
61
Clinical endpoints

ARR

Proportion of subjects experiencing a relapse

EDSS score

T25-FW score

Proportion of subjects with No Evidence of Disease Activity (NEDA) at Week 96
Other endpoints

SF-12 (domain score)

EQ-5D-5L VAS scores
The ARR will be summarized as number of relapses per subject per year, in which subject study 
duration is calculated as the time from first dose to last dose of study medication +1. NEDA will 
indicate an absence of select clinical (MS relapse and disease progression) 
 
outcomes.
12.5.
Methods of Analysis for Pharmacokinetic Endpoints
PK analyses will be performed using the PK population. Individual plasma concentrations will 
be listed by actual sampling times and summarized by nominal sampling times using descriptive 
statistics. Plots of individual and mean concentrations over time will also be generated. PK 
parameters will be calculated using noncompartmental analysis. Parameters will be estimated 
using actual elapsed time from dosing and summarized using descriptive statistics. A subject
listing of individual PK parameters will be provided.
Additionally, PK concentration data obtained from this study will may be combined with data 
from other studies to develop a population PK model, which will be reported separately.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
62
12.6.
Methods of Analysis for Safety Endpoints
The safety analysis will be carried out using the safety population. Reported AE terms will be 
coded using the Medical Dictionary for Regulatory Activities.
Safety assessments will be summarized using descriptive statistics along with supportive listings. 
The number and percentage of TEAEs will be summarized by system organ class, and preferred 
terms within each system organ class. SAEs and AEs resulting in treatment discontinuation will 
be summarized.
Observed values and change from baseline in laboratory parameters, vital signs, ECG 
parameters, and scores on the C-SSRS will be summarized by study visit. The number and 
percentage of subjects who have met potentially clinically significant criteria at any postbaseline 
visit will be summarized.
Listings will be provided for all safety endpoints.
12.7.
Interim Analyses
Not applicable.
12.8.
Sample Size Considerations
No formal sample size calculation is performed for this study. A sample size of approximately 
1000 subjects will contribute to the long-term safety experience of ALKS 8700 in subjects with 
RRMS, taking into account International Council for Harmonisation (ICH) guidance on the 
extent of patient exposures required to assess clinical safety for a new drug.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
63
13.
ETHICAL AND REGULATORY REQUIREMENTS
The Sponsor, any contracted third party, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol and applicable ICH and GCP guidelines and conduct 
the study according to local regulations.
The Investigators are responsible for demonstrating timely oversight of all clinical trial data from 
their site, including data external to the electronic data capture system, such as laboratory, 
imaging, and electronic clinical outcomes assessment data. Investigators must approve all their 
data on completed eCRFs by signing electronically, at the subject, visit, or casebook level, at any 
time prior to an interim lock or database lock, as well as before any subsequent re-lock. The 
electronic data capture system does not prohibit Investigator approval or signing in any way.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. The Investigator
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
13.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
13.2.
Ethics Committee
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
the Sponsor. After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
The Sponsor must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study. Protocol 
amendments will be subject to the same requirements as the original protocol.
Initial ethics committee approval as well as all materials approved by the ethics committee for 
this study, including the subject consent form and recruitment materials, must be maintained by 
the Investigator and made available for inspection.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
64
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, where required, the study site must submit a 
close-out letter to the ethics committee and the Sponsor.
13.3.
Changes to Final Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject. In this case, the appropriate regulatory authorities will be notified subsequent 
to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 13.4).
13.4.
Informed Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, informed consent with the approved ICF must be obtained.
A copy of the signed and dated ICF and assent must be given to the subject and/or the subject’s 
legally authorized representative. The original signed and dated ICF will be retained with the 
study records. Local regulations must be complied with in respect to the final disposition of the 
original and copies of the signed and dated ICFs.
Confirmation of informed consent and assent must also be documented in the subject’s medical 
record.
When additional information that may affect subjects’ willingness to continue in the study 
becomes available, the Investigators will be notified in a timely manner, according to all local 
and applicable law. An updated ICF may be required.
13.5.
Confirmation of Willingness to Continue in the Study
Written documentation of a subject’s willingness to continue participation in the study will be 
required if one or more of the following occurs during the study:

MS relapse

Disability progression (based on EDSS)




Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
66
13.8.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or its partnering company) with the subject before the subject makes a decision to 
participate in the study.
13.9.
Study Report Signatory
The Sponsor will designate one or more of the participating Investigators as a signatory for the 
study report. This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by the Sponsor.
The Sponsor will follow all applicable local regulations pertaining to study report signatories.
13.10.
Registration of Study and Disclosure of Study Results
The Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.
The Sponsor also will notify, when required, the regulatory authorities and ethics committees 
about the completion or termination of this study and send a copy of the study synopsis in 
accordance with necessary timelines.
13.11.
Retention of Study Data
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s Clinical Study Agreement (CSA) and in accordance with ICH 
guidelines/local regulatory requirements as follows:
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by the terms of 
the CSA. It is the responsibility of the Sponsor to inform the Investigator/institution as to when 
these documents no longer need to be retained. Prior to proceeding with destruction of records, 
the Investigator must notify the Sponsor in writing and receive written authorization from the 
Sponsor to destroy study records. In addition, the Investigator must notify the Sponsor of any 
changes in the archival arrangements including but not limited to archival at an offsite facility or 
transfer of ownership if the Investigator leaves the site.
Subjects’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
67
14.
KEY ROLES AND STUDY GOVERNANCE COMMITTEES
14.1.
Vendors
Biogen will ensure oversight of any study-related duties and functions carried out on its behalf
and will specify in writing all duties and functions that are transferred.
14.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including but not limited to 
study initiation, management of SAE reports, monitoring, and data management.
Before subjects are screened at each study site, the CRO will review study responsibilities with 
the Investigators and other study site staff, as appropriate.
14.1.2.
Interactive Response Technology
IRT will be used in this study. Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
14.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on eCRFs by a web-based 
electronic data capture tool configured by 
and hosted by 
.
14.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by the Sponsor to analyze all samples listed in Table 3
collected for this study. PK samples will be analyzed at a laboratory selected by the Sponsor.
14.2.
Study Committees
Not applicable.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
68
15.
ADMINISTRATIVE PROCEDURES
15.1.
Study Site Initiation
The Investigator must not screen any subjects prior to the Sponsor completing a study initiation 
visit. This initiation visit with the Investigator and other site staff, as appropriate, will include a 
detailed review of the protocol, study procedures, and study responsibilities.
15.2.
Quality Control and Quality Assurance
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness, and compliance, the study site should have processes in place for 
data review and quality control.
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. The Investigator is responsible for endorsing 
all eCRF data prior to any interim or final database lock.
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections. The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
15.3.
Case Report Forms
This study will use eCRFs. All eCRF data must be based on source documents or approved to be 
the original data (i.e., data directly reported on the eCRF). All eCRFs will be completed by the 
clinic staff prior to review by the Biogen monitor or designated representative.
The Biogen monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF.
15.4.
Confidentiality of Data
By signing this protocol, the Investigator affirms to Biogen that he or she will maintain in 
confidence information furnished to him or her by Biogen and will divulge such information to 
his or her respective IRB or ethics committee under an appropriate understanding of 
confidentiality with such board. All data will be considered the sole property of Biogen. Please 
refer to the CSA for details.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
69
15.5.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail). The 
Investigator should maintain a record of the location(s) of essential documents.
The Biogen monitor or designee will visit the study site at regular intervals during the study and 
after the study has completed, as appropriate. A clinical site monitoring plan will detail who 
performs the monitoring, how often, and the extent of review. It also will provide the monitoring 
strategy, with emphasis on subject safety, data integrity, and critical data and processes.
During these visits, eCRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved. Documentation of 
results will be provided to the Sponsor in a timely fashion to allow follow-up and verification of 
compliance with the monitoring plan. Remote evaluation of data (centralized monitoring) may 
also be conducted and reported as defined in the monitoring plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.
15.6.
Audits and Inspections
By signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of Biogen, a regulatory 
authority, and/or an IRB/ethics committee may visit the site to perform audits or inspections, 
including the drug storage area, study treatment stocks, drug accountability records, subject
charts and source documents, and other records relative to study conduct. The purpose of a 
Biogen audit or inspection is to systematically and independently examine all study-related 
activities and documents (e.g., laboratory reports, x-rays, workbooks, subjects’ medical records) 
to determine whether these activities were conducted, and data recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the ICH, and any applicable 
regulatory requirements.
The Investigator should contact Biogen immediately if contacted by a regulatory agency 
regarding an inspection.
15.7.
Study Funding
Biogen is the Sponsor of the study and is funding the study. All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
70
15.8.
Publications
Details are included in the clinical trial agreement for this study.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
71
16.
REFERENCES
Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting 
multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 
2014;13(7):657-65. Epub 2014 Apr 30.
Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing 
therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-27.
Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon β-1a at 5-year 
follow-up of CAMMS223 clinical trial. Neurology. 2012;78(14):1069-78.
Costello K, Halper J, Kalb R, et al. The use of disease-modifying therapies in multiple sclerosis: 
principles and current evidence. Multiple Sclerosis Coalition; 2014.
FDA. Tecfidera - Summary Review. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000SumR.pdf.
Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or 
glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-97. Erratum in: N Engl J 
Med. 2012 Oct 25;367(17):1673.
Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for 
relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-107.
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease 
progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group 
(MSCRG). Ann Neurol. 1996;39(3):285-94.
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76.
Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with 
relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-
controlled phase IIb study. Lancet. 2008;372(9648):1463-72.
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Epub 2010 Jan 20.
Kaufman M, Moyer D, Norton J. The significant change for the Timed 25-foot Walk in the 
multiple sclerosis functional composite. Mult Scler. 2000;6(4):286-90. Epub 2000/08/30.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
72
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. Epub 1983 Nov 01.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150(9):604-12.
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an 
international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical 
Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-11.
Maruish MEE. User's manual for the SF-12v2 Health Survey. 3rd ed. Lincoln, RI: 
QualityMetric, Incorporated; 2012.
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303.
Phillips JT, Fox RJ. BG-12 in multiple sclerosis. Semin Neurol. 2013;33(1):56-65. Epub 
2013/05/25.
Phillips JT, Hutchinson M, Fox R, et al. Managing flushing and gastrointestinal events 
associated with delayed-release dimethyl fumarate: Experiences of an international panel. 
Multiple Sclerosis and Related Disorders. 2014.
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77.
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a 
in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-504.
Ropper AH. The "poison chair" treatment for multiple sclerosis. N Engl J Med. 
2012;367(12):1149-50.
Tecfidera® Summary of Product Characteristics, Nov 2017, Biogen Idec Inc.
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
73
Tremlett H, Zhao Y, Rieckmann P, et al. New perspectives in the natural history of multiple 
sclerosis. Neurology. 2010;74(24):2004-15.
Utz KS, Hoog J, Wentrup A, et al. Patient preferences for disease-modifying drugs in multiple 
sclerosis therapy: a choice-based conjoint analysis. Ther Adv Neurol Disord. 2014;7(6):263-75.
Waldman AT, Gorman MP, Rensel MR, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82.


Protocol ALK8700-A301, Version 5.0
Long-Term Safety and Tolerability of ALKS 8700 in Adults With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
74
17.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Phase 3 Open Label Study to Evaluate the Long-Term 
Safety and Tolerability of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis”
and agree to conduct the study according to the protocol and the applicable ICH guidelines and 
GCP regulations, and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


 
SUMMARY OF CHANGES  
Protocol Amendment 3.0 
 
 
Study number: ALKS 8700 A301 
 
Study title: A Phase 3 Open Label Study to Evaluate the Long-term Safety and 
Tolerability of ALKS 8700 in Adults with Relapsing Remitting Multiple Sclerosis 
 
Amendment date: 26 Jun 2019 
 
 
 
 
 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451 
Telephone: +1 (781) 609-6000 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential 
information, which is the property of the Sponsor. No person is authorized to make it public 
without the written permission of the Sponsor. These restrictions or disclosures will apply 
equally to all future information supplied to you that is indicated as privileged or confidential. 
ALK8700-A301 | Protocol Amend_V3.0_Summary of Change_21Jun2019 | VV-TMF-452303 | 1.0
Downloaded by Jithu Roy on 31 Oct 2019


 
 
Alkermes, Inc. 
Protocol ALK8700-A301 (Amendment 3.0) 
CONFIDENTIAL 
 
Page 2 of 5 
 
1. 
SUMMARY AND RATIONALE OF AMENDMENT 
Language in the protocol is being updated to reflect what is being practiced in the conduct of the 
study, namely that all events of multiple sclerosis (MS) relapse are being recorded as adverse 
events (AEs). In addition, sample size numbers were made more flexible, sections were revised 
to allow better clarity of procedures, and last subject last visit date was revised to allow for 
additional rollover subjects from Study A302. The major changes are listed below: 
• Clarify language around MS relapse collection as an adverse event 
• Update sample size to approximately 1000 
• Clarify timing of disease-modifying therapy (DMT) allowance 
• Clarification to the lymphocyte monitoring section 
• Clarification of serious adverse event reporting 
• Update to Schedule of Assessments table 
 
 
• Update de novo pharmacokinetic (PK) sample size 
• Update estimated last subject last visit (LSLV) 
• Administrative changes to contact information, and clarifying language was also 
provided. 
Additional changes such as updates to the title page, the Table of Contents, List of 
Abbreviations, and headers/footers (to reflect the new document version and date) have been 
made. Corrections for grammatical and other minor consistency errors have also been made 
throughout the protocol. These changes are not described here. 
ALK8700-A301 | Protocol Amend_V3.0_Summary of Change_21Jun2019 | VV-TMF-452303 | 1.0
Downloaded by Jithu Roy on 31 Oct 2019


 
 
Alkermes, Inc. 
Protocol ALK8700-A301 (Amendment 3.0) 
CONFIDENTIAL 
 
Page 3 of 5 
 
2. 
OVERVIEW OF CHANGES 
Content Changes  
1. Change: Clarify language around MS relapse collection as an adverse event 
Description of Change:  
In Section 8.2.2, bullet 1 was clarified to indicate that any MS relapse as determined by the 
investigator required written documentation of a subject’s willingness to continue in the 
study. 
In Section 8.2.12, language was added to clarify that efficacy analyses related to MS relapse 
include only events of protocol-defined relapse. In addition, language was added to clarify 
the bulleted list of neurological symptoms. 
In Section 11.1, the following language was added to clarify the collection of AEs and SAEs 
for disability progression based on the EDSS and MS relapse: Disability progression based on 
the EDSS is captured in the MS efficacy assessments and is not to be recorded as an AE 
unless the event meets the definition of an SAE (see Section 11.2) Events of MS relapse, 
whether protocol-defined or not, are to be recorded as AEs (or as SAEs [see Section 
11.2]). and/or relapse of MS will be captured in the MS efficacy assessments, and not recorded 
as an AE, unless they meet the definition for an SAE see Section 11.2. 
Rationale for Change:  Language in the protocol is being updated to reflect what is being 
practiced in the conduct of the study, namely that all events of MS relapse are being recorded 
as AEs.   
Sections Impacted: Section 8.2.2 (Bullet 1); Section 8.2.12 (first sentence and last 3 bullets); 
Section 11.1 
2. Change: Update sample size to approximately 1000 
Description of Change: Expected sample size for the study was increased from 800 to 
approximately 1000. 
Rationale for Change: With increased sample size and enrollment for the ALK8700-A302 
study, more subjects have consequently rolled over to the ALK8700-A301 study. Accordingly, 
the estimated sample size for the ALK8700-A301 study is being updated. In addition, the 
rollover rate from study A302 was higher than expected (90%) which increased the sample 
size for A301.  
Sections Impacted: Section 2: Synopsis (Number of Subjects Planned, Sample Size 
Considerations); Section 14.1 
ALK8700-A301 | Protocol Amend_V3.0_Summary of Change_21Jun2019 | VV-TMF-452303 | 1.0
Downloaded by Jithu Roy on 31 Oct 2019




 
 
Alkermes, Inc. 
Protocol ALK8700-A301 (Amendment 3.0) 
CONFIDENTIAL 
 
Page 5 of 5 
 
Content Changes  
7. Change: Update de novo PK sample size 
Description of Change: The subset of de novo subjects that will contribute to the plasma 
samples for concentrations of ALKS 8700 analytes (eg, MMF, RDC-6567, and RDC-8439) 
considered appropriate for further evaluation was updated from n=50 to approximately 50. 
Rationale for Change: The language was updated to provide appropriate flexibility for the 
sample number. 
Sections Impacted: Section 2: Synopsis (Pharmacokinetics) and Section 13. 
8. Change: Update estimated LSLV 
Description of Change: The estimated date of last subject’s last visit was updated from Q4 
2019 to Q3 2021. 
Rationale for Change: A302 German subjects will be rolled over into A301 (2 year) study 
which will push back the A301 LPLV in Q4 2020 or somewhere in 2021. Q3 2021 was agreed 
by team. 
Sections Impacted: Section 2: Synopsis (Study Period) 
 
Administrative/Editorial Changes (Deleted text is indicated as strikethrough and new text 
as bold face) 
1. Update 
 medical director 
 was updated to 
, MD, FAASM. Address and phone 
numbers were also updated. 
2. Addition of Alkermes Global Safety Officer 
 was added to Table 1 Study Contact Information as the Alkermes Global 
Safety Officer  
3. Update 
 to 
 
All instances of 
 in the protocol were updated to 
. This included 
Section 8.2.3.1, Table 1 Study Contact Information, Section 11.5. 
4. Updated language for version of IB to be used as reference for “expectedness” of AE.  
In Section 11.4, the following sentence was updated: For clinical safety reporting purposes, the 
most recent version of the Investigator’s Brochure at the time of the event occurrence will 
be used as the reference document to designate event expectedness. 
 
ALK8700-A301 | Protocol Amend_V3.0_Summary of Change_21Jun2019 | VV-TMF-452303 | 1.0
Downloaded by Jithu Roy on 31 Oct 2019

































SAP_001.pdf: 
1 
STATISTICAL ANALYSIS PLAN
ALK8700-A301/NCT02634307
Study Title: 
A Phase 3 Open Label Study to Evaluate the Long-term Safety and 
Tolerability of ALKS 8700 in Adults with Relapsing Remitting Multiple 
Sclerosis 
Document Status: 
Version 2.0 
Document Date: 
15 April 2021 
Based on: 
Biogen ALK8700-A301 study protocol amendment Version 5.0 (dated 
27 September 2019) 
Sponsor: 
Biogen MA, Inc. 
225 Binney Street 
Cambridge, MA 02142 
USA 
CONFIDENTIAL 
The information contained in this Statistical Analysis Plan (SAP) is confidential and may not be 
reproduced or otherwise disseminated without the approval of Biogen, Inc. 


Product: ALKS 8700 (BIIB098)/DRF 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
2 
APPROVAL 
This document has been reviewed and approved by: 
, Ph.D. 
SMT Statistician 
Signature 
Date 
, Ph.D. 
 
Signature 
Date 
, MD 
 
 
Signature 
Date 
, MS 
SMT Medical Director 
Signature 
Date 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
3 
VERSION HISTORY 
SAP Version 
Date 
Primary Reasons for 
Amendment 
Version 1.0 
14 Dec 2016 
Final 
Version 2.0 
15 Apr 2021 
SAP amendment for 
COVID-19 impact etc. 
 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
4 
TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Study Objectives ...........................................................................................................8 
1.2. 
Summary of the Study Design ......................................................................................8 
2. 
SAMPLE SIZE CONSIDERATION ..........................................................................13 
3. 
DATA ANALYSES ...................................................................................................14 
3.1. 
Study Population .........................................................................................................14 
3.1.1. 
Definitions of Analysis Populations (Analysis Sets) ..................................................14 
3.1.1.1. 
Safety Population ........................................................................................................14 
3.1.1.2. 
Efficacy Population ....................................................................................................14 
3.1.1.3. 
Pharmacokinetic Population .......................................................................................14 
3.1.1.4. 
Subgroup Variables ....................................................................................................14 
3.1.2. 
Disposition ..................................................................................................................14 
3.1.3. 
Protocol Deviations ....................................................................................................15 
3.2. 
Demographics and Baseline Characteristics ...............................................................15 
3.3. 
Prior and Concomitant Medications ...........................................................................16 
3.4. 
Treatment Adherence Rate and Extent of Exposure ...................................................16 
3.5. 
Efficacy Analyses .......................................................................................................16 
3.5.1. 
General Considerations ...............................................................................................16 
 
16 
3.5.3. 
Clinical endpoints .......................................................................................................17 
3.5.4. 
Patient Reported Outcomes ........................................................................................19 
3.6. 
Safety Analyses ..........................................................................................................20 
3.6.1. 
General Considerations ...............................................................................................20 
3.6.2. 
Adverse Events ...........................................................................................................20 
3.6.3. 
Deaths, Serious and Other Significant Adverse Events ..............................................22 
3.6.4. 
Adverse Events of Special Interest .............................................................................22 
3.6.5. 
Clinical Laboratory Parameters ..................................................................................22 
3.6.6. 
Vital Signs and ECG Parameters ................................................................................25 
3.6.6.1. 
Vital Signs ..................................................................................................................25 
3.6.6.2. 
Electrocardiograms .....................................................................................................25 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
5 
3.6.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................26 
3.7. 
Pharmacokinetic Data Analysis ..................................................................................26 
3.8. 
Statistical Considerations for COVID-19 ...................................................................27 
4. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE 
(DMC) .........................................................................................................................28 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................29 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF DATA ...................30 
6.1. 
Analysis Visit Windows .............................................................................................30 
6.2. 
Handling Of Concentration Data Below The Lower Limit Of Quantification ...........30 
6.3. 
Handling of Partial Dates of Concomitant Medication ..............................................31 
6.4. 
Safety Data Handling ..................................................................................................31 
7. 
GENERAL STATISTICAL METHODOLOGY .......................................................32 
7.1. 
Reporting Precision ....................................................................................................32 
8. 
PROGRAMMING SPECIFICATIONS .....................................................................33 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) ............................................34 
10. 
REFERENCES ...........................................................................................................35 
 
LIST OF TABLES 
Table 1: 
Schedule of Visits and Assessments ...........................................................................10 
Table 2: 
Criteria for Potentially Clinically Significant (PCS) Laboratory Parameters ............23 
Table 3: 
Criteria for Potentially Clinically Significant (PCS) Vital Signs ...............................25 
Table 4: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF Values ..........26 
Table 5: 
C-SSRS Categories for Analysis ................................................................................26 
Table 6: 
Degree of Precision .....................................................................................................32 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................9 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
6 
ABBREVIATIONS 
The following abbreviations are used in the statistical analysis plan. 
Abbreviation or Term 
Explanation or Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARR 
Annualized Relapse Rate 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical [Classification System] 
AUClast 
Area Under the plasma Concentration versus time curve 
calculated using the trapezoidal method from time zero to the last 
observed concentration above the lower limit of quantification. 
Cmax 
Maximum Observed Concentration 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMF 
Dimethyl Fumarate 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
EQ-5D-5L 
Euroqol Group Health Outcome Measure (5-Level) 
ET 
Early Termination 
FAS 
Full Analysis Set 
FS 
Functional System 
GCP 
Good Clinical Practice 
GdE 
Gadolinium-Enhancing 
GI 
Gastrointestinal 
LDH 
Lactic Dehydrogenase 
MedDRA 
Medical Dictionary For Regulatory Activities 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
7 
Abbreviation or Term 
Explanation or Definition 
MMF 
Monomethyl Fumarate 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
NEDA 
No Evidence of Disease Activity 
PCS 
Potentially Clinically Significant 
PDEAE 
Post-discontinuation Adverse Event 
PK 
Pharmacokinetic 
QoL 
Quality of Life 
QTcB 
QT Interval Corrected Using Bazett’s Formula 
QTcF 
QT Interval Corrected Using Fridericia’s Formula 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
SAE 
Serious Adverse Event 
SF-12 
Short Form 12 Health Survey 
SF-12 MCS 
Short Form 12 Health Survey Mental Component Summary 
SF-12 PCS 
Short Form 12 Health Survey Physical Component Summary 
T25-FW 
Timed 25-Foot Walk 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time to Reach Cmax 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 
 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
8 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data presentation to be 
used for analyzing and reporting safety as well as efficacy data for study ALK8700-A301. This 
document has been prepared based on Biogen Inc. ALK8700-A301 study protocol amendment 
Version 5.0 (dated 27 September 2019) [1]. 
1.1. 
Study Objectives 
The objectives of this study are: 1) to evaluate the long-term safety and tolerability of 
ALKS 8700 (also known as BIIB098 and diroximel fumarate) for up to 96 weeks of treatment in 
adult subjects with RRMS and 2) to evaluate treatment effect over time in adult subjects with 
RRMS treated with ALKS 8700. 
1.2. 
Summary of the Study Design 
This is a multicenter open label study to evaluate the long-term safety and tolerability of 
ALKS 8700 administered up to 96 weeks for the treatment of RRMS. The target population for 
this study will be adults, aged 18 to 65 years, diagnosed with RRMS. 
Subjects will enter into the study in one of two ways:  
1. De Novo Subjects: Those who have not participated in any prior eligible study of 
ALKS 8700 
2. Rollover Subjects: Those who have completed the treatment period for any prior eligible 
study of ALKS 8700 
De Novo Subjects will be initially evaluated for eligibility at screening (Visit 1) that may last up 
to 21 days prior to Visit 2. For Rollover Subjects, Visit 2 will be the first visit of the study and 
there will not be a separate screening visit. For these subjects, Visit 2 of this study will occur at 
the time of or within 7 days of the subject’s end of treatment visit in the antecedent study. 
Completed assessments taken at the end of treatment visit of the antecedent study will be carried 
forward and do not need to be repeated at Visit 2 of this study unless otherwise specified in the 
schedule of assessments Table 1. At Visit 2, all eligible, consenting subjects will begin open 
label treatment. Any subject not currently receiving ALKS 8700 or DMF will initiate treatment 
with ALKS 8700 231 mg twice daily on Day 1 through Day 7 followed by 462 mg twice daily 
from Day 8 onwards. For those subjects already receiving ALKS 8700 or DMF prior to Day 1, 
the initial ALKS 8700 dose will be 462 mg twice daily starting from Day 1. 
Study drug includes ALKS 8700 231 mg administered as one capsule and ALKS 8700 462 mg 
administered as two, 231 mg capsules. Capsules will be administered orally, twice per day. Study 
staff will administer the first dose of ALKS 8700 at Visit 2 (Day 1). From that point on during 
the treatment period, the staff will dispense ALKS 8700 for subjects’ self-administration. 
Subjects will be instructed to take study drug with or without food. 
Starting on Day 8 of treatment, dose reduction to ALKS 8700 231 mg twice daily is permitted at 
the investigator’s discretion for subjects who are unable to tolerate ALKS 8700 462 mg twice 
daily. Once a subject has stabilized after dose reduction, attempts should again be made to 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
9 
achieve and maintain the target maintenance dose of ALKS 8700 462 mg twice daily. If a subject 
remains unable to tolerate ALKS 8700 462 mg twice daily after 1 month on treatment (ie, by 
Visit 4), further dose reduction will not be permitted and the subject will be discontinued from 
the study. 
The study may be stopped at any time or study sites may be closed at the sponsor’s discretion. 
During the 96-week treatment period (Visits 2-15), subjects will return to the clinic for periodic 
scheduled visits for the assessment of safety, tolerability, pharmacokinetics (in a subset of 
De Novo subjects in selected sites), and clinical status. Two safety and tolerability assessments 
by phone will be scheduled (one between Visits 2 and 3 and one between Visits 3 and 4). See 
Figure 1 or a study schematic. 
Subjects will return to the clinic for a safety follow up visit (Visit 16) 2 weeks after the end of 
treatment visit (Visit 15). Any subject who prematurely discontinues from the study will be 
asked to return to the clinic for an early termination (ET) visit (Visit 15) as well as a safety 
follow up visit 2 weeks later (Visit 16). 
Subjects who complete the study or who terminate the study early and have a last measured 
lymphocyte count < 0.8 × 103/μL will return to the clinic for additional lymphocyte count 
monitoring visits every 2 months starting from Visit 16 for a period of 6 months (i.e., a 
maximum of 3 visits or until lymphocyte counts reach normal limits (≥ 0.91 × 103 /μL), 
whichever occurs first. 
Figure 1: 
Study Design Schematic 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
 
 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
10 
Table 1: 
Schedule of Visits and Assessments 
 
Screening 
96-Week Open-Label Treatment1 
Visit 
12 
23 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 /ET 
16 
Follow-
up 
Day 
-21 to -1 
1 
15 
(±3) 
29 
(±3) 
57 
(±5) 
85 
(±5) 
113 
(±5) 
141 
(±5) 
169 
(±5) 
253 
(±5) 
337 
(±5) 
421 
(±5) 
505 
(±5) 
589 
(±5) 
673 
(±5) 
687 (±5) 
Week 
-3 to -1 
1 
2 
4 
8 
12 
16 
20 
24 
36 
48 
60 
72 
84 
96 
98 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
Review 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam6 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X5 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serology Testing8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry, Urinalysis, 
& Hematology Samples9 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs10 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standard 12-Lead ECG 
X 
X5 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
Pharmacokinetic 
Sampling11 
 
X5 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Timed 25-Foot Walk 
X 
X5 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
 
 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
11 
 
Screening 
96-Week Open-Label Treatment1 
Visit 
12 
23 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 /ET 
16 
Follow-
up 
Day 
-21 to -1 
1 
15 
(±3) 
29 
(±3) 
57 
(±5) 
85 
(±5) 
113 
(±5) 
141 
(±5) 
169 
(±5) 
253 
(±5) 
337 
(±5) 
421 
(±5) 
505 
(±5) 
589 
(±5) 
673 
(±5) 
687 (±5) 
Week 
-3 to -1 
1 
2 
4 
8 
12 
16 
20 
24 
36 
48 
60 
72 
84 
96 
98 
EDSS 
X 
X5 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
SF-12 
 
X5 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5L 
 
X5 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
C-SSRS12 
X 
X3,4,5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Drug 
Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Emergency Treatment 
Card15 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EDSS=Expanded Disability Status Scale; EQ-5D-5L=EuroQol Group health 
outcome measure 5-level version; ET=early termination; 
; SF-12=12-item Short Form health survey 
Note: Two safety and tolerability assessments by phone will be conducted (one between Visits 2 and 3 and one between Visits 3 and 4) 
 
1 Unscheduled visit may occur at any time as per protocol requirements 
2 Only De Novo Subjects will participate in the screening visit 
3 For Rollover Subjects, identical assessments taken at the last treatment visit in the antecedent study do not need to be repeated at Visit 2 in the current study 
4 Eligible, consenting De Novo Subjects will give written consent at screening. Eligible, consenting Rollover Subjects will give written consent prior to 
participating in any study-specific procedures at Visit 2. Written confirmation of a subject’s willingness to continue in the trial will be required if one or more 
of the following occur during the study: MS relapse, disability progression, 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
 
 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
12 
5 To be conducted pre-dose at Visit 2 
6 Full physical exam at screening. Brief physical exam, symptom-directed, at all other visits 
7 For Rollover Subjects, height will be carried over from information recorded in the antecedent ALKS 8700 study in which they participated 
8 Serology testing includes hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody 
9 9Urinalysis includes urine dipstick, urine microscopy (as applicable), urine beta-2-microglobulin, urine albumin, and urine creatinine 
10 Vital sign measurements include temperature, respiratory rate, blood pressure, and heart rate. Blood pressure, respiratory rate, and heart rate will be measured 
after the subject has been in a seated or supine position for at least 5 minutes 
11 Pharmacokinetic samples will be collected in a subset of de novo subjects at selected sites. Samples will be collected pre-dose, and at 0.5, 1, 2, 3, 4, 6, and 8 
hours after the morning dose on Days 1 and 29. Additional PK samples will be collected prior to and approximately 2-3 hours following the morning or 
evening dose on Days 15 and 57. Specifics of study visits where PK samples will be collected and PK sampling procedures will be provided to the study sites 
outside of this protocol. 
 
 
 
14 Use "Screening" version at screening; use "Since Last Visit" version at all other scheduled timepoints 
15 At Visit 2, dispense Emergency Treatment Card to De Novo Subjects and confirm possession/redispense if necessary for Rollover Subjects. At all other visits, 
confirm subject's possession of card and redispense if necessary 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
13 
2. 
SAMPLE SIZE CONSIDERATION 
A sample size of approximately 1000 patients will contribute to the long-term safety experience 
of ALKS 8700 in subjects with RRMS, to provide sufficient patient exposure to meet the ICH 
guidance on the extent of patient exposures required to assess clinical safety for a new drug. 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
14 
3. 
DATA ANALYSES 
3.1. 
Study Population 
The study population, defined as all enrolled subjects who receive at least one dose of 
ALKS 8700, will be divided into three enrollment groups for summarizing safety and efficacy 
data: 
1. De Novo Subjects  
2. Rollover Subjects who were in ALKS8700 treatment group 
3. Rollover Subjects who were in DMF treatment group 
3.1.1. 
Definitions of Analysis Populations (Analysis Sets) 
3.1.1.1. 
Safety Population 
The safety analysis set, defined as all enrolled subjects who receive at least one dose of 
ALKS 8700, will be used in the safety analyses. 
3.1.1.2. 
Efficacy Population 
The efficacy endpoints to assess treatment effect over time will be analyzed using data from the 
Full Analysis Set (FAS), defined as all subjects who receive at least one dose of ALKS 8700 and 
have had at least one post-baseline efficacy assessment. 
3.1.1.3. 
Pharmacokinetic Population 
The PK analyses will use the PK analysis set, defined as all subject who receive at least one dose 
of study drug and have at least one measureable concentration of MMF. Pharmacokinetic 
samples will be collected in a subset of approximately fifty de novo subjects at selected sites. 
3.1.1.4. 
Subgroup Variables 
Renal impact will be defined by baseline GFR as: normal (≥ 90 mL/min/1.73m2), mild 
(60 ≤ - < 90 mL/min/1.73m2) and moderate – severe (< 60 mL/min/1.73m2). 
Age subgroup will be defined as age < 55 and age ≥ 55 at baseline. 
3.1.2. 
Disposition 
Subject disposition will be summarized by enrollment group and overall in terms of the 
following: 
• Subjects enrolled in the study 
• Subjects in the safety population 
• Subjects in the FAS population 
• Subjects in the Pharmacokinetic Population 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
15 
• Subjects who completed the treatment period 
• Subjects who completed the study (treatment and follow up period) 
• Subjects who discontinued from the study during the treatment period 
• Subjects by the reason for early discontinuation 
Percentages of disposition are based on the subjects in the Safety Population. Reason for early 
discontinuation will be as indicated on the disposition electronic case report form (eCRF). A 
listing of disposition will be provided for all subjects. 
3.1.3. 
Protocol Deviations 
Subjects with major protocol deviations in the following categories will be summarized and 
listed by enrollment group and overall for each category as listed below: 
• Did not meet the inclusion/exclusion criteria 
• Received prohibited medications 
• Non-compliant with study medication, as defined by subjects taking less than 70% or 
more than 105% of the protocol specified amount of study medication 
• Other major protocol deviations 
3.2. 
Demographics and Baseline Characteristics 
For De Novo Subjects and Rollover Subjects who were in DMF treatment group in 
ALK8700 A302, demographics and baseline characteristics data will be collected at Visit 2. For 
Rollover Subjects who were in ALKS 8700 treatment group, these data will be carried over from 
information recorded in the antecedent ALK8700-A302 study unless otherwise specified. 
Demographic data, including age, age category (18-19, 20-29, 30-39, 40-49, 50-55, and > 55, as 
well as < 40, ≥ 40), gender, race, weight, body mass index (BMI), ethnicity and region (US, 
non-US) will be summarized by enrollment group and overall. 
Baseline disease characteristics will also be summarized by enrollment group and overall, using 
descriptive statistics. These include years since disease (MS) onset, years since diagnosis, 
number of relapses in the past 12 months, prior Disease modifying therapy, baseline Expanded 
Disability Status Scale (EDSS) scores and EDSS score category (0, 1-1.5, 2-2.5, 3-3.5, 4-4.5, and 
≥ 5). 
 
 
 
Medical history will be summarized by enrollment group and overall for the Safety Population. 
Demographic, baseline characteristics and medical history listings will be provided for all 
subjects. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
16 
3.3. 
Prior and Concomitant Medications 
Prior medications are defined as medications taken prior to the first dose of the study medication 
(i.e., medications with a stop date prior to the first date of study drug in the current study). 
Concomitant medications are defined as medications taken during the period between the first 
dose date and the last dose date of study drug, inclusive. Post-discontinuation medications are 
defined as medications taken after the last dose of study drug. All medications as documented by 
the investigator will be coded using the World Health Organization Anatomical Therapeutic 
Chemical (WHO-ATC) drug dictionary herbal enhanced version (2016, 1st quarter). 
Prior and concomitant medications will be summarized by the preferred drug name for the Safety 
Population, by enrollment group and overall. If a subject has taken a prior or concomitant 
medication more than once, the subject will be counted only once for the medication. All 
reported medications will be presented in the subject data listing. 
3.4. 
Treatment Adherence Rate and Extent of Exposure 
Treatment adherence will be defined as: (number of capsules taken) / (number of capsules 
expected to be taken) * 100. When a subject discontinues treatment early, the number of capsules 
that should have been taken is based upon the duration the subject was on treatment. 
Total number of days the subject is on study drug will also be summarized as a continuous 
variable and categorized into 12-week intervals. Days on study drug will be calculated as the 
number of days from date of first dose to date of last dose plus 1. 
Treatment adherence and exposure will be summarized by enrollment group and overall. 
Supportive listings will be provided. 
3.5. 
Efficacy Analyses 
3.5.1. 
General Considerations 
All efficacy analyses will be carried out using the FAS population. For rollover subjects, efficacy 
assessment in the antecedent ALK8700-A302 study will be carried over as baseline if visit 2 in 
current study is not collected. All efficacy endpoints will be summarized by enrollment group 
and overall. Supportive listings will be provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
17 
 
 
 
 
 
 
 
 
3.5.3. 
Clinical endpoints 
• The change from baseline in the EDSS score 
• Proportion of subjects experiencing a relapse at Week 96 
• Annualized Relapse Rate (ARR) at Week 96 
• Time to onset of 12-week confirmed disability progression 
• Change in 25-Foot Walk from Baseline 
• Proportion of subjects with No Evidence of Disease Activity (NEDA) at Week 96 
EDSS Score 
The EDSS is used to measure and evaluate MS patients’ level of functioning. The EDSS 
provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to 
people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the 
loss of ambulatory ability.  The range of main categories include (0) = normal neurologic exam; 
to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full 
daily activities; to (10) = death due to MS. In addition, it also provides eight subscale 
measurements called Functional System (FS) scores: pyramidal (motor function); cerebellar; 
brainstem, sensory; bowel and bladder; visual, cerebral or mental; and other. The Functional 
Systems (FS) are scored on a scale of 0 (low level of problems) to 5 (high level of problems) to 
best reflect the level of disability observed clinically. The total EDSS score is determined by two 
factors- gait and FS scores. EDSS scores below 4.0 are determined by the FS scores alone. EDSS 
scores between 4.0 and 9.5 are determined by both gait abilities and FS scores. For this study, the 
fatigue score should be recorded but not included in the calculation of the cerebral FS score. 
The EDSS score and change from baseline during the Treatment Period will be summarized by 
enrollment group and overall. 
Relapse 
A protocol-defined relapse consists of the following: 
• New or recurrent neurologic symptoms, not associated with fever or infection, lasting 
for at least 24 hours, accompanied by one or more of the following:  
− New objective neurological findings upon examination by the treating neurologist 
that are functionally consistent with findings on the EDSS (performed within 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
18 
7 days of onset of symptoms) with an increase over the prior visit of ≥ 0.5 for the 
total score, 
− An increase of ≥ 2 in one FS subscale scores and/or 
− An increase of ≥ 1 in two FS subscale scores, except bladder/cognitive changes. 
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse. New or recurrent neurologic symptoms that occur 
less than 30 days following the onset of a protocol-defined relapse will be considered part of the 
same relapse, i.e., if 2 relapses have onset days that are ≤ 29 days of one another, they will be 
counted only as 1 relapse, and the onset date used in the analysis will be the onset date of the 
first relapse. 
Assessment regarding protocol defined relapses will be summarized as frequency of relapses per 
subjects (0, 1, 2, 3, ≥ 4); along with estimated proportion of subjects experiencing a relapse at 
Week 96, which will be calculated with the use of the Kaplan–Meier product-limit method. 
Annualized Relapse Rate 
The annualized relapse rate for each enrollment group will be calculated as the total number of 
relapses experienced in the group divided by the total number of patient-years on study. In 
addition, the relapse rate for an individual patient will be calculated as the number of relapses for 
that patient divided by the number of patient-years followed. Based on these individual relapse 
rates, the mean and median for each enrollment group will be presented. 
Time to Onset of 12-week Confirmed Disability Progression 
The time to onset of 12-week confirmed disability progression is defined as the time from 
baseline to the first disability progression that is confirmed at the next regularly scheduled visit 
≥ 12 weeks after the initial disability progression. 
Disability progression is defined by one of the following: 
• an EDSS increase of at least 1.5 points from baseline EDSS = 0 
• an EDSS increase of at least a 1.0 point from baseline EDSS between 1.0 and 5.5 
(inclusive), or 
• an EDSS increase of at least 0.5 points from baseline EDSS = 6.0. 
The date of the initial EDSS assessment at which the minimum increase in the EDSS is met will 
be the date of onset of the progression (tentative progression). The progression is defined as 
confirmed when this minimum EDSS change is present on the next study visit occurring after 
12 weeks or longer from the onset of the progression. EDSS assessments within 30 days after a 
protocol-defined relapse will not be used for confirmation of disability progression. If a subject 
meets the defined criteria of confirmed progression and is also having a relapse, the subject will 
be required to meet the defined minimum criteria at the subsequent visit. 
Death due to MS before a confirmed disability progression will be counted as progression. If the 
subject was in the midst of a tentative progression at the time of death (e.g. the EDSS evaluation 
prior to death is a tentative progression), the progression date will be the date of the onset of the 
progression. Otherwise, the progression date will be the date of death. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
19 
Subjects who do not have a confirmed progression based on the above rules will be censored. 
The censor date will be the date of the last EDSS assessment in the study, unless the subject was 
in the midst of a tentative progression. For subjects with a tentative progression at the last study 
visit, the censor date will be the date of the onset of the progression. Subjects who withdraw 
from the study after the baseline visit but prior to the first clinical evaluation scheduled visit will 
be censored at baseline. 
Estimated proportion of subjects with 12-week confirmed progression at 48, 60, 72, 84, and 96 
weeks will be calculated with the use of the Kaplan–Meier product-limit method and reported by 
enrollment group and overall. 
Timed 25-foot walk (T25-FW) score 
The T25-FW is a reliable quantitative mobility and leg function performance test based on a 
timed 25-foot walk (T25-FW). The subject is directed to one end of a clearly marked 25-foot 
course and is instructed to walk 25 feet as quickly as possible, but safely. Subjects are allowed to 
use assistive devices (canes, crutches, walkers) as needed. The time is calculated from when the 
lead foot crosses the start point to when the subject has reached the 25-foot mark. The task is 
immediately administered again by having the subject walk back the same distance. The score 
for the T25-FW is the average of the two completed trials. 
The T25-FW score and change from baseline during the Treatment Period will be summarized 
by enrollment group and overall. 
No Evidence of Disease Activity (NEDA) 
Both NEDA-3 and NEDA-4 definitions will be used to identify subjects with NEDA. The 
definition of NEDA-3 encompasses a combination of three related measures of disease activity: 
no relapses, no confirmed disability progression sustained for 12 weeks as measured on EDSS 
and no MRI disease activity, defined as no new GdE lesions and no new or enlarging T2 
hyperintense lesions. The definition of NEDA-4 is the above definition of NEDA-3 with the 
addition of a mean annualized rate of brain volume loss (AR-BVL) of less than 0.4% where 
AR-BVL is derived from percentage brain volume change from baseline (PBVC) and is 
calculated as ((PBVC/100+1)^(365.25/days)–1)*100 [2]. 
Proportion of Subjects with NEDA-3 and NEDA-4 at Week 96 will be summarized by 
enrollment group and overall. Estimated proportion of subjects with NEDA-3 and NEDA-4 at 
week 96 will be estimated using Kaplan-Meier product-limit method and reported by enrollment 
group and overall. 
3.5.4. 
Patient Reported Outcomes 
The following patient reported outcomes will be summarized for each enrollment group and 
overall:  
• The change from baseline in the Short Form 12 Health Survey (SF-12) component 
and summary scores through Week 96 
• The changes from baseline in the EQ-5D-5L visual analog scale (VAS) scores 
through Week 96 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
20 
Short Form 12 Health Survey (SF-12) Component Scores 
Quality of life will be assessed using the 12-item Short-Form health survey Version 2 (SF 12v2) 
[3]. The 12-item Short Form or SF-12 is a generic quality of life (QOL) measure based on the 
SF-36 Health Survey. The SF-12 captures approximately 90% of the variance of the SF 36. The 
SF-12 provides two summary indices of health-related quality of life: the Physical Component 
Summary (SF-12 PCS) and the Mental Component Summary (SF-12 MCS). SF-12 PCS and 
SF12 MCS scores will be computed using the transformed scores of 12 questions and range from 
0 to 100 (Mean=50, standard deviation [SD] =10 in the general US population), where zero 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health [3]. 
EQ-5D-5L Visual Analog Scale (VAS) Scores 
The 5-level EQ-5D version (EQ-5D-5L) [4] is designed for self-completion by subjects and 
consists of 2 pages - the EQ-5D-5L descriptive system and the EQ visual analog scale (VAS). 
The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems. The 
EQ VAS records the respondent’s self-rated health on a vertical, visual analog scale where the 
anchors are labeled ‘Best imaginable health state’ (score of 100) and ‘Worst imaginable health 
state’ (score of 0). The EQ-5D-5L descriptive system can be converted into a single summary 
EQ-5D Index [5]. 
The Patient Reported Outcomes scores and changes from baseline during the Treatment Period 
will be summarized by enrollment group and overall. 
3.6. 
Safety Analyses 
3.6.1. 
General Considerations 
All safety analyses will be carried out using the safety analysis set (Section 3.1.1.1) and will be 
summarized by enrollment group and overall unless specified otherwise. 
3.6.2. 
Adverse Events 
All adverse events (AEs) will be coded by System Organ Class and Preferred Term using the 
Medical Dictionary for Regulatory Activities MedDRA version 20.1 or higher. The verbatim 
term will be included in the AE listings. 
AEs will be identified as emerging in the treatment period and the follow up period. During the 
treatment period, an AE will be considered as treatment-emergent AE (TEAE) if the event starts 
or worsens on or after the date of first dose of study drug in the current study. The Treatment 
Period is defined as the first dose start date to the date of end of treatment (EOT) in the current 
study, inclusive. 
During the follow up period, post-discontinuation emergent AEs (PDEAEs), defined as AEs that 
started or worsened after date of the EOT visit, will be summarized. For PDEAEs, the greatest 
severity before or on the date of the EOT visit will be used as the benchmark for the comparison 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
21 
of the AEs occurring during the follow up period. The Follow-up Period is defined as the period 
between the date of the EOT visit plus 1 day and the last study visit, inclusive. 
An overview table, including number of subjects with TEAEs, serious AEs (SAEs), AEs leading 
to study discontinuation, study drug-related TEAEs, and PDEAEs will be provided. Adverse 
events leading to study discontinuation and SAEs leading to death will be summarized in the 
period when the discontinuation or death occurred. 
The following summary tables will be provided for the treatment period by enrollment group and 
overall: 
• TEAEs by System Organ Class and Preferred Term 
• TEAEs by System Organ Class, Preferred Term, and severity 
• TEAEs by System Organ Class, Preferred Term, and relationship 
• Study drug related TEAEs by System Organ Class and Preferred Term 
• TEAEs experienced by ≥ 5% of subjects by System Organ Class and Preferred Term 
• SAEs by System Organ Class and Preferred Term 
• AEs leading to study discontinuation by System Organ Class and Preferred Term 
• Adverse Events of Special Interest by System Organ Class and Preferred Term 
In addition, an AE overview table and AEs by System Organ Class and Preferred Term for 
PDEAEs during the Follow-up Period will be provided. 
All AE tables will be sorted by System Organ Class and then Preferred Term in decreasing 
frequency based on all subjects in the Safety Population. 
A subject having the same AE (as determined by the coded MedDRA preferred term) more than 
once will be counted only once in the number and percentage of subjects calculation for that AE. 
Similarly, if a subject has more than one AE in a SOC, the subject will be counted only once in 
the total number and percentage of subjects with an AE for that SOC. If a subject has the same 
AE on multiple occasions, the highest severity (severe > moderate > mild) recorded for the event 
will be presented in the AE by severity summary. Similarly, if a subject has the same AE on 
multiple occasions, the closest relationship to study drug (related > not related, where related 
includes definitely related, probably related, and possibly related; and not related includes 
probably not related and definitely not related) recorded for the event will be presented in the AE 
by relationship summary. 
Renal impact defined by baseline GFR subgroup will be summarized for TEAE and SAE by 
System Organ Class and Preferred Term. 
Age subgroup (age < 55 and age ≥ 55 at baseline) will be summarized for TEAE and SAE by 
System Organ Class and Preferred Term. 
All AEs will be included in the listings. Supporting listings of SAEs, AEs leading to study 
discontinuation, and AEs leading to death will be provided. Subjects with PDEAEs in the 
Follow-up Period will also be listed. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
22 
3.6.3. 
Deaths, Serious and Other Significant Adverse Events 
The number and percentage of subjects with at least one SAE (regardless treatment emergent or 
not) will be summarized by System Organ Class and Preferred Term for the Safety Population. 
Deaths and AEs leading to discontinuation (regardless treatment emergent or not) will be 
summarized similarly. 
Supporting listings of serious AEs and AEs leading to study discontinuations will be provided. 
Subjects who died during the study will also be listed. 
3.6.4. 
Adverse Events of Special Interest 
Adverse events in the following categories of interest will be presented by system organ class 
and preferred terms: 
• Anaphylaxis and Angioedema (serious events only) 
• Infections (including progressive multifocal leukoencephalopathy (PML) and 
opportunistic infections) (serious events) 
• Opportunistic infections 
• Lymphopenia and Lymphopenia (lymphocyte relevant) 
• Liver injury 
• Malignancies 
• Pre-malignant conditions 
• Renal Injury 
• Cardiac Disorder 
• Gastrointestinal Tolerability AEs (serious or leading to discontinuation) 
• Abuse potential 
Supportive AE listing will be provided for each special interest group. 
3.6.5. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional units. Only scheduled laboratory 
parameters will be included in the summaries. All laboratory data, including those collected at 
unscheduled visits, will be included in the listings. Laboratory results (baseline and change from 
baseline) for chemistry and hematology parameters for each visit during the entire study will be 
summarized. Percent change of lymphocyte count for each visit will be summarized. 
For urinalysis, the number and percentage of subjects with abnormalities at any post-baseline 
visit will be summarized. In addition, the number and percentage of subjects with values 
considered potentially clinically significant (PCS) occurring at any post-baseline visit for 
selected parameters will be summarized. 
Clinical laboratory test values, scheduled or unscheduled, will be considered PCS if they meet 
PCS criteria listed in Table 2. The percentages will be calculated relative to the number of 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
23 
subjects with available non-PCS baseline values with respect to the specific criterion and at least 
1 post-baseline assessment. The numerator is the total number of subjects with a non-PCS 
baseline value with respect to the specific criterion and at least 1 post-baseline PCS value. A 
supportive listing will present all values for a parameter for subjects with at least one PCS value 
for that parameter. 
Shift tables for shift from baseline to any post baseline visits during treatment period will be 
provided for selected chemistry, hematology, and urinalysis parameters with conventional 
reference limits (limits provided by the performing laboratories) for the Safety Population. 
The following graphical displays will be presented by enrollment group and overall: 
• Mean along with the corresponding standard error (SE) for selected chemistry and 
hematology laboratory parameters. 
• Boxplots will be used to display summary statistics for the last assessment, maximum 
and minimum change from baseline values for selected chemistry and hematology 
laboratory parameters. 
Pregnancy and drug test data will be listed. 
Table 2: 
Criteria for Potentially Clinically Significant (PCS) Laboratory Parameters 
Category 
Parameter 
Criteria 
Hematology 
Hematocrit 
≤ 32% and 3 point decrease from baseline (Female) 
≤ 37% and 3 point decrease from baseline (Male) 
Hemoglobin 
≤ 9.5 g/dL (Female) 
≤ 11.5 g/dL (Male) 
Neutrophils 
< 1.5 × 103/uL 
Platelets 
< 75.1 × 103/uL 
≥ 700 × 103/uL 
WBCs - total, differential 
(absolute) 
≤ 2.8 × 103/uL 
≥ 16 × 103/uL 
lymphocytes 
< 0.5 × 109/L 
Eosinophils 
>1.0 × 103 cells/uL 
Chemistry 
ALT 
≥ 3 × ULN 
Albumin 
< 2.5 g/dL 
ALK-P 
≥ 3 × ULN 
AST 
≥ 3 × ULN 
Bicarbonate 
< 15 mmol/L 
> 31 mmol/L 
BUN 
> 30 mg/dL 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
24 
Category 
Parameter 
Criteria 
Calcium 
< 8.2 mg/dL 
> 12 mg/dL 
Chloride 
≤ 90 mmol/L 
≥ 118 mmol/L 
Creatine Kinase 
> 3 × ULN 
Creatinine 
≥ 2 mg/dL 
Gamma Glutamyltransferase  
≥ 3 × ULN 
Glucose  
< 50 mg/dL 
> 200 mg/dL 
HDL Cholesterol  
≤ 30 mg/dL 
Lactate Dehydrogenase  
> 3 × ULN 
LDL Cholesterol  
≥ 160 mg/dL 
Phosphate 
< 2 mg/dL 
> 5 mg/dL 
Potassium 
< 3 mmol/L 
> 5.5 mmol/L 
Prolactin 
> 1 × ULN 
Sodium 
< 130 mmol/L 
> 150 mmol/L 
Thyroid stimulating hormone 
(TSH) 
> 5.5 μIU/mL 
Total Bilirubin  
≥ 2 mg/dL 
Total Cholesterol  
> 300 mg/dL 
Triglycerides 
≥ 120 mg/dL (Female) 
≥ 160 mg/dL (Male) 
Uric Acid 
> 9 mg/dL 
> 8 mg/dL (Female) 
> 10 mg/dL (Male) 
Urinalysis 
Glucose 
at least 2+ 
Protein 
at least 2+ 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
25 
For liver function tests, the number and percentage of subjects will be summarized by upper limit 
of normal (ULN) category as follows: 
• ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALK-P 
(alkaline phosphatase) will be summarized by normal, > 3 × ULN, > 5 × ULN and 
> 10 × ULN. 
Number of subjects who meet Hy’s Law criteria (total Bilirubin > 2 × ULN and ALT or AST 
> 3 × ULN) will be summarized and corresponding listing will be presented. 
In addition, number of Subjects with Lymphopenia by Maximum NCI-CTCAE Toxicity Grade 
1-4 will be summarized. A listing with all post-discontinuation lymphocyte counts from subjects 
who require additional lymphocyte count monitoring visits, as per the protocol, will also be 
provided. 
3.6.6. 
Vital Signs and ECG Parameters 
3.6.6.1. 
Vital Signs 
Vital signs for each visit during the entire study will be summarized by enrollment group and 
overall. All vital signs data will be presented in the subject data listings.  
Number and percentage of subjects with vital sign values considered PCS occurring at any post-
baseline visit will be summarized by enrollment group and overall. Criteria for PCS are 
presented in Table 3 and will be presented for each criterion. The percentages will be calculated 
relative to the number of subjects with non-PCS baseline values with respect to the specific 
criterion and at least 1 post-baseline assessment. A supportive listing will present all values for a 
parameter for subjects with at least one PCS value for that parameter.  
In addition, the figure of mean change from baseline along with the corresponding SE will be 
summarized by visit and enrollment group, and overall for systolic blood pressure, diastolic 
blood pressure, and pulse rate. 
Table 3: 
Criteria for Potentially Clinically Significant (PCS) Vital Signs 
Parameter 
Criteria 
Systolic Blood Pressure 
Low: ≤ 90 mm Hg and decrease ≥ 20 mm Hg 
High: ≥ 180 mm Hg and increase ≥ 20 mm Hg 
Diastolic Blood Pressure 
Low: ≤ 50 mm Hg and decrease ≥ 15 mm Hg 
High: ≥ 105 mm Hg and increase ≥ 15 mm Hg 
Pulse Rate 
Low: ≤ 50 mm bpm and decrease ≥ 15 bpm 
High: ≥ 120 mm bpm and increase ≥ 15 bpm 
3.6.6.2. 
Electrocardiograms 
ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT interval, QTcB [QT 
interval corrected using Bazett’s method], QTcF [QT interval corrected using Fridericia’s 
method]) will be summarized for each visit during the entire study by enrollment group and 
overall. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
26 
Number and percentage of subjects with QTcB or QTcF parameter values considered PCS 
occurring at any post-baseline visit will be summarized by enrollment group and overall. Criteria 
for PCS are presented in Table 4 and will be presented for each criterion. A subject will be 
counted only once in the highest category for a given parameter based on the largest 
post-baseline value. The percentages will be calculated relative to the number of subjects with 
baseline value ≤ 450 msec and at least 1 post-baseline assessment in the safety analysis set. 
A supportive listing will present all values for a parameter for subjects with at least one PCS 
value for that parameter. 
Table 4: 
Criteria for Potentially Clinically Significant (PCS) QTcB and QTcF Values 
Parameter 
Criteria 
QTcB and QTcF 
> 450 to ≤ 480 msec 
> 480 to ≤ 500 msec 
> 500 msec 
Change from baseline > 60 msec 
Change from baseline > 60 msec 
3.6.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used to measure the presence and intensity of suicidal ideation 
and behavior. Suicidal behavior and suicidal ideation will be summarized by enrollment group 
and overall. The proportion of subjects who meet the criterion for each of these categories will 
be summarized as described in Table 5. 
Table 5: 
C-SSRS Categories for Analysis 
Category 
C-SSRS Item response is “YES” 
Suicidal behavior 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideation 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without intent to act 
Active suicidal ideation with some intent to act, without specific plan 
Active suicidal ideation with specific plan and intent 
3.7. 
Pharmacokinetic Data Analysis 
PK analyses will be performed using the PK analysis set. Individual plasma concentrations will 
be listed by actual sampling times and summarized by nominal sampling times using descriptive 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
27 
statistics. Plots of individual and mean concentrations over nominal time will also be generated. 
PK parameters will be calculated using non-compartmental analysis. Parameters will be 
estimated using actual elapsed time from dosing, and summarized using descriptive statistics. A 
subject listing of individual PK parameters will be provided. 
Non-compartmental analysis will be performed to estimate the PK parameters as data allow. 
Additionally, PK concentration data obtained from this study will may be combined with data 
from other studies to develop a population PK model, which will be reported separately. 
The PK parameters to be calculated includes, but is not limited to: 
• Cmax: Maximum observed concentration 
• tmax: Time to reach Cmax 
• AUClast: Area under the plasma concentration versus time curve calculated using the 
trapezoidal method from time zero to the last observed concentration above the lower 
limit of quantification. 
3.8. 
Statistical Considerations for COVID-19 
Due to the Coronavirus Disease 2019 (COVID-19) public health emergency, many data 
collection challenges arose in this study. However, additional efforts were made to collect more 
data related to COVID-19, including but not limited to protocol deviations, AEs for COVID-19, 
COVID-19 testing and vaccine for COVID-19, concomitant medication to treat COVID-19 AEs 
and vaccines to prevent COVID-19, and treatment and study discontinuation due to COVID-19 
etc. 
The impact of COVID-19 will be evaluated for the safety population. Data for subjects who 
discontinued the study due to COVID-19 will be summarized with the reason for discontinuation 
in the listing. An overview table, including the number of subjects with TEAEs, serious AEs 
(SAEs) related to COVID-19, will be provided by enrollment group and overall. All AEs related 
to COVID-19 will be included in the listings. COVID-19 related concomitant medication data 
will be summarized and included in the listings. Major protocol deviations related to COVID-19 
will be provided in the listings. The protocol deviations log may be used to summarize the 
impact of COVID-19 in this study. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
28 
4. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE 
(DMC) 
Interim analyses were planned for this study for regulatory submission. Interim SAP was 
specified separately. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
29 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
COVID-19 impact will be assessed and summarized for major protocol deviation, AE, 
concomitant medication, and subject disposition. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
30 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits upon scheduled time points as specified in Table 1 Schedule 
of Visits and Assessments. 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in the eCRF unless otherwise specified by the specification document for analysis datasets. There 
will be one valid value of assessment kept for each scheduled analysis visit in summary/ analysis 
statistics. 
Unscheduled visits are visits with data not collected at scheduled time points. Unscheduled visits 
will not be used for by-visit summary/analysis statistics unless specified otherwise. All 
unscheduled visits will be included as collected in eCRF in listings. 
6.2. 
Handling Of Concentration Data Below The Lower Limit Of 
Quantification 
For PK analysis, individual < LLOQ values will be converted using the following rules: 
• < LLOQ values will be set to “0” if before tmax or 
• < LLOQ values will be set to "missing" if after tmax For Tables and Listings: 
• For individual concentration values, the < LLOQ values are considered equal to 0 for 
the calculation of descriptive statistics, but reported as ‘< LLOQ’ in concentration 
listings. 
• For mean concentration values, if the mean is < LLOQ, ‘< LLOQ’ is reported in 
concentration tables. 
• For mean concentration-related PK parameter values (eg, Cmax, Clast, etc.), if the mean 
is < LLOQ, the mean of the value is reported in the PK tables. 
For Figures: 
• For individual and mean figures, < LLOQ values are presented as 0 before the last 
sampling time point (tlast) for the linear representation (no value for semi-log plot), 
and are not presented after tlast, 
During pharmacokinetic analysis, pre-dose values that are either missing or < LLOQ will be 
assigned a value of zero when calculating AUC values. 
PK concentration values < LLOQ will be treated as zero for the determination of summary 
statistics and will be treated as missing for the calculation of the geometric means. For the 
presentation of summary statistics, if at least 1 subject has a concentration value < LLOQ for the 
time point, then the minimum value will be displayed as “< LLOQ”. If more than 50% of the 
subjects have a concentration data value < LLOQ for the time point, then the minimum and 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
31 
median values will be displayed as “< LLOQ”. If all subjects have concentration data values 
<LLOQ for the time point, then all order statistics (minimum, median, maximum) will be 
displayed as “<LLOQ”. If the mean is less than the lower limit of quantification, the mean values 
will be displayed as “<LLOQ”. 
All original values will be presented in the by-subject listings. 
6.3. 
Handling of Partial Dates of Concomitant Medication 
Partial start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. In the 
case of completely missing stop dates, medication will be assumed to be ongoing. 
6.4. 
Safety Data Handling 
All efforts should be made to obtain the missing information from the Investigator. For C-SSRS, 
vital signs, laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only 
observed data will be used for analyses, and missing data will not be imputed, except for missing 
and partial start dates of AEs which are handled in this study as follows: 
1. Missing day: If AE start year and month are same as first dose year and month of study 
drug then set the missing day to first dose day; Otherwise set the missing day to 1st of the 
month; 
2. Missing both month and day: If AE start year is same as first dose year of study drug then 
set the missing month and day to first dose month and day; Otherwise set the missing 
month and day to 1st January; 
3. Missing day, month, and year: Set the missing date to first dose date of study drug; Note: 
If the imputed AE start date is later than AE end date then AE start date is set to the AE 
end date. 
 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
32 
7. 
GENERAL STATISTICAL METHODOLOGY 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of subjects in each category for categorical variables) will 
be provided by treatment group. All summary tables will be based on observed data, and missing 
values will not be imputed unless otherwise indicated. Measurements collected from 
unscheduled visits or repeated assessments will not be included in the by-visit summary tables or 
figures, but will be included in the derivation of the last post-baseline value during treatment, the 
analyses for the potentially clinically significant (PCS) post-baseline values, and subject listings. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings. 
7.1. 
Reporting Precision 
Summary statistics will be presented to the degree of precision in Table 6, unless otherwise 
specified: 
Table 6: 
Degree of Precision 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, Quartiles, 
Confidence limit boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places 
Minimum, Maximum 
The same as the raw data, up to 2 decimal places 
p-value 
Rounded to 3 decimal places and therefore presented as 
0.xxx; p-values smaller than 0.001 as ‘< 0.001’; p-values 
greater than 0.999 as ‘> 0.999’. 
Percentage 
One decimal place. A percentage of 100% will be reported 
as 100%. Percentages of zero will be reported as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12–0.30). 
For PK concentrations and parameters the precision for summary statistics will be defined by the 
measurement resolution. 
For weight, height, and body mass index (BMI), one decimal place will be used for summary 
statistics. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
33 
8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
34 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
Mock-up tables and listings will be provided in a separate document. 


Product: ALKS 8700 (BIIB098)/DRF 
 
 
 
         Statistical Analysis Plan 
Study: ALK8700-A301  
Version: 2.0 
 
35 
10. 
REFERENCES 
1. Biogen ALK8700-A301 Clinical Study Protocol Amendment Version 5.0 (dated 27 Sep 
2019) 
2. Kappos, Ludwig, et al. "Inclusion of brain volume loss in a revised measure of ‘no evidence 
of disease activity’(NEDA-4) in relapsing–remitting multiple sclerosis." Multiple Sclerosis 
Journal 22.10 (2016): 1297-1305.  
3. Kosinski, Mark, et al. User's manual for the SF-12v2 health survey: with a supplement 
documenting the SF-12® health survey. QualityMetric incorporated, 2007. 
4. van Reenen, Mandy, and B. Janssen. "EQ-5D-5L User guide. Basic information on how to 
use the EQ-5D-5L instrument. Version 2.1, April 2015." (2015). 
5. Van Hout, Ben, et al. "Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-
5D3L value sets." Value in Health 15.5 (2012): 708-715.