Clinical trial NCT02410278
Conditions: Multiple Sclerosis
Sponsor: Biogen
Start date: 2015-03-12; Completion date: 2017-04-27
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate whether montelukast can reduce the severity of gastrointestinal (GI) events, measured by the Gastrointestinal Symptom Rating Scale (GSRS), after oral administration of dimethyl fumarate (DMF) in participants with relapsing forms of Multiple Sclerosis (MS). The secondary objectives of this study are as follows: To evaluate whether montelukast after oral administration of DMF in participants with relapsing forms of MS decreases discontinuations due to GI events and reduces the number of participants taking symptomatic therapies for GI events; To investigate the effect of montelukast on the incidence of flushing events after oral administration of 240 mg DMF in participants with relapsing forms of MS.

Detailed description:

Arms: arm 1: DMF as described in the United States Prescribing Information (USPI) plus 10mg montelukast tablet once daily according to the prevailing product label (Singulair) arm 2: DMF as described in the USPI plus matched placebo
Interventions: intervention 1: dimethyl fumarate intervention 2: montelukast intervention 3: Placebo
Intervention descriptions: intervention 1: Starting dose of 120 mg twice daily orally After 7 days, maintenance dose of 240 mg twice daily orally intervention 2: As described in the treatment arm intervention 3: Matched placebo

Protocol documents:
Prot_SAP_000.pdf: 






Protocol 109MS414                                                                                                                                      Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
TABLE OF CONTENTS
1.
SPONSOR INFORMATION .......................................................................................9
2.
LIST OF ABBREVIATIONS AND DEFINITIONS.................................................10
3.
SYNOPSIS .................................................................................................................11
4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 
109MS414...................................................................................................................21
4.1.
Study Schematic .........................................................................................................21
4.2.
Schedule of Events .....................................................................................................22
4.3.
Additional Information ...............................................................................................25
4.4.
Gastrointestinal Symptom Rating Scale .....................................................................25
5.
INTRODUCTION......................................................................................................26
5.1.
Profile of Previous Experience ...................................................................................26
5.1.1.
Nonclinical Experience With Dimethyl Fumarate .....................................................26
5.1.2.
Clinical Experience With Dimethyl Fumarate ...........................................................26
5.2.
Study Rationale...........................................................................................................28
5.3.
Rationale for Dose and Schedule Selection................................................................29
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................30
6.1.
Objectives ...................................................................................................................30
6.1.1.
Primary Objective.......................................................................................................30
6.1.2.
Secondary Objectives .................................................................................................30
6.1.3.
Exploratory Objective.................................................................................................30
6.2.
Endpoints....................................................................................................................30
6.2.1.
Primary Endpoint........................................................................................................30
6.2.2.
Secondary Endpoints ..................................................................................................31
6.2.3.
Exploratory Endpoints................................................................................................31
7.
STUDY DESIGN .......................................................................................................32
7.1.
Study Overview ..........................................................................................................32
7.2.
Overall Study Duration and Follow-Up .....................................................................33
7.2.1.
Screening Visit............................................................................................................33
7.2.2.
Screening Period.........................................................................................................33
7.2.3.
Randomization Visit...................................................................................................33
7.2.4.
DMF-GI Monitoring Period .......................................................................................33


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
5
7.2.5.
Treatment....................................................................................................................34
7.2.6.
Post-Treatment............................................................................................................34
7.3.
Study Stopping Rules .................................................................................................34
7.4.
End of Study ...............................................................................................................34
8.
STUDY POPULATION.............................................................................................35
8.1.
Inclusion Criteria ........................................................................................................35
8.2.
Exclusion Criteria.......................................................................................................35
9.
ENROLLMENT AND RANDOMIZATION PROCEDURES..................................37
9.1.
Enrollment and Screening...........................................................................................37
9.2.
Randomization of Subjects.........................................................................................37
9.3.
Blinding Procedures....................................................................................................37
10.
TREATMENT OF SUBJECTS..................................................................................38
10.1.
Study Treatment Schedule and Administration..........................................................38
10.1.1.
Dimethyl Fumarate .....................................................................................................38
10.1.1.1.
Treatment Precautions ................................................................................................38
10.1.1.2.
Treatment Adherence..................................................................................................38
10.1.2.
Montelukast and Placebo............................................................................................38
10.1.2.1.
Administration............................................................................................................38
10.1.2.2.
Treatment Precautions ................................................................................................39
10.1.2.3.
Treatment Adherence..................................................................................................39
10.2.
Continuation of Treatment..........................................................................................39
10.3.
Concomitant Therapy and Procedures........................................................................39
10.3.1.
Prohibited Concomitant Medications .........................................................................39
10.3.2.
Symptomatic Therapy to Treat Dimethyl Fumarate-Related Gastrointestinal 
Events .........................................................................................................................39
10.4.
Recording Concomitant Medication...........................................................................40
11.
STUDY TREATMENT MANAGEMENT................................................................41
11.1.
Dimethyl Fumarate .....................................................................................................41
11.1.1.
Dimethyl Fumarate Accountability ............................................................................41
11.2.
Montelukast and Placebo............................................................................................41
11.2.1.
Montelukast and Placebo Accountability...................................................................41


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
6
12.
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR 
THE STUDY ..............................................................................................................42
13.
EFFICACY ASSESSMENTS ....................................................................................43
13.1.
Clinical Efficacy Assessments....................................................................................43
13.2.
Exploratory Assessments............................................................................................43
13.3.
Future Biomarker and Genetic Assessments (Optional) ............................................43
14.
SAFETY ASSESSMENTS ........................................................................................45
14.1.
Clinical Safety Assessments.......................................................................................45
15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................46
15.1.
Definitions ..................................................................................................................46
15.1.1.
Adverse Event.............................................................................................................46
15.1.2.
Serious Adverse Event................................................................................................46
15.2.
Monitoring and Recording Events..............................................................................46
15.2.1.
Adverse Events ...........................................................................................................46
15.2.2.
Serious Adverse Events..............................................................................................47
15.2.3.
All Events ...................................................................................................................47
15.2.4.
Immediate Reporting of Serious Adverse Events.......................................................47
15.2.4.1.
Deaths .........................................................................................................................48
15.3.
Safety Classifications..................................................................................................48
15.3.1.
Relationship of Events to Study Treatment................................................................48
15.3.2.
Severity of Events.......................................................................................................49
15.3.3.
Expectedness of Events ..............................................................................................49
15.4.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................49
15.5.
Procedures for Handling Special Situations ...............................................................50
15.5.1.
Overdose.....................................................................................................................50
15.5.2.
Medical Emergency....................................................................................................50
15.5.3.
Contraception Requirements ......................................................................................50
15.5.4.
Pregnancy ...................................................................................................................50
15.5.5.
Regulatory Reporting..................................................................................................51
15.5.6.
Unblinding for Medical Emergencies.........................................................................51
15.6.
Investigator Responsibilities.......................................................................................51
15.7.
Biogen Responsibilities ..............................................................................................52


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
7
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........53
16.1.
Description of Objectives and Endpoints ...................................................................53
16.2.
Description of Endpoints............................................................................................53
16.3.
Demography and Baseline Disease Characteristics....................................................53
16.4.
Efficacy Data ..............................................................................................................53
16.4.1.
Analysis Population....................................................................................................53
16.4.2.
General Methods of Analysis .....................................................................................53
16.4.3.
Primary Endpoint Analysis.........................................................................................53
16.4.4.
Secondary Endpoints Analysis ...................................................................................53
16.4.5.
Exploratory Endpoints Analysis.................................................................................54
16.5.
Safety Data..................................................................................................................54
16.5.1.
Analysis Population....................................................................................................54
16.5.2.
Methods of Analysis...................................................................................................54
16.6.
Interim Analyses.........................................................................................................54
16.7.
Sample Size Considerations .......................................................................................54
17.
ETHICAL REQUIREMENTS ...................................................................................55
17.1.
Declaration of Helsinki...............................................................................................55
17.2.
Institutional Review Board (IRB)...............................................................................55
17.3.
Subject Information and Consent ...............................................................................55
17.4.
Subject Data Protection ..............................................................................................56
17.5.
Compensation for Injury.............................................................................................56
17.6.
Conflict of Interest......................................................................................................56
17.7.
Registration of Study and Disclosure of Study Results..............................................56
18.
ADMINISTRATIVE PROCEDURES.......................................................................57
18.1.
Study Site Initiation....................................................................................................57
18.2.
Quality Assurance.......................................................................................................57
18.3.
Monitoring of the Study..............................................................................................57
18.4.
Study Funding.............................................................................................................57
18.5.
Publications.................................................................................................................57
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................58
19.1.
External Contract Organizations.................................................................................58


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
8
19.1.1.
Contract Research Organization.................................................................................58
19.1.2.
Interactive Voice/Web Response System...................................................................58
19.1.3.
Electronic Data Capture..............................................................................................58
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................58
19.1.5.
Home Visiting Company............................................................................................58
19.2.
Study Committees.......................................................................................................58
19.3.
Changes to Final Study Protocol ................................................................................58
19.4.
IRB Notification of Study Completion or Termination..............................................59
19.5.
Retention of Study Data..............................................................................................59
19.6.
Study Report Signatory...............................................................................................59
20.
REFERENCES ...........................................................................................................60
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................61
LIST OF TABLES
Table 1:
Schedule of Events .....................................................................................................22
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................21




Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
10
2.
LIST OF ABBREVIATIONS AND DEFINITIONS
AE
adverse event
ANCOVA
analysis of covariance
CNS
central nervous system
CRF
case report form
DMF
dimethyl fumarate
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
eDiary
electronic diary
ET
early termination
GCP
Good Clinical Practice
Gd
gadolinium
GI
gastrointestinal
GSRS
Gastrointestinal Symptom Rating Scale
ICF
informed consent form
ICH
International Conference on Harmonisation
ITT
Intent-to-treat
IXRS
Interactive Voice and Web Response System
MMF
monomethyl fumarate
MRI
magnetic resonance imaging
MS
multiple sclerosis
Nrf2
nuclear factor (erythroid-derived 2)-related factor 2
PHI
protected health information
RNA
ribonucleic acid
RRMS
relapsing-remitting multiple sclerosis
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
US
United States
USPI
United States Prescribing Information
Wk
week


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
11
3.
SYNOPSIS
This is a brief summary.  For details, refer to the body of the protocol.
Protocol Number:
109MS414
Protocol Title:
A Multicenter, Double-Blind, Placebo-Controlled Study of 
Montelukast on Gastrointestinal Tolerability in Patients With 
Relapsing Forms of Multiple Sclerosis Receiving 
TECFIDERA® (Dimethyl Fumarate) Delayed-Release 
Capsules
Version Number:
3
Name of Study Treatment:
TECFIDERA® (dimethyl fumarate)
Study Indication:
Relapsing forms of multiple sclerosis (MS)
Phase of Development:
4
Rationale for the Study:
Two large Phase 3 studies (Study 109MS301 [DEFINE] and
Study 109MS302 [CONFIRM]) and 1 Phase 2 study 
(Study C-1900) of dimethyl fumarate (DMF) in patients with 
relapsing-remitting MS demonstrated substantial benefits 
over placebo across a range of clinical and radiologic 
measures of disease activity.  While the overall safety profile 
was favorable in these studies, the incidence of adverse 
events (AEs) associated with gastrointestinal (GI)
tolerability, including diarrhea, nausea, abdominal pain, 
vomiting, and dyspepsia, was increased in DMF-treated 
patients compared with those who received placebo.
This study will investigate the impact of 10 mg montelukast 
once daily on GI tolerability in patients with relapsing forms 
of MS receiving DMF delayed-released capsules in order to 
potentially increase patient compliance and adherence to 
treatment and ultimately maximize the therapeutic potential 
of DMF.
Study Objectives and 
Endpoints:
Objectives
Primary:
The primary objective of this study is to evaluate whether 
montelukast can reduce the severity of GI events, measured 
by the Gastrointestinal Symptom Rating Scale (GSRS), after 






Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
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MA Inc.
14
Subjects will be required to be ≥75% compliant in the 
14 days prior to randomization to remain eligible to 
participate in the study.  Subjects will also use the eDiary to 
record DMF dosing, randomized study medication dosing, 
and any symptomatic concomitant medications/procedures.  
Subsequently, eligible subjects will initiate DMF therapy and 
record GI-related events in the eDiary for up to 28 days
(DMF-GI Monitoring Period).  During this period, subjects 
will take DMF, and GSRS scores will be monitored.  
Subjects who reach a specific threshold (GSRS score of ≥3 
in 1 question for 1 day or a GSRS score of ≥2 in 1 question 
for 2 consecutive days) will receive an alert through their
eDiary to start taking randomized study treatment the same 
day, in accordance with the prescribing and labeling 
information.  Subjects who do not meet the threshold by the 
end of the 28 days will be discontinued from the study.  
Eligible subjects, who reach the GSRS score threshold and 
initiate randomized study treatment (montelukast or 
placebo), will return to the study site at Weeks  0, 2, 4, 8 ,
and at Week 10 for evaluation by study site staff (visits at 
Weeks 2 and 8 can alternatively be performed remotely by a 
contracted home health nurse). Weeks  2, 4, and 8 will have a 
visit window of ±2 days, and Week 10 will have a visit 
window of ± 3 days. The Safety Follow-Up Telephone 
Interview will be conducted 2 weeks (±5 days) after the 
Week 10 study visit or date of the Early Termination Visit.
Subjects who withdraw from the study after initiating 
randomized study treatment will not be replaced.
The dose of DMF used will be as described in the United 
States Prescribing Information (USPI).  Subjects will take 
DMF for up to 14 weeks and the randomized study treatment
(montelukast or placebo), concomitantly, for 8 weeks and 
record pertinent information regarding GI-related events in 
an eDiary.
Information on AEs and serious adverse events (SAEs) will 
be collected for possible correlation with GI-related events.  
For the purposes of this study, relapses of MS will not be 
considered AEs, and data related to relapses will only be 
captured if they are deemed an SAE or result in a subject’s 
discontinuation.  Relapses of MS resulting in hospitalization 
are considered SAEs but will not be reported as SAEs in the 
study unless the relapse is complicated by other SAEs or is 


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
15
fatal.
Rationale for Dose and 
Schedule Selection:
Dimethyl fumarate (DMF) will be taken in accordance with 
the USPI.  The starting dose for DMF is 120 mg twice daily
orally.  After 7 days, the dose should be increased to the 
maintenance dose of 240 mg twice daily orally.
Montelukast will be taken per product label: one 10-mg 
tablet once daily in the evening.
Study Location:
United States (US)
Number of Planned Subjects:
It is expected that approximately 295 subjects will be 
initially randomized to obtain the number of planned dosed 
subjects.
Approximately 118 subjects in total will be dosed with 
randomized study treatment, with approximately 59 subjects 
dosed with randomized study treatment per treatment arm.
Not all randomized subjects will be eligible to be dosed with 
randomized study treatment.  Randomized subjects will be 
required to reach a predefined threshold of GI symptom 
severity before dosing with randomized study treatment will 
be initiated.
Study Population:
This study will be conducted in subjects with relapsing forms 
of MS.  Detailed criteria are presented in the protocol.
Treatment Groups:
DMF + montelukast or DMF + placebo
Duration of Treatment and 
Follow-up:
The duration of a subject’s participation will be up to 
18 weeks, including a 2-week (+14 days) Screening Period, 
up to 14 weeks of DMF therapy, including 8 weeks of 
concomitant randomized study treatment, and the Safety 
Follow-Up Telephone Interview.  Subjects who discontinue 
the study early will complete the same assessments specified 
for the Week 10 Visit.


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
16
Criteria for Evaluation: 
This study is to be conducted in subjects with relapsing 
forms of MS.  To be eligible to participate in this study, 
candidates must meet the following eligibility criteria at the 
Screening Visit:
1. Have the ability to understand the purpose and risks 
of the study and provide signed and dated informed 
consent and authorization to use protected health 
information in accordance with national and local 
subject privacy regulations.
2. Age ≥18 years at the time of informed consent.
3. Reside in the US and have a confirmed diagnosis of a 
relapsing form of MS and satisfy the therapeutic 
indication as described in the local label.
4. Female subjects of childbearing potential who are not 
surgically sterile must practice effective 
contraception during their participation in the study 
and be willing and able to continue contraception for 
30 days after they complete or withdraw from the 
study.  All men must practice effective contraception 
and should not donate sperm, throughout the study 
and for at least 90 days after their last dose of study 
treatment.
5. As perceived by the Investigator, have the ability to 
comply with all requirements of the study protocol 
and to operate the eDiary required to record 
GI-related events.
Candidates will be excluded from study entry if any of the 
following exclusion criteria exist at the Screening Visit or at 
the timepoint defined in the individual criterion:
1. Inability to comply with the study requirements or, at 
the discretion of the Investigator, is deemed 
unsuitable for study participation.
6. Female subjects who are currently pregnant or 
breastfeeding or who are considering becoming 
pregnant during the study.
7. History of significant GI disease (e.g., irritable bowel
disease, peptic ulcer disease, history of major GI 
surgery, eosinophilic GI disease, or food allergies).
8. Chronic use (≥7 consecutive days) of bismuth 


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
17
subsalicylate, simethicone, calcium carbonate, 
loperamide, proton-pump inhibitors, or ondansetron 
within 1 month prior to the Screening Visit.  From 
Screening up to Day 10, use of such therapies is not 
permitted.  From Day 11 (inclusive), subjects are 
permitted to take these therapies.
9. Use of the following medications:  montelukast, 
immunotherapy, mast cell stabilizers, or parenteral, 
inhaled, or oral steroids up to 1 month prior to the 
Screening Visit.  Use of these medications is also not 
permitted for the duration of the study (except for the 
use of montelukast as per study protocol) and will 
lead to discontinuation.
10. Treatment with montelukast is contraindicated for 
any reason.
11. Exposure to fumarates in the 3 months prior to the 
Screening Visit.  Exposure is also not permitted for 
the duration of the Screening Period.
12. Have 1 or more major comorbidities that, in the 
opinion of the Investigator, may affect the outcome of 
the study.
13. History of malignancy (except for basal cell 
carcinoma that had been completely excised prior to 
study entry), severe allergic or anaphylactic reactions 
or known drug hypersensitivity, abnormal laboratory 
results indicative of any significant disease, and/or a 
major disease that would preclude participation in a 
clinical study.
14. Prior confirmed diagnosis or medical history of 
chronic eosinophilia.
15. Current enrollment in any other interventional 
clinical studies.
16. Subjects meeting the inclusion criteria as defined in 
Section 8.1, and who do not meet any of the 
exclusion criteria will be eligible to commence with a 
2-week (+14 days) Screening Period.  At the end of 
the Screening Period (at the Randomization Visit), 
GSRS scores and concomitant medication will be 
evaluated.  Subjects who meet the following criterion 
will be discontinued and counted as screen failures:  a 
GSRS score of ≥5 in 1 question for 1 day, a GSRS 


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
18
score of ≥4 in 1 question for 2 consecutive days, or a 
GSRS score of ≥3 in 1 question for 3 consecutive 
days.
17. Subjects who did not meet the required eDiary 
compliance (≥75%) in the 14 days prior to 
randomization.










Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
23
Assessment
Screening 
Visita
Screening 
Period
(2 Weeks 
+14 Days)
Randomization 
Visita
(Week -4)
DMF-GI 
Monitoring 
Period
(up to 28 Days)
Wk 
0a,b
Wk 
2c
Wk 
4a
Wk 
8c
Wk 
10a/ET
Safety 
Follow-
Upd
(± 5 days)
Dispense DMF With 
Dosing Instructions
X
DMF Administration 
(Daily)
DMF administration will occur every day as per the USPI
Randomization
X
Dispense 
Randomized Study 
Treatments
Xn
Randomized Study 
Treatment 
Administration 
(Daily)
Randomized study treatment 
administration will occur 
every day as per the 
prescribing information.
SAEs
SAE data will be collected from the signing of the informed consent up to the Safety Follow-Up Telephone Interview.  MS 
relapses resulting in hospitalization are considered SAEs but will not be reported as SAEs in the study unless the relapse is
complicated by other SAEs or is fatal.
AEs
AE data will be collected from the first dose of DMF up to the Safety 
Follow-Up Telephone Interview.
Note:  Weeks  2, 4, and 8 will have a visit window of ±2 days, and Week 10 will have a visit window of ± 3 days.
Abbreviations:  AE = adverse event; 
; DMF = dimethyl fumarate; DNA = deoxyribonucleic acid; eDiary = electronic diary; EDSS = Expanded 
Disability Status Scale; ET = early termination; GI = gastrointestinal; GSRS = Gastrointestinal Symptom Rating Scale; 
; 
; MS = multiple sclerosis;
; RNA = ribonucleic acid; SAE = serious adverse event; USPI = United States Prescribing 
Information;Wk = week.
a This visit must be performed in clinic.
b Subjects will receive an alert through the eDiary if their GSRS scores reach the appropriate threshold.  This alert will tell the subject to begin taking the randomized study 
treatment the same day.  At this time, study site should arrange the Week 0 Visit as soon as possible after the first administration of randomized study treatment.  Visit dates will 
be measured from the first administration of randomized study treatment.
c This visit may be performed remotely if more convenient for the subject; site must telephone the subject to document concomitant medications/procedures and AEs.
d The safety follow-up will be performed as a telephone interview 2 weeks (±5 days) after the Week 10/ET visit.
e GI symptom and eDiary compliance assessment.
f Including height and weight measurements and vital signs (temperature, blood pressure, and sitting blood pressure).
g Medical history, including MS disease status, will include collection of information on duration of MS, relapse history, EDSS score, and treatment for MS.
h Dipstick test (only for women of childbearing potential).


Protocol 109MS414                                                                                                                                          Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
24
i
 
j Serum, RNA, and DNA samples will be collected for biomarker analysis and future use analysis in subjects who provide additional consent.  A single DNA sample can be taken 
at any of prespecified timepoints.
k Subjects will be required to record their daily GI symptoms in the eDiary every day from the Screening Visit up to Week 10.
l eDiaries will be returned if (1) the subject fails during the Screening Period, (2) the subject does not reach the required GI symptom threshold during the DMF-GI Monitoring 
Period, or (3) the subject completes or discontinues the study.
m Subjects who do not reach the GI symptom threshold during the DMF-GI Monitoring Period (a GSRS score of ≥5 in 1 question for 1 day, ≥4 in 1 question for 2 consecutive 
days, or ≥3 in 1 question for 3 consecutive days) will be discontinued.
n Subjects are dispensed randomized study treatment at this visit but must not begin taking the medication until alerted about their eDiary.


Protocol 109MS414
Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
25
4.3.
Additional Information
After initial eligibility has been confirmed at the Screening Visit, subjects will enter a 
2-week (+14 days) Screening Period.  At the end of this period, eligible subjects will return to
the clinic for a Randomization Visit.  The eligibility criteria will be rechecked, and additionally, 
the gastrointestinal (GI) symptoms noted in an electronic diary (eDiary) will be assessed.  
Individuals with Gastrointestinal Symptom Rating Scale (GSRS, Section 4.4) score of ≥5 in 
1 question for 1 day, a GSRS score of ≥4 in 1 question for 2 consecutive days, or a GSRS score 
of ≥3 in 1 question for 3 consecutive days will be discontinued and counted as screen failures.  
An eDiary compliance check will also be performed.  Subjects will be required to be ≥75% 
compliant in the 14 days prior to randomization to remain eligible to participate in the study.  
Subjects who fulfill the eligibility criteria and meet the GI symptom assessment criteria will be 
randomized to 1 of 2 treatment arms.  At this time, subjects will start commercial dimethyl 
fumarate (DMF) and will receive (but will not begin taking) their randomized study treatment.  
Subjects will then enter the DMF-GI Monitoring Period (up to 28 days).  During this period, 
subjects will take DMF and note their daily GI symptoms in the eDiary.  If at any time during 
this period, the GSRS scores noted are ≥3 in 1 question for 1 day or ≥2 in 1 question for 
2 consecutive days, the subject will receive an alert through his/her eDiary to start taking the 
randomized study treatment the same day.  Any subjects who do not reach this threshold during 
the 28-day period will be discontinued from the study.  It will be the decision of the Investigator
to continue with DMF therapy after the subject has been withdrawn from the study.
4.4.
Gastrointestinal Symptom Rating Scale
The GSRS is a weekly recall scale that has been modified for daily recall in this study.
The 7 severities of each of the 15 questions of the GSRS have a number assigned and will be 
summarized for a GSRS score as follows:

no discomfort at all = 0

minor discomfort = 1

mild discomfort = 2

moderate discomfort = 3

moderately severe discomfort = 4

severe discomfort = 5

very severe discomfort = 6


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
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26
5.
INTRODUCTION
5.1.
Profile of Previous Experience
5.1.1.
Nonclinical Experience With Dimethyl Fumarate
In nonclinical studies, DMF and its primary metabolite, monomethyl fumarate (MMF), were 
found to promote stabilization, nuclear translocation, and transcriptional activity of nuclear 
factor (erythroid-derived 2)-related factor 2 (Nrf2) as well as expression of Nrf2 target genes in 
cultured human cells and in vivo [Linker 2011].  Previous ex vivo and in vivo studies have 
demonstrated a central role of the Nrf2 pathway in protection of cells and tissues against 
oxidative, metabolic, and inflammatory stress.  Loss of Nrf2 function via genetic silencing has 
been shown to cause exaggerated inflammatory response and lead to development of systemic 
autoimmunity and central nervous system (CNS) alterations, including widespread gliosis and 
white matter lesions. Conversely, pharmacological agents known to activate Nrf2 have been 
shown in nonclinical studies to exert anti-inflammatory effects, protect neurons from oxidative 
and excitotoxic stress-induced death, and improve the blood-brain barrier integrity of the CNS.  
Activation of the Nrf2 pathway by Tecfidera® (DMF) gastro-resistant hard capsules (hereinafter 
referred to as DMF) in multiple sclerosis (MS) may contribute to inhibition of inflammation and 
help support CNS integrity by promoting cellular resistance to oxidative stress.
5.1.2.
Clinical Experience With Dimethyl Fumarate
Clinical Pharmacokinetic Studies
In single-dose and short-term multiple-dose studies in healthy volunteers and subjects with MS, 
DMF was rapidly converted to its major metabolite (MMF) upon oral administration.  Exposure 
(maximum plasma concentration and area under the curve) was generally dose proportional 
across the dose range (120 to 360 mg) and dosing frequencies (twice daily and 3 times daily) 
studied.  No accumulation of exposure was detected with repeated dosing due to rapid 
elimination of the drug.  In these studies, DMF was most frequently associated with flushing; no 
serious adverse events (SAEs) or deaths in healthy volunteers who received DMF were reported.
Clinical Efficacy and Safety in Multiple Sclerosis
The DMF clinical development program at the time the DMF marketing authorization 
applications were filed included 6 clinical studies in subjects with MS.  In 4 of the studies 
(Phase 2 and 3 placebo-controlled efficacy and safety studies and their uncontrolled extensions), 
2513 subjects with relapsing-remitting multiple sclerosis (RRMS) received DMF and were 
followed for periods up to 6 years, with an overall exposure of 6133 patient-years. 
Approximately 1056 subjects received >2 years of treatment with DMF.
Study C-1900 was a Phase 2, randomized, multicenter, placebo-controlled, double-blind, 
parallel-group, dose-ranging study composed of 2 parts: a 24-week double-blind, 
placebo-controlled safety and efficacy phase (Part 1) followed by a 24-week dose-blinded, safety 
extension phase (Part 2).  The primary efficacy endpoint was the total number of new gadolinium 


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
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(Gd)-enhancing lesions at Weeks 12, 16, 20, and 24 (calculated as the sum of the 4 magnetic 
resonance imaging [MRI] scans).  A total of 257 subjects were randomly assigned to receive 
120 mg DMF once daily, 120 mg DMF 3 times daily, or 240 mg DMF 3 times daily.  Subjects 
treated with 240 mg DMF 3 times daily had a 69% reduction in the mean number of new 
Gd-enhancing lesions versus placebo as measured on monthly MRI from Weeks 12 to 24 of the 
study, and a 48% and 53% reduction in new or enlarging T2 hyperintense lesions and new 
nonenhancing T1 hypointense lesions at Week 24 compared with placebo, respectively.
For both Phase 3 studies, the primary and secondary endpoints assessed the effect of DMF versus 
placebo on measures of relapse and disability progression, as well as MRI disease activity.  Each 
study was a randomized, double-blind, and placebo-controlled study in which subjects were 
treated for 2 years.
In Study 109MS301 (DEFINE), 1237 subjects were randomized in a 1:1:1 ratio to receive 
240 mg DMF twice daily, 240 mg DMF 3 times daily, or matching placebo.  The primary 
endpoint was the proportion of subjects relapsed at 2 years.  Dimethyl fumarate twice daily and 
3 times daily reduced the risk of relapse at 2 years by 49% (p < 0.0001) and 50% (p < 0.0001), 
respectively.  A significant reduction in the risk of 12-week confirmed progression was 
observed.  In this study, the estimated proportion of placebo-treated subjects with 12-week 
confirmed progression at 2 years was 0.271 compared with 0.164 for twice daily and 0.177 for 
3 times daily (38% reduction for twice daily and 34% reduction for 3 times daily relative to 
placebo; p = 0.0050 and p = 0.0128, respectively).  Dimethyl fumarate twice daily and 3 times 
daily reduced the number of new or newly enlarging T2 hyperintense lesions that developed over 
2 years by 85% and 74%, respectively, compared with placebo (p < 0.0001 for both 
comparisons).  Dimethyl fumarate twice daily and 3 times daily reduced the odds of having 
greater Gd-enhancing lesion activity at 2 years by 90% and 73%, respectively, compared with 
placebo (p < 0.0001 for both comparisons).  The most common adverse events ([AEs]; incidence 
≥5%) that occurred at an incidence ≥3% higher in the total DMF group than the placebo group 
included flushing and hot flush, GI-related events (diarrhea, nausea, abdominal pain upper, 
abdominal pain, and dyspepsia), skin events (pruritus, rash, and erythema), proteinuria, alanine 
aminotransferase/serum glutamate-pyruvate transaminase increased, and albumin urine present.
In Study 109MS302 (CONFIRM), 1430 subjects were randomized in a 1:1:1:1 ratio to 240 mg 
DMF twice daily, 240 mg DMF 3 times daily, DMF-matching placebo, or 20 mg glatiramer 
acetate subcutaneous injection once daily.  The primary endpoint was the annualized relapse rate 
at 2 years.  Treatment with DMF 240 mg administered twice daily and 3 times daily reduced the 
annualized relapse rate at 2 years by 44% and 50.5%, respectively, compared with placebo 
(p < 0.0001 for both comparisons).  Compared with placebo, treatment with 240 mg DMF twice 
daily and 3 times daily significantly reduced the number of new or enlarging T2 hyperintense 
lesions that developed over 2 years by 71% and 73%, respectively (p < 0.0001 for both 
comparisons).  Treatment with DMF twice daily and 3 times daily significantly reduced the 
number of new T1 hypointense nonenhancing lesions that developed over 2 years by 57% and 
65%, respectively, compared with placebo (p < 0.0001 for both comparisons).  Treatment with 
DMF twice daily and 3 times daily significantly reduced the proportion of subjects who relapsed 
at 2 years by 34% (p = 0.0020) and 45% (p < 0.0001), respectively, compared with placebo.  
Numerical changes in disability progression favoring DMF were seen:  the estimated proportion 


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
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28
of subjects with 12-week confirmed progression at 2 years was 16.9% for placebo, 12.8% for 
twice daily, and 13% for 3 times daily (21% reduction for twice daily and 24% reduction for 
3 times daily relative to placebo; p = 0.2536 and p = 0.2041, respectively).  The most common 
AEs (incidence ≥5% in the total DMF group) that occurred at an incidence ≥3% higher in the 
total DMF group than in the placebo group included flushing and hot flush, GI-related events 
(diarrhea, nausea, abdominal pain upper, abdominal pain, and vomiting), upper respiratory tract 
infections, and skin events (pruritus, rash, and erythema).  Additional information on DMF is 
provided in the Full Prescribing Information.
5.2.
Study Rationale
Two large Phase 3 studies and 1 Phase 2 study of DMF in subjects with RRMS demonstrated 
substantial benefits over placebo across a range of clinical and radiologic measures of disease 
activity (Phase 3 Study 109MS301 [DEFINE], Phase 3 Study 109MS302 [CONFIRM], and 
Phase 2 Study C-1900).  While the overall safety profile was favorable in these studies, the 
incidence of AEs associated with GI tolerability, including diarrhea, nausea, abdominal pain, 
vomiting, and dyspepsia, was increased in DMF-treated subjects compared with those who 
received placebo.  Between 27% and 38% of all DMF-treated subjects in the 3 studies 
experienced GI events within the first 3 months of treatment, and whereas 11% to 16% of 
subjects used GI-related symptomatic therapies, it was unclear whether these were taken in 
response to a GI-related AE that occurred in conjunction with dosing or if the therapy was 
effective.  The incidence of these events was higher during the first month of treatment and 
decreased in the second and subsequent months of treatment.  The majority of subjects reported 
these AEs to be of mild to moderate severity.  Nevertheless, study discontinuations due to GI 
events were increased in DMF-treated subjects (≤5%) compared with placebo-treated subjects 
(≤2%, pooled Phase 2 and Phase 3 subjects).  In addition, a recently completed single-arm, 
open-label, Phase 4 Study (109MS403 [MANAGE]) as well as a placebo-controlled study of 
Pepto-Bismol® (bismuth subsalicylate) on GI tolerability (Study 109HV110 [PREVENT]) 
showed similar results in terms of time course, severity, and incidence of GI events.  
Histopathology from biopsies taken from a subset of subjects in PREVENT suggested some 
evidence of GI mucosal eosinophil infiltration. In an independent, open-label, 30-day study
(21 subjects) investigating the effect of montelukast in DMF-related GI symptoms, GI symptoms
were significantly attenuated in the majority of subjects; GSRS scores decreased on average by 
81% within 72 hours [Tornatore and Amjad 2014]. The effect of montelukast may suggest that 
the pathogenesis of the GI symptoms with DMF could be due to a local immunomodulatory
effect of DMF. Montelukast is an approved product for asthma with a well-established safety 
profile [[SINGULAIR® USPI 2014]]. If a larger randomized, controlled study could 
demonstrate a benefit on decreasing the known GI tolerability events during initiation of therapy, 
it would be a clear benefit for subjects choosing DMF to treat MS who experience GI side 
effects.
This study will investigate the impact of 10 mg montelukast once daily on GI tolerability in 
patients with relapsing forms of MS receiving DMF delayed-released capsules in order to 
potentially increase patient compliance and adherence to treatment and ultimately maximize the 
therapeutic potential of DMF.


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
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5.3.
Rationale for Dose and Schedule Selection
Dimethyl fumarate will be taken in accordance with the United States (US) Prescribing 
Information (USPI). The starting dose for DMF is 120 mg twice daily orally.  After 7 days, the 
dose should be increased to the maintenance dose of 240 mg twice daily orally. Montelukast 
will be taken per product label: one 10-mg tablet once daily in the evening.  






Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
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7.
STUDY DESIGN
7.1.
Study Overview
This multicenter study will evaluate the effect of montelukast on GI tolerability with relapsing 
forms of MS treated with DMF at approximately 50 study sites in the US.  It is expected that
approximately 295 subjects will be initially randomized to obtain approximately 118 subjects 
dosed with randomized study treatment (59 subjects dosed with randomized study treatment per 
treatment arm).  Not all randomized subjects will be eligible to be dosed with randomized study 
treatment.  Randomized subjects will be required to reach a predefined threshold of GI symptom 
severity before dosing with randomized study treatment will be initiated.  Subjects who withdraw 
from the study after initiating randomized study treatment will not be replaced.
Subjects will enter a 2-week (+14 days) Screening Period and record pertinent information 
regarding GI-related events to allow characterization of background GI-related events using the 
eDiary. Subjects will be required to be ≥75% compliant in the 14 days prior to randomization to 
remain eligible to participate in the study.  Subsequently, eligible subjects will initially take 
DMF (120 mg twice daily orally for the first week, 240 mg twice daily orally thereafter) for up 
to 28 days (DMF-GI Monitoring Period) and record GI-related events in the eDiary. During this 
period, subjects will take DMF, GSRS scores will be monitored, and subjects who reach a 
specific threshold will receive an alert through the eDiary to start taking randomized study 
treatment (10 mg once daily montelukast or placebo) the same day in accordance with the 
prescribing and labeling information.  Subjects who do not meet the threshold or do not 
demonstrate ≥75% compliance with the eDiary in the 14 days prior to randomization will be 
discontinued.  Subjects will also use the eDiary to record DMF dosing, randomized study
medication dosing, and any symptomatic concomitant medications/procedures.  Eligible subjects 
will return to the study site at Weeks 0, 2, 4, 8 and at Week 10 for evaluation by study site staff.  
Weeks  2, 4, and 8 will have a visit window of ±2 days, and Week 10 will have a visit window of 
± 3 days. If more convenient for the subject, visits at Weeks 2, and 8 may be performed remotely 
by a contracted home health nurse.  The Safety Follow-Up Telephone Interview will be 
conducted 2 weeks (±5 days) after the Week 10 study visit or date of the Early Termination (ET)
Visit.
The dose of DMF used will be as described in the USPI.  Subjects will take DMF for up to 
14 weeks, including 8 weeks with the concomitant randomized study treatment (montelukast or 
placebo), and will record pertinent information regarding GI-related events in an eDiary.
Information on AEs and SAEs will be collected for possible correlation with GI-related events.  
For the purposes of this study, relapses of MS will not be considered AEs, and data related to 
relapses will be captured only if the event is deemed an SAE (see Section 15.1.2) or results in a 
subject’s discontinuation.  Relapses of MS resulting in hospitalization are considered SAEs and 
will be reported to the FDA. However, they will not be reported as SAEs in the study unless the 
relapse is complicated by other SAEs or is fatal.
See Figure 1 for a schematic of the study design.


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
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7.2.
Overall Study Duration and Follow-Up
The study period consists of a 2-week (+14 days) Screening Period, up to a total of 14 weeks of 
DMF therapy (including DMF-GI Monitoring Period and randomized treatment administration
period), including 8 weeks of concomitant randomized study treatment (DMF + montelukast or 
DMF + placebo), and the Safety Follow-Up Telephone Interview.  The duration of a subject’s
participation will be up to 18 weeks.  Subjects who discontinue the study early will complete the 
same assessments specified for the Week 10 Visit.  Refer to Section 1 for the timing of 
assessments to be performed in this study.
7.2.1.
Screening Visit
Subject eligibility for the study will be determined at the Screening Visit after receipt of the 
signed and dated informed consent form (ICF).  Eligible subjects will be given an eDiary after 
training on how to use the device.
7.2.2.
Screening Period
During this 2-week (+14 days) period, subjects will record pertinent information regarding 
GI-related events every day in the eDiary.  Individuals with a GSRS score of ≥5 in 1 question for 
1 day, a GSRS score of ≥4 in 1 question for 2 consecutive days, or a GSRS score of ≥3 in 
1 question for 3 consecutive days during the Screening Period will be discontinued and counted 
as screen failures.  
7.2.3.
Randomization Visit
Subjects will return to the study site for a recheck of eligibility criteria (only GSRS scores and 
concomitant medications/procedures will be checked).  Individuals with GSRS score of ≥5 in 
1 question for 1 day, a GSRS score of ≥4 in 1 question for 2 consecutive days, or a GSRS score 
of ≥3 in 1 question for 3 consecutive days during the Screening Period will be discontinued and 
counted as screen failures.  Subjects will be required to be ≥75% compliant in the 14 days prior 
to randomization to remain eligible to participate in the study, and sites should continue to 
monitor eDiary compliance throughout the study.  Concomitant medications/procedures will be 
checked to ensure compliance with study restrictions.  Once eligibility has been rechecked and it 
is confirmed that a subject is eligible to continue on the study, blood samples will be collected 
for the assessment of clinical laboratory parameters and serum biomarkers (optional).  Eligible 
subjects will be randomized and provided with blinded randomized study treatment (montelukast 
or placebo) at this time.
Eligible subjects will receive commercial DMF through their specialty pharmacy or, in the case 
of insufficient insurance coverage, through the Biogen Patient Services Free Drug Program, for 
up to 14 weeks.  The Investigator will submit the DMF prescription to Patient Services during 
the Screening Visit, and DMF will be shipped directly to subjects.
7.2.4.
DMF-GI Monitoring Period
The duration of the DMF-GI Monitoring Period will be up to 28 days.  On the first full day after 
the Randomization Visit, subjects will start taking DMF per the prescribing instruction.  Subjects 


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
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34
will make daily entries in the eDiary, recording pertinent information regarding GI-related events 
to allow the characterization of events that occur while taking DMF.  During this period, if a 
subject meets the threshold of a GSRS score of ≥3 in 1 question for 1 day or a GSRS score of ≥2 
in 1 question for 2 consecutive days, the subject will receive an alert through his/her eDiary to 
begin taking the randomized study treatment the same day.  Any subject who does not reach the 
GSRS threshold during the DMF-GI Monitoring Period will be discontinued.
7.2.5.
Treatment
Eligible subjects will take DMF for up to 14 weeks (from the start of the DMF-GI Monitoring 
Period to Week 10) and blinded randomized study treatment (either montelukast or placebo) for
8 weeks (from Weeks 0 to 8).
Subjects will be asked to return to the study site at Weeks 0, 2, 4, 8, and 10/ET for blood 
sampling for assessment of clinical laboratory parameters and AEs (optional serum biomarker
samples will be drawn at Weeks 4 or 10/ET).  Visits at Weeks 0, 4, and 10/ET must be 
performed at the study site.  If more convenient for the subject, visits at Weeks 2 and 8 may be 
performed remotely by a contracted home health nurse; in this situation, an appropriately 
qualified person from the study site must call the subject on each occasion to document any 
concomitant medication/procedures and AEs. Study windows are ±2 days for the Weeks  2, 4, 
and 8 Visits and ±3 days for the Week 10/ET Visit. Study site should arrange the Week 0 Visit as 
soon as possible after the first administration of randomized study treatment.  
7.2.6.
Post-Treatment
Two weeks (±5 days) after the Week 10 Visit or date of the ET Visit, subjects will be 
interviewed by telephone as a safety follow-up (collection of information on any AEs, SAEs, or 
changes in concomitant medications/procedures).
7.3.
Study Stopping Rules
Biogen may terminate this study at any time, after informing Investigators, institutional review 
boards (IRBs), and regulatory authorities when applicable.  Investigators will be notified by 
Biogen or designee if the study is placed on hold, completed, or closed.
7.4.
End of Study
The end of study is the last subject, last assessment collection for final collection of data for the 
primary outcome.


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
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8.
STUDY POPULATION
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the Screening Visit:
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.
2. Age ≥18 years at the time of informed consent.
3. Reside in the US and have a confirmed diagnosis of a relapsing form of MS and satisfy 
the therapeutic indication as described in the local label.
4. Female subjects of childbearing potential who are not surgically sterile must practice 
effective contraception during their participation in the study and be willing and able to 
continue contraception for 30 days after they complete or withdraw from the study.  All 
men must practice effective contraception and should not donate sperm, throughout the 
study and for at least 90 days after their last dose of study treatment.
5. As perceived by the Investigator, have the ability to comply with all requirements of the 
study protocol and to operate the eDiary required to record GI-related events.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the Screening Visit or at the timepoint defined in the individual criterion listed:
1. Inability to comply with the study requirements or, at the discretion of the Investigator, is 
deemed unsuitable for study participation.
2. Female subjects who are currently pregnant or breastfeeding or who are considering 
becoming pregnant during the study.
3. History of significant GI disease (e.g., irritable bowel disease, peptic ulcer disease, 
history of major GI surgery, eosinophilic GI disease, or food allergies).
4. Chronic use (≥7 consecutive days) of bismuth subsalicylate, simethicone, calcium 
carbonate, loperamide, proton-pump inhibitors, or ondansetron within 1 month prior to 
the Screening Visit.  From Screening up to Day 10, use of such therapies is not permitted.  
From Day 11 (inclusive), subjects are permitted to take these therapies.
5. Use of the following medications: montelukast, immunotherapy,  mast cell stabilizers, or 
parenteral, inhaled, or oral steroids up to 1 month prior to the Screening Visit.  Use of 
these medications is also not permitted for the duration of the study (except for the use of 
montelukast as per study protocol) and will lead to discontinuation.
6. Treatment with montelukast is contraindicated for any reason.


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
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7. Exposure to fumarates in the 3 months prior to the Screening Visit.  Exposure is also not 
permitted for the duration of the Screening Period.
8. Have 1 or more major comorbidities that, in the opinion of the Investigator, may affect 
the outcome of the study.
9. History of malignancy (except for basal cell carcinoma that had been completely excised 
prior to study entry), severe allergic or anaphylactic reactions or known drug 
hypersensitivity, abnormal laboratory results indicative of any significant disease, and/or 
a major disease that would preclude participation in a clinical study.
10. Prior confirmed diagnosis or medical history of chronic eosinophilia.
11. Current enrollment in any other interventional clinical studies.
12. Subjects meeting the inclusion criteria as defined in Section 8.1, and who do not meet 
any of the exclusion criteria will be eligible to commence with a 2-week Screening 
Period.  At the end of the Screening Period (at the Randomization Visit), GSRS scores 
and concomitant medication will be evaluated.  Subjects who meet the following criterion 
will be excluded from further study participation:  a GSRS score of ≥5 in 1 question for 
1 day, a GSRS score of ≥4 in 1 question for 2 consecutive days, or a GSRS score of ≥3 in 
1 question for 3 consecutive days.
13. Subjects who did not meet the required eDiary compliance (≥75%) in the 14 days prior to 
randomization.


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
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9.
ENROLLMENT AND RANDOMIZATION PROCEDURES
Once the investigational site has been activated for study participation, subjects may be enrolled 
if they have met the inclusion criteria in Section 8.1 and have not been excluded based on the 
exclusion criteria in Section 1.
9.1.
Enrollment and Screening
Subjects must be consented before any screening tests or assessments are performed.  At the time 
of consent, the subject will be considered enrolled into the study.  Participating study sites are 
required to document all screened candidates initially considered for inclusion in this study.  If a 
subject is excluded from the study, the reasons for exclusion will be documented in the subject’s 
source documents and on the screening log.  Subjects will be screened and eligibility will be 
confirmed after all screening assessments (Screening Visit and 2-week [+14 days] Screening 
Period) have been completed and after the Investigator has verified that they are eligible per the 
criteria in Sections 8.1 and 1.
9.2.
Randomization of Subjects
Subjects must be consented before any screening baseline tests or assessments are performed.  At 
the time of consent, the subject will be registered into the study.  Participating study sites are 
required to document all registered candidates initially considered for randomization in the 
study.  If the subject is not randomized in the study, the reasons will be documented in the 
subject’s source documents and on the registration log.
Subjects will be randomized at the Randomization Visit.  At this visit, eligible subjects will be 
randomized to 1 of 2 treatment arms (DMF + montelukast or DMF + placebo) in a 1:1 ratio.  
Subjects will be instructed not to take the blinded randomized study treatment until they receive 
an alert through their eDiary.  This alert will appear if a subject meets the criteria of GSRS score 
of ≥3 in 1 question for 1 day or a GSRS score of ≥2 in 1 question for 2 consecutive days.
No subjects may begin treatment prior to randomization and assignment of a unique subject 
identification number.  Any subject identification numbers that are assigned will not be reused, 
even if the subject does not receive treatment.  Subject identification numbers will be assigned 
by the Interactive Voice and Web Response System (IXRS).
Refer to the Study Reference Manual for details on registration.
As confirmation, Biogen will provide the Investigator with verification of the subject’s 
registration.  
9.3.
Blinding Procedures
All study staff will be blinded to the subject treatment assignments.  To maintain the study blind, 
it is imperative that subject treatment assignments are not shared with the subjects, their families, 
or any member of the study team, either at the study site or at Biogen, except the unblinded 
Pharmacist (or designee) and the unblinded Pharmacy Monitor.


Protocol 109MS414                                                                                                                                         Version 3
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10.
TREATMENT OF SUBJECTS
Refer to Section 11 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment.
10.1.
Study Treatment Schedule and Administration
Refer to Section 4.1 for a schematic on the study design.
10.1.1.
Dimethyl Fumarate
Subjects will receive a supply of commercial DMF through their specialty pharmacy or, in the 
case of insufficient insurance coverage, through the Biogen Patient Services Free Drug Program.
Dimethyl fumarate should be administered according to the prevailing product label (i.e., USPI).  
Dimethyl fumarate will be administered orally as 120 mg twice daily during the first 7 days and 
as 240 mg twice daily thereafter.
Subjects should swallow each DMF capsule whole.  The capsule and its contents are not to be 
crushed, divided, dissolved, sucked, or chewed.
Subjects are to contact the Investigator immediately if more than the prescribed dose is taken.
If a dose is missed, the missed dose can be taken if there is at least 4 hours between the morning 
and evening doses.  Otherwise, treatment should be continued with the next dose as planned.
After Day 10, dose modifications are at the discretion of the Investigator.  The prevailing product 
label (i.e., USPI) should be used as a guideline.  Dose modifications should be captured in the 
case report form (CRF).
10.1.1.1.
Treatment Precautions
Refer to the Package Insert for the treatment precautions.
10.1.1.2.
Treatment Adherence
Compliance with dosing will be monitored and recorded by study site staff.  Subjects are to 
return all unused DMF and used and unused packaging at each visit.  Study site staff will be 
responsible for recording study treatment accountability and treatment compliance information 
based on the unused study treatment returned by the subject at each visit.
10.1.2.
Montelukast and Placebo
10.1.2.1.
Administration
Montelukast (10 mg once daily in the evening) should be administered according to the 
prevailing product label (Singulair®).  Randomized treatments (montelukast or placebo) will be 
administered only until Week 8 of the study.


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If a subject does not remember to take a dose within 8 hours of the scheduled time (i.e., at least 
4 hours before the next scheduled dose), the dose should be skipped, and the next dose should be 
taken as scheduled.  Doses should not be doubled-up, or a missed dose taken the next day, to 
make up for missed doses.
10.1.2.2.
Treatment Precautions
Refer to the Package Insert for treatment precautions [SINGULAIR® USPI 2014].
10.1.2.3.
Treatment Adherence
Compliance with dosing will be monitored and recorded by study site staff.  Subjects are to 
return all unused study treatment and used and unused packaging at each visit.  Study site staff 
will be responsible for recording study treatment accountability and treatment compliance 
information based on the unused study treatment returned by the subject at each visit.
10.2.
Continuation of Treatment
Dimethyl fumarate and montelukast are approved treatments in the US, and continuing treatment 
following completion of the study requirements will be left to the discretion of the subject and 
Investigator.
10.3.
Concomitant Therapy and Procedures
A concomitant therapy is any drug or substance administered between the time the subject is 
enrolled in the study and the Safety Follow-Up Telephone Interview/ET Visit.
Apart from the treatments listed below and those listed in the exclusion criteria (see Section 1), 
the use of concomitant medications is left to the discretion of the Investigator.  The prevailing 
product label should be used as a guideline.
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy and physical 
therapy) or diagnostic assessment (e.g., blood gas measurement and bacterial cultures) performed 
between the time the subject is enrolled in the study and the Safety Follow-Up Telephone 
Interview/ET Visit.
10.3.1.
Prohibited Concomitant Medications
Use of symptomatic treatments to treat GI symptoms is prohibited, with the exception of 
therapies described below.
10.3.2.
Symptomatic Therapy to Treat Dimethyl Fumarate-Related Gastrointestinal
Events
From Day 10 onward, but not before, subjects may use the following medications: bismuth 
subsalicylate, simethicone, calcium carbonate, loperamide, proton-pump inhibitors, and 
ondansetron.


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10.4.
Recording Concomitant Medication
All concomitant therapies or procedures must be recorded on the subject’s CRF according to 
instructions for CRF completion.  The reason for initiation of such therapies or procedures must 
also be recorded on the CRF.


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11.
STUDY TREATMENT MANAGEMENT
Study site staff should review procedures for the handling and administration of DMF, 
montelukast, and placebo with subjects at the Randomization Visit, in addition to referring 
subjects to the relevant USPI for specific instructions on the handling, administration, storage, 
and preparation of study treatments.
11.1.
Dimethyl Fumarate
Dimethyl fumarate will be obtained via commercial methods and should be handled, 
administered, stored, and disposed of according to the prevailing Package Insert.  For further 
details on the DMF drug product, refer to the local USPI for more information.
11.1.1.
Dimethyl Fumarate Accountability
Subjects are to be instructed to bring all unused DMF to the study site.  The site will perform and 
document accountability based on the DMF that the subject presents at the study visits.
11.2.
Montelukast and Placebo
Montelukast and placebo must be stored in a secure location.  Accountability for this is the 
responsibility of the Investigator or qualified site staff.  More details concerning this 
responsibility are included in Section 11.2.1.
Montelukast and placebo must only be dispensed by a Pharmacist or appropriately trained staff 
and only to subjects participating in this study.  Once montelukast or placebo is dispensed to a 
subject, it can only be taken by that subject.
Additionally, Investigators should manage the treatment of subjects in compliance with the 
prevailing product label for montelukast treatment and ensure that subjects are fully informed 
about the potential risks and benefits of their treatments.
11.2.1.
Montelukast and Placebo Accountability
The study site must maintain accurate records demonstrating dates and amounts of montelukast 
and placebo treatment received, to whom dispensed (subject-by-subject accounting), amount 
returned by subject, and accounts of any montelukast or placebo accidentally or deliberately 
destroyed. Subjects are to be instructed to return all montelukast and placebo kits, both used and 
unused, to the site.  Unless otherwise notified, all montelukast and placebo kits, both used and 
unused, must be saved for study treatment accountability.  At the end of the study, reconciliation 
must be made between the amount of montelukast and placebo supplied and dispensed; after 
reconciliation, montelukast and placebo will be destroyed at the study site or returned to Biogen.  
A written explanation must be provided for any discrepancies.


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12.
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
AND/OR THE STUDY
A subject must permanently discontinue study treatment and be withdrawn from the study for 
any of the following reasons:

Failure to meet the required eDiary compliance criteria (≥75%) in the 14 days prior to 
randomization.

Failure to meet the GSRS score criteria during the DMF-GI Monitoring Period.

The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

The subject uses prohibited concomitant medications (as outlined in Sections 1 and 
10.3.1).

The subject withdraws consent.

At the discretion of the Investigator for medical reasons or for noncompliance.

The subject has a concurrent illness or injury, or abuses alcohol or drugs to the extent 
that, in the judgment of the Investigator and/or Sponsor, it would affect assessments 
of clinical status to a significant degree.
The reason for discontinuation of study treatment and withdrawal from the study must be 
recorded in the subject’s CRF.
Subjects who discontinue study treatment will be withdrawn from the study.  Whenever possible, 
subjects who prematurely discontinue study treatment should complete an ET Visit (undergoing 
the same assessments as the Week 10 Visit).




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treatment.  Background and dynamic (on-study) clinical disease characteristics and associated 
biomarker data will be utilized to predict subsequent disease worsening (severity), identify 
high-risk patient subgroups, and identify predictors of response to DMF treatment.
Refer to Section 4.2 for the timing of assessments.


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14.
SAFETY ASSESSMENTS
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed at multiple timepoints between the 
Screening Visit and Week 12/ET Visit:

AEs

SAEs
Refer to Section 4.2 for the timing of assessments.


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15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING
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 must be given the names and telephone numbers of study 
site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation 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 laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product.
15.1.2.
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, or

results in a congenital anomaly/birth defect.
An SAE may also be any other medically important event 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.)
15.2.
Monitoring and Recording Events
15.2.1.
Adverse Events
Any non-SAE (including flushing) experienced by the subject between the time of first dose of 
study treatment and the Safety Follow-up Telephone Interview is to be recorded on the CRF, 
regardless of the severity of the event or its relationship to study treatment.
There are 2 exceptions to this:


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
Any GI-related AE experienced by the subject between the time of the first dose of 
DMF and study completion is to be recorded by the subject in his/her eDiary.  Any GI 
AEs that lead to permanent study discontinuation or withdrawal or are serious must 
be recorded.

Non-SAEs of MS relapse will not be collected unless leading to permanent treatment 
discontinuation or study withdrawal.
Nonserious GI AEs should be recorded in the eDiary and not in the eCRF.
For subjects who permanently discontinue DMF during the study, AEs should be recorded 
through the Safety Follow-Up Telephone Interview conducted 2 weeks (±5 days) after the 
subjects’ Final Clinic Visit.
15.2.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of signing informed consent and the 
Safety Follow-Up Interview is to be recorded on an SAE Form, regardless of the severity of the 
event or its relationship to study treatment.  For subjects who permanently discontinue DMF 
during the study, SAEs should be reported through the Safety Follow-Up Telephone Interview
after the subjects’ Final Clinic Visit.  All SAEs must be reported to 
.
Any SAE ongoing when the subject completes the study or withdraws from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.
15.2.3.
All Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2.

The relationship of the event to study treatment as defined in Section 15.3.1.

The severity of the event as defined in Section 15.3.2.
15.2.4.
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 
 within 24 hours of the study 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.






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Investigator between the subject’s consent to participate 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.
15.5.
Procedures for Handling Special Situations
15.5.1.
Overdose
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to 
within 
24 hours.  An overdose should be reported even if it does not result in an AE.  Overdoses do not 
need to be recorded in the CRF; dosing information is recorded on a CRF.
15.5.2.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator or designee should 
contact the 
 Medical Advisor listed in the current Contact List (found in the Study 
Reference Manual) or the 
 24-Hour Urgent Medical Contact Center at 
 or 
 (alternative number). 
15.5.3.
Contraception Requirements
All women of childbearing potential must practice effective contraception throughout the study 
and for 30 days after they complete or withdraw from the study.  All men must practice effective 
contraception and should not donate sperm, throughout the study and for at least 90 days after 
their last dose of study treatment.
The Investigator must discuss contraceptive measures with the subject in relation to protocol 
requirements when initially determining suitability and desire to prescribe.
15.5.4.
Pregnancy
The Investigator should refer to the approved local label for guidance if female subjects become 
pregnant during the study.
At the Screening Visit and the Randomization Visit, female subjects of childbearing potential 
should be asked about their pregnancy status and possible pregnancies/spontaneous abortions 
since the last visit or contact.  Spontaneous abortions are considered to be SAEs and must be 
reported as such.  The Investigator should report the pregnancy to 
 
(using the Pregnancy Form provided) within 24 hours of the site becoming aware of the 
pregnancy. The Investigator should follow the outcome of the pregnancy and provide the 
outcome to
using the appropriate Pregnancy Form.


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If the partner of a male subject receiving DMF becomes pregnant at any time during the study, 
the Investigator should follow the pregnancy outcome and report any congenital anomaly or birth 
defect as an SAE to 
.
15.5.5.
Regulatory Reporting
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered.
Appropriate personnel in Biogen Safety and Benefit-Risk Management (or designee) will 
unblind SUSARs for the purpose of regulatory reporting.  Biogen will submit SUSARs (in 
blinded or unblinded fashion) to Regulatory Agencies according to local law.  Biogen will 
submit SUSARs to Investigators in a blinded fashion.
15.5.6.
Unblinding for Medical Emergencies
In this study, emergency decoding will be made available to the Investigator and designated 
personnel at Biogen and the contract research organization through an IXRS.
In a medical emergency when knowledge of the subject’s treatment assignment may possibly 
influence the subject’s clinical care, the Investigator may access the subject’s treatment 
assignment by IXRS.  However, prior to unblinding, the Investigator should attempt to contact 
the 
 Medical Advisor listed in the current Contact List (found in the Study Reference 
Manual) to discuss the emergency.  It is of note that the 
 Mediacal Advisor cannot 
provide approval for unblinding.
The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency, nor to personnel involved 
with the analysis and conduct of the study.
15.6.
Investigator Responsibilities
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, 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 the pregnancy.

Complete an SAE Form for each serious event and fax it to 
within 24 hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to 
 within 24 hours of the study site staff 
becoming aware of new information.


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
Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Report SAEs to local IRBs, as required by local law.
15.7.
Biogen Responsibilities
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor or designee
is responsible for reviewing with study site staff the definitions of AE and SAE, as 
well as the instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central IRBs, and 
Investigators of SAEs, as required by local law, within required time frames.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
16.1.
Description of Objectives and Endpoints
The objectives for this study are presented in Section 6.1.
16.2.
Description of Endpoints
The endpoints for this study are presented in Section 6.2.
16.3.
Demography and Baseline Disease Characteristics
Demographics and background disease data will be summarized by presenting frequency 
distributions or summary statistics.
16.4.
Efficacy Data
16.4.1.
Analysis Population
The intent-to-treat (ITT) population defined below will be used for the efficacy analysis.
The ITT population is defined as all randomized subjects who receive at least 1 dose of 
randomized study treatment (montelukast or placebo).
16.4.2.
General Methods of Analysis
In general, continuous variables will be presented with summary statistics (mean, standard 
deviation, median, and range), and categorical variables will be presented with frequency 
distributions.  All analyses will be conducted using 2-sided tests at the type I error rate (α-level) 
of 0.05 unless otherwise stated.  All efficacy analyses will be conducted using the efficacy 
population.
16.4.3.
Primary Endpoint Analysis
Change from Day 0 to Day 10 in GSRS rating will be computed.  The proportion of subjects 
with worsening in GI AEs, defined as increases in GSRS ratings, will be estimated to obtain the 
rate of worsening in the 2 arms.  The difference in the rate of worsening in GI AEs will be 
analyzed using a chi-square test and the logistic regression model, adjusting for covariates and 
confounding factors.
16.4.4.
Secondary Endpoints Analysis
The average change of GI severity score from Day 0 to Week 10 will be analyzed using an 
analysis of covariance (ANCOVA) model to adjust for covariates and confounding factors such 
as early drop-outs.  Time to first worsening and time to recovery from the last worst GSRS score 
to Day 0 GSRS score will be analyzed using Kaplan-Meier methods and a Cox proportional 




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17.
ETHICAL REQUIREMENTS
Biogen and the Investigator must comply with all instructions, regulations, and agreements in 
this protocol and applicable International Conference on Harmonisation (ICH) and Good Clinical 
Practice (GCP) guidelines and conduct the study according to local regulations.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Institutional Review Board (IRB)
The Investigator must obtain IRB approval of the protocol, ICF, and other required study 
documents prior to starting the study.
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the IRB.  A copy of the approved ICF must be provided to Biogen.  After 
approval, the ICF must not be altered without the agreement of the relevant IRB and Biogen.
It is the responsibility of the Principal Investigators to ensure that all aspects of institutional 
review are conducted in accordance with current governmental regulations.
Biogen must receive a letter documenting IRB 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.
A progress report must be submitted to the IRB at required intervals and not less than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the IRB and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations.  Written informed consent must be obtained from all subjects participating in a 
clinical study conducted by Biogen.
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject.  The subject 
must be given sufficient time to consider whether to participate in the study.
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s medical record prior to 
any testing under this protocol, including screening tests and assessments.


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Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Biogen to use and disclose PHI (i.e., subject-identifiable health information) in compliance with 
local law.
The signed consent form will be retained with the study records.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., PHI authorization in North 
America).
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partner(s) and designee(s), IRBs, and 
various government health agencies may inspect the records of this study.  Every effort will be 
made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform on-site audits.  The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested.
18.3.
Monitoring of the Study
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories.
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of the 
study and after the study has completed, as appropriate.
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.
The monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contract(s) between the institution, Investigator, and Biogen.
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
Biogen will be responsible for all administrative aspects of this study including, but not limited 
to, study initiation, monitoring, management of AEs, and data management.
19.1.
External Contract Organizations
19.1.1.
Contract Research Organization
will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, management of SAE reports, and data management.  Before subjects 
are screened at each study site, 
will review study responsibilities with the Investigators 
and other study site staff, as appropriate.
19.1.2.
Interactive Voice/Web Response System
An IXRS will be used in this study.  Before subjects are screened or enrolled, the IXRS vendor 
will provide each study site with appropriate training and a user manual.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on electronic CRFs.  Electronic 
data will be captured and managed using an electronic data capture (EDC) system supported and 
configured by the EDC vendor.  
 will provide oversight to the EDC.
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze all samples collected for this study.
19.1.5.
Home Visiting Company
A home visiting company has been selected by Biogen to perform home visits, where permitted, 
if appropriate.
19.2.
Study Committees
Not applicable.
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the IRBs 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 IRBs 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, Biogen 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.


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In the event of a protocol modification, the subject consent form may require similar 
modifications (see Sections Error! Reference source not found. and 17.3).
19.4.
IRB Notification of Study Completion or Termination
Where required, the Health Authorities and IRBs must be notified of completion or termination 
of this study, and sent a copy of the study synopsis in accordance with necessary timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including, but not limited to, 
archival at an off-site facility or transfer of ownership if the Investigator leaves the site.
19.6.
Study Report Signatory
Biogen will designate one of the participating Study 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 Biogen.


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60
20.
REFERENCES
Linker RA, Lee DH, Ryan S, van Dam A, Conrad R, Bista P, et al. Fumaric acid esters exert 
neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.
Brain. 2011;134(3):678-92.
Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in 
neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678-
92. Epub 2011/03/01.
SINGULAIR® (montelukast sodium) Package Insert. Whitehouse Station, NJ: Merck & Co., 
Inc.; July 2014.
Tornatore C, Amjad F. Attenuation of dimethyl fumarate-related gastrointestinal symptoms with 
montelukast [poster]. Presented at the 68th Annual Meeting of the American Academy of 
Neurology; 2014 April 26 – May 3; Philadelphia, PA.


Protocol 109MS414                                                                                                                                         Version 3
Phase 4 Study of GI Tolerability in DMF-Treated Subjects With Relapsing Forms of MS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen
MA Inc.
61
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Double-Blind, Placebo-Controlled Study of 
Montelukast on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple 
Sclerosis Receiving TECFIDERA® (Dimethyl Fumarate) Delayed-Release Capsules,” 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)


Signature Page
Document Name: 109MS414 Protocol V3 Final 01-Feb-2016
Document Title: A Multicenter, Double-Blind, Placebo-Controlled Study of Montelukast
on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis
Receiving TECFIDERA® (Dimethyl Fumarate) Delayed Release Capsules
Signed by
Role
Date / Time (UTC)
Signing as Approver
02/05/2016 21:21:11
Signing as Reviewer
02/05/2016 17:15:11


1
109MS414 / NCT02410278 
Biogen - BG00012 in MS 
Statistical Analysis Plan 
BIOGEN  
STATISTICAL ANALYSIS PLAN 
A Multicenter, Double-Blind, Placebo-Controlled Study of Montelukast on 
Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis 
Receiving TECFIDERA®  (Dimethyl Fumarate) Delayed-Release Capsules 
______________________________________________________________________ 




 
3  
TABLE OF CONTENTS 
Table of Contents 
1 
INTRODUCTION ......................................................................................................... 6 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 6 
2.1 
Primary Objective and Endpoint ................................................................................... 6 
2.2 
Secondary Objectives and Endpoints ............................................................................ 6 
2.3 
Exploratory Objectives and Endpoints ......................................................................... 7 
3 
STUDY DESIGN ............................................................................................................ 7 
3.1 
Study Overview ............................................................................................................ 7 
3.1 
Definition of the GSRS threshold ................................................................................. 9 
3.2 
Overall Study Duration and Follow-Up ........................................................................ 9 
4 
SCHEDULE OF EVENTS .......................................................................................... 10 
5 
INTERIM ANALYSIS ................................................................................................ 13 
6 
SAMPLE SIZE JUSTIFICATION ............................................................................ 13 
7 
STATISTICAL ANALYSIS METHODS .................................................................. 13 
7.1 
Analysis population .................................................................................................... 13 
7.1.1 Modified ITT population ......................................................................................... 13 
7.1.2 Safety population ...................................................................................................... 13 
7.1 
Analysis of baseline data ............................................................................................ 14 
7.2 
Study subjects ............................................................................................................. 14 
7.2.1 Analysis population .................................................................................................. 14 
7.2.2 Accounting of Subjects ............................................................................................. 15 
7.2.3 Protocol Deviations ................................................................................................... 15 
7.2.4 Demographic and Baseline Characteristics ............................................................ 15 
7.2.5 MS Treatment History ............................................................................................. 15 
7.2.6 Medical History ......................................................................................................... 16 
7.2.7 Extent of Exposure and eDiary Compliance .......................................................... 16 
7.2.8 Concomitant Medications ........................................................................................ 17 
7.3 
Efficacy Analysis ........................................................................................................ 17 
7.3.1 Analysis Population .................................................................................................. 17 
7.3.2 GSRS score ................................................................................................................ 17 
7.3.3 Analysis Methods-Primary endpoints ..................................................................... 18 
7.3.4 Analysis Methods-Secondary endpoints ................................................................. 18 
7.3.5 Analysis methods-Exploratory endpoints ............................................................... 21 


 
4  
7.4 
Safety Data .................................................................................................................. 22 
7.4.1 Safety analysis Population ....................................................................................... 22 
7.4.2 Analysis Methods ...................................................................................................... 22 
8 
LIST OF TABLES ....................................................................................................... 23 
9 
LIST OF LISTINGS .................................................................................................... 26 
10 
LIST OF FIGURES ..................................................................................................... 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
5  
 
 
 
 
 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
 
 
CI 
confidence interval 
CRF 
case report form 
DMF 
dimethyl fumarate 
eDiary 
electronic diary 
ET 
early termination 
GI 
gastrointestinal 
GSRS 
Gastrointestinal Symptom Rating Scale 
 
 
 
 
ITT 
intent-to-treat 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model for repeated measures 
MS 
multiple sclerosis 
OR 
odds ratio 
 
 
PT 
preferred term 
Q1 
25th percentile 
Q3 
75th percentile 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
 
SD 
standard deviation 
SOC 
System Organ Class 
WHO 
World Health Organization 
 
 


 
6  
1 
INTRODUCTION 
This statistical analysis plan (SAP) reflects detailed statistical methods to be used for 
studying Montelukast on Gastrointestinal Tolerability in patients with Relapsing Forms of 
Multiple Sclerosis receiving Tecfidera® (Dimethyl Fumarate) Delayed-Release Capsules. 
The SAP is based on the final version of protocol 109MS414 (Version 3) dated 01 
February 2016.  
 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective and Endpoint 
The primary objective of this study is to evaluate whether Montelukast can reduce the 
severity of gastrointestinal (GI) events, measured by the Gastrointestinal Symptom Rating 
Scale (GSRS), after oral administration of Dimethyl Fumarate (DMF) in subjects with 
relapsing forms of multiple sclerosis (MS). 
The primary endpoint of this study is the proportion of subjects with a worsening in the 
severity of GI adverse events (AEs), measured by the average change from Day 0 to Day 
10 in GSRS score. If a patient takes the randomized study treatment one day after his or 
her GSRS score reaches the GI threshold, Day 0 is defined as the day prior to the first 
dose of randomized study treatment. If a patient takes the randomized study treatment on 
the same day when the GSRS score reaches the GI threshold, Day 0 is defined as the day 
with the first dose of randomized study treatment. If a patient missed the randomized 
study treatment for a few days after the GSRS score reached the GI threshold, Day 0 is 
the day immediately prior to the first dose when the GI threshold was reached. Day 10 is 
defined as 10 days after Day 0.   
 
2.2 
Secondary Objectives and Endpoints 
The secondary objectives in this study population are: 
• To evaluate whether Montelukast after oral administration of DMF in subjects 
with relapsing forms of MS: 
− decreases discontinuations due to GI events 
− reduces the number of subjects taking symptomatic therapies for GI events 
• To investigate the effect of Montelukast on the incidence of flushing events 
after oral administration of 240 mg DMF in subjects with relapsing forms of 
MS 
The secondary endpoints are: 
• Average change of GI severity scores from Day 0 to Day 10, as measured by the 
total change of GSRS scores from Day 0 over the first 10 days (Day 1 to Day 
10), divided by the total number of days with GSRS recorded 
• Average change of GI severity scores from Day 0 to Week 10, as measured by the 
total change of GSRS score from Day 0 over the first 10 weeks (Day 1 to Week 
10), divided by the total number of days with GSRS recorded 






 
9  
 
 
3.1 
Definition of the GSRS threshold 
Two definitions of the GSRS threshold were used in this study.  
Definition in the version 1 of the protocol: GSRS score of ≥5 in one question for 1 day or 
a GSRS score of ≥4 in one question for 2 consecutive days or GSRS score of ≥3 in one 
question for 3 consecutive days.  
Definition in the 2nd and higher Protocol versions:  GSRS score of ≥3 in one question for 
1 day or a GSRS score of ≥2 in one question for 2 consecutive days.  
 
3.2 
Overall Study Duration and Follow-Up 
The study period consists of a 2-week (+14 days) Screening Period, up to a total of 14 
weeks of DMF therapy (including DMF-GI Monitoring Period and randomized treatment 
administration period), including 8 weeks of concomitant randomized study treatment 
(DMF + Montelukast or DMF + placebo), and the Safety Follow-Up Telephone 
Interview.  The duration of a subject’s participation will be up to 18 weeks.  Subjects who 
discontinue the study early will complete the same assessments specified for the Week 10 
Visit.   


 
10  
4 
SCHEDULE OF EVENTS 
 
Table 1 includes details on the schedule of activities in Study 109MS414. 
 
 
Table 1: 
Schedule of Activities 
 
Assessment 
Screening 
Visita 
Screening 
Period 
(2 weeks 
+14 days) 
Randomization 
Visita  
(Week -4) 
DMF-GI 
Monitoring 
Period 
(up to 28 days) 
Wk 0a,b 
Wk 2c 
Wk 4a 
Wk 8c 
Wk 10a/ET 
Safety 
Follow-Upd 
(± 5 days) 
Clinic Visit 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
Xe 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
 
 
 
 
 
 
 
 
 
Medical History (incl. 
MS disease status)g 
X 
 
 
 
 
 
 
 
 
 
Alcohol Consumption 
X 
 
 
 
 
 
 
 
 
 
Tobacco Use 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testingh 
X 
 
X 
 
 
 
 
 
 
 
Concomitant 
Medications/ 
Procedures 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Blood Biomarkers 
(optional)j 
 
 
X 
 
 
 
X 
 
X 
 


 
11  
Assessment 
Screening 
Visita 
Screening 
Period 
(2 weeks 
+14 days) 
Randomization 
Visita  
(Week -4) 
DMF-GI 
Monitoring 
Period 
(up to 28 days) 
Wk 0a,b 
Wk 2c 
Wk 4a 
Wk 8c 
Wk 10a/ET 
Safety 
Follow-Upd 
(± 5 days) 
Dispense eDiary 
X 
 
 
 
 
 
 
 
 
 
eDiary Training 
X 
 
 
 
 
 
 
 
 
 
eDiary Entries (Daily)k 
 
 
 
Return eDiary to 
Clinicall  
 
 
Xm 
Xm 
 
 
 
 
X 
 
Dispense DMF With 
Dosing Instructions 
 
  
X 
 
 
 
 
 
 
 
DMF Administration 
(Daily) 
 
 
DMF administration will occur every day as per the USPI 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Dispense Randomized 
Study Treatments 
 
 
Xn 
 
 
 
 
 
 
 
Randomized Study 
Treatment 
Administration (Daily) 
 
 
 
 
Randomized study treatment administration will occur 
every day as per the prescribing information. 
 
 
SAEs 
SAE data will be collected from the signing of the informed consent up to the Safety Follow-Up Telephone Interview.  MS relapses resulting in hospitalization are 
considered SAEs but will not be reported as SAEs in the study unless the relapse is complicated by other SAEs or is fatal. 
AEs 
 
 
 
AE data will be collected from the first dose of DMF up to the Safety Follow-Up Telephone Interview. 
Note:  Weeks  2, 4, and 8 will have a visit window of ±2 days, and Week 10 will have a visit window of ± 3 days. 
Abbreviations:  AE = adverse event; 
 DMF = dimethyl fumarate; DNA = deoxyribonucleic acid; eDiary = electronic diary; EDSS = Expanded Disability Status 
Scale; ET = early termination; GI = gastrointestinal; GSRS = Gastrointestinal Symptom Rating Scale; 
 
; MS = multiple 
sclerosis;
; RNA = ribonucleic acid; SAE = serious adverse event; USPI = United States Prescribing Information;Wk = week. 
a This visit must be performed in clinic. 
b Subjects will receive an alert through the eDiary if their GSRS scores reach the appropriate threshold.  This alert will tell the subject to begin taking the randomized study treatment the same 
day.  At this time, study site should arrange the Week 0 Visit as soon as possible after the first administration of randomized study treatment.  Visit dates will be measured from the first 
administration of randomized study treatment.  
c This visit may be performed remotely if more convenient for the subject; site must telephone the subject to document concomitant medications/procedures and AEs. 
d The safety follow-up will be performed as a telephone interview. 
e GI symptom and eDiary compliance assessment. 


 
12  
f Including height and weight measurements and vital signs (temperature, blood pressure, and sitting blood pressure). 
g Medical history, including MS disease status, will include collection of information on duration of MS, relapse history, EDSS score, and treatment for MS. 
h Dipstick test (only for women of childbearing potential). 
i 
 
 
j Serum, RNA, and DNA samples will be collected for biomarker analysis and future use analysis in subjects who provide additional consent.  A single DNA sample can be taken at any of 
prespecified timepoints. 
k Subjects will be required to record their daily GI symptoms in the eDiary every day from the Screening Visit up to Week 10. 
l eDiaries will be returned if (1) the subject fails during the Screening Period, (2) the subject does not reach the required GI symptom threshold during the DMF-GI Monitoring Period, or (3) the 
subject completes or discontinues the study. 
m Subjects who do not reach the GI symptom threshold during the DMF-GI Monitoring Period (a GSRS score of ≥5 in 1 question for 1 day, ≥4 in 1 question for 2 consecutive days, or ≥3 in 1 
question for 3 consecutive days) will be discontinued. 
n Subjects are dispensed randomized study treatment at this visit but must not begin taking the medication until alerted about their eDiary.


 
13  
5 
INTERIM ANALYSIS 
No interim analysis will be performed. The study will be stopped for administrative 
reasons. Enrollment will be closed when approximately 60 patients are randomized and 
dosed up to Day 10. Enrolled patients will be followed until they complete the safety 
follow up visit. Results will be reviewed at the group level when these patients complete 
the study up to Day 10, and at the subject level when these patients complete the whole 
study. 
 
6 
SAMPLE SIZE JUSTIFICATION 
Assuming that 40% of the placebo subjects will be improving (by chance) without any 
intervention, a total sample size of 118 (dosed with randomized study treatment), 59 per 
treatment arm (after randomization), would provide approximately 80% power to detect a 
30% difference between the treatment arm and placebo arm in proportion of subjects with 
any improvement in GI severity, as measured by the average change from Day 0 in GSRS 
score to Day 10. Power was estimated assuming a 15% early discontinuation rate.  
 
7 
STATISTICAL ANALYSIS METHODS 
The statistical software, SAS®, will be used for all summaries and statistical analyses.  
Summary statistics will be used throughout.  For continuous endpoints, the summary 
statistics will generally include: the number of subjects with data, mean, standard 
deviation (SD), median, 25th and 75th percentile (Q1, Q3), minimum and maximum.  For 
categorical endpoints, the summary statistics will generally include:  number of patients 
randomized and dosed, the number of patients with data, and the number and percent of 
subjects with data in each category. 
All statistical tests will be 2-sided with a type I error rate of 5%, unless otherwise 
specified.    
 
7.1 
Analysis population 
7.1.1 Modified ITT population  
The modified intent-to-treat (modified ITT) population consists of all patients who were 
randomized, received at least one dose of DMF treatment, received at least one dose of 
study treatment (Montelukast or placebo) on/after the first DMF dose date, and had at 
least one GSRS score measurement during the Day 1 – Day 10 period. 
 
7.1.2 Safety population 
Montelukast/placebo safety analysis population 
 
The primary safety analysis population consists of all patients who received at least 1 
dose of randomization study treatment (Montelukast or placebo). 


 
14  
 
DMF safety analysis population 
 
The DMF safety analysis population will consists of all patients who received at least 1 
dose of DMF.  Selected analyses will be presented in the DMF safety analysis population. 
 
7.1 
Analysis of baseline data 
 
Baseline GSRS score is defined as the score collected at Day 0.  
Baseline data of demographics and disease characteristics are defined as data collected at 
the Screening visit. If there is more than one value on or before the screening visit, the 
Baseline value will be selected from all measurements collected before or on the date of 
the screening visit; the value closest to the date of screening visit will be used as the 
Baseline value.  
Definition of baseline value for clinical laboratory data 
Tecfidera baseline value 
The Tecfidera baseline value is defined as the measurement collected before or on the 
date of the Randomization visit. If there is more than one value on or before the 
Randomization visit date, then the Tecfidera baseline value will be selected from all 
measurements collected before or on the date of the Randomization visit; the value 
closest to the date of Randomization visit will be used as the Tecfidera baseline value.  
Montelukast baseline value 
The Montelukast baseline value is defined as the measurement collected before or on the 
date of first dose of Montelukast /placebo. If there is more than one value on or before the 
first dose date of Montelukast /placebo, then the Montelukast baseline value will be 
selected from all measurements collected prior to or on the date of the first dose of 
Montelukast/placebo; the value closest to the date of the first dose date will be used as the 
Montelukast baseline value.  
 
7.2 
Study subjects 
7.2.1 Analysis population 
Unless otherwise stated, the analysis population for the efficacy analyses will be the 
modified ITT population. Safety analyses will be summarized in the Montelukast/placebo 
safety analysis population, while selected outputs will be performed in the DMF safety 
analysis population. 
 


 
15  
7.2.2 Accounting of Subjects 
The following subject categories will be summarized for this study using numbers and 
percentages based on all patients enrolled in the study: 
 Number of subjects randomized 
 Number of subjects who were dosed with DMF (DMF safety analysis population) 
 Number of subjects dosed with study treatment (modified ITT population, 
Montelukast/placebo safety analysis population) 
 Number of subjects completed study treatment 
 Number of subjects discontinued study treatment 
• Reason for study treatment discontinuation 
 Number of subjects continuing DMF at the Week 10 visit  
 Number of subjects discontinued DMF by Week 10 or at Week 10 
• Reason for DMF treatment discontinuation 
 Number of subjects completed the study  
 Number of subjects withdraw from the study  
• Reason for study withdrawal 
Subjects who discontinued treatment or withdrew from the study and the reasons for 
discontinuation or withdrawal will be listed. In certain cases, case report form (CRF) text 
detailing the reasons for discontinuation may suggest additional clarification of the reason 
provided on the CRF.  Therefore, additional information for subject accounting may be 
presented, utilizing reasons for discontinuing treatment from the study reclassified based 
on the detailed CRF text.       
7.2.3 Protocol Deviations 
Protocol deviations identified in the study will be listed.  
7.2.4 Demographic and Baseline Characteristics 
Demographic data, including age (years), age category (<= 40, > 40) and gender will be 
summarized.  In addition, baseline height, weight, body mass index (BMI), systolic blood 
pressure, diastolic blood pressure and temperature will also be summarized.  
Baseline disease characteristics will also be summarized using descriptive statistics.  
These include years since disease (MS) onset, years since diagnosis, days from the most 
recent pre-study relapse, total number of relapses in the past 12 months, 2 years and 3 
years and Baseline EDSS score.  
7.2.5 MS Treatment History 
MS treatment prior to the study will be summarized by the type of approved therapy. 
Number and percentage of patients with a particular approved therapy will be presented. 


 
16  
7.2.6 Medical History 
Medical history and MS disease history will be summarized as the number and 
percentage of patients with history of a medical condition in each body system.  
 
7.2.7 Extent of Exposure and eDiary Compliance 
Montelukast/placebo treatment exposure and compliance 
The total number of days on study treatment (Montelukast or placebo) will be 
summarized for the modified ITT population. The number of days on study treatment is 
calculated as the number of days from the date of the first dose of the study treatment 
(Montelukast or Placebo) to the date of the last dose of study treatment, plus 1. 
In addition, the number of doses of study treatment taken between Day 0 and Day 10 will 
be summarized for the modified ITT population. 
Study treatment compliance rate will also be summarized in the modified ITT population.  
Study treatment compliance rate will be defined as the total number of study treatment 
doses taken divided by the total number of study treatment doses expected to be taken. 
Study treatment compliance will be summarized in each of the following periods: 
• From Day 0 to Day 10 
• From Day 0 to Week 8 
DMF treatment exposure and compliance 
 
In the DMF safety analysis population, the total number of days on DMF will be 
summarized. The number of days on DMF is calculated as the number of days from the 
date of the first dose of DMF after randomization to the date of the last dose of DMF, 
plus 1.  
 
In addition, the number of doses of DMF taken between Day 0 and Day 10 will be 
summarized for the modified ITT population. 
 
The DMF compliance rate will also be summarized.  The DMF compliance rate will be 
defined as the total number of DMF doses taken divided by the total DMF doses expected 
to be taken during the period. DMF compliance will be summarized in the modified ITT 
population in each of the following periods: 
• From the randomization visit to Week 10   
• From the randomization visit to Day 0 
• From Day 0 to Day 10   
• From Day 0 to Week 10   
Time on study 
 


 
17  
Time on study, based on the number of days from the date of the first dose of DMF to the 
last date on study plus 1, will also be summarized, for the Montelukast/placebo safety 
analysis population. The last known date on the study will be taken as the last 
visit/evaluation date from all relevant data for a subject. 
 
GSRS compliance 
 
GSRS score compliance rate will be summarized in the modified ITT population. GSRS 
score compliance rate will be defined as the total number of days when the GSRS score is 
recorded divided by the total number of days when the GSRS score is expected to be 
recorded. GSRS score compliance will be summarized in each of the following periods: 
 
• From Day 0 to Day 10 
• Form Day 0 to Week 10 
 
7.2.8 Concomitant Medications 
Concomitant medications, any drug or substance administered on or after the day of the 
first dose of DMF will be summarized. Concomitant medications will be coded using the 
World Health Organization (WHO) drug dictionary.  
Data on concomitant medications treating for GI symptoms are collected in the eDairy. 
Data on concomitant medications treating for non-GI symptoms are collected in the CRF. 
Number and percentage of patients taking concomitant medication will be summarized.  
 
7.3 
Efficacy Analysis  
7.3.1 Analysis Population 
The primary analysis population will be the modified intent-to-treat (modified ITT) 
population defined in 7.1.1. 
 
7.3.2 GSRS score 
GSRS is an interview-based rating scale consisting of 15 items for assessment of GI 
symptoms. Items are scored for intensity on a 7-grade Likert scale, defined by descriptive 
anchors such that 0 = none, 1 = minor, 2 = mild, 3 = moderate, 4 = moderately severe, 5 = 
severe, and 6 = very severe discomfort. The overall GSRS score is the mean of these 15 
items, varying from 0 to 6; a score of 0 indicates that no symptoms are present, and a 
score of 6 indicates the worst possible degree of all symptoms.  In addition, these 15 
items can be grouped into 5 dimensions: abdominal pain syndrome (3 items, abdominal 
pain, hunger pain and nausea), reflux syndrome (2 items, heartburn and acid 
regurgitation), indigestion syndrome (4 items, abdominal distension, increased flatulence, 
borborygmus and eructation), diarrhea syndrome (3 items, loose stools, diarrhea and 
urgency of defecation) and constipation syndrome (3 items, constipation, hard stools and 


 
18  
feeling of incomplete evacuation). A dimension score is calculated as the mean of the 
items belonging to the specific syndrome. The primary analysis will be based on the 
overall GSRS score and sensitivity analysis will be based on the 5 dimension score as 
appropriate.  
7.3.3 Analysis Methods-Primary endpoints 
 
Proportion of subjects with a worsening in the severity of GI AEs, measured by the 
average change from Day 0 to Day 10 in GSRS score  
 
The average change of the GSRS score from Day 0 (baseline) to Day 10 will be 
calculated as the sum of changes from baseline in GSRS score over the first 10 days 
divided by the total number of days with GSRS recorded. A positive average change of 
GSRS score from Day 0 to Day 10 means a patient has an overall worsened GI severity. 
A negative average change of GSRS score from Day 0 to Day 10 means an overall 
improved GI severity.  
 
The proportion of subjects with worsening will be summarized by treatment and will be 
estimated from a weighted logistic regression model adjusted for age, weight and baseline 
GSRS score as continuous variables. Each patient included in this model will be assigned 
a weight defined as the proportion of days with GSRS score recorded. The weight is used 
to account for the missing data when patients do not report the GSRS score. The odds 
ratio (OR) for the Montelukast treatment group compared to placebo will be reported.  
The corresponding P-value from the likelihood ratio test of the null hypothesis that the 
OR = 1 will be given. Profile likelihood 95% profile likelihood confidence interval (CIs) 
will be given for the odds ratio.                                                                       
 
SAS procedure “genmod” or SAS procedure “logistic” will be used to perform the 
primary analysis. Below is the example of SAS procedure genmod: 
 
proc genmod data=ds1 descending;*assuming ds1 is the name of the data 
set 
  class trtpn; 
  model worsec = trtpn weight age gsrsb/dist=bin link=logit lrci; 
  weight pdays; 
  lsmeans trtpn / pdiff cl; 
  contrast "difference between treatments" trtpn -1 1; 
run; 
 
Depending on the GSRS, study treatment and/or the DMF compliance, sensitivity 
analysis may be performed among patients with a compliance rate from Day 0 to Day 10 
above a certain threshold. A chi-squared test for the difference in the rate of worsening 
between the two treatment groups may also be performed.  
 
7.3.4 Analysis Methods-Secondary endpoints 
 
 
Average change of GI severity scores from Day 0 to Day 10, as measured by the total 
change of GSRS scores from Day 0 over the first 10 days (Day 1 to Day 10), divided 
by total number of days with GSRS recorded 
 


 
19  
Average change of GI severity scores from Day 0 (baseline) to Day 10 will be calculated 
as the sum of changes from baseline in GSRS score over the first 10 days divided by the 
total number of days with GSRS recorded.  The average change will be summarized by 
treatment and analyzed using an analysis of covariance (ANCOVA) model adjusted for 
age, weight and baseline GSRS score. To adjust for missing data, a weight defined as the 
proportion of days with GSRS score recorded will be assigned to each subject. The 
difference of the average GSRS score between the two treatment arms will be tested. 
 
Normality assumption of the ANCOVA will be tested. If violated, a rank based 
ANCOVA will be used.  
 
A sensitivity analysis using a mixed-effects model for repeated measures (MMRM) for 
the change of the GSRS score from baseline will be conducted. The model will be 
adjusted for age, weight and baseline GSRS score as continuous variables, and will have 
unstructured variance-covariance structure. The primary test based on the model will be 
the test of the null hypothesis of no difference between the two treatment groups in the 
average change from Day 0 (baseline) between Day 1 and Day 10. Trajectory plot of the 
change in GSRS score with 95% CIs, by time and by treatment group, estimated from the 
model, will be presented. Trajectory plot of the mean change in GSRS score by day will 
be presented as well.  
 
Depending on the GSRS, study treatment and/or DMF compliance, sensitivity analysis 
may be performed using MMRM in patients with a compliance rate from Day 0 to Day 10 
above a certain threshold. 
 
Average change of GI severity scores from Day 0 to Week 10 as measured by total 
change of GSRS scores from Day 0 over the first 10 weeks (Day 1 to Week 10) 
divided by total number of days with GSRS recorded 
 
Average change of GI severity scores from Day 0 (baseline) to Week 10 will be 
calculated as the sum of changes from baseline in GSRS score over the first 10 weeks 
divided by the total number of days with GSRS recorded. This endpoint will be analyzed 
by the MMRM as in the analysis of the above endpoint. Sensitivity analyses using 
ANCOVA model for the average change may be performed. Trajectory plots of mean 
change and the model based estimated mean change from baseline in GSRS score (with 
95% CIs), by time and by treatment group, will be presented.  
 
 
Time to first worsening of GSRS in GI severity 
 
The GI severity is worsened if the GSRS score increases from baseline (Day 0). Time to 
first worsening of GSRS in GI severity is defined as the number of days from Day 0 to 
the first date with a worsened GSRS score. If a patient does not experience any worsening 
from Day 0 to Day 10, his/her time to first worsening will be censored at Day 10 or the 
day of study treatment (Montelukast/PBO) discontinuation, whichever comes first.  
 
Time to the first worsening of GSRS by treatment arm will be analyzed using the Kaplan-
Meier method and the Cox’s proportional hazards model adjusted for age, weight and 


 
20  
baseline GSRS score. If the proportionality assumption does not hold, a log-rank test will 
be used. 
 
 
Time to recovery to Day 0 GSRS score from the last occurrence of the worst score in 
GI severity 
 
The GI severity is recovered to Day 0 GSRS score if the GSRS score is smaller than or 
equal to the Day 0 score. Time to recovery to Day 0 score from the last occurrence of the 
worst score is defined as the date of recovery minus the date of the last occurrence of the 
worst score. If a patient does not experience a worsening in GSRS score, the last 
occurrence of the worst score is Day 0 and time to recovery is 1. If a patient experiences a 
worsening of GSRS score but does not experience a recovery before Week 8, his/her time 
to recovery will be censored at Week 8 or the day of study treatment (Montelukast/PBO) 
discontinuation or the day of switching to other GI medications listed in I/E criterion 8, 
whichever comes first.  
 
Time to recovery to Day 0 GSRS score from the last occurrence of the worst score will be 
analyzed using the Kaplan-Meier method and the Cox’s proportional hazards model. 
 
 
Average change of GSRS score from Day 0 to Week 1, 2, 3, 4, 5, 6 and 8 
 
Average change of GSRS score from baseline (Day 0) to Week 1, 2, 3, 4, 5, 6 and 8 will 
be summarized; a repeated measures model for the change of the GSRS score from 
baseline, adjusted for age, weight and baseline GSRS score, will be used to estimate 
effect at each time point. Sensitivity analyses using ANCOVA model for the average 
change may be performed. 
Average change of GSRS score from Day 0 to 72 hours from the initiation of 
randomized study treatment 
 
Average change of GSRS score from baseline (Day 0) to 72 hours (Day 3) from the 
initiation of randomized study treatment will be summarized and analyzed by the repeated 
measures method. No sensitivity analysis will be performed. 
 
Proportion of subjects who take GI symptomatic therapy during the study 
 
From Day 10 onward, subjects are allowed to use symptomatic therapy to treat DMF-
related GI events. The proportion of subjects who take GI symptomatic therapy from Day 
10 to Week 10 will be summarized by treatment and analyzed using the Chi-squared test. 
 
Percentage of subjects who discontinue DMF therapy due to the GI-related adverse 
events from Day 0 to Week 10 
 
The proportion of subjects who discontinue DMF due to the GI-related adverse events 
from Day 0 to Week 10 will be summarized by treatment and analyzed using the Chi-
squared test.  
 








 
24  
Table 3: Summary of alcohol consumption and tobacco use 
Table 4: Summary of medical history  
Table 5: Summary of MS disease history  
Table 6: Summary of prior disease-modifying MS treatment history  
Table 7: Summary of time on study treatment  
Table 8: Summary of time on DMF treatment  
Table 9: Summary of time on study 
Table 10.1: Number of doses of study treatment taken between Day 0 and Day 10   
Table 10.2: Number of doses of DMF treatment taken between Day 0 and Day 10   
Table 11.1: Summary of GSRS compliance rate 
Table 11.2: Summary of study treatment compliance rate 
Table 11.3: Summary of DMF compliance rate from randomization visit to Week 10 
Table 11.4: Summary of DMF compliance rate from Day 0 to Day 10 and to Week 10 
Table 11.5: Summary of DMF compliance rate from randomization visit to Day 0 
Table 12: Summary of concomitant medications  
Table 13: Summary of primary endpoint  
Table 14: Summary of primary endpoint among patients with GSRS e-Diary compliance 
rate >= 80%, at least 5 doses of study medication, and at least 10 doses of DMF in the 
Day 0 – Day 10 period 
Table 15.1: Summary of average change of GI severity score from baseline (Day 0) by 
ANCOVA, Day 1 to Day 10: overall and by dimension 
Table 15.2: Summary of average change of GI severity score from baseline (Day 0) by 
ANCOVA with additional covariates, Day 1 to Day 10: overall and by dimension 
Table 16: Summary of average change of GI severity score from baseline (Day 0) by 
repeated measures analysis, Day 1 to Day 10: overall and by dimension 
Table 17: Summary of average change of GI severity score from baseline (Day 0) by 
ANCOVA, Day 1 to Day 10, among patients with GSRS e-Diary compliance rate >= 
80%, at least 5 doses of study medication, and at least 10 doses of DMF in the Day 0 – 
Day 10 period Table 18: Summary of average change of GI severity score from baseline 
(Day 0) by repeated measures analysis, Day 1 to Week 10: overall and by dimension  
Table 19: Summary of time to first worsening in GSRS score 
Table 20: Summary of time to recovery to Day 0 GSRS score from the last occurrence of 
worst post-baseline GSRS score 
Table 21: Summary of average change of GSRS score from baseline (Day 0) by repeated 
measures analysis, Day 1 to Weeks 1-8  
Table 22: Summary of average change of GSRS score from baseline (Day 0) by repeated 
measures analysis, at 72 hours from the initiation of randomized study treatment (Day 1 – 
Day 3)  


 
25  
Table 23: Summary of primary endpoint by baseline demographic and disease 
characteristics 
Table 24: Summary of average change of GI severity score from baseline (Day 0), 
repeated measures analysis, Day 1 to Day 10, by baseline demographic and disease 
characteristics 
Table 25: Summary of average change of GI severity score from baseline (Day 0), 
repeated measures analysis, Day 1 to Week 10, by baseline demographic and disease 
characteristics 
Table 26: Summary of proportion of subjects who take GI symptomatic therapy during 
the study 
Table 27: Summary of proportion of subjects who discontinue DMF therapy due to GI-
related adverse events from Day 0 to Week 10 
Table 28: Summary of proportion of subjects who experience flushing events 
Table 29: Summary of biomarker scores, changes and percent changes from Tecfidera 
baseline, by treatment group and visit, DMF safety analysis population 
Table 30: Summary of biomarker scores, changes and percent changes from Montelukast 
baseline, by treatment group and visit, Montelukast/placebo safety analysis population 
Table 31.1: Summary of selected hematology parameters, change and percent change 
from Montelukast baseline, by treatment group and visit, Montelukast/placebo safety 
analysis population 
Table 31.2: Summary of selected hematology parameters, change and percent change 
from Tecfidera baseline, by treatment group and visit, DMF safety analysis population 
Table 32.1: Summary of hematology abnormalities by CTC grades, by treatment group 
and visit, DMF safety analysis population 
Table 32.2: Summary of hematology abnormalities by CTC grades, by treatment group 
and visit, Montelukast /placebo safety analysis population 
Table 33.1: Incidence of adverse events by system organ class and preferred term, 
Montelukast/placebo safety analysis population 
Table 33.2: Incidence of adverse events by system organ class and preferred term, DMF 
safety analysis population 
Table 34.1: Incidence of serious adverse events by system organ class and preferred term, 
Montelukast/placebo safety analysis population 
Table 34.2: Incidence of serious adverse events by system organ class and preferred term, 
DMF safety analysis population 
Table 35.1: Incidence of adverse events leading to the study treatment discontinuation by 
system organ class and preferred term, Montelukast/placebo safety analysis population  
Table 35.2: Incidence of adverse events leading to DMF discontinuation by system organ 
class and preferred term, DMF safety analysis population  
Table 36.1: Incidence of adverse events leading to study withdrawal by system organ 
class and preferred term, Montelukast/placebo safety analysis population  


 
26  
Table 36.2: Incidence of adverse events leading to study withdrawal by system organ 
class and preferred term, DMF safety analysis population  
Table 37: Incidence of adverse events by system organ class, preferred term and severity, 
DMF safety analysis population  
Table 38: Incidence of adverse events by system organ class, preferred term and by 
relationship to the study treatment or DMF, DMF safety population 
 
Supporting tables for Figures 1, 2, 5 and 6: 
 
Table P1: Summary of change in GSRS score from baseline (Day 0) by repeated 
measures analysis, Day 1 to Day 10  
 
Table P2: Summary of change in GSRS score from baseline (Day 0) by repeated 
measures analysis, Week 1 to Week 10  
 
9 
LIST OF LISTINGS 
Listing 1: Listing of subjects who discontinued treatment and/or withdrew from study 
Listing 2: Listing of serious adverse events  
Listing 3: Listing of adverse events led to study withdrawal  
Listing 4: Listing of death 
Listing 5: Listing of out of normal range laboratory results  
 
 
10 LIST OF FIGURES 
Figure 1: Mean (SE) change in GSRS score from baseline (Day 0), by time and treatment 
group, Day 1 to Day 10 
Figure 2: Model-based estimated mean change in GSRS score from baseline (Day 0), 
with 95% CI, by time and treatment group, Day 1 to Day 10 
Figure 3: Kaplan-Meier plot for time to the first worsening of GSRS score from Day 0 
GSRS score, by treatment group 
Figure 4: Kaplan-Meier plot for time to recovery to Day 0 score from the last occurrence 
of worst GSRS score, by treatment group 
Figure 5: Mean (SE) change in GSRS score from baseline (Day 0), by time and treatment 
group, Day 1 to Week 10 
Figure 6: Model-based estimated mean change in GSRS score from Day 0, by time and 
treatment group, Day 1 to Week 10