Conditions: Relapsing Multiple Sclerosis
Keywords: Relapsing Multiple Sclerosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1047
Healthy volunteers: no

Brief summary:
To make laquinimod 0.6 mg available for all subjects who completed the placebo-controlled MS-LAQ-302 study according to the protocol and to evaluate the long-term safety, tolerability and effect on disease course of daily oral laquinimod 0.6 mg in subjects with relapsing multiple sclerosis.

Detailed description:

Arms:
arm 1: One capsule containing 0.6 mg laquinimod to be administered orally once daily.

Interventions: intervention 1: Laquinimod
Intervention descriptions: intervention 1: One capsule containing 0.6 mg laquinimod to be administered orally once daily.

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol with Amendment 02
(including Statistical Analysis Plan)
A Multinational, Multicenter, Open-Label, Single-Assignment
Extension of the MS-LAQ-302 (BRAVO) Study, to Evaluate the
Long-Term Safety, Tolerability and Effect on Disease Course of
Daily Oral Laquinimod 0.6 mg in Subjects with Relapsing Multiple
Study Number MS-LAQ-302E
NCT01047319 
Protocol with Amendment 02 Approval Date: 25 February 2016


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
1
 
TEVA PHARMACEUTICAL INDUSTRIES LTD., ISRAEL
CLINICAL STUDY PROTOCOL
Study Title: 
A Multinational, Multicenter, Open-Label, Single-Assignment 
Extension of the MS-LAQ-302 (BRAVO) Study, to Evaluate the 
Long-Term Safety, Tolerability and Effect on Disease Course of 
Daily Oral Laquinimod 0.6 mg in Subjects with Relapsing Multiple 
Sclerosis
Protocol No: 
MS-LAQ-302E
EudraCT/IND No: 
2009-015815-42 / 071287
Clinical Phase: 
III Open-Label Extension Study
Protocol Version Date: 
September 16, 2009
Global Amendment # 1
17 July 2014
Global Amendment # 2
25 February 2016
Principal Investigators:
 
 United States
Denmark
Sponsor:
Teva Pharmaceutical Industries, Ltd
5 Basel St, Petach-Tikva 49131, Israel
Authorized Representative
(Signatory)
Teva Pharmaceutical Industries, Ltd.
Sponsor’s Medical Expert
Sponsor’s Safety Officer
 
 
Teva Pharmaceutical Industries, Ltd
Teva Pharmaceutical Industries, Ltd
This clinical study will be conducted in accordance with the Sponsor's Standard Operating Procedures 
(SOPs), current Good Clinical Practice (GCP), the provisions of ICH (International Conference on 
Harmonization) Guidelines and EU Directives
CONFIDENTIAL
The information in this document is considered privileged and confidential, and may not be disclosed to 
others except to the extent necessary to obtain Institutional Review Board/Ethics Committee approval, 
informed consent and the approval of local regulatory authorities as required by local law.


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
2
PROTOCOL REVIEW & APPROVAL


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
PROTOCOL REVIEW & APPROVAL..........................................................................................2
1.
SYNOPSIS .................................................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................14
3.
INTRODUCTION......................................................................................................17
3.1.
Background.................................................................................................................17
3.1.1.
General........................................................................................................................17
3.1.2.
Study Drug..................................................................................................................17
3.2.
Nonclinical Experience...............................................................................................18
3.2.1.
Pharmacology .............................................................................................................18
3.2.2.
Metabolism and Pharmacokinetics.............................................................................18
3.2.3.
Toxicology..................................................................................................................19
3.3.
Clinical Experience.....................................................................................................20
3.3.1.
Clinical Pharmacology Studies...................................................................................20
3.3.2.
Clinical Safety and Efficacy Studies ..........................................................................21
3.4.
Known and Potential Risks and Benefits to Human Subjects....................................24
3.4.1.
Details of Important Adverse Drug Reactions: ..........................................................25
3.4.1.1.
Liver Enzyme Elevations:...........................................................................................25
3.4.1.2.
Elevated Blood Fibrinogen Level...............................................................................26
3.4.1.3.
Elevated Blood C-Reactive Protein Level..................................................................27
3.4.1.4.
Back and Neck Pain....................................................................................................27
3.4.1.5.
Appendicitis................................................................................................................27
3.4.1.6.
Hematological Changes..............................................................................................27
3.4.1.7.
Cardiovascular Events (Laquinimod 1.2 and 1.5 mg) ................................................27
3.4.2.
Potential Safety Issues with Laquinimod ...................................................................28
3.4.2.1.
Pregnancy ...................................................................................................................28
3.4.2.2.
Cancer.........................................................................................................................29
3.4.2.3.
Cardiotoxicity and Systemic Inflammation................................................................29
4.
STUDY OBJECTIVES ..............................................................................................30
4.1.
Ancillary Studies ........................................................................................................30
5.
STUDY DESIGN .......................................................................................................31


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Amended Protocol 02
BRAVO Extension Study
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5.1.
Overview And Plan.....................................................................................................31
5.2.
Revealing the MS-LAQ-302 Study Treatment Assignment during the Open-
Label Study.................................................................................................................31
5.3.
Rationale for Study Design, Dose and Population .....................................................31
6.
STUDY POPULATION.............................................................................................33
6.1.
Inclusion Criteria ........................................................................................................33
6.2.
Exclusion Criteria.......................................................................................................33
7.
MEDICATIONS/THERAPIES – ALLOWED AND DISALLOWED .....................35
7.1.
Allowed Concomitant Medications/Therapies ...........................................................35
7.2.
Disallowed Concomitant Medications During Study.................................................35
8.
STUDY CONDUCT...................................................................................................37
8.1.
Study Period................................................................................................................37
8.2.
Detailed Study Plan ....................................................................................................41
8.2.1.
Baseline Visit (Month 0E) (Visit 0E) (Termination visit of the MS-LAQ-302 
study) Procedures: ......................................................................................................41
8.2.2.
Scheduled Treatment Visits [Months 1E (Visits 1E) and Onwards]..........................43
8.2.3.
Termination/ Early Discontinuation ...........................................................................46
8.2.4.
Early Treatment Discontinuation................................................................................48
8.2.4.1.
Criteria for Early Treatment Discontinuation.............................................................48
8.2.5.
Post Early Discontinuation Follow-Up Visit..............................................................49
8.2.6.
Safety Stopping Rules.................................................................................................50
8.2.6.1.
Liver Enzymes............................................................................................................50
8.2.6.2.
Pregnancy ...................................................................................................................50
8.2.6.3.
Cancer.........................................................................................................................51
8.2.6.4.
Liver Impairment........................................................................................................52
8.2.6.5.
Renal Impairment .......................................................................................................52
8.2.7.
Replacement of Withdrawn Subjects..........................................................................52
8.2.8.
Temporary Discontinuation of Study Drug Treatment...............................................52
8.2.9.
Unscheduled Visit.......................................................................................................52
8.2.9.1.
Unscheduled Samples.................................................................................................54
8.2.9.2.
Visits during Relapses (Scheduled and Unscheduled) ...............................................55
9.
INVESTIGATIONAL MEDICINAL PRODUCTS/STUDY DRUGS......................56
9.1.
Treatment Administered .............................................................................................56


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
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9.2.
Method of Assigning Subjects Numbers ....................................................................56
9.3.
Description of Investigational Medicinal Product/Study Drug ..................................56
9.4.
Packaging and Labeling..............................................................................................56
9.5.
Distribution and Shipment..........................................................................................57
9.6.
Storage, Dispensing and Return .................................................................................57
9.7.
Verification of Compliance With Treatment Regimen ..............................................58
9.8.
Accountability and Compliance .................................................................................58
10.
ASSESSMENT METHODS ......................................................................................60
10.1.
Efficacy Assessment Methods....................................................................................60
10.1.1.
On-Study Relapse Evaluation & Determination.........................................................60
10.1.2.
Neurological Evaluations............................................................................................60
10.1.3.
MSFC..........................................................................................................................61
10.1.4.
Modified Fatigue Impact Scale (MFIS)......................................................................61
10.1.5.
Binocular Low- Contrast Visual Acuity.....................................................................61
10.1.6.
The General Health Status: Short-Form General Health Survey (SF-36) ..................62
10.1.7.
Ancillary Study: Economic Impact: The Work Productivity and Activities 
Impairment (WPAI-GH) Questionnaire (Ancillary Study, US sites only):................62
10.2.
Safety Parameters .......................................................................................................62
10.2.1.
Adverse Events ...........................................................................................................62
10.2.1.1.
Protocol-Defined Adverse Events for Expedited Reporting ......................................63
10.2.2.
Abdominal Computed Tomography Scan ..................................................................63
10.2.3.
Safety Laboratory Evaluations ...................................................................................63
10.2.3.1.
Urgent Safety Laboratory Panel .................................................................................65
10.2.4.
Vital Signs and Weight...............................................................................................66
10.2.5.
ECG ............................................................................................................................66
10.2.6.
Physical Examination .................................................................................................66
10.2.7.
Glomerular Filtration Rate Estimation .......................................................................66
10.2.8.
Cardiovascular Risk Assessment and Management ...................................................67
11.
SAFETY AND PHARMACOVIGILANCE..............................................................68
11.1.
Adverse Event.............................................................................................................68
11.2.
Serious Adverse Event................................................................................................69
11.2.1.
SAE Reporting............................................................................................................70
12.
STATISTICAL METHODOLOGY...........................................................................73


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
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12.1.
Sample Size Rationale................................................................................................73
12.2.
Randomization Procedure...........................................................................................73
12.3.
Subjects Analysis Sets ................................................................................................73
12.4.
Definition of baseline values ......................................................................................73
12.5.
Efficacy Assessment...................................................................................................73
12.6.
Safety And Tolerability Assessments.........................................................................74
12.6.1.
Data presentation ........................................................................................................74
12.6.2.
Adverse Events ...........................................................................................................74
12.6.3.
Laboratory Data..........................................................................................................74
12.6.4.
ECG ............................................................................................................................74
12.6.5.
Vital Signs ..................................................................................................................74
12.6.6.
Drug Tolerability & Drop-Out Assessment................................................................74
13.
REGULATORY AND ETHICAL ISSUES...............................................................75
13.1.
Compliance with Regulations Applicable to Clinical Trials......................................75
13.2.
Informed Consent .......................................................................................................75
13.3.
Subject Confidentiality...............................................................................................75
13.4.
Ethics Committee (EC) / Institutional Review Board (IRB)......................................75
13.5.
Protocol Amendments ................................................................................................76
13.6.
Declaration of the End of the Clinical Trial ...............................................................76
13.7.
Liability And Insurance ..............................................................................................76
14.
DOCUMENTATION .................................................................................................77
14.1.
Study File and Site Documents...................................................................................77
14.2.
Study Documents Supplied by the Sponsor................................................................77
14.3.
Maintenance and Retention of Records......................................................................78
15.
DATA HANDLING ...................................................................................................79
15.1.
Data Collection via Remote Data Capture (RDC)......................................................79
15.2.
Discrepancy Handling ................................................................................................80
15.3.
Data Correction...........................................................................................................80
15.4.
Data Extract ................................................................................................................80
15.5.
Source Documents......................................................................................................80
15.6.
Electronic CRF ...........................................................................................................80
15.7.
Additional Documents and Records...........................................................................81
16.
QUALITY ASSURANCE AUDITS ..........................................................................82


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
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16.1.
Good Clinical Practice................................................................................................82
16.2.
Quality Laboratory Standards.....................................................................................82
16.3.
Quality Assurance Program........................................................................................82
16.4.
Regulatory Inspections ...............................................................................................82
17.
STUDY MONITORING ............................................................................................83
17.1.
Monitors/CRAs and Monitoring Visits ......................................................................83
17.2.
Primary Source Documents........................................................................................83
18.
CLINICAL PRODUCT COMPLAINTS ...................................................................85
18.1.
Product Complaint Information Needed from the Investigational Center..................85
18.2.
Handling of Study Drug at the Investigational Center ...............................................86
18.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................86
18.4.
Documenting a Product Complaint ............................................................................86
19.
USE OF INFORMATION AND PUBLICATION ....................................................87
19.1.
Confidential Information ............................................................................................87
20.
STUDY PERSONNEL...............................................................................................88
20.1.
Investigative Site ........................................................................................................88
20.1.1.
The Principal Investigator...........................................................................................88
20.1.2.
The Study Physician/Neurologist ...............................................................................88
20.1.3.
Study Coordinator or Designee ..................................................................................88
20.2.
The Sponsor................................................................................................................88
20.2.1.
Global Clinical Leader................................................................................................88
20.2.2.
Clinical Operations Manager......................................................................................88
20.2.3.
Data Management & Biostatistics ..............................................................................88
20.2.4.
Local Clinical Management........................................................................................89
20.2.5.
Clinical Research Associate/Monitor .........................................................................89
20.2.6.
Global Drug Safety and Pharmacovigilance...............................................................89
20.2.7.
Medical Monitor.........................................................................................................89
21.
STUDY COMMITTEES............................................................................................90
21.1.
Steering Committee ....................................................................................................90
21.2.
Data Monitoring Committee (DMC)..........................................................................90
21.3.
Clinical Advisory Board (CAB) .................................................................................91
21.4.
Publication Committee ...............................................................................................91


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
8
22.
INVESTIGATOR’S AGREEMENT..........................................................................92
23.
REFERENCES ...........................................................................................................93
24.
RATIONALE FOR PROTOCOL AMENDMENT AND SUMMARY OF
CHANGES .................................................................................................................94
24.1.
Global Amendment #2................................................................................................94
24.2.
Global Amendment #1..............................................................................................112
25.
CHANGES TO PATIENT ENTRY CRITERIA......................................................132
APPENDIX A.
DEFINITIONS ................................................................................................133
APPENDIX B.
NEUROSTATUS.............................................................................................136
APPENDIX C.
MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 
INDUCERS ..............................................................................................................147
APPENDIX D.
LIST OF MEDICATIONS THAT SHOULD BE USED WITH 
CAUTION ................................................................................................................149
APPENDIX E.
GUIDANCE ON SAFETY MONITORING...................................................151
APPENDIX F.
MODIFIED FATIGUE IMPACT SCALE (MFIS) .........................................163
APPENDIX G.
MSFC ADMINISTRATION INSTRUCTIONS.............................................166
APPENDIX H.
LOW-CONTRAST SLOAN LETTER CHART TESTING FOR 
PATIENTS WITH MULTIPLE SCLEROSIS .........................................................174
APPENDIX I.
LOW-CONTRAST TUMBLING-E CHART TESTING FOR 
PATIENTS WITH MULTIPLE SCLEROSIS .........................................................178
APPENDIX J.
WORK PRODUCTIVITY AND ACTIVITIES IMPAIRMENT –
GENERAL HEALTH V2.0 (WPAI-GH) QUESTIONNAIRE ...............................183
APPENDIX K.
THE SF-36V2™ HEALTH SURVEY............................................................185


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
9
LIST OF TABLES
Table 1:
ALLEGRO: Summary of Efficacy Results ................................................................22
Table 2:
BRAVO: Summary of Efficacy Results.....................................................................23
Table 3:
Tabulated List of Adverse Reactions..........................................................................25
Table 4:
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for Alanine Aminotransferase, Aspartate Aminotransferase and 
Gamma Glutamyl Transpeptidase Tests.....................................................................26
Table 5:
Study Task Flow Chart for Extension Phase..............................................................38
Table 6:
A Partial List of Moderate/Strong CYP3A4 Inhibitors Disallowed 2 Weeks 
Prior to and During the Treatment Period and 30 Days After Last Dose.................147
Table 7:
A Partial List of CYP3A4 Inducers..........................................................................148
Table 8:
A Partial List of of CYP3A4 Substrates with a Narrow Therapeutic Index.............149
Table 9:
A Partial List of Drugs that are Mainly Metabolized by 
Cytochrome P450 1A2 .............................................................................................150
Table 10:
Study Task Flow Chart for Returning Subjects after Planned Pregnancy................159


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
10
1.
SYNOPSIS
Protocol Number:
MS-LAQ-302E
Eudract/IND Numbers:
2009-015815-42 / 071287
Study Title:
A multinational, multicenter, open-label, single-assignment extension of the MS-LAQ-
302 (BRAVO) study, to evaluate the long-term safety, tolerability and effect on disease 
course of daily oral laquinimod 0.6 mg in subjects with relapsing multiple sclerosis
Number of Centers:
All centers that randomized subjects in the MS-LAQ-302 study
Clinical Phase:
III, open-label extension study
Study Duration:
Treatment phase: starting from completion of the MS-LAQ-302E study (Termination 
visit), and may continue to participate in the MS-LAQ-302E study as long as the Sponsor 
continues the development of laquinimod 0.6 mg for relapsing remitting multiple 
sclerosis (RRMS).
Study Population:
Subjects who completed the Termination visit of the MS-LAQ-302 double-blind 
treatment phase according to the MS-LAQ-302 protocol, signed an informed consent 
form for the open-label extension study and met all eligibility criteria for this study. 
Study Objective(s):
To make laquinimod 0.6 mg available for all subjects who completed the placebo-
controlled MS-LAQ-302 study according to the protocol and to evaluate the long-term 
safety, tolerability and effect on disease course of daily oral laquinimod 0.6 mg in 
subjects with relapsing multiple sclerosis.
Study Design:
This is a multinational, multicenter, open-label, single-assignment extension of the MS-
LAQ-302 study, to evaluate the long-term safety, tolerability and effect on disease course 
of daily oral laquinimod 0.6 mg in subjects with relapsing multiple sclerosis.
Eligible subjects will be treated with laquinimod 0.6 mg capsules once daily. 
Subjects completing the full-duration of the double-blind MS-LAQ-302 study 
(completion of Termination visit) according to the MS-LAQ-302 protocol will be offered 
the opportunity to enter the MS-LAQ-302E study. In this open-label study, the subjects 
will be treated with laquinimod 0.6 mg (regardless of their initial treatment assignment 
during the MS-LAQ-302 study, whether oral or injectable) as long as the Sponsor 
continues the development of laquinimod 0.6 mg for RRMS.
Scheduled in-clinic visits will be conducted at Baseline (Month 0E) (the Termination 
visit of MS-LAQ-302 will serve as the baseline visit of MS-LAQ-302E) and at months 
1E, 2E, 3E, 6E and every 6 months thereafter, until Termination/early discontinuation.
The following assessments will be performed at the specified time points: 

Vital signs will be measured at each study visit. At month 0E [Baseline 
(Termination visit of the MS-LAQ-302 study)] vital signs will be measured 
also 30 and 60 minutes after the administration of the first dose of 
laquinimod 0.6 mg. 

Weight will be measured at all visits until Termination/Early
discontinuation.

A physical examination will be performed at months 0E [Baseline
(Termination visit of the MS-LAQ-302 study)], 6E, 12E and then every 12 
months (every other scheduled visit) thereafter, until Termination/Early 
discontinuation visit. 


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
11

The following safety clinical laboratory tests will be performed:

Complete blood count (CBC) with differential – at all scheduled visits

Serum chemistry (including electrolytes, liver enzymes, direct and total 
bilirubin, pancreatic amylase, creatine phosphokinase [CPK], and 
estimated glomerular filtration rate) – at all scheduled visits

Hematology.

A urine dipstick beta-human Chorionic Gonadotropin (β-hCG) test will 
be performed in women of child-bearing potential (at site) - at all 
scheduled visits except Termination/Early discontinuation visit

Serum β-hCG in women of child-bearing potential - at all scheduled 
study visits

Starting after visit Month 3E a urine dipstick β-hCG test will be 
performed at home in women of child-bearing potential every 28 (±2) 
days. The subject will be contacted by telephone within 72 hours after 
the test is scheduled to be performed and will be asked specific 
questions regarding the test. In case of suspected pregnancy (positive 
urine β-hCG test result, delay of menstruation or any other reason 
suggesting pregnancy), the caller will make sure that the study drug has 
been discontinued and the subject will be instructed to arrive to the site 
as soon as possible with all study drugs. 

Serum conventional high-sensitivity C-reactive protein (hs-CRP) and 
fibrinogen at all scheduled visits

In case of abnormal CPK result: troponin and CPK-MB will be tested. 
In case of CPK >2000 U/L urine myoglobin will be tested and the 
following tests will be repeated: CPK, CPK MB, blood urea nitrogen, 
creatinine, electrolytes including potassium, calcium, phosphate, 
hs-CRP and fibrinogen.

Lipase will be tested in case of abnormal pancreatic amylase results 

The use of effective contraception will be ascertained at every visit.

Following Visit Month 6E, all subjects will be regularly contacted by 
telephone every 3 months between the scheduled visits and asked a general 
question regarding their well-being (for women of child-bearing potential, 
there is no need to perform a separate call, as this question will be a part of 
the monthly pregnancy urine test call)

Electrocardiography (ECG), neurological evaluations, including Expanded 
Disability Status Scale (EDSS), 25 foot walk test/Ambulation Index (AI), 
Functional systems (FS), MS Functional Composite (MSFC), subject-
reported fatigue as assessed by the Modified Fatigue Impact Scale (MFIS), 
general health status and quality of life parameters will be assessed by the 
Short-Form general health survey (SF-36) subject-reported questionnaire
and Binocular low-contrast visual acuity using the 100%, 2.5% and 1.25% 
contrast level charts [Sloan letter or Tumbling-E] will be performed at 
months 0E [Baseline (Termination visit of the MS-LAQ-302 study)], 6E 
and then at every scheduled study visit thereafter, until Termination/early
discontinuation visit

Adverse events (AEs) will be monitored throughout the study


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
12

Concomitant medications will be monitored throughout the study

Relapses will be confirmed/monitored throughout the study
The allowed treatment for a relapse will be intravenous Methylprednisolone 1 g/day or 
oral steroids for up to 5 consecutive days.
Subjects who discontinue treatment for any reason will continue follow-up according to 
scheduled visits.
Ancillary studies: 

The effect of general health and symptom severity on work will be assessed 
by the work productivity and activities impairment General Health (WPAI-
GH) questionnaire at months 0E [Baseline (Termination visit of the MS-
LAQ-302 study)], 6E and then at every scheduled study visit thereafter, 
until Termination/Early discontinuation visit (this assessment will be 
performed in all subjects from US sites only).
As of the implementation of Protocol Amendment #1, all neurological/medical 
assessments may be performed by a single Study Physician/Neurologist since all the sites 
are now in Period 2 of the study.
Female subjects of childbearing potential who may want to get pregnant in the future, and 
are interested in re-starting laquinimod treatment following delivery and cessation of 
breastfeeding may be able to re-enroll in the study after meeting inclusion/exclusion 
criteria. Re-enrollment will be permitted on a case-by-case basis. Notwithstanding, Teva 
is under no obligation to re-enroll such subjects and reserves the right to re-enroll or 
reject enrolment of such returning subjects for no reason and on its sole discretion. A new 
informed consent form should be signed before re-enrollment.
Number of Subjects:
One thousand, three hundred and thirty two subjects were randomized to the MS-LAQ-
302 study. One thousand forty seven subjects who completed the Termination visit of the 
MS-LAQ-302 study according to the MS-LAQ-302 protocol, signed an informed consent 
form for the open-label extension study and met all eligibility criteria for this study 
enrolled to the MS-LAQ-302E study. 
Inclusion/Exclusion
Criteria:
Inclusion Criteria:
1.
Subjects must have completed the Termination visit of MS-LAQ-302
(completion of all Termination visit activities) according to the MS-LAQ-302
protocol. 
2.
Women of child-bearing potential (for example women who are not 
postmenopausal or surgically sterilized) must practice two acceptable methods 
of birth control for the duration of the study and until 30 days after the last dose 
of study medication [acceptable methods of birth control in this open label 
extension phase include: intrauterine devices, barrier methods (condom or 
diaphragm with spermicide), and hormonal methods of birth control (e.g. oral 
contraceptive, contraceptive patch, and long-acting injectable contraceptive)].
3.
Subjects must be willing and able to comply with the protocol requirements for 
the duration of the study. 
4.
Subjects must be able to comprehend, sign and date a written informed consent 
prior to entering the MS-LAQ-302E study.
Exclusion Criteria:
1.
Premature discontinuation from the MS-LAQ-302 study, for any reason. 


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
13
2.
Pregnancy [according to urine dipstick β-hCG test performed at Baseline 
(Month 0E) visit] or breastfeeding. 
3.
Subjects with clinically significant or unstable medical or surgical condition 
detected or worsened during the MS-LAQ-302 study, which preclude safe 
participation and completion of the MS-LAQ-302E study. Acute exacerbation of 
MS will not exclude participation in the MS-LAQ-302E study.
4.
Use of inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to 
baseline visit (V0E, Month 0E).
Route and Dosage Form:
One capsule containing 0.6 mg laquinimod to be administered orally once daily.
Outcome Measures:
To assess the long-term safety and tolerability of daily oral laquinimod 0.6 mg in subjects 
with relapsing multiple sclerosis.
Safety and Tolerability Outcome Measures:
Safety:

AEs

Vital signs

ECG findings

Clinical laboratory parameters
Tolerability:

Proportion of subjects (%) who prematurely discontinued from the study, 
reason of discontinuation and the time to withdrawal.

Proportion of subjects (%) who prematurely discontinued from the study 
due to AEs and the time to withdrawal
To assess the long-term effect of laquinimod 0.6 mg on disease course, as assessed by 
several parameters:

Number of confirmed relapses

Progression of disability as measured by the EDSS score (including FS and 
AI)

Progression of disability as measured by the MSFC score

Binocular low-contrast visual acuity using the 100%, 2.5% and 1.25% 
contrast level charts [Sloan letter or Tumbling-E]

Subject-reported fatigue as assessed by the MFIS General health status and 
quality of life parameters as assessed by the SF-36
Statistical 
Considerations:
An estimate of sample size is not applicable, since it is an active extension study. 
Summary statistics will be prepared for demographic, safety and efficacy variables.


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
14
2.
LIST OF ABBREVIATIONS
9-HPT
9-Hole Peg Test
ACTH
Adrenocorticotrophic Hormone
ADME
Absorption/Distribution/Metabolism/Elimination
AE
Adverse Event
AhR
Aryl Hydrocarbon Receptor
AI
Ambulation Index
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (SGPT)
ARR
Annualized Relapse Rate
AST
Aspartate Aminotransferase (SGOT)
AUC
Area Under the Concentration by Time Curve
BP
Blood Pressure
ß-hCG
Beta-human Chorionic Gonadotropin
CA
Competent Authority
CAB
Clinical Advisory Board
CBC
Complete Blood Count
CCSVI
Chronic Cerebrospinal Venous Insufficiency
CHMP
Committee for Medicinal Product for Human Use
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
CPK
Creatine Phosphokinase
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C-reactive Protein
CSU
Clinical Supplies Unit
CT
Computed Tomography
CYP
Cytochrome P450
DLC
Dioxin-like Compound
DM
Data Management
DMC
Data Monitoring Committee
EAE
Experimental Autoimmune Encephalomyelitis
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDSS
Expanded Disability Status Scale
EU
European Union
FDA
Food and Drug Administration
FS
Functional Systems
GCP
Good Clinical Practice
g
gram
GdE
Gadolinium Enhancing


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GFR
Glomerular filtration rate
GGT
Gamma Glutamyl Transpeptidase
HAV
Hepatitis A Virus
HBc
Hepatitis B core antigen
HCV
hepatitis C Virus
HDL
High Density Lipoprotein
hs-CRP
High-sensitivity C-reactive Protein
I3C
Indole-3-Carbinol
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IFN-β
Interferon-beta
Ig
Immunoglobulin
IM
Intramuscular
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent-To-Treat
IV
Intravenous
IVIG
Intravenous Immunoglobulin
IVRS/ IWRS
Interactive Voice/Web Response System
L
Liter
LCM
Local Clinical Management
LDL
Low Density Lipoprotein
LKM
Liver Kidney Microsome
LSO
Local Safety Officer
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MFIS
Modified Fatigue Impact Scale
mg
Milligram
ml
Milliliter
MOA
Mechanism of Action
MRI
Magnetic Resonance Imaging
MS
Multiple Sclerosis
MSFC
Multiple Sclerosis Functional Composite
PASAT
Paced Auditory Serial Addition Task
PK
Pharmacokinetics
QA
Quality Assurance
RBC
Red Blood Cell (Count)
RDC
Remote Data Capture
RRMS
Relapsing Remitting Multiple Sclerosis
SAE
Serious Adverse Event
SF-36
Short-Form General Health Survey


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SOP
Standard Operating Procedures
SUSAR
Suspected, Unexpected Serious Adverse Reaction
TCDD
Tetrachloro-p-dibenzodioxin
Tmax
Time to Maximum Plasma Drug Concentration
ULN
Upper Limit of the Normal Range
US
United States
WBC
White Blood Cell
WPAI-GH
Work Productivity and Activities Impairment – General Health


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3.
INTRODUCTION
3.1.
Background
3.1.1.
General
Multiple Sclerosis (MS) is a chronic, relapsing or progressive, inflammatory demyelinating 
disease of the central nervous system (CNS), which leads to disability of various degrees and has 
different progression rates in different patients. Its prevalence rate varies between races and 
geographical latitude. MS is a common disease, affecting approximately 2,500,000 people
world-wide, the majority being in the temperate areas in Europe and North America. Women are 
affected 1.5-2 times more frequently than men (EMEA MS Guideline 2006). There is, as yet, no 
cure. Treatment has been aimed at controlling symptoms and slowing progression of disease
(Neuhaus et al 2003). Authorized disease-modifying drugs for Relapsing Remitting Multiple 
Sclerosis (RRMS) given by injection include interferon-beta (IFN-β) 1a (Avonex®1, Rebif®2) or
1b (Betaseron®3, Extavia®4), glatiramer acetate (Copaxone®5), mitoxantrone (Novantrone®6),
natalizumab (Tysabri®7; for patients non-responsive to other medications), and alemtuzumab 
(Lemtrada™8). Oral disease modifying treatments for RRMS include fingolimod (Gilenya®9), 
teriflunomide (Aubagio®10), and dimethyl fumarate (Tecfidera®11). Oral symptomatic treatment 
with dalfampridine (Ampyra®12) is approved for the improvement of walking in adult patients 
with MS with walking disability (Expanded Disability Status Scale [EDSS] 4.0-7.0).
3.1.2.
Study Drug
The investigational medicinal product (IMP), laquinimod, also known by the laboratory code 
TV-5600 or ABR-215062 sodium salt, is a quinoline-3-carboxamide derivative. It is an oral 
formulation indicated for the treatment of RRMS.
Laquinimod relates to a predecessor compound, roquinimex. It is the result of a structure
activity-relationship screening program whose aim was to identify a new, pharmacologically 
modified substance active in MS animal models which, when compared to roquinimex, would 
have a superior safety profile. Roquinimex demonstrated clinical efficacy in MS in Phase 2
studies. However, serious cardiopulmonary toxicities (including myocardial infarction, 
                                                
1 Avonex is a registered trademark of Biogen Idec
2 Rebif is a registered trademark of EMD Serono, Inc
3 Betaseron is a registered trademark of Bayer
4 Extavia is a registered trademark of Novartis Pharmaceuticals
5 Copaxone® is a registered trademark of Teva Pharmaceutical Industries Ltd.
6 Novantrone is a registered tradfemark of Serono Inc.
7 Tysabri is a registered trademark of Biogen Idec.
8 Lemtrada is a registered trademark of Genzyme corporation
9 Gilenya is a registered trademark of Novartis Pharmaceuticals
10 Aubagio is a registered trademark of Genzyme corporation
11 Tecfidera is a registered trademark of Biogen Idec
12 Ampyra is a registered trademark of Acorda therapeutics


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pericarditis and pleuritis) occurring during Phase 3 studies led to early termination of these 
studies.
Laquinimod has demonstrated efficacy in various types of experimental autoimmune 
encephalomyelitis (EAE) models, as well as in cuprizone induced demyelination, all accepted 
models of MS. 
The precise mechanism of action (MOA) of laquinimod in MS is still under investigation. 
Available data support that laquinimod is an immunomodulator that acts in the periphery and 
within the CNS. The suggested mode of action of laquinimod includes modulation of peripheral 
inflammation and direct modulation of the CNS resident parenchymal cells, including down-
regulation of the astrocytic pro-inflammatory response (a process known as astrogliosis). By 
these suggested protective mechanisms, laquinimod restricts peripheral inflammation as well as 
tissue damage and neurodegeneration in MS. 
Laquinimod demonstrates a predictable and linear pharmacokinetics (PK) profile (see
Section 3.3.1) characterized by high plasma protein binding (>98%), high oral bioavailability
(~90%), low oral clearance (~0.09 L/h), low apparent volume of distribution (~10 L) and long 
half-life (~80 h). Laquinimod is extensively metabolized predominantly by Cytochrome P450 
(CYP) 3A4.
3.2.
Nonclinical Experience
3.2.1.
Pharmacology
In models of MS (EAE and cuprizone), the MOA of laquinimod includes modulation of the 
peripheral inflammation and CNS-resident inflammatory response resulting in down regulation 
of myelin and axonal damage. These effects are compatible with interference of NF-κB 
activation and may represent a novel protective mechanism which down regulates peripheral and 
central inflammation, tissue damage and neurodegeneration in CNS demyelinating diseases.
3.2.2.
Metabolism and Pharmacokinetics
Laquinimod is rapidly absorbed resulting with high oral bioavailability of 80% to 90% in all 
animal species tested and its exposure was shown to increase proportionally without major sex 
differences. Low or no accumulation of parent drug and/or metabolites in tissues was observed. 
Laquinimod does not preferentially distribute to skin and eyes, and no uptake of radioactivity 
was registered in melanin-containing structures in either skin or eye. Laquinimod-related 
radioactivity was shown to be covalently bound to plasma and liver proteins in vitro however no 
adduct was found in human in-vivo. 
Laquinimod metabolism is mostly CYP3A4-mediated biotransformation, resulting in a few 
hydroxylated and dealkylated minor metabolites which could undergo further glucuronidation. 
All circulating plasma human metabolites were formed in animal test species at adequate
exposure levels. Laquinimod was shown to cause a marked decrease of CYP3A4 activity and is a 
strong inducer of CYP1A enzymes. CYP1A induction is a biomarker of activation of the Aryl 


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Hydrocarbon Receptor (AhR) transcription factor; activation of this pathway by laquinimod has 
been demonstrated.
For a complete overview of the Absorption/Distribution/Metabolism/Elimination (ADME)-PK 
program of laquinimod, please refer to the laquinimod Investigator’s Brochure (IB).
3.2.3.
Toxicology
The nonclinical safety program of laquinimod has encompassed separate investigations on vital 
organ systems, single and repeat dose toxicity in mice (duration up to 13 weeks), rats (duration 
up to 26 weeks), and dogs (duration up to 52 weeks), genotoxicity, carcinogenicity studies in 
p53+/- transgenic mice and in rats, toxicity to reproduction, photosafety testing, immunotoxicity 
evaluation, and local tolerance.
Safety pharmacology studies in the rat and dog did not demonstrate significant effects of 
laquinimod on the function of cardiovascular, respiratory, central nervous, renal and 
gastrointestinal systems providing safety margins in the range of 100- to 810-fold above the 
intended clinical dose of 0.6 mg/day based on maximal plasma concentrations.
Overall, the non-clinical safety program identified several safety issues. Specifically, the 
toxicities identified are pro-inflammatory effects (including thyroiditis), mild liver toxicity, and 
mild reductions of red blood cell (RBC) indices. In general, the severity of these effects was 
dose-related and toxicity was mostly reversible upon drug discontinuation. The nature of these 
toxic events allows adequate monitoring in the clinical setting (for details please refer to the 
laquinimod IB). 
Laquinimod was neither mutagenic nor clastogenic in in vitro and in vivo assays. Laquinimod 
treatment resulted in the formation of micronuclei in vitro and in vivo through an aneugenic 
mechanism, with broad safety margin (>99) above the intended clinical dose of 0.6 mg/day. 
The carcinogenicity program consisted of a 26-week study in transgenic p53+/- mice and a 
2-year rat study. The study in transgenic p53+/- mice did not show an increase in 
treatment-related neoplastic findings at any tested dose. In the 2-year rat carcinogenicity study, 
increased incidence of uterine adenocarcinomas was observed in high dose female rats. It is the 
sponsor’s position that this finding is likely due to a decrease in the incidence of prolactin 
secreting pituitary adenomas that was observed in this study. In contrast to rodents, in humans,
prolactin is not a luteinizing hormone and does not affect the estrogen:progesterone ratio; 
therefore the mechanism proposed by the sponsor is not considered relevant to humans. A higher 
incidence of thyroid follicular cell adenomas was observed in high dose male rats. This lesion is 
considered to be related to laquinimod’s induction of liver enzymes and consequently enhanced 
clearance of thyroid hormones in rats, a well-characterized rat-specific mechanism proposed by 
the sponsor, that is not considered relevant to humans. In addition, an increase in the incidence of 
oral cavity tumors was noted in mid and high dose female rats (2/60 in each group). The oral 
effects may relate to the AhR activation properties of laquinimod since similar lesions were seen 
following lifelong exposure of rats to other AhR activators. However, the incidence of oral 
cavity tumors in rats treated with laquinimod was lower than that seen with industrial chemicals 
such as 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) (NTP TR-521 2006) and dioxin-like 


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compounds (DLCs), and was more similar to the incidence seen with the dietary ingredient 
indole-3-carbinol (I3C) found in cruciferous vegetables. Of note, the oral tumors seen with I3C 
were considered by the US National Toxicology Program as irrelevant for I3C risk assessment 
(NTP TR-584 2014). No increased incidence of oral tumors was seen in humans exposed to 
TCDD, indicating a species specific response in rats. Therefore, oral cavity tumors induced by 
laquinimod in rats after a lifelong exposure do not imply an elevated carcinogenicity risk in 
humans. Humans, in general, also seem to be less sensitive to AhR activation by laquinimod than 
rats, as shown by the differential gene expression profiles discussed in the IB.
A standard pre- and post-natal toxicity study and a follow-up investigational study in rats 
demonstrated urogenital malformations in female rat offspring exposed in utero to laquinimod at 
doses similar to the clinical dose of 0.6 mg/day based on exposure. A slight delay in puberty and 
reduction in fertility were noted in rat offspring exposed in utero to laquinimod at doses slightly 
higher than the clinical dose of 0.6 mg/day in humans. The mechanism leading to the 
malformations in rats is unknown. Induction of urogenital malformations in rodents has been 
reported for a variety of agents including sex hormones and the AhR agonist TCDD. Several 
studies were performed to investigate the potential hormonal modulating activity of laquinimod, 
but no such effects were demonstrated at clinically relevant levels. An AhR mediated effect 
cannot be excluded since it plays a distinct role in developmental processes in many 
experimental animals. However, the relevance to humans of the teratogenic effects seen in 
rodents is questionable. In a pre- and post-natal toxicity study in monkeys, the high dose level 
was associated with higher incidence of prenatal loss which limited the number of monkeys that 
could be evaluated, but there were no treatment-related malformations at doses up to 28-fold the 
expected plasma exposure at intended clinical dose of 0.6 mg/day. 
Based on the above, humans should not be exposed to laquinimod during pregnancy.
A complete overview of the safety pharmacology and non-clinical safety program of laquinimod 
is presented in the laquinimod IB.
In the planned clinical study, potential risks will be mitigated by careful screening of subjects, 
frequent and proactive monitoring of subjects and appropriate stopping rules. Furthermore, an 
independent data monitoring committee (DMC) is assigned to assess the data (see Section 21.2).
3.3.
Clinical Experience
Detailed information concerning all clinical studies with laquinimod is presented in the IB.
3.3.1.
Clinical Pharmacology Studies
Laquinimod is considered to have high oral bioavailability with linear, time independent and 
predictable PK, characterized by high plasma protein binding (>98%), high oral bioavailability 
(~90%), low oral clearance (~0.09 L/h), low apparent volume of distribution (~10 L), and long 
half-life (~80 h). Absorption under fasting conditions is rapid and maximal plasma levels 
attained generally within 1 hour after laquinimod administration. Concomitant administration 
with a high-fat high-calorie meal results in reduction of the absorption rate reflected by 
prolongation of the time to maximal plasma drug concentration (Tmax) to approximately 5 hours 


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and reduction of the maximum plasma concentration (Cmax) by 30%. Food however did not 
significantly affect the overall extent of absorption area under the concentration by time curve
(AUC).
Laquinimod is extensively metabolized, predominantly by CYP3A4. Laquinimod metabolites 
levels in plasma are very low and parent laquinimod is the main systemically circulating entity. 
Laquinimod PK is affected by moderate and strong CYP3A4 inhibitors (2.5- and 3.1-fold 
increase in laquinimod systemic exposure, respectively) and strong CYP3A4 inducers. 
Laquinimod 0.6 mg is a weak inhibitor of CYP3A4 and a strong inducer of CYP1A2. For 
additional information, please refer to the IB.
Studies in subjects with mild and moderate hepatic impairment resulted in an increase of 
laquinimod exposure by approximately 1.3- and 2.3-fold, respectively. In subjects with moderate 
renal impairment laquinimod exposure was increased by 1.4-fold. A physiologically based 
pharmacokinetic model was further used to predict the effect of hepatic impairment and renal 
impairment on the pharmacokinetics of laquinimod after single and multiple doses of 0.6 to 
1.5 mg in comparison to healthy subjects (Study DP-2015-017). The model predictions indicated 
that mild hepatic impairment and moderate renal impairment would result in further modest 
increases in exposure to laquinimod following multiple 0.6 mg dose administration based on 
unbound drug concentration (1.71-fold and 1.65-fold, respectively). More significant increases in 
laquinimod exposure, in particular in terms of unbound drug fraction, are predicted in patients 
with moderate and severe hepatic impairment (3.41- and 6.51-fold, respectively) and severe renal 
impairment (1.86-fold). The model predictions indicated similar increases in systemic 
laquinimod exposure with a given stage of organ impairment across the 0.6 to 1.5 mg dose range 
following single or multiple dose administration, demonstrating that the dose proportional 
pharmacokinetics of laquinimod is maintained in subjects with hepatic impairment (mild to 
severe) and renal impairment (moderate to severe) across this dose range.
3.3.2.
Clinical Safety and Efficacy Studies
Results of Phase 2 clinical studies led to the definition of 0.6 mg as the minimal effective dose in 
MS.
The Phase 3 of the clinical development of laquinimod for MS comprised of 2 pivotal studies, 
ALLEGRO and BRAVO. ALLEGRO met its primary end point for reduction of annualized 
relapse rate (ARR; 23% reduction, p=0.0024) and 3 key secondary end-points (EDSS, 
cumulative gadolinium enhancing [GdE]) T1 lesions and cumulative new T2 lesions) were met 
(Table 1). 


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Table 1:
ALLEGRO: Summary of Efficacy Results
End-Points
% reduction (p-value)
ARR
23% (0.0024)
EDSS progression (3m confirmation)
36% (0.0122)
EDSS progression (6m confirmation)a
48% (0.0023)
Cumulative number of GdE T1 lesions
37% (0.0003)
Cumulative number of new T2 lesions 
30% (0.0002)
Brain Atrophya
32.8%a (< 0.0001)
MSFC z-score
51% (0.59)
a Post Hoc analysis
ARR = annualized relapse rate, EDSS = expanded disability status scale, GdE = gadolinium 
enhancing, 
MSFC = Multiple Sclerosis Functional Composite
Overall, the BRAVO study did not meet its primary endpoint (ARR; 17.7% reduction, 
p=0.0746), and some explanations for this result are proposed based on lack of power to detect 
the observed effect and post-hoc analyses showing baseline magnetic resonance imaging (MRI)
imbalance in favor of the placebo group. It is Teva’s assessment that the results obtained after a 
covariate analysis correcting for these baseline imbalances (ARR; 21.3%, p=0.0264) represent 
the true effect of laquinimod 0.6 mg in this patient population (Table 2).


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Table 2:
BRAVO: Summary of Efficacy Results
End-Points
Laquinimod 0.6 mg
Interferon Beta-1a 
(AVONEX®, Biogen Idec Inc)
Original
Corrected
Original
Corrected
% reduction 
(p-value)
% reduction 
(p-value)
% reduction 
(p-value)
% reduction 
(p-value)
ARR
17.7% (0.0746)
21.3% (0.0264)
25.9% (0.0067)
28.7% (0.0021)
Brain atrophy
27.6% (0.0001)
27.4% (<0.0001)
-10% (0.14)
-9% (0.14)
EDSS progression (3 m 
confirmation)
31.3% (0.06)
33.5% (0.04)
25.8% (0.13)
28.7% (0.09)
EDSS progression (6 m 
confirmation)a
39% (0.0423) b
40.6% (0.0423b)
26.6% (0.1686)
28.3% (0.1426)
MSFC z-score
77% (0.15)
77% (0.15)
66% (0.2)
66% (0.2)
Cumulative number of 
GdE T1 lesionsc
21.5% (0.07)
21.7% (0.062)
61.5% (<0.0001)
60% (<0.0001)
Cumulative number of 
new T2 lesionsc
16.5% (0.08)
18.7% (0.037)
51.1% (<0.0001)
52.3% (<0.0001)
a Post hoc analysis
b p-value calculated based on log rank test
c Exploratory endpoint
ARR = annualized relapse rate, EDSS = expanded disability status scale, MSFC = Multiple Sclerosis Functional 
Composite, GdE = gadolinium enhancing
The observed clinical benefits of laquinimod indicate a distinctive efficacy profile with a 
pronounced effect on disability which appears to be larger than that predicted by the common
relationship between relapse rate and disability observed for other disease modifying therapies
(Sormani et al 2010). This effect was consistent between the 2 studies (EDSS; ALLEGRO: 
35.9% [p=0.0122], BRAVO: 33.5% [p=0.0413]. In addition, treatment with laquinimod 
demonstrated reduction in brain atrophy: ALLEGRO: 32.8% [p<0.0001], BRAVO13 : 27.4% 
[p<0.0001]).
On 30 December 2015 the DMC for the LAQ-MS-305 (CONCERTO) and TV5600-CNS-20006
(ARPEGGIO) studies held an unscheduled meeting to review cardiovascular events. The DMC 
found an imbalance in serious cardiovascular events in the high dose treatment arms (1.2 mg in 
CONCERTO, 1.5 mg in ARPEGGIO). Due to these events and the DMC recommendation to 
stop all laquinimod treatment arms above 0.6 mg in the MS trials, the 1.2 mg treatment arm in 
the CONCERTO study was discontinued as of 01 January 2016. The risk/benefit balance of this 
dose was considered negative at that point.
The DMC did not identify any overt cardiovascular risk in the 0.6 mg treatment arm, but felt that 
long term monitoring for emergence of any signal is necessary. Therefore, the 0.6 mg treatment 
arms in the CONCERTO and ARPEGGIO studies will be continued while the sponsor closely 
                                                
13 Results corrected for two MRI parameters found to imbalanced at baseline. Original results were: EDSS: 31.3%, 
p=0.0628; Brain Atrophy: 27.6%, P=0.0001


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monitors cardiovascular events in all laquinimod studies, such as this one. This is discussed 
further in Section 3.4.1.7.
3.4.
Known and Potential Risks and Benefits to Human Subjects
Unless noted otherwise, characterization of the safety profile (important risks and adverse drug 
reactions) of laquinimod is based on the pivotal MS studies, in which laquinimod was 
administered to a total of 983 MS patients at a dose of 0.6 mg/day for up to 2 years. Very 
common or important adverse reactions include headache, abdominal pain, back and neck pain 
and appendicitis. Mild liver enzyme elevations (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], and gamma-glutamyl transpeptidase [GGT]) have been reported 
commonly, but Hy’s law criteria have not been met and there have been no cases of liver failure. 
Treatment with laquinimod may be associated with some additional laboratory abnormalities, 
including hematological changes (hemoglobin decreased/anemia, white blood cell (WBC) count
increased, platelets decreased) and elevation of blood C-reactive protein (CRP) or fibrinogen 
levels; these laboratory changes are generally mild and asymptomatic.
The safety profile of laquinimod is provided in detail below.
Table 3 presents the list of possible adverse drug reactions.
The following definitions apply to the frequency terminology used hereafter:

very common (≥ 1/10)

common (≥1/100 to < 1/10)

uncommon (≥1/1000 to < 1/100)

rare (≥1/10000 to < 1/1000)

very rare (< 1/10000)

not known (cannot be estimated from the available data)
Note: the table has been updated in line with the updated Reference Safety Information; 
myocardial infarction and cerebrovascular accident are now included.


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Table 3:
Tabulated List of Adverse Reactions
Cardiac disorders 
Uncommon:
Myocardial infarction
Infections and infestations 
Common: 
Urinary tract infection, skin infections
Uncommon:
Appendicitis, furuncle
Blood and lymphatic system disorders
Common:
Anemiaa,
Very common:
Decreased platelets, Increased white blood cells
Psychiatric disorders
Common: 
Anxiety 
Nervous system disorders
Very Common: Headache 
Rare:
Cerebrovascular accident
Respiratory, thoracic and mediastinal disorders
Common: 
Cough, bronchospasm 
Uncommon: 
Asthma
Gastrointestinal disorders
Very Common: 
Abdominal pain
Common: 
Constipation, toothache, abdominal distension , nausea, and vomiting
Uncommon: 
Dry mouth
Hepatobiliary disorders 
Common: 
Liver enzymes increaseda (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], gamma-glutamyl transpeptidase [GGT])
Musculoskeletal and connective tissue disorders 
Very Common: 
Back and neck pain
Common: 
Arthralgia
Uncommon:
Bursitis
Reproductive system and breast disorders 
Common: 
Menstruation disorders and uterine bleeding 
General disorders and administration site conditions
Common: 
Peripheral edema 
Investigations 
Common: 
Blood fibrinogen increased, blood amylase increased, creatinine decreased, C-reactive protein 
increasedb
Renal and urinary disorders
Uncommon: 
Micturition urgency
a For liver enzyme elevations and anemia - see below.
b Blood C-reactive protein increased was observed at doses higher than 0.6 mg.
3.4.1.
Details of Important Adverse Drug Reactions:
3.4.1.1.
Liver Enzyme Elevations:
Treatment with laquinimod has been associated with mostly mild, asymptomatic and reversible 
liver enzyme elevations (Table 4) that generally occurred within 6 months after initiation of 
treatment.


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In clinical trials, laquinimod was discontinued if elevation of liver enzymes exceeded 5 times the 
upper limit of the normal range (ULN) for more than two weeks in the absence of a clear 
alternative explanation; if the elevation exceeded 8 times the ULN, laquinimod was discontinued 
without further delay.
Table 4:
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for Alanine Aminotransferase, Aspartate Aminotransferase and 
Gamma Glutamyl Transpeptidase Tests
The percentages listed in the 
table below refer to all patients
with normal values at baseline
Test
Range of Increase
Placebo
Laquinimod 0.6 mg
AST (IU/L)
Patients with Normal 
Test at Baseline:
N = 977
Patients with Normal 
Test at Baseline:
N = 950
> 1 and ≤3 x ULN*
83 (8.5%)
159 (16.7%)
> 3 and ≤5 x ULN
6 (0.6%)
9 (0.9%)
> 5 and ≤8 x ULN
4 (0.4%)
1 (0.1%)
> 8 x ULN
2 (0.2%)
0 (0.0%)
ALT (IU/L)
Patients with Normal 
Test at Baseline:
N = 930
Patients with Normal 
Test at Baseline:
N = 888
> 1 and ≤3 x ULN
165 (17.7%)
262 (29.5%)
> 3 and ≤5 x ULN
5 (0.5%)
30 (3.4%)
> 5 and ≤8 x ULN
6 (0.6%)
5 (0.6%)
> 8 x ULN
7 (0.8%)
5 (0.6%)
GGT(IU/L)
Patients with Normal 
Test at Baseline
N =930
Patients with Normal 
Test at Baseline
906
>1 and <3x ULN
90 (9.7%)
147 (16.2%)
> 3 and <5x ULN
11 (1.2%)
22 (2.4%)
> 5 and <8x ULN
1 (0.1%)
6 (0.7%)
ULN = Upper limit of normal range; AST = aspartate aminotransferase; ALT = alanine aminotransferase ; GGT=
Gamma Glutamyl Transpeptidase ; IU/L = international units/L
3.4.1.2.
Elevated Blood Fibrinogen Level 
Treatment with laquinimod has been associated with an increased incidence (43% versus 34%; 
laquinimod versus placebo) of shifts of blood fibrinogen to levels that are above normal, without 
clinical manifestations. Maximal fibrinogen level did not exceed 2.5×>ULN; maximal fibrinogen 
level was 9.0 g/L in the laquinimod group and 8.4 g/L in the placebo group until month 24 of the 
pivotal MS studies.


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3.4.1.3.
Elevated Blood C-Reactive Protein Level
An increase in blood CRP level has not been found in clinical studies in subjects treated with 
laquinimod at a dose of 0.6 mg/day. In the pivotal trials, until month 15, the proportion of 
patients with elevations in both CRP and fibrinogen was slightly higher in the laquinimod group 
compared to placebo. An increase of CRP and fibrinogen was seen in the dose-escalating studies 
with higher doses than 0.6 mg.
3.4.1.4.
Back and Neck Pain
Treatment with laquinimod has been associated with an increased incidence of back and neck 
pain. Back and neck pains usually occurred during the first 3 months of treatment, were 
generally of mild severity, but occasionally occurred at a later time point, were of longer 
duration or required symptomatic treatment.
3.4.1.5.
Appendicitis
Treatment with laquinimod has been associated with an increased incidence of appendicitis.
There was no characteristic pattern for this risk in terms of duration of treatment and no 
predisposing factors were identified. This diagnosis should be considered in patients with typical 
symptoms.
3.4.1.6.
Hematological Changes

Hemoglobin decrease/Anemia: Treatment with laquinimod has been associated with a 
mild, asymptomatic, non-progressive decrease of the hemoglobin level, which 
occurred early after initiation of treatment and was usually transient without cessation 
of therapy or need for anti-anemic therapy.

Decreased platelets: Treatment with laquinimod has been associated with a generally 
mild decrease of the platelet count, without clinical manifestations.

Increased WBC: Treatment with laquinimod has been associated with a generally 
mild increase of the total WBC count that was consistent across WBC subtypes, 
without clinical manifestations.
3.4.1.7.
Cardiovascular Events (Laquinimod 1.2 and 1.5 mg)
On 30 December 2015, a DMC review of 8 unblinded cases from the CONCERTO and 
ARPEGGIO studies found an imbalance in serious cardiovascular events in the high dose 
treatment arms in the study: 6 cases in the CONCERTO 1.2 mg treatment arm, compared to no 
events in the 0.6 mg or placebo treatment arms, along with a cerebral infarct in a 31-year old 
man on the 1.2 mg treatment arm. In the ARPEGGIO study, 1 heart attack event was identified 
in the laquinimod 1.5 mg treatment arm. The decisions were largely based on data from 
15 November 2015 when total exposure in CONCERTO was 3070 patient-years in 
2199 individuals and total exposure in ARPEGGIO was 35 patient-years in 191 individuals.


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
28
Due to the above, the 0.6 mg treatment arm will be continued in the CONCERTO and 
ARPEGGIO studies while the sponsor closely monitors cardiovascular events in all laquinimod 
studies, including the present study. Additional measures implemented in this protocol 
amendment include an additional emphasis on disallowed medications, medications and stopping 
rules for organ impairment (ie, factors which may increase laquinimod exposure), as well as 
regular evaluation and treatment management of major modifiable cardiovascular risk factors, 
and collection of unscheduled blood samples, eg, for clinical laboratory tests.
The DMC also recommend that study subjects continuing on laquinimod 0.6 mg be re-consented 
with information about the cardiovascular risk seen in higher doses.
Currently the mechanism of the cardiovascular events remains unknown. Although no specific 
time-to-event patterns have been identified, cardiovascular risk factors and demographics may 
play a role. Different pre-existing risk factors were noted, including hypertension, high 
cholesterol, and/or smoking history. While all cases exhibited signs of myocardial tissue injury, 
the cardiac work-up in these cases revealed heterogeneous etiologies. Of note, the cases all had 
some established cardiovascular risk factors, including patients with probable myocarditis or 
with probable familial hypercholesterolemia. Further investigation into potential predictors and 
the potential causality are ongoing.
3.4.2.
Potential Safety Issues with Laquinimod
3.4.2.1.
Pregnancy
Studies in rats have shown reproductive toxicity including teratogenicity (urogenital 
malformations) at doses similar to the clinical dose of 0.6 mg/day in humans. Delay in puberty 
and reduced fertility were noted in rat offspring exposed to laquinimod in utero at doses higher 
than the clinical dose of 0.6 mg/day in humans (Section 3.2.3). The relevance to humans of these 
findings is not known, but cannot be excluded. 
Exposure to laquinimod during pregnancy must be avoided. 
To prevent such exposure, women who are of childbearing potential (for example women who 
are not postmenopausal or surgically sterilized) must practice an acceptable method of birth 
control (Section 8.2.6.2) for 30 days before taking the study treatment, and two acceptable 
methods of birth control throughout treatment duration and until 30 days after the last dose of 
study medication. Acceptable methods of birth control include: intrauterine devices, barrier 
method (condom or diaphragm with spermicide) and hormonal methods of birth control (eg, oral 
contraceptive, contraceptive patch and long-acting injectable contraceptive). Use of acceptable 
contraception should be ascertained at every study visit.
In addition, regular pregnancy testing is required during the study. If pregnancy is suspected 
despite all recommended precautions (e.g., positive urine beta-human chorionic gonadotropin 
[β-hCG] test result, delay of menstruation or any other reason suggesting pregnancy), treatment 
should be discontinued immediately. The subject should be reminded of the potential risk to the 
fetus, and all options, including termination of pregnancy, should be discussed. 


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
29
All subjects should be counseled by the investigator about the potential teratogenicity and 
delayed risks for a child exposed in uterus to laquinimod and the need to use acceptable
contraception and avoid pregnancy throughout treatment with laquinimod and for 30 days after 
the last dose of treatment was administered.
3.4.2.2.
Cancer
The two year carcinogenicity studies in rats demonstrated an increase in uterine and oral cancers
(see Section 3.2.3). It is the sponsor’s position that these findings are likely related to 
species-specific mechanisms, regardless, a relevance of these cancers to humans cannot be 
definitively excluded. Available phase 3 and extension clinical trial data show no association of 
laquinimod 0.6 mg/day with an increased risk of cancer. 
3.4.2.3.
Cardiotoxicity and Systemic Inflammation
In clinical studies performed with laquinimod’s predecessor molecule, roquinimex, 
pericarditis/pleuritis and ischemic heart disorders were identified as important safety concerns. 
Serious toxicities that occurred during Phase 3 trials led to discontinuation of these trials. 
Roquinimex demonstrated serious toxicities including increased rates of myocardial infarction, 
pericarditis, and pleuritis that were observed in three Phase 3, placebo-controlled studies in MS 
patients. The mechanism by which roquinimex caused these events was not identified, but they 
were considered to be possible manifestations of a systemic inflammatory response, an 
assessment which was also supported by roquinimex nonclinical findings. A thorough analysis 
was done on the laquinimod safety data (which is mostly reflective of the 0.6 mg/day dose) to 
evaluate similar potential safety issues. Based on 2347 patients exposed to laquinimod 0.6 mg for 
over 10000 patient-years, as well as the patients exposed to 0.6 mg in the CONCERTO and 
ARPEGGIO studies, analyses showed that these safety issues do not constitute a clear signal for 
laquinimod in doses up to 0.6 mg/day. However, at doses of 1.2 and 1.5 mg, laquinimod 
manifested clinical evidence of myocardial infarction.


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
30
4.
STUDY OBJECTIVES

To make treatment with oral laquinimod 0.6 mg available to all subjects who 
participated in the MS-LAQ-302 study (regardless of their treatment assignment, 
whether oral or injectable) and who completed the Termination visit of this study 
according to the MS-LAQ-302 protocol as long as the Sponsor continues the 
development of laquinimod 0.6 mg for RRMS. 

To assess the long-term safety and tolerability of laquinimod 0.6 mg once daily in 
subjects with relapsing MS. 

To assess the long-term effects of laquinimod 0.6 mg on the disease course, as 
measured by clinical efficacy outcomes, which were evaluated in the MS-LAQ-302 
study in this subject population.
4.1.
Ancillary Studies
The following ancillary study will be performed in a subset of subjects:

The effect of general health and symptom severity on work will be assessed by the 
work productivity and activities impairment will be assessed by the General Health 
(WPAI-GH) questionnaire (see Appendix J) at months 0E [Baseline (Termination 
visit of the MS-LAQ-302 study)], 6E and then at every scheduled study visit 
thereafter, until Termination/Early discontinuation visit (this assessment will be 
performed in all subjects from United States [US] sites only). 


Protocol MS-LAQ-302E
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31
5.
STUDY DESIGN
5.1.
Overview And Plan
This is a multinational, multicenter, open-label, single-assignment extension of the 
MS-LAQ-302 study, to evaluate the long-term safety, tolerability and effect on disease course of 
daily oral laquinimod 0.6 mg in subjects with relapsing MS.
Eligible subjects will be treated with laquinimod 0.6 mg capsules once daily. 
Subjects completing the full duration of the double-blind MS-LAQ-302 study (completion of the 
Termination visit) (regardless of their treatment assignment in this study, oral or injectable 
treatment) according to the MS-LAQ-302 protocol will be offered the opportunity to enter into 
the open label extension MS-LAQ-302E study. In this open-label study they will be treated with 
laquinimod 0.6 mg once daily.
Scheduled in-clinic visits will be conducted at Baseline (month 0E; the Termination visit of 
MS-LAQ-302 will serve as the baseline visit of MS-LAQ-302E) and at months 1E, 2E, 3E, 6E 
and every 6 months thereafter, as long as the Sponsor continues the development of laquinimod 
0.6 mg for RRMS. At this time point, subjects will be invited to attend a Termination visit.
Subjects who discontinue treatment for any reason will continue follow-up according to 
scheduled visits.
As of the implementation of Protocol Amendment #1, the medical/neurological assessments of 
the subjects at each clinical site will no longer be performed differently since all the sites are 
now in study period 2. In this period, there will be no need for 2 separate physicians to assess the 
subjects in the MS-LAQ-302E study. Subjects participating in the MS-LAQ-302E study will be 
assessed by a single physician/Neurologist ("Study Physician/ Neurologist").
5.2.
Revealing the MS-LAQ-302 Study Treatment Assignment during the 
Open-Label Study
The investigator may request the Sponsor to provide the original treatment allocation of the 
subject in the MS-LAQ-302 study (laquinimod 0.6mg or placebo, in case the subject was 
assigned to oral treatment). This will be possible only after transition to Period 2. 
5.3.
Rationale for Study Design, Dose and Population
The open-label extension MS-LAQ-302E study is designed to: 

Provide laquinimod 0.6 mg once daily to all subjects who successfully complete the 
double-blind, placebo-controlled MS-LAQ-302 study for as long as the Sponsor 
continues the development of laquinimod 0.6 mg for RRMS.


Protocol MS-LAQ-302E
Amended Protocol 02
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32

Provide information on laquinimod's long-term safety, tolerability and effect on 
disease course in this subject population.
The 0.6 mg daily dose was selected, since this was the dose used in the double-blind, 
placebo-controlled MS-LAQ-302 study. 


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
33
6.
STUDY POPULATION
One thousand, three hundred and thirty-two (1332) subjects were randomized to the MS-LAQ-
302 study. All subjects who complete the Termination visit of the MS-LAQ-302 study
(according to the MS-LAQ-302 protocol), meet the eligibility criteria and sign an informed 
consent form will be enrolled to the MS-LAQ-302E study.
6.1.
Inclusion Criteria
Subjects must meet all inclusion criteria in order to be eligible for the study:
1. Subjects must have completed the Termination visit of MS-LAQ-302 (completion of all 
Termination visit activities) according to the MS-LAQ-302 protocol. 
2. Women of child-bearing potential (for example women who are not postmenopausal or 
surgically sterilized) must practice two acceptable methods of birth control for the 
duration of the study and until 30 days after the last dose of study medication [acceptable 
methods of birth control in this open label extension phase include: intrauterine devices, 
barrier methods (condom or diaphragm with spermicide), and hormonal methods of birth 
control (e.g. oral contraceptive, contraceptive patch, and long-acting injectable 
contraceptive)].
3. Subjects must be willing and able to comply with the protocol requirements for the 
duration of the study. 
4. Subjects must be able to comprehend, sign and date a written informed consent prior to 
entering the MS-LAQ-302E study.
6.2.
Exclusion Criteria
Any of the following conditions will exclude the subject from entering the study:
1. Premature discontinuation from the MS-LAQ-302 study, for any reason. 
2. Pregnancy [according to urine dipstick β-hCG test performed at Baseline (Month 0E) 
visit] or breastfeeding. 
3. Subjects with clinically significant or unstable medical or surgical condition detected or 
worsened during the MS-LAQ-302 study, which preclude safe participation and 
completion of the MS-LAQ-302E study. Acute exacerbation of MS will not exclude 
participation in the MS-LAQ-302E study. 
4. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline visit (V0E, Month 0E).
Female subjects of childbearing potential who may want to get pregnant in the future, and are 
interested in re-starting laquinimod treatment following delivery and cessation of breastfeeding 


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
34
may be able to re-enroll in the study after meeting inclusion/exclusion criteria in Appendix E. 
Re-enrollment will be permitted on a case-by-case basis. Notwithstanding, Teva is under no 
obligation to re-enroll such subjects and reserves the right to re-enroll or reject enrolment of such 
returning subjects for no reason and on its sole discretion. A new informed consent form should 
be signed before re-enrollment (see Appendix E).


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
35
7.
MEDICATIONS/THERAPIES – ALLOWED AND DISALLOWED
7.1.
Allowed Concomitant Medications/Therapies
Symptomatic MS agents, such as anti-cholinergic and spasmolytic drugs, are permitted at 
clinically appropriate doses. 
Short-term treatment with corticosteroids will be allowed during relapses; Allowed treatment for 
relapses is a fixed dose of intravenous (IV) methylprednisolone 1 g/day or oral steroids for a 
maximum of five consecutive days. No tapering off is allowed.
Other medications, excluding those mentioned in Section 7.2 may be given concomitantly as 
needed for the subject’s welfare.
Topical and inhaled steroids are allowed at the discretion of the Study Physician/Neurologist, for 
indications other than MS.
Administration of all medications, including indication, dose, frequency, and route of 
administration will be recorded in the source documentation file and in the electronic Case 
Report Form (eCRF).
Clinical studies have shown laquinimod 0.6 mg to be a strong inducer of CYP1A2. Subjects 
taking drugs that are metabolized by CYP1A2 (examples listed in Appendix D) should be 
advised that plasma levels of these drugs could decrease when combined with laquinimod. In 
general, as a precautionary measure, it is recommended to avoid the use of CYP1A2 substrates in 
clinical trials of laquinimod. Therapeutic alternatives may be considered in the appropriate 
clinical context. Additional information on concomitant use of laquinimod and CYP1A2 
substrates is presented in the laquinimod IB.
Drug-Drug interaction studies have been performed with laquinimod doses of 0.6 mg and 
1.2 mg. These studies show that laquinimod at both doses is a weak inhibitor of CYP3A4. 
Subjects taking drugs that are metabolized by CYP3A4 (specifically those with a Narrow 
Therapeutic Index listed in Appendix D) should be advised that plasma levels of these drugs 
could increase when combined with laquinimod.
7.2.
Disallowed Concomitant Medications During Study

Natalizumab (Tysabri®)

Fingolimod (Gilenya)

IFN-β 1a or 1b

Dimethyl fumarate (Tecfidera)

Glatiramer Acetate (Copaxone®)


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
36

Teriflunomide (Aubagio)

Alemtuzumab (Lemtrada)

Cladribine

Rituximab

Ocrelizumab

Atacicept

Belimumab

Ofatumumab

Inducers of CYP3A4 such as rifampin and carbamazepine (for more examples see
Appendix C). Use of CYP3A4 inducers may result in reduced laquinimod plasma 
concentrations and may reduce its effectiveness.

Moderate or strong inhibitors of CYP3A4; for example, ketoconazole and 
erythromycin (as listed in Appendix C) are disallowed for 2 weeks prior to the 
baseline visit through to 30 days after the final dose of laquinimod. Laquinimod is 
extensively metabolized predominantly by CYP3A4, and ketoconazole and 
fluconazole, strong and moderate inhibitors of CYP3A4, were found to inhibit the 
metabolism, leading to 2.5- and 3.1-fold increases in laquinimod exposure, 
respectively.

Mitoxantrone (Novantrone®)

Oral and parenteral steroids (except if given as defined by protocol for treatment of a 
relapse as specified in Section 7.1)

Adrenocorticotrophic hormone (ACTH)

Chemotherapeutic agents

Cytotoxic agents

Cyclophosphamide

IV Immunoglobulin (Ig)

Plasmapheresis

Any other experimental agents

Other Immunosuppressive or immunomodulating agents


Protocol MS-LAQ-302E
Amended Protocol 02
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37
8.
STUDY CONDUCT
8.1.
Study Period
The study assessments will be performed according to the summary of the Study Task Flow 
Sheet (see Table 5 – Study Task Flow Chart).
A month in the treatment period is defined as 30 days ± 4 days.
The study, in which all eligible subjects will be treated with daily laquinimod 0.6 mg, will last as 
long as the Sponsor continues the development of laquinimod 0.6 mg for RRMS. Subjects who 
discontinue treatment for any reason will continue follow-up according to scheduled visits.


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
38
Table 5:
Study Task Flow Chart for Extension Phase
Visit
V0Ea
V1E
V2E
V3E
V4E
Every 6 
months
Every 12 
months
Every 24 
months
Termination /
Early 
Discontinuation
Unscheduled 
Visitb, c
Month
0E
1E
2E
3E
6E
Informed Consent
X
Eligibility Criteria
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Cardiovascular risk factor assessment and 
managementd
X
X
First Dose at Site
Xe
Physical Examination
X
X
X
X
X
X
Vital Signs
Xf
X
X
X
X
Xg
Xg
Xg
Xg
X
ECG
X
X
X
X
X
X
X
Safety Laboratory Evaluation (CBC, 
Chemistry, markers of inflammation, 
estimated GFR)
X
X
X
X
X
X
X
X
X
X
Serum hCGh
X
X
X
X
X
X
X
Urine β-hCGh(on site)
X
X
X
X
X
X
X
X
X
Ascertaining use of effective contraception
X
X
X
X
X
X
X
X
X
X
Urine hCGh (self check, at home)
EVERY 1 MONTH BETWEEN 
SCHEDULED VISITS
Adverse Events
X
X
X
X
X
X
X
X
X
X
Neurological examination (EDSS/FS/AI/ 25 
foot walk)
X
X
X
X
X
X
X
Evaluation of Relapsei
X
X
X
X
X
X
X
X
X
X
MSFCj
X
X
X
X
X
X
Binocular Low-Contrast Visual Acuity
X
X
X
X
X
X


Protocol MS-LAQ-302E
Amended Protocol 02
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39
Visit
V0Ea
V1E
V2E
V3E
V4E
Every 6 
months
Every 12 
months
Every 24 
months
Termination /
Early 
Discontinuation
Unscheduled 
Visitb, c
Month
0E
1E
2E
3E
6E
MFIS
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
WPAI-GH (ancillary study, US sites only)
X
X
X
X
X
X
Mandatory phone calls (pregnancy tests)k
EVERY 1 MONTH BETWEEN 
SCHEDULED VISITS
Mandatory phone call (general well-being, 
all subjects)l
EVERY 3 MONTHS 
BETWEEN SCHEDULED VISITS
Drug Compliance & Dispensing
X
X
X
X
X
X
X
X
Xm
X
Termination Documentation and Notification 
of Early Termination
X
Unscheduled Samples
Xn
Subjects who are discontinued from study treatment will be encouraged to continue all scheduled visits and procedures until completion of the study (with the 
exception of procedures associated with drug dispensing and accountability, pregnancy testing, and GFR estimation [including body weight measurement]).
a The Termination visit of the MS-LAQ-302 study will serve as the Baseline visit of the MS-LAQ-302E study. Therefore, all activities, excluding Urine β-hCG 
(on site), informed consent, eligibility criteria and first dose at site are a part of the Termination visit of the MS-LAQ-302 study and therefore should not be 
repeated. However, in case there is a gap of more than 3 days between Termination visit day of the MS-LAQ-302 study and day on which the first dose of 
laquinimod 0.6mg is administered in the MS-LAQ-302E study, all baseline activities/assessment described above (those that should have been a part of the 
MS-LAQ-302 study Termination visit as well as the new ones) will have to be repeated in an unscheduled visit (on the day the subject will receive the first 
dose).
b Vital signs and AEs are mandatory activities in an unscheduled visit. All other activities are optional and may be performed as deemed necessary by the 
investigator. Chest X-ray may also be performed in this visit. 
c Post treatment follow up visit in cases of early discontinuation (In which vital signs, review of AEs and concomitant medications, as well as pregnancy test are 
mandatory. All other marked activities are optional).
d In addition, an evaluation should take place as soon as possible for subjects already in the study, following approval of Amendment #2
e In case the subject took the last dose of the MS-LAQ-302 study on the Termination visit day, the first dose of the MS-LAQ-302E study will be taken at the site 
within 3 days from baseline visit day. The rest of the baseline visit activities will be performed at the original baseline visit day (Termination visit day of the 
MS-LAQ-302 study).
f Post-dose vital signs will be measured at Baseline and after 30 and 60 minutes, where as the pre-dose vital signs will be taken from the last measurement in the 
MS-LAQ-302 study. In case the subject takes the first dose of the MS-LAQ-302E study NOT at the Termination visit of the MS-LAQ-302 study, pre-dose vital 
signs should be measured as well. This is not relevant for the Termination/Early discontinuation visit.


Protocol MS-LAQ-302E
Amended Protocol 02
BRAVO Extension Study
40
g Weight will be measured at all visits until Termination/Early discontinuation.
h For women of childbearing potential
i Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator
j Within the MSFC evaluation, the PASAT and 9-HOLE Peg tests will be performed at months 0E (Baseline; Termination visit of the MS-LAQ-302 study), 6E 
and every 6 months, while the Timed 25-foot walk test will be performed each time a neurological evaluation is performed
k For women of child-bearing potential; to be performed within 72 hours after the scheduled home pregnancy test. The call will be documented in the source 
documents
l The call will be documented in the source documents. For women of child-bearing potential, there is no need to perform a separate call, as this question will be a 
part of the monthly pregnancy urine test call.
m Only drug retrieval
n Unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or samples for potential biomarker analyses may be collected at the 
discretion of the investigator or medical monitor at any time to assist with further investigations of cardiovascular events or other clinical event of interest. The 
samples should be collected as soon as possible in association with the event.
AE = adverse event, AI = ambulation index, β-hCG = beta-human chorionic gonadotropin, CBC = complete blood count, ECG = electrocardiogram, 
EDSS = Kurtzke’s expanded disability status scale, FS = functional systems, GFR = glomerular filtration rate, MFIS = modified fatigue impact scale, 
MSFC = multiple sclerosis functional composite, PASAT: Paced Auditory Serial Addition Task, SF-36 = Short-Form General Health Survey, US = United 
States, WPAI-GH = Work Productivity and Activities Impairment – General Health


Protocol MS-LAQ-302E
Amended Protocol 02
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41
8.2.
Detailed Study Plan
8.2.1.
Baseline Visit (Month 0E) (Visit 0E) (Termination visit of the MS-LAQ-302
study) Procedures:
After completion of all procedures of the Termination visit of the MS-LAQ-302 study according 
to the MS-LAQ-302 protocol, and placing a call to the interactive voice response system (IVRS)
to notify the subject's completion of the MS-LAQ-302 study, the subject will be offered to 
participate in the MS-LAQ-302E study. The subject will be informed about all aspects of the 
study, including scheduled study visits and activities, and must sign and date the informed 
consent form. A copy of the informed consent form must be given to the subject. Eligibility for 
participation in the MS-LAQ-302E study will be established by the investigator. 
The Baseline visit of the MS-LAQ-302E open-label extension study will occur at the 
Termination visit of the MS-LAQ-302 study. Therefore, many of the activities/assessments of 
the Termination visit of the MS-LAQ-302 study will serve as the Baseline visit (Month 0E) 
procedures of the MS-LAQ-302E study.
The following list includes all Baseline (Month 0E) activities. These activities were performed 
under the scope of the Termination visit of the MS-LAQ-302 study and therefore should not be 
repeated, unless otherwise specified. 

Vital signs (temperature, pulse, blood pressure [BP] and weight)

Physical examination 

Complete neurological examination including functional systems (FS), ambulation 
index (AI), 25 foot walk, EDSS

Multiple Sclerosis Functional Composite (MSFC)

The general health status and MS-related quality of life, will be assessed using the 
Short-Form general health survey (SF-36) subject-reported questionnaire (see 
Appendix K)

The effect of general health and symptom severity on work will be assessed using the 
WPAI-GH questionnaire (see Appendix J) (This assessment will be performed in all 
subjects from US sites only). 

Evaluation of a relapse 

Electrocardiogram (ECG)

Review of concomitant medications

AE recording


Protocol MS-LAQ-302E
Amended Protocol 02
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42

Safety laboratory tests including:

Serum pregnancy test (β-hCG) for women of child-bearing potential. In case of 
positive result, the subject will not be eligible to participate in the extension and 
will be considered a screening failure for the extension phase.

Urinalysis

Hematology (Complete blood count [CBC], including differential)

Serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin, 
pancreatic amylase and creatine phosphokinase [CPK]). 

Markers of inflammation (serum conventional CRP and fibrinogen)

Subject-reported fatigue will be assessed by the Modified Fatigue Impact Scale 
(MFIS) (see Appendix F)
Binocular low-contrast visual acuity assessment, using 100%, 2.5% and 1.25% contrast charts 
[Sloan letter or Tumbling E (see Appendix H and Appendix I)]. 
New activities to be performed at Baselinea,b,c visit (Month 0E, Visit 0E) (not part of the
MS-LAQ-302 Termination visit) are:

Subjects will be given all the necessary supplies and detailed instructions for 
administration of IMP, which will be reviewed with the subject during the visit. In 
addition, subjects will be instructed to contact the study center if any questions or 
problems arise.

Urine pregnancy test (β-hCG) for all women of child-bearing potential. In case of 
positive result, the subject will not be eligible to participate in the study.

For all subjects who are female of child-bearing potential:

The use of effective contraception will be ascertained at each study visit (should 
be recorded in the source documents).
                                                
a In case the subject took the last dose of the MS-LAQ-302 study on the Termination visit day, the first dose of the 
MS-LAQ-302E study will be taken at the site within 3 days from baseline visit day. The rest of the baseline visit 
activities will be performed at the original baseline visit day (Termination visit day of the MS-LAQ-302 study).
b In case the subject does NOT take the first dose of the MS-LAQ-302E study at the Termination visit of the MS-
LAQ-302 study, pre-dose vital signs should be measured as well
c In case there is a gap of more than 3 days between Termination visit day of the MS-LAQ-302 study and day on 
which the first dose of laquinimod 0.6mg is administered in the MS-LAQ-302E study, all baseline 
activities/assessment described above (those that should have been a part of the MS-LAQ-302 study Termination 
visit as well as the new ones) will have to be repeated in an unscheduled visit (on the day the subject will receive 
the first dose).


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
Subjects will be instructed during each visit about the teratogenicity and potential 
delayed risks for a child exposed in uterus to laquinimod

Subjects will be reminded about (should be recorded in the source documents)
importance of stopping the study drug and informing the site in any case of 
suspected pregnancy (positive home urine test result, delay of menstruation or any 
other reason suggesting pregnancy)

A call to the IVRS will be made to allocate a pack number for the open-label 
extension phase

First dose administration of the IMP.

Post-dose vital signs (30 & 60 minutes, pulse and BP only) (pre-dose vital signs will 
be taken from the Termination visit vital signs measurement).

AE recording will be performed upon any subjects’ complaint following study drug 
administration (if relevant) or staff observation.

Subjects will be instructed to contact the study site in the event of any change in their 
medical condition, the appearance of any AEs or any symptom suggestive of a 
relapse.
8.2.2.
Scheduled Treatment Visits [Months 1E (Visits 1E) and Onwards]
Subjects will visit the study center at months 1E, 2E, 3E, 6E (visits 1E, 2E, 3E, 4E, respectively) 
and then every 6 months thereafter. Subjects who discontinue treatment for any reason will 
continue follow-up according to scheduled visits.
Following approval of Global Amendment #2, subjects continuing on laquinimod 0.6 mg will be 
re-consented with information about the cardiovascular risk seen in higher doses (see 
Section 3.4.1.7).
The following procedures and evaluations will be performed at each scheduled visit:

Vital signs (temperature, pulse, BP).

Review concomitant medications (ensuring no disallowed medication is being used).

Record of AEs.

Evaluation of relapse.

Subject compliance (IMP accountability).

Review instructions on IMP administration and dispensing.

For all subjects who are female of child-bearing potential:


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
The use of effective contraception will be ascertained at each study visit (should 
be recorded in the source documents)

Subjects will be instructed during each visit about the teratogenicity and potential 
delayed risks for a child exposed in uterus to laquinimod

Subjects will be reminded about (should be recorded in the source documents)
importance of stopping the study drug and informing the site in any case of 
suspected pregnancy (positive home urine test result, delay of menstruation or any 
other reason suggesting pregnancy) and importance of performing the home 
pregnancy urine tests every one month (starting after visit Month 3E)

Safety laboratory tests:

Serum pregnancy test (β-hCG) for women of child-bearing potential

Urine pregnancy test (β-hCG) for women of child-bearing potential. In case of 
positive result, study drug should not be dispensed, until results of serum β-hCG 
test is available and pregnancy is either confirmed or excluded (see Appendix E). 
In case of suspected pregnancy, the rest of the visit activities should be performed 
as well

Hematology (CBC with differential)

Serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin,
pancreatic amylase, CPK, and estimated GFR)

Markers of inflammation (serum conventional high-sensitivity C-reactive protein
[hs-CRP] and fibrinogen).

IVRS call to obtain pack number.
The following procedures and evaluations will be performed at Month 6E (visit 4E) and at all 
scheduled visits thereafter:

Complete neurological examination including FS, EDSS, AI and Timed 25 Foot 
walk.

MSFC.

Binocular low-contrast visual acuity assessment, using 100%, 2.5% and 1.25% 
contrast charts [Sloan letter or Tumbling E (see Appendix H and Appendix I)]. 

Subject-reported fatigue will be assessed by the MFIS (see Appendix F).

The general health status and MS-related quality of life, will be assessed using the 
SF-36 subject-reported questionnaire (see Appendix K).


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
The effect of general health and symptom severity on work will be assessed using the 
WPAI-GH questionnaire (see Appendix J) (This assessment will be performed in all 
subjects from US sites only).
In addition, the following procedures/assessment will be performed:

Physical examination will be performed at months 6E (Visit 4E), 12E (Visit 5E) and 
then every 12 months thereafter (every other scheduled visit).

ECG will be performed at month 6E (visit 4E) and at every scheduled visit thereafter.

Weight will be measured at all visits.

Evaluation and management of major modifiable cardiac risk factors (eg, diabetes, 
high blood pressure, hyperlipidemia, tobacco smoking) will be performed every 
12 months, with referral to treatment and follow-up in a suitable clinic if needed. In 
addition, an evaluation should take place as soon as possible for subjects already in 
the study, following approval of Amendment #2.

The sequence of assessments should be as follows:

SF-36 subject-reported questionnaire (see Appendix K)

MFIS (see Appendix F)

WPAI-GH questionnaire (see Appendix J) (This assessment will be performed in 
all subjects from US sites only)

The 9-Hole Peg Test (9-HPT) and Paced Auditory Serial Addition Task (PASAT)
components of the MSFC (Timed 25 Foot walk may be performed later) (see 
Appendix G)

The rest of the visit activities, as depicted above.

Starting from Month 3E (Visit 3E), the following actions will be taken for female 
subjects of child-bearing potential:

The subject will be provided with home pregnancy urine β-hCG test kits and will 
be guided how to perform the test. The site staff will schedule the home test to be 
performed every 28 ± 2 days. 

In order to verify whether the test has been performed and to record the result of 
the test (see Appendix E), a mandatory phone call will be performed by the Study
Neurologist/ Physician or by the site’s nurse/ study coordinator within 72 hours 
after the test was scheduled to be performed. In case of a suspected pregnancy, the 
caller will make sure that the study drug has been stopped and the subject will be 
instructed to arrive to the study site as soon as possible to return all study drugs.


Protocol MS-LAQ-302E
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
Following Month 6E Visit, all subjects will be regularly contacted by telephone every 
3 months between the scheduled visits and asked a general question regarding their 
well-being (for women of child-bearing potential, there is no need to perform a 
separate call, as this question will be a part of the monthly pregnancy urine test call).
Performance of this call will be documented in the source documents.
8.2.3.
Termination/ Early Discontinuation
The Termination visit date may be different in each country. Upon a decision of the Sponsor to 
stop the development of laquinimod 0.6 mg for MS patients, the local clinical trial management 
will notify the site teams when to invite the subjects to the site, in order to perform the 
Termination visit. 
Subjects who have performed all Termination visit activities (in case the Sponsor decides to stop 
the development of laquinimod 0.6 mg for MS patients) will be regarded as completers. 
Early discontinuation is defined as any withdrawal from the study prior to the completion of the 
treatment period. The treatment period is defined between Month 0E visit (Visit 0E, Baseline)
(Termination visit of the MS-LAQ-302 study) (after administration of the first dose) and 
Termination visit, included. Subjects who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures until completion of the study (with 
the exception of procedures associated with drug dispensing and accountability, pregnancy 
testing, and GFR estimation [including body weight measurement]).
All reasons for discontinuation of therapy will be documented in the source documents as well as 
the eCRF comment form. Only one reason (the most severe) for early discontinuation should be 
recorded in the eCRF Termination form. 
In the event that the study IMP was discontinued early, the following forms should be completed 
as close to the last dosing date as possible: 

Termination/ Early discontinuation visit form

Last visit that the subject attended
The following procedures and evaluations will be performed at this visit:

Vital signs (temperature, pulse, BP, weight) 

Physical examination 

Safety laboratory tests:

Serum pregnancy test (β-hCG) for women of child-bearing potential

Hematology (CBC with differential)


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
Serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin, 
pancreatic amylase, CPK, and estimated GFR)

Markers of inflammation (serum conventional hs-CRP and fibrinogen)

ECG 

Review concomitant medications. Note: moderate/strong CYP3A4 inhibitors are 
disallowed during the 30 days after the last dose has been administered. For 
information on the use of CYP1A2 substrates following laquinimod cessation, please 
refer to the laquinimod IB.

Record of AEs

If an AE is still ongoing, or a new AE is present at the termination visit, it will be 
followed until resolution or until it is considered stable or chronic and will be 
recorded in the subject's source documents and in the eCRF. 

Complete neurological examination including FS, AI, EDSS and Timed 25 Foot walk 

MSFC

For all subjects who are female of child-bearing potential:

The use of effective contraception will be ascertained (should be recorded in the 
source documents) and all subjects will be reminded to continue using two
acceptable methods of contraception up to 30 days from the date of the last dose 
of the IMP

Subjects will be instructed about the teratogenicity and potential delayed risks for 
a child exposed in uterus to laquinimod

Subjects will be reminded about (should be recorded in the source documents)
importance of stopping the study drug and informing the site in any case of 
suspected pregnancy (positive home urine test result, delay of menstruation or any 
other reason suggesting pregnancy)

Binocular low-contrast visual acuity assessment, using 100%, 2.5%, and 1.25% 
contrast charts [Sloan letter or Tumbling E (see Appendix H and Appendix I)] 

Evaluation of relapse 

Subject-reported fatigue will be assessed by the MFIS (see Appendix F)

The general health status and MS-related quality of life, will be assessed using the 
SF-36 subject-reported questionnaire (see Appendix K)


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
The effect of general health and symptom severity on work will be assessed using the 
WPAI-GH questionnaire (see Appendix J) (This assessment will be performed in all 
subjects from US sites only)

Subject compliance (IMP accountability)

IVRS call to report subject’s Termination/Early discontinuation
8.2.4.
Early Treatment Discontinuation
Subjects who are discontinued from study treatment will be encouraged to continue all scheduled 
visits and procedures until completion of the study (with the exception of procedures associated 
with drug dispensing and accountability, pregnancy testing, and GFR estimation [including body 
weight measurement]).
An early termination visit should be completed for all subjects who prematurely discontinue 
from the study and do not agree to or cannot continue all scheduled visits and procedures. It 
includes subjects who took at least one dose in the MS-LAQ-302E study.
Every attempt should be made to follow the early discontinued subjects. The subjects who 
prematurely discontinue the study should be treated by the investigator in a customary manner. 
In case of early discontinuation due to ongoing AE, manifestation of a severe degree of 
intolerance to IMP and/or ongoing MS relapse, the subject should remain under medical 
observation and followed until the medical condition returns to baseline or is considered stable or 
chronic.
8.2.4.1.
Criteria for Early Treatment Discontinuation
A subject may withdraw or be withdrawn from the study for the following reasons:
1. Subject withdrew consent
2. Sponsor requested subject to be withdrawn (this does not include declaration of study 
termination by the Sponsor)
3. Request of primary care physician or investigator
4. Protocol violation/ Non-compliance
5. Lost to follow-up/failure to return
6. AE (specify primary AE in the AE log) 
7. Pregnancy
8. Planned pregnancy
9. Lack of efficacy (according to the Investigator’s decision)


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10. Death
Any attempt should be made to clarify and to document the exact reason for discontinuation.
8.2.5.
Post Early Discontinuation Follow-Up Visit 
Note: This section specifically pertains to subjects that discontinue treatment early but do not 
agree to continue follow up.
In case of early discontinuation due to AE, the subject should be invited to attend an unscheduled 
visit, which will serve as a post-treatment follow-up visit. The post-treatment follow-up visit 
should occur at 30 +/- 4 days from the last dose taken in the study.
Women of child bearing potential should continue using two acceptable contraception methods 
up to 30 days after the last study drug dose was taken. 
Moderate and strong CYP3A4 inhibitors are disallowed during the 30 days after the last dose has 
been administered.
The following procedures will be performed during this visit:

Mandatory procedures:

Vital signs

Review of concomitant medications

Evaluation of AEs

Pregnancy test (serum hCG test only; for women of child bearing potential)

Optional procedures:

Evaluation of a suspected relapse/follow-up 

ECG

Physical examination

Neurological examination 

Safety laboratory tests

Chest X-ray


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8.2.6.
Safety Stopping Rules
8.2.6.1.
Liver Enzymes
In any increase of ALT or AST to ≥ 2 times ULN the “Guidance on Safety Monitoring” (see 
Appendix E) should be thoroughly followed.
In the following circumstances, study drug will be discontinued immediately and liver enzymes 
will be monitored according the guidance in Appendix E:

Any increase in ALT or AST to ≥3 times ULN, combined with International 
Normalized Ratio (INR) >1.5 or total bilirubin >2xULN 

Any increase in ALT or AST to ≥3 times ULN, which is accompanied by nausea, 
vomiting, fever, rash, or eosinophilia 

Any increase in ALT or AST to levels ≥5 but <8 times ULN, which is persistent for 
≥2 weeks of repeated measurements.

Any increase in ALT or AST to levels ≥8 times ULN

In any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
8.2.6.2.
Pregnancy
Pregnancy reports should be forwarded to the Pharmacovigilance for data-entry to the global 
safety database. This includes also normal pregnancies without AE. The pregnancies reporting 
procedure should be the same as the SAE reporting procedure.
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and presence or absence of any birth defect, congenital 
abnormalities or maternal and newborn complications. Pregnancy follow-up should be recorded 
on a specific eCRF provided by Local Clinical Trial Management.
To further emphasize the importance of use of effective contraception and avoidance of 
pregnancy under laquinimod exposure (see Section 3.4), and to reduce as much as possible the 
exposure to laquinimod if a pregnancy occurs despite all recommended measures, all subjects 
who are women of childbearing potential will be instructed about the teratogenicity and potential 
delayed risks for a child exposed in uterus to laquinimod. 
To strengthen the preventative measures, the measures for pregnancy prevention now include: a 
requirement for two contraception methods (as recommended by the DMC) and a requirement 
for using a contraception method 30 days prior to enrollment. Furthermore a serum beta β-hCG 
test prior to enrollment and additional follow up measures and clarifications are added. These 
subjects will also be counseled about the importance stopping treatment immediately if 
pregnancy is suspected (based on a positive pregnancy test, delay of menstruation or any other 
reason to suspect pregnancy).


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Acceptable methods of birth control include intrauterine devices, barrier methods (condom or 
diaphragm with spermicide), and hormonal methods of birth control (oral contraceptive, 
contraceptive patch, long-acting injectable contraceptive).
The subjects' understanding of the importance of preventive pregnancy measures and their ability 
to follow the required instructions will be ensured by the investigator and documented in source 
documents.
Additionally, monthly pregnancy tests (urine dipstick and/or serum pregnancy β-hCG test, as 
applicable per the relevant time point) will be performed (except for where subjects have 
discontinued study drug but are continuing to attend study visits for follow-up). 
All pregnancies of women participating in study and that occur during the study, or within 
30 days after the last dose of treatment was administered, are to be reported immediately to the 
individual identified in the clinical study personnel contact information Section 20 of this 
protocol, and the investigator must provide the LSO/CRO with the pregnancy form. The process 
for reporting a pregnancy is the same as that for reporting a SAE (see Section 11). 
Any woman who becomes pregnant during the study will discontinue treatment. Subjects who 
become pregnant will be monitored for the outcome of the pregnancy (including spontaneous or 
voluntary termination). If the pregnancy continues to term, the outcome (health of the infant up 
to 8 weeks of age), details of birth, and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the sponsor. Any 
complication of pregnancy during the study and any complication of pregnancy that the 
investigator becomes aware of after termination from the study will be reported as an AE or 
SAE, as appropriate.
If the pregnancy does not continue to term, one of the following actions will be taken:

For a spontaneous abortion, report as a SAE

For an elective abortion due to developmental anomalies, report as a SAE

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form
8.2.6.3.
Cancer
Subjects that are diagnosed with a malignant solid or liquid tumor while participating in the 
study should stop study drug.


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8.2.6.4.
Liver Impairment
To avoid exposures to higher levels of laquinimod (see Section 3.3.1), a stopping rule related to 
liver impairment has been introduced. Subjects who develop any chronic liver disease associated 
with hepatic function impairment while participating in the study should stop study medication.
8.2.6.5.
Renal Impairment
To avoid exposures to higher levels of laquinimod (see Section 3.3.1), a stopping rule related to 
renal impairment has been introduced. Subjects who develop renal disease associated with 
moderate or severe functional impairment, defined as glomerular filtration rate (GFR) 
≤60 mL/min/1.73 m2, while participating in the study should stop study medication temporarily 
and the GFR assessment should be repeated. If the renal impairment is confirmed (GFR 
≤60 mL/min/1.73 m2), the subject should stop study medication permanently.
8.2.7.
Replacement of Withdrawn Subjects
Not applicable.
8.2.8.
Temporary Discontinuation of Study Drug Treatment
Temporary discontinuation is defined as missing of more than three consecutive doses. Skipping 
of 14 or more consecutive doses will be considered as a major protocol violation.
The reasons for temporary IMP/study drug discontinuation should be recorded in the appropriate 
Section of the IMP/study drug dispensing and return form in the eCRF and the local clinical 
management (LCM) should be notified.
The subject will report any temporary discontinuation to the investigator and will be instructed 
by the investigator regarding continuation of treatment.
8.2.9.
Unscheduled Visit
An unscheduled visit may be performed at any time during the study at the subject's request or as 
deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded.
The reasons for the unscheduled visit may be:

Appearance of a new AE or an AE follow-up

Change in concomitant medications

Possible relapse

Relapse follow-up

Laboratory follow-up


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
Post early-discontinuation follow-up visit (see Section 8.2.5)

IMP dispensing, accountability and/or replacement

Subject compliance

Delayed baseline visit

Other (should be specified)
Should the visit be related to a relapse, this will be clearly indicated on the eCRF and the Study
Neurologist/Physician will carry out a complete neurological evaluation (FS/AI/EDSS/ Timed 25 
Foot walk).
Additional analyses may be performed by the investigator and stated in the source 
documentation:

Mandatory Unscheduled Visit Procedures

Vital signs

Evaluation of AEs

Optional Unscheduled Visit Procedures

Evaluation of a suspected relapse/follow-up 

ECG

Physical examination

Neurological examination 

Safety laboratory tests (including estimation of GFR)

In case of drug dispensing/replacement call IVRS to obtain a pack number

IMP accountability

Subject compliance

Review of concomitant medications

For female subjects of child-bearing potential, serum or urine β-hCG test may be 
performed 


Protocol MS-LAQ-302E
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
Female subjects of child-bearing potential will be questioned to ascertain use of 
effective contraception and will be reminded about (should be recorded in the 
source documents):
o
The importance of contraception
o
Importance of stopping the study drug and informing the site in any case of 
suspected pregnancy (positive urine β-hCG test result, delay of menstruation 
or any other reason suggesting pregnancy)
o
Importance of performing the home pregnancy urine tests every one month 
(starting after visit Month 3E)
8.2.9.1.
Unscheduled Samples 
According to the judgment of the investigator or medical monitor, the following unscheduled 
samples may be collected to assist with further investigations of cardiovascular events or other 
clinical event of interest:

urgent safety laboratory test panel (see Section 10.2.3.1)

pharmacokinetic blood sample

sample for potential biomarker analysis
8.2.9.1.1. Unscheduled Pharmacokinetic Samples
Unscheduled pharmacokinetic blood samples may be collected at the discretion of the 
investigator or medical monitor at any time to assist with further investigations of cardiovascular 
events or other clinical event of interest. The samples should be collected as soon as possible in 
association with the event.
Details of sample collection and processing are provided in the Laboratory Manual.
8.2.9.1.2. Unscheduled Biomarker Samples
Unscheduled samples for potential biomarker assessments may be collected at the discretion of 
the investigator or medical monitor at any time to assist with further investigations of 
cardiovascular events or other clinical event of interest. The samples should be collected as soon 
as possible in association with the event.
Potential biomarker assessments to better understand laquinimod MoA, as well as to explore 
response predictive markers for efficacy or safety, may include 1) cytokines and other soluble 
marker levels; 2) RNA analysis; 3) proteomic profile; and/or 4) other relevant biomarkers.
Details of sample collection and processing are provided in the Laboratory Manual. Since new 
biomarker techniques continue to be developed, the method and laboratory that will be 
recommended cannot be anticipated.


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8.2.9.2.
Visits during Relapses (Scheduled and Unscheduled)
Subjects will be instructed to contact their study site within 48 hours should any symptoms 
suggestive of a relapse occur (see Appendix A).
The Study Neurologist/Physician will evaluate the subject within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥48 hours. 
The relapse assessment will be documented in the source documents and in the eCRF 
accordingly. A complete neurological assessment, including FS, AI EDSS and Timed 25 Foot 
walk, will be performed by the Study Neurologist/Physician.
The decision as to whether the neurological change is considered a relapse will be made by the 
Study Neurologist/Physician, based on the criteria listed in Appendix A.
Corticosteroids therapy (as described in Section 7.1) may be given for a confirmed relapse at the 
discretion of the Study Neurologist/Physician and must be recorded in the source documents and 
eCRF.
8.2.9.2.1. Relapse Follow-up:
Upon a confirmed relapse, subject’s neurological condition must be followed up closely within 
scheduled or unscheduled visits. The stabilization of a relapse date/ approximate date should be 
indicated in the source document and the eCRF. 
Every attempt should be made to document the resolution of relapses.
At all the follow up visits for a confirmed relapse a full neurological examination (EDSS 
including FS and AI and 25 foot walk) must be performed. This should be done at a visit that is 
close to stabilization or no later than 2 weeks after stabilization date.


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9.
INVESTIGATIONAL MEDICINAL PRODUCTS/STUDY DRUGS
9.1.
Treatment Administered
All subjects will be administered one capsule of laquinimod 0.6 mg to be taken orally at the same 
hour every day.
Capsules should be swallowed with a glass of water. 
Subjects are allowed to omit study drug up to 3 consecutive days.
9.2.
Method of Assigning Subjects Numbers
The same randomization number which was used to identify a certain subject in the MS-LAQ-
302 study will serve this purpose in the MS-LAQ-302E study as well. At baseline (month 0E, 
visit 0E) (Termination visit of the MS-LAQ-302 study), the investigator will enter the subject's 
number (the same as was used in the MS-LAQ-302 study) to the IVRS in order to dispense the 
study drug. 
The IVRS will keep track of subjects' visits and status. 
9.3.
Description of Investigational Medicinal Product/Study Drug
Laquinimod 0.6 mg capsules are manufactured in compliance with current GMP standards and 
guidelines applicable to IMPs by Teva Pharmaceutical Industries Ltd. Israel. Laquinimod 0.6 mg
capsules are white opaque cap and body; hard gelatin capsules filled with white to off-white 
granulate.
9.4.
Packaging and Labeling
The study drug is packaged in round 50 cc white high density polyethylene bottles containing 35 
capsules. The bottles are capped with child-resistant polypropylene caps, each equipped with a 
silica desiccant insert. 
The primary packaging is performed under the responsibility of the Clinical Manufacturing Unit 
of Teva Pharmaceutical Industries Ltd. The secondary packaging and labeling for subjects is 
performed under the responsibility of the Clinical Supplies Unit (CSU) of Teva Pharmaceutical 
Industries Ltd, according to European Union (EU) regulations and International Conference on 
Harmonisation (ICH) guidelines as adopted by the Food and Drug Administration (FDA) – Good 
Clinical Practice (GCP) (E6).

Each bottle will be identified by a unique bottle number. 

The label on the bottles will include a fixed information section (to include the 
product name, storage conditions, instructions etc.) and variable information section. 


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
For all countries except Germany, the fixed information section will be a multi 
lingual booklet fixed on the bottle. It will bear information such as the study number, 
dosage, and directions for use, storage conditions and precautions. This part will be 
translated to all languages and meet all regulatory demands required for all 
participating countries. The front cover will contain an index to guide the subject to 
the relevant page.

Due to local regulatory requirements, for Germany only, this section will be a single 
panel label in German that will contain a fixed part and a tear off section.

The variable information section will include 3 parts: One detachable part, which will 
be attached to the subject’s file upon bottle dispensing, one part to remain on the 
bottle and the third may be used according to local needs (pharmacy, prescription, 
etc). The variable information section will include the following variable data: batch 
number, bottle number, and expiration date (all to be pre-printed) and blank fields for 
the dispensing investigator's name, visit number and subject number. These blank 
fields will be manually filled-in by the Investigator upon provision of bottle to the 
subject.
9.5.
Distribution and Shipment
Distribution and shipment of IMPs will be performed by a Contract Research Organization 
(CRO), according to the distribution guidelines. IVRS will manage supply at depots and sites for 
all countries except Germany. For Germany, the IVRS will not be used and each site's clinical 
research associate (CRA) will request supplies for initial and re supply shipments. The supplies 
will be ordered in accordance with the ‘Guidelines for demands planning and inventory 
management policy at site.
The IMP bottles will be packed and shipped at room temperature (15-25oC/59-77oF) in 
appropriate storage boxes. If the IMP supplies appear to be damaged/ missing upon arrival at the 
investigational site, the Sponsor should be contacted immediately.
Each shipment of IMPs supplies for the study will contain a shipment form describing the 
content of shipment. This form will assist in maintaining current and accurate inventory records. 
When a shipment is received, the site investigator/ site coordinator/pharmacist will acknowledge 
receipt of the IMP supply by making "Confirm Shipment” call (via the IVRS/IWRS). For 
Germany, the site will have to sign the shipment form and fax it to the depot.
When a shipment is received in a depot, acknowledgement of receipt of the IMP supply will be 
performed by the CSU.
Importing of the IMP by an EU member will be carried out according to the provisions of 
Directive 2001/20/EC, Article 13.
9.6.
Storage, Dispensing and Return
IMP supplies will be kept in a secure, limited-access, temperature-controlled storage area. 


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Only authorized personnel will have access to the IMP. The study site personnel at each site will 
be responsible for correct storage and handling of the IMP. 
All IMP bottles must be stored at room temperature (15-25oC/59-77oF).
Apart of Termination visit, the IMP bottles will be dispensed to the subject at the study site at 
each study visit starting at baseline visit (Month 0E; Termination visit of the MS-LAQ-302
study). The bottles will be assigned to subjects by using an IVRS/IWRS. After assigning a bottle 
number to the subject, the site personnel should fill in the subject’s number, the visit number and 
the dispensing investigator's name on the label of the dispensed bottle as well as on the 
detachable parts that would be attached to the subject’s file.
At each visit from baseline (Month 0E; Termination visit of the MS-LAQ-302 study) to Month 
3E visit the subject will receive 1 bottle of IMP (baseline, Month 1E and Month 2E). At visit 
month 3 the subject will receive 3 bottles of IMP. From visit month 6 onward the subject will 
receive 6 IMP bottles according to visit duration, an amount that will suffice until the following 
scheduled dispensing visit.
Subjects will be instructed to return all used empty bottles and unused IMP at each visit. The Site 
Investigator/site coordinator is responsible for performing IMP accountability at the site. The 
Monitor is responsible for the accountability of the returned IMPs.
9.7.
Verification of Compliance With Treatment Regimen
At each study visit the investigator /site coordinator will assess the subject’s compliance with the 
prescribed regimen for the study medication. This will include checks of protocol compliance 
and use of study drug in order to assess the reliability of subject-generated data. Subjects who 
fail to comply with the study requirements may be withdrawn from the study, following 
consultation with the Sponsor. 
Compliance with the dosing regimen will be determined by performing IMP accountability of 
returned bottles of the used and unused IMP. The number of used and unused capsules will be 
recorded on the eCRF by site personnel. Percent compliance will be calculated as the number of 
used capsules divided by the number of total capsules expected to be used, multiplied by 100. 
Subjects with less than 75% overall compliance during the entire study will be considered non-
compliant.
9.8.
Accountability and Compliance
IMP accountability records must be maintained at the site at all times.
Upon Teva's (or Teva's designee) monitor visit at the site, accountability of the returned IMPs 
should be performed and recorded by the monitor. The subject number, the date, batch number, 
bottle number and quantity of IMP returned by the subject will be checked for correctness and 
recorded via the IVRS or on the appropriate accountability forms, to be provided by the CSU.


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During the study, all IMPs (used and unused bottles) and the corresponding accountability forms
(if applicable) must be returned by the monitor to the Sponsor or Sponsor’s designee (CRO) on 
an on-going basis for reconciliation and destruction. A photocopy of these records must be kept 
at the study sites.


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10.
ASSESSMENT METHODS
10.1.
Efficacy Assessment Methods
10.1.1.
On-Study Relapse Evaluation & Determination

Subjects will be instructed to telephone their study site within 48 hours should any 
symptoms suggestive of a relapse appear.

The Study Neurologist/Physician will evaluate the subject once any symptom 
suggestive of a relapse occurs.

In case of a suggestive relapse during a scheduled or unscheduled visit in:

The evaluation of symptoms as well as the neurological evaluations/ EDSS will 
be made by the Study Physician/Neurologist.

Based on the assessment of symptoms and the EDSS/FS evaluation, the Study 
Physician/Neurologist will decide whether a subject experienced a relapse and 
will treat the subject as needed. 

In any case, the neurological evaluation of the subject by the Study 
Physician/Neurologist will be performed within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥ 48 hours.

In the case of an ongoing or just-started relapse at the study Termination/Early 
discontinuation visit, subjects will be followed up until relapse stabilization (see 
Section 8.2.9.2.1).
10.1.2.
Neurological Evaluations
A complete neurological assessment will be performed at Months 0E [Baseline (Termination 
visit of the MS-LAQ-302 study)], 6E and every 6 months thereafter until Termination/Early 
discontinuation of the study. Every effort should be made to ensure that the same 
Neurologist/Physician performs the neurological assessment at all visits for a particular subject.
FS and EDSS will be assessed based on a slightly modified neurological examination 
(Neurostatus: L. Kappos, Dept. of Neurology, University Hospital, CH-4031/Basel. Version 
12/05) (see Appendix B). The results will be recorded on standardized and validated examination 
forms (will appear in the source documents) as well as in the eCRF.
Mental Functional System Score 1b (due to mild fatigue) will contribute to the EDSS score while 
mental Functional System Score 1a will not contribute to the EDSS score.


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10.1.3.
MSFC
The MS Functional Composite consists of 3 clinical examinations, the results of which are 
combined using z-scores. The three clinical examinations include the PASAT, Timed 25 Foot 
walk and 9-HPT.
The PASAT and 9-HPTs will be performed at Months 0E [Baseline (Termination visit of the 
MS-LAQ-302 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/Early discontinuation visit.
The Timed 25 Foot walk test will be performed each time neurological evaluation is performed.
Appendix G presents the instructions for administering the MSFC.
10.1.4.
Modified Fatigue Impact Scale (MFIS)
Subject-reported fatigue will be assessed by the MFIS at months 0E [Baseline (Termination visit 
of the MS-LAQ-302 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/Early discontinuation visit. 
The MFIS is a validated specific subject-reported outcome measure that was developed to 
evaluate the impact of fatigue on the lives of people with MS. The instrument will be self-
administrated during the visit and consists of total score and 3 subscales to assess the impact of 
fatigue on:
1. Cognitive function (10 items)
2. Physical function (10 items)
3. Psychosocial function (20 items)
The subject is asked to circle the appropriate response on a Likert scale: 0 – no problem; 1 –
small problem; 2 - moderate problem; 3 – big problem; 4 – extreme problem. The MFIS takes
approximately 10 minutes to complete and has good internal consistency as measured by
Cronbach’s alpha (0.98 for full sample analysis of the entire questionnaire and >0.87 for all
subscale items by group) and has been shown to be able to discriminate between different patient
populations as well as between groups with different severity levels in MS (Appendix F).
10.1.5.
Binocular Low- Contrast Visual Acuity
It has been demonstrated that low-contrast visual acuity, as measured using the Sloan Charts has 
a substantial capacity to capture visual dysfunction in subjects with MS. 
The low-contrast visual acuity will be assessed binocularly at Months 0E [Baseline (Termination 
visit of the MS-LAQ-302 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/Early discontinuation visit, along with the MSFC assessments. At each visit, the 
letter acuity will be captured using 100%, 2.5% and 1.25% contrast charts, from a distance of 2 


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meters, with the subject’s usual distance correction. In case the subject is not familiar with the 
English/Roman alphabet, the Tumbling E charts will be used. 
Appendix H and Appendix I present the instructions for administering the binocular low-contrast 
visual acuity test.
10.1.6.
The General Health Status: Short-Form General Health Survey (SF-36)
The general health status will be assessed by the SF-36 (see Appendix K) subject-reported 
questionnaire at months 0E [Baseline (Termination visit of the MS-LAQ-302 study)], 6E and 
every 6 months (every scheduled visit) thereafter, until Termination/Early discontinuation visit. 
The SF-36 is a generic, self-administered health-related quality of life instrument. In this study 
the instrument will be self-administrated during the visit.
The SF-36 has been proven to be valid and reliable in a large number of indications 
(e.g., cardiovascular disease, low back pain, diabetic foot ulcers, total knee replacement and 
dialysis) and subject populations. It was developed in the US and was constructed such that its 
36 questions represent 8 of the most important health concepts. The 8 domains of the SF-36 are: 
physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-
emotional, and mental health. In addition, a single question assesses reported health transition. In 
addition to the 8 SF-36 domains, 2 summary scores can be evaluated: the physical health 
component summary score and the mental health component summary score. The SF-36 is the 
most widely used measure of health-related quality of life in relapsing-remitting MS and can 
usually be completed in 5 to 10 minutes. 
10.1.7.
Ancillary Study: Economic Impact: The Work Productivity and Activities 
Impairment (WPAI-GH) Questionnaire (Ancillary Study, US sites only):
The WPAI-GH was developed for assessing productivity losses by measuring the effect of 
general health and symptom severity on work as well as usual activity productivity. The WPAI-
GH instrument consists of 6 questions that ask the subject the number of hours missed from work 
and usual activities as well as the number of hours in which work or usual activities were limited 
over the past 7 days. The instrument is self-interview and takes about 5 minutes to complete. 
This questionnaire will be administered at months 0E [Baseline (Termination visit of the 
MS-LAQ-302 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/Early discontinuation visit. This assessment will be performed in all subjects from 
US sites only.
10.2.
Safety Parameters
10.2.1.
Adverse Events
AEs will be recorded from when a subject has signed the Informed Consent Form and 
throughout the study, including the follow-up period. They should be reviewed and updated at 
each subsequent visit and during any phone contact with the subject.


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10.2.1.1.
Protocol-Defined Adverse Events for Expedited Reporting
Ischemic cardiac events (such as myocardial infarction, unstable angina, acute coronary 
syndrome etc), and cerebrovascular events (such as cerebral arterial occlusion, cerebral ischemia, 
etc) should be reported to the sponsor within 48 hours, including completion of the 
corresponding dedicated CRF.
10.2.2.
Abdominal Computed Tomography Scan
In case of pancreatitis or suspected pancreatitis, an abdominal computed tomography (CT) scan 
should be performed as soon as possible in order to clarify the diagnosis and enable assessment 
of severity of this condition. An MRI may be performed as an alternative to the CT scan.
10.2.3.
Safety Laboratory Evaluations
Unless specified otherwise all laboratory testing will be performed by a central laboratory
facility. The following tests will be performed: (except the tests requiring close follow up due to 
safety stopping rules specified in Section 8.2.6 and in the Safety Monitoring Guidance
Appendix E).
Laboratory tests (including pregnancy test for women of child bearing potential) will be 
performed at each scheduled study visit (in unscheduled visit upon need).

Serum Chemistry

Glucose

Creatinine (including estimation of GFR)

Bilirubin (direct and total)

Urea

AST (SGOT)

ALT (SGPT)

GGT

Total Protein

Albumin

hs-CRP 

CPK
o
In case of abnormal CPK result: troponin and CPK-MB will be tested


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○
In case of CPK > 2000 U/L urine myoglobin will be tested and the following 
tests will be repeated: CPK, CPK-MB, blood urea nitrogen, creatinine, 
electrolytes including potassium, calcium, phosphate, hs-CRP and fibrinogen

Alkaline Phosphatase (ALP)a

Pancreatic Amylase

Lipase will be tested in case of abnormal pancreatic amylase results (see 
Appendix E for guidance on monitoring subjects with elevated pancreatic amylase 
levels)

Electrolytes

Sodium

Potassium

Calcium 

Phosphorous

Coagulation

Fibrinogen
INR (to be performed in local laboratory, only if required according to Safety Monitoring 
Guidance, Appendix E).

Pregnancy tests:

Serum β-hCG pregnancy tests (to be performed in women of child-bearing 
potential, at all scheduled study visits)

Urine β-hCG pregnancy test (to be performed in women of child-bearing 
potential), at all scheduled study visits (excluding Termination) and every 
28 ± 2 days, at home, starting from visit Month 3E.
Pregnancy tests do not need to be performed for women who have discontinued study treatment 
but are continuing to attend scheduled study visits for follow-up.

Hematology

Hemoglobin
                                                
a Those tests may also be performed in a local lab according to the Safety Monitoring Guideline.


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
Mean Corpuscular Hemoglobin (MCH)

Mean Corpuscular Volume (MCV)

MCHC

Hematocrit

RBC count

WBC count + differential 

Platelet count

Serology (to be performed only in a confirmed abnormality of liver enzymes, 
according to Appendix E):

Anti-hepatitis A virus (HAV) IgM antibodies

Hepatitis B Surface antigen

Anti- hepatitis B core antigen (HBc) IgM antibodies

Anti- hepatitis C virus (HCV) IgG antibodies

Anti-nuclear antibodies

Anti-Smooth Muscle (Sm) antibodies

Anti-Liver-Kidney Microsomes (LKM)-1 antibodies
10.2.3.1.
Urgent Safety Laboratory Panel
Unscheduled urgent safety laboratory samples may be collected at the discretion of the 
investigator or medical monitor at any time to assist with further investigations of cardiovascular 
events or other clinical event of interest. The samples should be collected as soon as possible in 
association with the event.
The following tests (and others, if required) will be performed on these samples:

serum chemistry panel, including fibrinogen and hs-CRP

hematology panel

CPK-MB

troponin I


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10.2.4.
Vital Signs and Weight
Vital signs (temperature, pulse and BP) will be completed at all scheduled and unscheduled 
visits.
BP and pulse will be recorded in a sitting position after resting for 5 minutes. 
All measurements and time of measurements will be recorded in the source documents.
Body weight will be measured at all visits until Termination/Early discontinuation, and as long 
as the subject continues study drug treatment. 
10.2.5.
ECG
ECG will be performed at months 0E [Baseline (Termination visit of the MS-LAQ-302 study)]
and every 6 months thereafter, until Termination/Early discontinuation visit. 
The subject should rest for at least 10 minutes before measurement is taken. Twelve-lead ECG 
should be performed following the subject being in a supine position for 5 minutes.
The interpretation of the ECG will be made only locally, by the investigator, and the clinical 
evaluation remains under the investigator’s/ local cardiologist responsibility. Therefore, the 
investigator/local cardiologist will be responsible to determine whether ECG findings are of 
clinical significance. 
The ECG will be evaluated by the investigator at time of performance (signed and dated) and the 
printout should be kept in the source documentation file. When potentially clinically significant 
findings are detected by the Site Investigator, a cardiologist should be consulted for a definitive 
interpretation. All communications and diagnoses should be filed in the source documentation 
file.
The investigator’s interpretation of the ECG will be recorded in the eCRF.
10.2.6.
Physical Examination
Physical examination will be performed at months 0E [Baseline (Termination visit of the 
MS-LAQ-302 study)], 6E, 12E and then every 12 months thereafter, until Termination/Early 
discontinuation visit.
Any finding on physical examination (whether a new condition or worsening of a pre-existing 
condition) should be recorded as an AE.
10.2.7.
Glomerular Filtration Rate Estimation
Significant changes in laquinimod exposure, in particular in terms of unbound drug fraction, are 
predicted in patients with moderate and severe renal impairment (see Section 3.3.1). 
Consequently, GFR will be estimated at all visits to monitor renal function in the study in order 
to identify subjects with potentially impaired laquinimod clearance. Subjects with a confirmed 


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GFR ≤60 mL/min/1.73 m2 should stop study medication temporarily and the GFR assessment 
should be repeated. If the renal impairment is confirmed (GFR ≤60 mL/min/1.73 m2), the subject
should stop study medication permanently (see Section 8.2.6.5).
10.2.8.
Cardiovascular Risk Assessment and Management
Evaluation and management of major modifiable cardiac risk factors (eg, diabetes, high blood 
pressure, hyperlipidemia, tobacco smoking) will be performed at the time points indicated in 
Table 5. In addition, an evaluation should take place as soon as possible for subjects already in 
the study, following approval of Amendment #2.
Cardiovascular risk management should be conducted according to evidence-based, local 
standard-of-care procedures. Subjects will undergo referral to a suitable clinic if needed.


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11.
SAFETY AND PHARMACOVIGILANCE
11.1.
Adverse Event
An AE is defined as any untoward medical occurrence in a clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with the treatment.
In the study, any event occurring after the clinical trial subject has signed the study Informed 
Consent should be recorded and reported as an AE.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an IMP, whether or not 
considered related to the IMP.
A new condition or the worsening of a pre-existing condition will be considered an AE. Stable 
chronic conditions such as arthritis that is present prior to study entry and do not worsen during 
the study will not be considered AEs. 
Worsening of the disease under study will be measured by MS relapse or by EDSS parameters, 
and should only be recorded as an AE if the outcome is more serious than would normally be 
expected from the normal course of the disease in a particular subject.
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it:

Results in subject’s withdrawal by the investigator

Is associated with a serious adverse event (SAE)

Is associated with clinical signs or symptoms

Is considered by the physician to be of clinical significance
The intensity or severity of the AE will be characterized as:

Mild: 
AE which is easily tolerated

Moderate: AE sufficiently discomforting to interfere with daily activity.

Severe: 
AE which prevents normal daily activities.
Unlabeled/ Unexpected AE - A reaction which is not included in the Adverse Reaction 
section of the relevant Reference Safety Information by its specificity, severity, outcome or 
frequency. The safety reference of this study is the IB.
The relationship of an AE to the study drug is characterized as:


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TERM
DEFINITION
CLARIFICATION
No 
Reasonable 
Possibility
This category applies to those 
adverse events which, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc.) or to those 
adverse events, which after careful 
medical consideration at the time 
they are evaluated, are judged to 
be unrelated to the test drug.
An adverse event may be considered as “No 
Reasonable Possibility” if it is clearly due to 
extraneous causes or when (must have two):
It does not follow a reasonable temporal sequence 
from the administration of the test drug.
It could readily have been produced by the subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject.
It does not follow a known pattern of response to the 
test drug. 
It does not reappear or worsen when the drug is re-
administered.
Reasonable 
Possibility
This category applies to those 
adverse events for which, after 
careful medical consideration at 
the time they are evaluated, a 
connection with the test drug 
administration cannot be ruled out 
with certainty or felt with a high 
degree of certainty to be related to 
the test drug.
An adverse event may be considered as “Reasonable 
Possibility” if or when (at least two of the 
following):
It follows a reasonable temporal sequence from 
administration of the drug.
It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, 
environmental or toxic factors or other modes of 
therapy administered to the subject.
It disappears or decreases on cessation or reduction 
in dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the drug, yet drug-relatedness 
clearly exists.
It follows a known pattern of response to the test 
drug.
The date of onset, a description of the AE, severity, seriousness, action taken, relationship to the 
study drug, outcome of the event and date of resolution will be recorded.
11.2.
Serious Adverse Event
An SAE is defined as an AE that results in any of the following:

death

life-threatening

requires hospitalization or prolongs existing inpatients’ hospitalization

results in persistent or significant disability or incapacity


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
results in a congenital abnormality or birth defect

an important medical event which requires medical intervention to prevent any of the 
above outcomes
Important medical events are those which may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
resulting in an AE will normally be considered serious by this criterion.
Inpatient hospitalization or prolongation of existing hospitalization means that hospital inpatient 
admission and/or prolongation of hospital stay were required for treatment of AE, or that they 
occurred as a consequence of the event. It does not refer to pre-planned elective hospital 
admission for treatment of a pre-existing condition that has not significantly worsened, or to 
diagnostic procedure. It does not refer either to hospitalization for IV steroid treatment of a 
relapse, unless it is a worsening of condition beyond expected disease progression (as described 
below).
The term "life-threatening" in the definition of "serious" refers to an event in which the subject
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.
Any new SAE that occurs after the study period and is considered to be related (reasonable 
possibility) to the IMP or study participation should be recorded and reported immediately. The 
study period for the purpose of SAE reporting is defined as the period from the subject's 
signature on the informed consent form until the end of the follow-up period (30 days following 
the last dose). 
11.2.1.
SAE Reporting
In order to satisfy regulatory requirements, any SAE, whether deemed IMP-related or not, must 
be reported to the CRO as soon as possible after the investigator or coordinator has become 
aware of its occurrence. The SAE form completion and reporting must not be delayed even if all 
of the information is not available at the time of the initial contact.
The SAE should be submitted within 24 hours of becoming aware of the event to the CRO. The 
CRO will forward the report to the appropriate Pharmacovigilance unit at Teva or the Local 
Safety Officer (LSO) who will forward the SAE report to the the appropriate Pharmacovigilance 
unit at Teva:


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SAE originated in Europe and rest of the world should be sent to:
Global Drug Safety and Pharmacovigilance Unit (Israel)
SAE originated in USA will be sent to:
Teva USA clinical safety mailbox
SAE originated in Canada will be sent to:
Teva Canada safety mailbox
SAE originated in Germany will be sent to:
Teva Germany safety mailbox
Only in the event of difficulty transmitting the form via email, send the form via fax, or contact 
the sponsor’s study personnel identified above for further instruction. Additional information 
(follow-up) about any SAE unavailable at the initial reporting should be forwarded by the site 
within 24 hours of the information becoming available to the CRO. 
For both initial and follow-up SAE reports the CRO forwards this information to the appropriate 
Pharmacovigilance unit at Teva or the LSO who forwards it to the appropriate 
Pharmacovigilance unit at Teva within 48 hours. The Pharmacovigilance units at Teva will 
submit a summary of the clinical course of the SAEs back to the CRO/ LSO for local submission 
to the regulatory authorities (competent authorities [CA]) and Ethics Committee 
(EC)/Institutional Review Board (IRB) and investigators according to regulations.
The following information should be provided to accurately and completely record the event:
1. Investigator Name and Center Number
2. Subject Number
3. Clinical Event
a.
description
b. date of onset
c.
severity
d. treatment


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e.
relationship to study drug (causality)
f.
action taken regarding study drug
4. If the AE results in Death 
a.
cause of death (whether or not the death was related to study drug)
b. autopsy findings (if available)
5. Medical History case report form (CRF) (copy)
6. Concomitant Medication CRF (copy)
7. Any relevant reports (laboratory, discharge, X-ray, etc) 
This information should be sent to the LCM/ LSO who will forward the information to the 
appropriate Pharmacovigilance Centre at Teva. 
In the EU the procedures for notification of suspected unexpected serious adverse reactions 
(SUSARs) shall be carried out in accordance with EU Directives. SAEs should be reported by 
the Sponsor to EC/IRB according to local requirements.
In non-EU countries, SAEs should be reported by the site to their local EC/IRB as dictated by 
their board’s policies and procedures.
Subjects who have had an SAE during the treatment period must be followed clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are 
otherwise explained. 
Any newly emergent SAEs after treatment is discontinued or the subject has completed the study 
and is considered to be related to the IMP or study participation should be recorded and reported 
immediately. The post-study period for the purpose of SAE reporting is routinely for up to 30 
days following last visit of the study or until SAE is resolved or stabilized. In certain cases, such 
as where the drug has a long half-life, a longer follow-up period may be required.


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12.
STATISTICAL METHODOLOGY
A total of up to 1332 subjects, who were enrolled in study MS-LAQ-302 are expected to be 
recruited into this study. 
The statistical analyses of this study will be exploratory in nature. Continuous variables will be 
presented by descriptive statistics (mean, standard deviation, minimum, median and maximum 
values), by treatment group. For categorical variables, treatment group counts and percentage 
from total subject population will be tabulated.
12.1.
Sample Size Rationale
Subjects that completed the full double-blind treatment period of protocol MS-LAQ-302 will be 
eligible for inclusion in this trial. MS-LAQ-302 subjects have no obligation to enter this study, 
therefore the number of subjects in this study is not determined, but is expected to be less than 
1332 subjects. 
12.2.
Randomization Procedure
As this is an open label single arm study, no randomization procedure is applied.
12.3.
Subjects Analysis Sets
A single analysis set is defined for this clinical trial. This analysis set is:
Intent-to-treat analysis set (ITT): Consists of all subjects who have been enrolled to the study and 
received at least one dose of IMP. In accordance with the ITT principle, all subjects randomized 
will be kept in their originally assigned treatment group.
12.4.
Definition of baseline values
The last observed values from study MS-LAQ-302 will serve as the baseline values for this 
study.
12.5.
Efficacy Assessment
The statistical analyses of this study will be exploratory in nature. Continuous variables will be 
presented by descriptive statistics (mean, standard deviation, minimum, median and maximum 
values), for the whole study population, as well as by original treatment group in study MS-
LAQ-302. For categorical variables, counts and percentage from total subject population will be 
tabulated, as well as counts and percentages by original treatment group in study MS-LAQ-302.


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12.6.
Safety And Tolerability Assessments
12.6.1.
Data presentation
All data summary tables will be presented for the whole study population, as well as by original 
treatment group in study MS-LAQ-302.
12.6.2.
Adverse Events
The incidence and frequency of AEs will be presented by System Organ Class and preferred 
terminology according to the Medical Dictionary for Regulatory Activities (MedDRA)
dictionary. AEs will also be presented by System Organ Class, High Level Term and preferred 
terminology. 
Data will be tabulated by gender, maximal severity, maximal outcome and maximal relationship 
to the tested drug. 
SAEs and seriousness criteria will be listed, tabulated and discussed on a case by case basis as 
well.
12.6.3.
Laboratory Data
Laboratory quantitative parameters will be summarized and presented by using descriptive 
statistics. 
All laboratory values recorded during the study will be individually listed and flagged for values 
outside reference ranges and potential clinical significance.
12.6.4.
ECG
Distribution of Subjects by Investigators ECG Interpretation will be presented.
The ECG interpretation of the investigators will be individually listed. 
12.6.5.
Vital Signs 
Vital signs parameters will be summarized and presented by using descriptive statistics. 
Incidence of measurements of potential clinical significance will be provided.
Vital signs parameters recorded during the study will be individually listed and flagged for 
potential clinical significance values. 
12.6.6.
Drug Tolerability & Drop-Out Assessment
The number and percentage of subjects who failed to complete the study will be provided. 
The number and percentage of subjects who prematurely discontinued from the study due to AE
will be provided.


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13.
REGULATORY AND ETHICAL ISSUES
13.1.
Compliance with Regulations Applicable to Clinical Trials
The study will be conducted according to the laws, regulations and administrative provisions 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use, as applicable by national legislation and EU Directives and 
US 21 CFR Part 11, 50, 54, 56, 312.
13.2.
Informed Consent
The principles of Informed Consent, according to the Declaration of Helsinki and its updates,
ICH guidelines on GCP, 21 CFR part 50 of the FDA regulations and/or EU Directives, will be 
followed. A subject should not enter a clinical study until he/she has been properly informed, has 
been given time to contemplate participation, and has freely given his/her consent by signing and 
dating the EC/IRB approved informed consent form. This must be done prior to performing any 
study related procedures.
The proposed consent form and any other documents relevant to the consent process must be 
submitted to the EC/IRB, together with the protocol, and must be approved prior to study start.
A copy of the fully signed and dated Informed Consent Form and any other documents relevant 
to the consent process will be given to the subject and the original will be maintained at the site.
Subjects continuing on laquinimod 0.6 mg will be re-consented with information about the 
cardiovascular risk seen in higher doses (see Section 3.4.1.7).
13.3.
Subject Confidentiality
All subject data will be identified by a subject identification number. 
After obtaining subject’s consent, the investigator will permit the study monitor, independent 
auditor or regulatory agency personnel to review that portion of the subject’s medical record that 
is directly related to the study. This shall include all study relevant documentation including 
subject medical history to verify eligibility, laboratory tests results, admission/discharge 
summaries for hospital admissions occurring while the subject is on study and autopsy reports 
for deaths occurring during the study (if applicable).
13.4.
Ethics Committee (EC) / Institutional Review Board (IRB)
The study must have unconditional approval in writing, by an appropriate EC/IRB. A copy of the 
Letter of Approval from the EC/IRB, which contains the list of the documents approved, must be 
received by Teva/CRO prior to site activation


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Any amendments to the protocol or subsequent changes to the informed consent form as a result 
of changes to the protocol and/or IB that is approved by Teva, must also be approved by the 
EC/IRB and documentation of this approval provided to Teva. Records of the EC/IRB review 
and approval of all documents pertaining to this study must be kept on file by the investigator 
and are subject to the Sponsor’s audit and/or regulatory authority inspection, during or after 
completion of the study. 
SAEs must also be reported to the EC/IRB by the investigator or the Sponsor.
Periodic status reports must be submitted to the EC/IRB as required, as well as notification of 
completion of the study and a final report where applicable. A copy of all reports submitted to 
the EC/IRB must be sent to the Sponsor.
13.5.
Protocol Amendments
Changes to the protocol should only be made by an approved protocol amendment. Protocol 
amendments must be approved by the Regulatory/CAs (if applicable), Central EC/IRB (if 
applicable) and/or each respective site’s EC/IRB (if applicable), prior to implementation.
For clinical trial sites located in EU Member States, the procedures outlined in Directive 
2001/20/EC, Article 10(a), are applicable.
13.6.
Declaration of the End of the Clinical Trial
For clinical trial sites located in EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC, Article 10(c).
For those countries outside EU local regulations will be followed.
13.7.
Liability And Insurance
A Certificate of Clinical Trials Insurance will be provided to the study centers by Teva 
Pharmaceutical Industries, Ltd, where required.


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14.
DOCUMENTATION
14.1.
Study File and Site Documents
Prior to the initiation of the study, the following items must be received by the Sponsor from the 
site:
1. Confidential Disclosure Agreement 
2. Signed protocol, and amendment(s) page(s)
3. The Principal Investigator’s curriculum vitae and where required current medical license
4. Signed Clinical Study Agreement
5. Competent/Regulatory Authority written approval (if applicable)
6. EC/IRB written approval for the protocol, amendment(s), Informed Consent Form, 
Subject Information Sheet (if applicable), advertisements (if applicable)
7. EC/IRB Membership list or an official statement from the EC/IRB stating the EC/IRB is 
in compliance with 21 CFR part 56 and/or EU Directive on GCP
8. Hospital Management written opinion (if applicable)
9. Financial Disclosure Form (FDA Form 1572 in US)
10. Data protection form (for EU countries only)
11. Local laboratory certification and normal ranges (if applicable)
14.2.
Study Documents Supplied by the Sponsor
The Sponsor will supply the investigator with the following items:

Current version of the IB

CRFs or a hard copy of the eCRF in PDF format (Master CRF)

Subjects study binder, including ‘source pages’ to be used during the study if hospital 
clinic records are not to be used (if applicable)

User manual for Remote Data Capture (RDC®)

Regulatory Binder


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
Country Model Informed Consent Form

Central Laboratory Certification and Normal Ranges

Insurance Certificate 

Operations Manual
14.3.
Maintenance and Retention of Records
It is the responsibility of the investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation.

Investigators will be instructed to retain all study records required by Teva and 
regulatory authorities in a secure and safe facility with limited access for one of the 
following time periods based on notification from Teva

A period of at least two years from last marketing authorization and notification from 
Sponsor

Or a period of at least two years after discontinuation of clinical development of the 
investigational product as confirmed by Teva

Or longer if required by local regulations
The investigator will be instructed to consult with Teva before disposal of any study records and 
to provide written notification to Teva of any change in the location, disposition, or custody of 
the study files.


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15.
DATA HANDLING
15.1.
Data Collection via Remote Data Capture (RDC)
The site teams should be trained to use the RDC® system. In any case of change in study teams, 
appropriate training will be given. 
Teva will provide each study site with one hard copy of the reference template for data collection 
tools (Master CRF).
Data will be entered at the site by the Site Investigator, Study Coordinator, the Site Coordinator 
or other appropriately designated and trained study personnel, using the validated Oracle Clinical 
RDC® application, which provides a framework for entering clinical data on a CRF. The Oracle 
Clinical RDC® application is integrated with the Teva clinical data management (DM) validated 
system, conforms to 21 CFR part 11 requirements.
The eCRFs are used to record study data and are an integral part of the study and subsequent 
reports. Therefore, the CRFs must be completed for each enrolled subject, according to the 
subject’s source data on a per-visit basis.
Subjects should not be identified by name. Appropriately coded identification must be used. The 
Site Investigator must keep a separate log of subject names, non-identifiable initials (if 
applicable) and addresses (i.e., Subject Identification Log).
Each entered CRF must be approved by the Site Investigator on a per-visit basis and verified 
against the subject’s source documents by the CRA/monitor. Each entry will be monitored by the 
CRAs and the DM personnel. Once all the CRFs for a subject have been approved, verified, 
reviewed and cleaned, the subject's CRFs will be locked. Site Investigators, Site Coordinators, 
CRAs, DM personnel, Medical Monitors and quality assurance (QA) personnel will be trained 
by authorized Teva staff on the use of the RDC® application before receiving authorization to
use the application. The assignment of user privileges will be according to the following user 
roles:

Site Coordinator (SITE): data entry

Study Coordinator (COOR): data entry and updating, discrepancy handling

Site Investigator: data entry and updating, discrepancy handling and CRF approval

CRA: discrepancy handling and CRF verification

Medical Monitor: discrepancy handling.

DM: data updating, discrepancy handling, data locking


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
QA: read only for data audit

Read Only: browsing of data only
15.2.
Discrepancy Handling
The internal consistency and data integrity of the study database are defined by a validated set of 
rules. A deviation from this set of pre-defined computerized rules creates a database discrepancy 
which can be handled using the RDC® application DM facility. Any modification in these rules 
requires re-validation according to departmental Standard Operating Procedures (SOPs).
There are 2 main types of discrepancies:

Automatic discrepancies are generated automatically during data entry or following 
execution of logical checks

Manual discrepancies can be generated by a system user any time
Note that the RDC® application discrepancy management facility is fully supported by an 
accepted regulatory audit trail of procedures and logs.
15.3.
Data Correction
Data correction can also be performed using the validated RDC® application update facility. For 
each instance of data modification, the system requires the reason and justification for change. 
The system keeps a full audit trail of the data values, date and time of modification, and the 
electronic signature of the user who performed the change. 
15.4.
Data Extract
The Oracle Clinical® system stores the data in generic tables. The data is extracted from Oracle 
Clinical® to SAS® on a per data collection module basis. Each extracted file contains all the 
visits of the corresponding form. The data is extracted on a scheduled basis for DM and data 
analysis purposes.
15.5.
Source Documents
Prescription forms, label logs, laboratory test results and ECG strips/interpretations, as well as all 
other source documents should be maintained and kept at the study site in the subject study 
binder.
15.6.
Electronic CRF
At the end of the study, the Sponsor will supply the site investigator a copy of the site's subject 
electronic CRF in PDF format.


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15.7.
Additional Documents and Records
Subject Screening and Assignment Log – A listing of all subjects who signed the informed 
consent and entered the MS-LAQ-302E study.
Subject Identification Log – A listing of all randomized subjects. This allows linking of the 
enrolled subject to the study. Information should include, but is not limited to: subjects’ name, 
date of birth and contact information and subject non-identifiable initials (if applicable). This 
confidential list will be maintained by the investigational site and should not be forwarded to the 
Sponsor. 
Drug Accountability Log - This form documents the total amount of study drug dispensed to and 
returned by each subject (if applicable).


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16.
QUALITY ASSURANCE AUDITS
16.1.
Good Clinical Practice
The study described in this protocol will be carried out according to the local regulatory 
requirements and ICH accepted standards of GCP. All procedures described in this protocol will 
be performed according to approved written SOPs unless otherwise stated.
16.2.
Quality Laboratory Standards
Laboratory tests/evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards. See Central Laboratory Manual unless otherwise stated.
16.3.
Quality Assurance Program
This clinical trial may be audited according to the Teva QA program.
The purpose of these audits is to determine whether the study is being conducted and monitored 
in compliance with the protocol as well as recognized GCP guidelines and local regulations. 
These audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent inspection by any regulatory authority. Such audits, if 
necessary, will be pre-arranged with the site and conducted within a reasonable time frame.
16.4.
Regulatory Inspections
The study may be inspected by regulatory agencies. These inspections may take place at any 
time during or after the study and are based on the national regulations, as well as ICH 
guidelines.


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17.
STUDY MONITORING
17.1.
Monitors/CRAs and Monitoring Visits
The Study Monitor/CRA will be responsible for ensuring adherence to FDA, EU Directives, ICH 
guidelines and the Sponsor’s SOPs. Study Monitors for this trial will be provided by the 
Sponsor. The monitors will follow the current “Guideline for the Monitoring of Clinical 
Investigators” supplied by the FDA or will operate according to the EU Directives and in 
compliance with ICH guidelines.
Experienced independent monitors or monitors from CROs will also be trained in Teva’s SOPs, 
study protocol and the study monitoring conventions. 
Regular monitoring of study data at each site will be performed as defined by the study specific 
monitoring plan. Individual sites will be monitored to verify that enrollment rate, data recording, 
and protocol adherence are satisfactory. The frequency of monitoring individual sites may 
fluctuate depending upon enrollment rate, quantity of data collected and the complexity of the 
study, and will be described in the monitoring plan.
These monitoring visits will be performed for the purposes of verifying adherence to the protocol 
and the completeness and accuracy of data entered on the CRF. The study monitor will verify 
CRF entries by comparing them with the primary source documents (hospital/clinic/office 
records), which will be made available for this purpose. The monitor will review the 
maintenance of regulatory documentation and drug accountability. The monitor will review the 
progress of the study with the investigator and other site personnel on a regular basis. At the end 
of the study, a close-out monitoring visit will be performed. Monitoring visits will be arranged in 
advance with site personnel at a mutually acceptable time. Sufficient time must be allowed by 
the site personnel for the monitor to review CRFs and relevant source documents. The 
coordinator and/or investigator should be available to answer questions or resolve data 
clarifications. Adequate time and space for these visits will be made available by the 
investigator.
17.2.
Primary Source Documents
The investigator must maintain primary source documents to support CRF data entries. These 
documents, which are considered “source data”, may include but are not limited to:

Demographic information

Evidence supporting the diagnosis/condition for which the subject is being studied

General information supporting the subject’s participation in the study

Medical history and physical findings


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
Hospitalization or Emergency Room records (if applicable)

Each study visit by date, including any relevant findings/notes by the investigator(s), 
occurrence (or lack) of AEs, and changes in medication usage, including the date the 
study drug was commenced and stopped

Any additional visits during the study

Any relevant telephone conversations with the subject regarding the study or possible 
AEs

Original, signed informed consent forms for study participation
The investigator must also retain all subject specific printouts/reports of tests/ procedures 
performed as a requirement of the study. During monitoring visits the monitor will need to verify 
data in the eCRFs against these source data.


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18.
CLINICAL PRODUCT COMPLAINTS
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product complaint include but are not limited 
to:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the investigational center
with more or less than the designated number of units inside)

incorrect packaging, or incorrect or missing labeling/labels

unexpected or unanticipated taste or odor, or both

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving a drug product, all relevant samples (eg, the remainder of the subject’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible.
18.1.
Product Complaint Information Needed from the Investigational 
Center
In the event that the product complaint form cannot be completed, the investigator will obtain the 
following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

subject identifier (subject study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies


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
subject number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return Yes/No

product was taken or used according to protocol Yes/No

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
18.2.
Handling of Study Drug at the Investigational Center
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the study drug.
If it is determined that the investigational center must return all study drug, the sponsor will 
provide the information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected subject.
18.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 11).
18.4.
Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint,
and any actions taken to resolve the complaint and to preserve the safety of the subject. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product.


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19.
USE OF INFORMATION AND PUBLICATION
19.1.
Confidential Information
All information supplied by Teva in connection with this study and not previously published, is 
considered confidential information. This information includes, but is not limited to, the IB, 
clinical protocol, CRFs and other scientific data. Any data collected during the study are also 
considered confidential. This confidential information shall remain the sole property of Teva, 
shall not be disclosed to others without the written consent of Teva, and shall not be used except 
in the performance of this study.
The information developed during the conduct of this clinical study is also considered 
confidential, and will be used by Teva in connection with the development of the drug. The 
information may be disclosed as deemed necessary by Teva. To allow the use of the information 
derived from this clinical study, the investigator is obliged to provide Teva with complete test 
results and all data developed in this study. 
The Sponsor has full ownership of the original CRFs completed as part of the study.
By signing the clinical study protocol, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. The authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement.
The information obtained during this study may be made available to other investigators who are 
conducting similar studies.
It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by all sites performing the protocol.
Should the investigator wish to publish the results of this study, the investigator agrees to provide 
Teva with a manuscript for review 60 (sixty) days prior to submission for publication. 
Teva retains the right to delete from the manuscript information that is confidential and 
proprietary and to object suggested publication and/or its timing (at the Company’s sole 
discretion).
In the event that Teva chooses to publish the data from this study a copy will be provided to the 
investigator at least 30 days prior to the expected date of submission to the intended publisher.


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20.
STUDY PERSONNEL
20.1.
Investigative Site
20.1.1.
The Principal Investigator
At each investigational center, a physician will be appointed to serve as a principal investigator 
and will have overall responsibility to lead the site study team (Neurologist, radiologists, 
technician and clinical coordinator as appropriate) and aspects of the study at the respective site. 
The Principal Investigator will oversee the accrual of appropriate subjects, the conduct of the 
study according to the trial protocol and the collection of required data.
20.1.2.
The Study Physician/Neurologist
The Study Physician/ Neurologist will be responsible for the general medical evaluations as well 
as the neurological assessments. The Study Physician will make the decision as to whether the 
neurological change is considered a relapse, based on EDSS/FS scores obtained by him/her. 
20.1.3.
Study Coordinator or Designee
A study coordinator or other staff member designated by the Principal Investigator will be 
responsible for subject scheduling and completion of all subjects’ eCRFs and recording of AEs. 
He/she will instruct the subject on proper study drug administration. He/she will collect and 
forward blood samples and requests to the appropriate laboratories, will obtain and forward 
laboratory results and perform other duties delegated by the Principal Investigator as instructed.
20.2.
The Sponsor
20.2.1.
Global Clinical Leader
The Global Clinical Leader maintains overall responsibility for the study and is responsible for 
ensuring good conduct and adequate resources; for providing high-quality study management 
and DM and for the coordination of all study committees.
20.2.2.
Clinical Operations Manager
The Clinical Operations Manager is responsible for day-to-day operations of the study, and also 
for coordinating and handling all subject study data from the investigational sites. This includes 
daily maintenance of all study aspects and study status on internal periodic reports.
20.2.3.
Data Management & Biostatistics
Global Biostatistics and DM units are responsible for the adequate performance of the DM
application (Oracle Clinical); the conduct of the routine DM procedures; and the performance of 
the statistical analysis as defined in this protocol. All procedures will be performed according to 
the common units' SOPs in line with ICH regulations.


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At the discretion of the Sponsor DM may be performed by a CRO.
20.2.4.
Local Clinical Management
The LCM is responsible for the local day-to-day activities of the study and to ensure that the 
Sponsor supplies adequate resources to provide high quality study management, monitoring and 
DM. The LCM is responsible for submitting safety reports to local regulatory authorities, 
EC/IRB and investigators, where required.
20.2.5.
Clinical Research Associate/Monitor
The CRA/monitor is responsible for monitoring the conduct of the study at the study centers. 
Monitoring visits will be arranged in advance, at a mutually acceptable time, with site personnel. 
Refer to Section 17.1 in this protocol for detailed monitoring activities.
20.2.6.
Global Drug Safety and Pharmacovigilance
Global Drug Safety & Pharmacovigilance is responsible for: reviewing safety issues that arise 
during the study, assessing and evaluating the causality of SAEs occurring during the study and 
submission of relevant SAEs to health authorities/CA as per regulations.
20.2.7.
Medical Monitor
The Medical Monitor is responsible for reviewing all safety clinical data in an ongoing basis 
through the course of the study. The medical monitor is reviewing individual safety subject’s 
safety data as well as listings and tabulated safety data. 
The medical monitor is responsible to evaluate any emerging data driven safety issues during the 
course of the study, and alert the clinical leader responsible LCM/CRA, safety officer and notify 
the DMC. 
The action plan of any safety emerged issues will be coordinated by the medical monitor and 
clinical leader. The narratives of any safety issues with medical importance will be prepared by 
the medical monitor. 
The medical monitor is also responsible to follow up the safety emerged issues through the 
study, their capture within the eCRF, and SAE reports (if necessary), and the execution of the 
action plan/follow up of a subject as recommended by safety officer and DMC.
The medical monitor is responsible to prepare the safety information periodical reports for the 
DMC meetings and present the data during the open session of the DMC meetings.


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21.
STUDY COMMITTEES
21.1.
Steering Committee
The Steering Committee may offer expert opinion as to clinical aspects of the protocol design 
and may be consulted during the course of the study. Periodical teleconferences will be held to 
assess and discuss clinical and operative progress of the study. Protocol amendments, safety 
issues and potential publications will be discussed with the committee and recommendations 
may be made to the Sponsor as appropriate. The Steering Committee will include designees from 
the participating countries/regions Principal Investigators.
21.2.
Data Monitoring Committee (DMC)
The DMC will be composed of external independent physicians with expertise in MS, internal 
medicine, cardiology, as well as a specialist in hepatic diseases and a statistician. Ad-hoc 
consultations may be made with additional specialists as will be deemed necessary during the 
course of the study. 
The DMC responsibilities are:

To review the progress of the trial and the accumulation of data, both periodically and 
on an ad-hoc basis, in order to ensure subjects’ welfare.

To oversee the emerging safety data of the study.

To review efficacy data, as deemed necessary.

To assess whether there is any basis upon which to recommend modification or 
premature termination of the study.
The DMC Chairperson is responsible for all DMC interactions with the Sponsor, through the 
clinical leader. The clinical leader is responsible for addressing safety issues identified by the 
DMC. He/she will report to the DMC about the risk management plan established by the 
Sponsor.
A DMC plan/charter will be prepared in the first meetings of the DMC, and signed by the DMC 
members and Sponsor’s designees. The charter describes the function and manner of operation of 
the DMC.
DMC meetings will take place at a set schedule, according to study characteristics, needs, and 
progress. 
Meetings may be in a teleconference or face to face, according to study needs. 


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In case of need for an urgent discussion of a safety issue, the DMC chair or the Sponsor may call 
an unscheduled meeting.
Participants of the meetings are: DMC chair, DMC members, clinical leader, study medical 
monitor, and Sponsors’ DMC statistician. 
DMC meeting minutes and conclusions are a part of the study’s documents and risk management 
plan.
All DMC reports should be available upon request to regulatory and ethical authorities.
The Sponsor will work closely with the committee to provide the necessary data for review. The 
list of DMC members will be detailed in the DMC plan/charter.
21.3.
Clinical Advisory Board (CAB)
The Clinical Advisory Board (CAB) will be responsible for the clinical development plan of the 
study including all clinical issues regarding study design and conduct. For a list of CAB 
members please refer to the Operation Manual.
The committee’s responsibilities will include involvement in:

design of the clinical development plan

design of study protocols

interpretation of results analysis upon study completion
21.4.
Publication Committee
The publication committee will be responsible for developing the publication plan consistent 
with the study end points and out comes, and the needs of the medical community and the 
Sponsor.
This committee will be composed of the chair of the steering committee, designees from the 
CAB, which are taking a pivotal role in the study, and also the Sponsor’s designee.
The publication plan will be prepared in the after completion of subject recruitment into the 
study.
This plan will determine the publication policy of the study outcomes and recommend on the 
main publishers. The plan will be consistent with Teva policy on use of confidential information 
(see Section 19.1).


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22.
INVESTIGATOR’S AGREEMENT
TEVA Pharmaceutical Industries, Ltd.
Protocol No. MS-LAQ-302E
I have carefully read the foregoing protocol including all appendices and agree that it contains all 
the necessary information for conducting the study safely.
I will conduct this study in strict accordance with this protocol and according to the current GCP 
guidelines and will attempt to complete the study within the time designated.
I will provide copies of the protocol and all other information relating to pre-clinical and prior 
clinical experience submitted by the Sponsor to all personnel to whom I am responsible, who 
participate in the study. I will discuss this information with them to assure that they are 
adequately informed regarding the drug and conduct of the study.
I agree to keep records on all subject information (CRFs, shipment and drug return forms and all 
other information collected during the study) in accordance with the current GCP and local 
regulations.
Principal Investigator’s name
Teva Representative's name
Signature
Signature
Date
Date
Institution


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23.
REFERENCES
EMEA Guideline on Clinical Investigation of Medicinal Products for the Treatment of Multiple 
Sclerosis (CPMP/EWP/561/98 Rev. 1, Nov 2006)
Neuhaus O, Archelos JJ, Hartung HP. Immunomodulation in multiple sclerosis: from 
immunosuppression to neuroprotection. Trends Pharmacol Sci 2003;24:131-138.
NTP TR-521: National Toxicology Program. NTP technical report on the toxicology and 
carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in 
female Harlan Sprague-Dawley rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser. 2006 
Apr;(521):4-232.
NTP TR-584: National Toxicology Program. NTP technical report on the toxicology studies of 
indole-3-carbinol (CAS No. 700-06-1) in F344/N rats and B6C3F1/N mice and toxicology and 
carcinogenesis studies of indole-3-carbinol in Harlan Sprague Dawley rats and B6C3F1/N mice 
(Gavage Studies). Draft - Scheduled Peer Review Date: May 22, 2014.
Sormani MP, Bonzano L, Roccatagliata L, Mancardi GL, Uccelli A, Bruzzi P. Surrogate 
endpoints for EDSS worsening in multiple sclerosis. A meta-analytic approach. Neurology. 2010 
Jul 27;75(4):302-9.


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24.
RATIONALE FOR PROTOCOL AMENDMENT AND SUMMARY 
OF CHANGES
24.1.
Global Amendment #2
At the time of issuance of this amendment there are 714 ongoing subjects in the study.
The primary purpose of this amendment is to introduce additional safety measures due to 
cardiovascular findings in other MS studies where higher doses of laquinimod (1.2 and 1.5 mg) 
were administered. These cardiovascular events resulted in the discontinuation of patients treated 
with 1.2 and 1.5 mg from the respective studies in line with the DMC recommendations (see 
Section 3.4.1.7). The DMC also recommend that study subjects continuing on laquinimod 0.6 mg 
be reconsented with information about the cardiovascular risk seen in higher doses. The 
concerned investigators and ECs/IRBs were informed in advance of these recommendations and 
the planned amendment. Changes include:

all ongoing subjects will be asked to re-consent to a revised form that includes 
information on the cardiovascular risk findings at higher doses of laquinimod (1.2 and 
1.5 mg)

stopping rules added for renal and hepatic impairment (to avoid administration of  
laquinimod in the event of organ impairment, which may lead to increased exposure)

GFR monitoring (and measurement of weight) will be performed at all visits, to assess 
renal function

extra emphasis placed on moderate/strong inhibitors of CYP3A4 being disallowed (again, 
these could lead to increased laquinimod exposure)

unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or 
samples for potential biomarker analyses may be collected at the discretion of the 
investigator or medical monitor at any time to assist with further investigations of 
cardiovascular events or other clinical event of interest. The samples should be collected 
as soon as possible in association with the event

addition of cardiovascular risk assessment and management procedure

ischemic cardiac events and cerebrovascular events are now classed as protocol-defined 
adverse events for expedited reporting, and should be reported to the sponsor within 
48 hours, including completion of the corresponding dedicated CRF

Table 3 amended to show additional events in line with the updated Reference Safety 
Information


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
Subjects who are discontinued from study treatment will be encouraged to continue all 
scheduled visits and procedures until completion of the study (with the exception of 
procedures associated with drug dispensing and accountability, pregnancy testing, and 
GFR estimation [including body weight measurement])
In addition to the major revisions this amended protocol includes:

added recommendation to avoid the use of CYP1A2 substrates

change to the listed address of the sponsor (for consistency with other clinical trial related 
documents, only the headquarters address is listed in the protocol)

change to the Clinical Project Physician

language related to oral cavity tumors update to make consistent with current IB

product complaint section added

addition of CT scan or MRI in case of pancreatic or suspected pancreatitis 

removal of urinalysis and anemia panel from the clinical laboratory evaluations

in the study flow chart, ascertaining use of effective contraception at termination/early 
discontinuation has been added to make consistent with the text
These changes did not alter the study population or endpoints.
Rationales for the major changes are given and all substantive changes are listed in the summary 
table below.
Deletions are indicated with a strikethrough, additions with an underline.


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Reason/Justification for 
change
TITLE PAGE
Teva Pharmaceutical Industries, Ltd
12 Hatrufa St., P.O. Box 8077 Sapir Industrial Zone
Netanya, Israel
5 Basel St, Petach-Tikva 49131, Israel
Teva Pharmaceutical Industries, Ltd
5 Basel St, Petach-Tikva 49131, Israel
Change of address (for 
consistency with other 
clinical trial related 
documents, only the 
headquarters address is 
listed in the protocol)
 
Teva Pharmaceutical Industries, Ltd
Teva Pharmaceutical Industries, Ltd
Change of Sponsor’s 
Safety Officer
Section 3.1.1. General
Authorized disease-modifying drugs for Relapsing Remitting 
Multiple Sclerosis (RRMS) given by injection include 
interferon-beta (IFN-β) 1a (Avonex®, Rebif®) orinterferon
beta 1b (Betaseron®, Extavia®), glatiramer acetate 
(Copaxone®), mitoxantrone (Novantrone®), and natalizumab 
(Tysabri®; for patients non-responsive to other medications), 
and alemtuzumab (Lemtrada™). Oral disease modifying 
treatments for RRMS include fingolimod (Gilenya®), 
teriflunomide (Aubagio®), and dimethyl fumarate (Tecfidera®)
and alemtuzumab (Lemtrada™).
Authorized disease-modifying drugs for Relapsing Remitting 
Multiple Sclerosis (RRMS) given by injection include interferon-beta 
(IFN-β) 1a (Avonex®, Rebif®) or 1b (Betaseron®, Extavia®), 
glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®), 
natalizumab (Tysabri®; for patients non-responsive to other 
medications), and alemtuzumab (Lemtrada™). Oral disease modifying 
treatments for RRMS include fingolimod (Gilenya®), teriflunomide 
(Aubagio®), and dimethyl fumarate (Tecfidera®).
Correction; Lemtrada is 
not administered orally.
Section 3.1.2. Study Drug
(new text)
Laquinimod relates to a predecessor compound, roquinimex. It is the 
result of a structure activity-relationship screening program whose 
aim was to identify a new, pharmacologically modified substance 
active in MS animal models which, when compared to roquinimex, 
would have a superior safety profile. Roquinimex demonstrated 
clinical efficacy in MS in Phase 2 studies. However, serious 
cardiopulmonary toxicities (including myocardial infarction, 
pericarditis and pleuritis) occurring during Phase 3 studies led to early 
termination of these studies.
Additional information 
added to give context.
Section 3.2.2. Metabolism and Pharmacokinetics
Laquinimod was shown to cause a marked decrease of 
CYP3A4 activity and is a potent strong inducer of CYP1A 
Laquinimod was shown to cause a marked decrease of CYP3A4 
activity and is a strong inducer of CYP1A enzymes.
Change of terminology 
for consistency with the 


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enzymes.
IB
Section 3.2.3. Toxicology
Finally, a small In addition, an increase in the incidence of 
oral cavity squamous cell carcinomastumors was noted in mid 
and high dose female rats (2/60 in each group). The oral 
effects may relate to the AhR activation properties of 
laquinimod since similar lesions were seen following lifelong 
exposure of rats to other AhR activators. However, the 
incidence of oral cavity tumors in rats treated with laquinimod 
was lower than that seen with industrial chemicals such as 
2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) (NTP TR-521) 
and dioxin-like compounds (DLCs), and was more similar to 
the incidence seen with the dietary ingredient indole-3-
carbinol (I3C) found in cruciferous vegetables. Of note, the 
oral tumors seen with I3C were considered by the US National 
Toxicology Program as irrelevant for I3C risk assessment 
(NTP TR-584). No increased incidence of oral tumors was 
seen in humans exposed to TCDD, indicating a species 
specific response in rats. Therefore, oral cavity tumors 
induced by laquinimod in rats after a lifelong exposure do not 
imply an elevated carcinogenicity risk in humans. Humans, in 
general, also seem to be less sensitive to AhR activation by 
laquinimod than rats, as shown by the differential gene 
expression profiles discussed in the IB with other AhR 
activators, including industrial chemicals (such as 2,3,7,8
tetrachloro p dibenzodioxin [TCDD] and dioxin like 
compounds [DLCs]) and the dietary ingredient indole 3
carbinol (I3C) found in cruciferous vegetables. However, the 
incidence of oral cavity tumors in rats treated with laquinimod 
was lower than that seen with TCDD and DLCs, and was 
more similar to the incidence seen with I3C. Importantly, the 
oral cavity tumors seen with TCDD in rats did not translate 
into increased incidence of oral tumors in exposed humans, 
indicating a species difference in this response between rats 
and humans. It should be noted that several lines of evidence 
suggest that the oral lesions seen in rats are mediated by direct 
contact of the rat oral mucosa with high concentrations of 
laquinimod in the dosing solution during the gavage 
In addition, an increase in the incidence of oral cavity tumors was 
noted in mid and high dose female rats (2/60 in each group). The oral 
effects may relate to the AhR activation properties of laquinimod 
since similar lesions were seen following lifelong exposure of rats to 
other AhR activators. However, the incidence of oral cavity tumors in 
rats treated with laquinimod was lower than that seen with industrial 
chemicals such as 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) (NTP 
TR-521) and dioxin-like compounds (DLCs), and was more similar 
to the incidence seen with the dietary ingredient indole-3-carbinol 
(I3C) found in cruciferous vegetables. Of note, the oral tumors seen 
with I3C were considered by the US National Toxicology Program as 
irrelevant for I3C risk assessment (NTP TR-584). No increased 
incidence of oral tumors was seen in humans exposed to TCDD, 
indicating a species specific response in rats. Therefore, oral cavity 
tumors induced by laquinimod in rats after a lifelong exposure do not 
imply an elevated carcinogenicity risk in humans. Humans, in 
general, also seem to be less sensitive to AhR activation by 
laquinimod than rats, as shown by the differential gene expression 
profiles discussed in the IB.
Updated for consistency 
with the IB


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Reason/Justification for 
change
procedure. An effect on the oral mucosa in rats is not 
considered relevant to humans, who take laquinimod as a 
capsule that dissolves in the stomach. Based on sponsor’s 
calculations, in the human stomach, the local concentration of 
laquinimod is expected to be low, and the type of epithelium 
exposed is not considered sensitive to the effects of 
laquinimod, with safety margins greater than 13 (dogs), 20 
(rats) and 1000 (mice) for exposure in the stomach.
Section 3.3.1. Clinical Pharmacology Studies
Laquinimod PK is affected by moderate and strong CYP3A4 
inhibitors (2.5- and 3.1-fold increase in laquinimod systemic 
exposure, respectively) and strong CYP3A4 inducers and 
moderate hepatic impairment. Laquinimod 0.6 mg is a weak 
inhibitor of CYP3A4 and a strong inducer of CYP1A2. For 
additional information, please refer to the IB.
Studies in subjects with mild and moderate hepatic 
impairment resulted in an increase of laquinimod exposure by 
approximately 1.3- and 2.3-fold, respectively. In subjects with 
moderate renal impairment laquinimod exposure was 
increased by 1.4-fold. A physiologically based 
pharmacokinetic model was further used to predict the effect 
of hepatic impairment and renal impairment on the 
pharmacokinetics of laquinimod after single and multiple 
doses of 0.6 to 1.5 mg in comparison to healthy subjects
(Study DP-2015-017). The model predictions indicated that 
mild hepatic impairment and moderate renal impairment 
would result in further modest increases in exposure to 
laquinimod following multiple 0.6 mg dose administration 
based on unbound drug concentration (1.71-fold and 1.65-
fold, respectively). More significant increases in laquinimod 
exposure, in particular in terms of unbound drug fraction, are 
predicted in patients with moderate and severe hepatic 
impairment (3.41- and 6.51-fold, respectively) and severe 
renal impairment (1.86-fold). The model predictions indicated 
similar increases in systemic laquinimod exposure with a 
given stage of organ impairment across the 0.6 to 1.5 mg dose 
range following single or multiple dose administration, 
demonstrating that the dose proportional pharmacokinetics of 
Laquinimod PK is affected by moderate and strong CYP3A4 
inhibitors (2.5- and 3.1-fold increase in laquinimod systemic 
exposure, respectively) and strong CYP3A4 inducers. Laquinimod 0.6 
mg is a weak inhibitor of CYP3A4 and a strong inducer of CYP1A2. 
For additional information, please refer to the IB.
Studies in subjects with mild and moderate hepatic impairment 
resulted in an increase of laquinimod exposure by approximately 1.3-
and 2.3-fold, respectively. In subjects with moderate renal impairment 
laquinimod exposure was increased by 1.4-fold. A physiologically 
based pharmacokinetic model was further used to predict the effect of 
hepatic impairment and renal impairment on the pharmacokinetics of 
laquinimod after single and multiple doses of 0.6 to 1.5 mg in 
comparison to healthy subjects (Study DP-2015-017). The model 
predictions indicated that mild hepatic impairment and moderate renal 
impairment would result in further modest increases in exposure to 
laquinimod following multiple 0.6 mg dose administration based on 
unbound drug concentration (1.71-fold and 1.65-fold, respectively).
More significant increases in laquinimod exposure, in particular in 
terms of unbound drug fraction, are predicted in patients with 
moderate and severe hepatic impairment (3.41- and 6.51-fold,
respectively) and severe renal impairment (1.86-fold). The model 
predictions indicated similar increases in systemic laquinimod 
exposure with a given stage of organ impairment across the 0.6 to 1.5 
mg dose range following single or multiple dose administration, 
demonstrating that the dose proportional pharmacokinetics of 
laquinimod is maintained in subjects with hepatic impairment (mild to 
severe) and renal impairment (moderate to severe) across this dose 
range.
Updated for consistency 
with the IB


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Reason/Justification for 
change
laquinimod is maintained in subjects with hepatic impairment 
(mild to severe) and renal impairment (moderate to severe) 
across this dose range.
Section 3.3.2. Clinical Safety and Efficacy Studies
(new text)
On 30 December 2015 the DMC for the LAQ-MS-305 (CONCERTO) 
and TV5600-CNS-20006 (ARPEGGIO) studies held an unscheduled 
meeting to review cardiovascular events. The DMC found an 
imbalance in serious cardiovascular events in the high dose treatment 
arms (1.2 mg in CONCERTO, 1.5 mg in ARPEGGIO). Due to these 
events and the DMC recommendation to stop all laquinimod 
treatment arms above 0.6 mg in the MS trials, the 1.2 mg treatment 
arm in the CONCERTO study was discontinued as of 01 January 
2016. The risk/benefit balance of this dose was considered negative at 
that point.
The DMC did not identify any overt cardiovascular risk in the 0.6 mg 
treatment arm, but felt that long term monitoring for emergence of 
any signal is necessary. Therefore, the 0.6 mg treatment arms in the 
CONCERTO and ARPEGGIO studies will be continued while the 
sponsor closely monitors cardiovascular events in all laquinimod 
studies, such as this one. This is discussed further in Section 3.4.1.7.
Information regarding 
safety findings in the 
CONCERTO and
ARPEGGIO studies
Section 3.4.
Known and Potential Risks and Benefits to Human Subjects
Note: the table has been updated in line with the updated 
Reference Safety Information; myocardial infarction and 
cerebrovascular accident are now included.
Table 3: Tabulated List of Adverse Reactions in the Pooled 
ALLEGRO and BRAVO Studies
...
Cardiac disorders 
Uncommon:
Myocardial infarction
...
Nervous system disorders
Very Common: Headache
Rare:
Cerebrovascular accident
Note: the table has been updated in line with the updated Reference 
Safety Information; myocardial infarction and cerebrovascular 
accident are now included.
Table 3: Tabulated List of Adverse Reactions
...
Cardiac disorders 
Uncommon:
Myocardial infarction
...
Nervous system disorders
Very Common:
Headache
Rare:
Cerebrovascular accident
Update to Reference 
Safety Information
Section 3.4.1.7.
Cardiovascular Events (Laquinimod 1.2 and 1.5 mg)
(new section)
On 30 December 2015, a DMC review of 8 unblinded cases from the 
CONCERTO and ARPEGGIO studies found an imbalance in serious 
cardiovascular events in the high dose treatment arms in the study: 6 
Information regarding 
safety findings in the 
CONCERTO and 


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Reason/Justification for 
change
cases in the CONCERTO 1.2 mg treatment arm, compared to no 
events in the 0.6 mg or placebo treatment arms, along with a cerebral 
infarct in a 31 year old man on the 1.2 mg treatment arm. In the 
ARPEGGIO study, 1 heart attack event was identified in the 
laquinimod 1.5 mg treatment arm. The decisions were largely based 
on data from 15 November 2015 when total exposure in CONCERTO 
was 3070 patient-years in 2199 individuals and total exposure in 
ARPEGGIO was 35 patient-years in 191 individuals.
Due to the above, the 0.6 mg treatment arm will be continued in the 
CONCERTO and ARPEGGIO studies while the sponsor closely 
monitors cardiovascular events in all laquinimod studies, including 
the present study. Additional measures implemented in this protocol 
amendment include an additional emphasis on disallowed 
medications, medications and stopping rules for organ impairment (ie, 
factors which may increase laquinimod exposure), as well as regular 
evaluation and treatment management of major modifiable 
cardiovascular risk factors, and collection of unscheduled blood 
samples, eg, for clinical laboratory tests.
The DMC also recommend that study subjects continuing on 
laquinimod 0.6 mg be re consented with information about the 
cardiovascular risk seen in higher doses.
Currently the mechanism of the cardiovascular events remains 
unknown. Although no specific time-to-event patterns have been 
identified, cardiovascular risk factors and demographics may play a 
role. Different pre existing risk factors were noted, including 
hypertension, high cholesterol, and/or smoking history. While all 
cases exhibited signs of myocardial tissue injury, the cardiac work-up 
in these cases revealed heterogeneous etiologies. Of note, the cases all 
had some established cardiovascular risk factors, including patients 
with probable myocarditis or with probable familial 
hypercholesterolemia. Further investigation into potential predictors 
and the potential causality are ongoing.
ARPEGGIO studies
Section 3.4.2.2. Cancer
It is the sponsor’s position that these findings are likely related 
to the administration procedure or to species-specific 
mechanisms
It is the sponsor’s position that these findings are likely related to 
species-specific mechanisms
Administration procedure 
no longer considered a 
factor


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Reason/Justification for 
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Section 3.4.2.3. Cardiotoxicity and Systemic Inflammation
Roquinimex demonstrated clinical efficacy in MS in Phase 2 
studies. However, serious toxicities (including myocardial 
infarction, pericarditis and pleuritis) that occurred during 
Phase 3 trials led to discontinuation of these trials. 
Roquinimex demonstrated serious toxicities including 
increased rates of myocardial infarction, pericarditis, and 
pleuritis that were observed in three Phase 3, placebo-
controlled studies in MS patients. The mechanism by which 
roquinimex caused these events was not identified, but they 
were considered to be possible manifestations of a systemic 
inflammatory response, an assessment which was also 
supported by roquinimex nonclinical findings. A thorough 
analysis was done on the laquinimod safety data (which is 
mostly reflective of the 0.6 mg/day dose) to evaluate similar 
potential these safety issues. Based on 2347 patients exposed 
to laquinimod 0.6 mg for over 10000 patient-years, as well as 
the patients exposed to 0.6 mg in the CONCERTO and 
ARPEGGIO studies, analyses showed that these safety issues 
do not constitute a clear signal for laquinimod in doses up to 
0.6 mg/day. However, at doses of 1.2 and 1.5 mg, laquinimod 
manifested clinical evidence of myocardial infarctionThis 
analysis showed that none of these safety issues constitute a 
signal of concern for laquinimod. 
Serious toxicities that occurred during Phase 3 trials led to 
discontinuation of these trials. Roquinimex demonstrated serious 
toxicities including increased rates of myocardial infarction, 
pericarditis, and pleuritis that were observed in three Phase 3, 
placebo-controlled studies in MS patients. The mechanism by which 
roquinimex caused these events was not identified, but they were 
considered to be possible manifestations of a systemic inflammatory 
response, an assessment which was also supported by roquinimex 
nonclinical findings. A thorough analysis was done on the laquinimod 
safety data (which is mostly reflective of the 0.6 mg/day dose) to 
evaluate similar potential safety issues. Based on 2347 patients 
exposed to laquinimod 0.6 mg for over 10000 patient-years, as well as 
the patients exposed to 0.6 mg in the CONCERTO and ARPEGGIO 
studies, analyses showed that these safety issues do not constitute a 
clear signal for laquinimod in doses up to 0.6 mg/day. However, at 
doses of 1.2 and 1.5 mg, laquinimod manifested clinical evidence of 
myocardial infarction.
Information added on 
safety of 0.6 mg dose
Section 5.1. Overview And Plan (Other sections affected by this change: Section 8.1. Study Period; Section 8.2.2. Scheduled Treatment Visits [Months 1E 
(Visits 1E) and Onwards]; Section 8.2.6.1. Liver Enzymes)
(new text)
Subjects who discontinue treatment for any reason will continue 
follow-up according to scheduled visits.
Additional follow-up 
added for safety reasons
Section 7.1. Allowed Concomitant Medications/Therapies
Short-term treatment with corticosteroids will be allowed 
during acute relapses
Short-term treatment with corticosteroids will be allowed during 
relapses
Treatment can be used for 
any relapses (not just 
acute relapses)
Clinical studies have shown laquinimod 0.6 mg to be a potent 
strong inducer of CYP1A2. Subjects taking drugs that are 
metabolized by CYP1A2 (examples listed in Appendix D) 
should be advised that plasma levels of these drugs could 
decrease when combined with laquinimod. In general, as a 
precautionary measure, it is recommended to avoid the use of 
Clinical studies have shown laquinimod 0.6 mg to be a strong inducer 
of CYP1A2. Subjects taking drugs that are metabolized by CYP1A2 
(examples listed in Appendix D) should be advised that plasma levels 
of these drugs could decrease when combined with laquinimod. In 
general, as a precautionary measure, it is recommended to avoid the 
use of CYP1A2 substrates in clinical trials of laquinimod. Therapeutic 
Wording made consistent 
with IB


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Reason/Justification for 
change
CYP1A2 substrates in clinical trials of laquinimod. 
Therapeutic alternatives may be considered in the appropriate 
clinical context. Additional information on concomitant use of 
laquinimod and CYP1A2 substrates is presented in the 
laquinimod IB.Physicians should consider increasing the dose 
of such medications upon initiation of laquinimod treatment; 
in this case, dose reduction of the CYP1A2 inhibitor should be 
considered if laquinimod is stopped.
alternatives may be considered in the appropriate clinical context. 
Additional information on concomitant use of laquinimod and 
CYP1A2 substrates is presented in the laquinimod IB.
Section 7.2. Disallowed Concomitant Medications During Study (Other sections affected by this change: Section 8.2.3. Termination/ Early Discontinuation)
Interferons IFN-β 1a or 1b
...
Moderate or strong inhibitors of CYP3A4; for example, 
ketoconazole and erythromycin (as listed in Appendix C) are 
disallowed for 2 weeks prior to the baseline visit through to 30 
days after the final dose of laquinimod. Laquinimod is 
extensively metabolized predominantly by CYP3A4, and 
ketoconazole and fluconazole, strong and moderate inhibitors 
of CYP3A4, were found to inhibit the metabolism, leading to 
2.5  and 3.1 fold increases in laquinimod exposure, 
respectively.
IFN-β 1a or 1b
...
Moderate or strong inhibitors of CYP3A4; for example, ketoconazole 
and erythromycin (as listed in Appendix C) are disallowed for 2 
weeks prior to the baseline visit through to 30 days after the final dose 
of laquinimod. Laquinimod is extensively metabolized predominantly 
by CYP3A4, and ketoconazole and fluconazole, strong and moderate 
inhibitors of CYP3A4, were found to inhibit the metabolism, leading 
to 2.5  and 3.1 fold increases in laquinimod exposure, respectively.
Clarification
Section 8.2.3.
Termination/ Early Discontinuation
(new text)
Subjects who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures until 
completion of the study (with the exception of procedures associated 
with drug dispensing and accountability, pregnancy testing, and GFR 
estimation [including body weight measurement]).
Additional follow-up 
added for safety reasons

Subjects will be reminded about (should be 
recorded in the source documents) 
importance of stopping the study drug and 
informing the site in any case of suspected 
pregnancy (positive home urine test result, 
delay of menstruation or any other reason 
suggesting pregnancy) and importance of 
performing the home pregnancy urine tests 
every one month (starting after visit Month 
3E)

Subjects will be reminded about (should be 
recorded in the source documents) importance of 
stopping the study drug and informing the site in 
any case of suspected pregnancy (positive home 
urine test result, delay of menstruation or any other 
reason suggesting pregnancy)
Pregnancy tests not 
required in this context.


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Reason/Justification for 
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Section 8.2.4. Early Treatment Discontinuation (Other sections affected by this change: Section 10.2.3.
Safety Laboratory Evaluations; APPENDIX 
E. GUIDANCE ON SAFETY MONITORING)
Subjects who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures 
until completion of the study (with the exception of 
procedures associated with drug dispensing and 
accountability, pregnancy testing, and GFR estimation 
[including body weight measurement]).
An early termination visit should be completed for all subjects 
who prematurely discontinue from the study and do not agree 
to or cannot continue all scheduled visits and procedures. It 
includes subjects who took at least one dose in the MS-LAQ-
302E study.
Subjects who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures until 
completion of the study (with the exception of procedures associated 
with drug dispensing and accountability, pregnancy testing, and GFR 
estimation [including body weight measurement]).
An early termination visit should be completed for all subjects who 
prematurely discontinue from the study and do not agree to or cannot 
continue all scheduled visits and procedures. It includes subjects who 
took at least one dose in the MS-LAQ-302E study.
Clarification
Section 8.2.5. Post Early Discontinuation Follow-Up Visit
(new text)
Note: This section specifically pertains to subjects that discontinue 
treatment early but do not agree to continue follow up.
Clarification
In case of early termination of the study AE for which the 
relationship with the study drug is characterized as 
‘Reasonable Possibility’,Moderate and strong CYP3A4 
inhibitors are disallowed during the 30 days after the last dose 
has been administered.
Moderate and strong CYP3A4 inhibitors are disallowed during the 30 
days after the last dose has been administered.
Text removed as this 
restriction is more general
Section 8.2.6.2. Pregnancy
Teva considers the prevention of exposure to laquinimod 
during pregnancy to be of great importance, and following 
consultation with the CHMP and DMC has decided to 
introduce additional language and measures for pregnancy 
prevention in this amendment and in a revised informed 
consent form.
(text deleted)
Text removed as was 
specific to a previous 
amendment
Additionally, monthly pregnancy tests (urine dipstick and/or 
serum pregnancy β hCG test, as applicable per the relevant 
time point) will be performed (except for where subjects have 
discontinued study drug but are continuing to attend study 
visits for follow up).
Additionally, monthly pregnancy tests (urine dipstick and/or serum 
pregnancy β hCG test, as applicable per the relevant time point) will 
be performed (except for where subjects have discontinued study drug 
but are continuing to attend study visits for follow up).
Clarification
Section 8.2.6.3. Invasive Cancer (Other sections affected by this change: APPENDIX E. GUIDANCE ON SAFETY MONITORING)
Subjects that are diagnosed with a malignant solid or liquid 
tumor invasive cancer while participating in the study should 
stop study medication and discontinue their study participation
drug.
Subjects that are diagnosed with a malignant solid or liquid tumor
while participating in the study should stop study drug.
Correction of 
terminology; also, 
subjects diagnosed with a 
tumor should only be 


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Original text with changes shown
New wording
Reason/Justification for 
change
discontinued from the 
study drug, not from the 
study.
Section 8.2.6.4. Liver Impairment
(new section)
To avoid exposures to higher levels of laquinimod (see Section 3.3.1), 
a stopping rule related to liver impairment has been introduced. 
Subjects who develop any chronic liver disease associated with 
hepatic function impairment while participating in the study should 
stop study medication.
New stopping rule to 
avoid higher exposures to 
laquinimod
Section 8.2.6.5. Renal Impairment
(new section)
To avoid exposures to higher levels of laquinimod (see Section 3.3.1), 
a stopping rule related to renal impairment has been introduced. 
Subjects who develop renal disease associated with moderate or 
severe functional impairment, defined as glomerular filtration rate 
(GFR) ≤60 mL/min/1.73 m2, while participating in the study should 
stop study medication temporarily and the GFR assessment should be 
repeated. If the renal impairment is confirmed (GFR ≤60 
mL/min/1.73 m2), the subject should stop study medication 
permanently.
New stopping rule to 
avoid higher exposures to 
laquinimod
Section 8.2.9. Unscheduled Visit
(new text)

For female subjects of child-bearing potential, 
serum or urine β-hCG test may be performed 
Urine test was included in 
flow chart but not in text, 
so has been added to text 
for consistency.
Serum test has been 
added to flow chart and 
text.
Section 8.2.9.1. Unscheduled Samples
(new section)
According to the judgment of the investigator or medical monitor, the 
following unscheduled samples may be collected to assist with further 
investigations of cardiovascular events or other clinical event of 
interest:

urgent safety laboratory test panel (see Section 10.2.3.1)

pharmacokinetic blood sample

sample for potential biomarker analysis
Additional samples can 
be collected


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Original text with changes shown
New wording
Reason/Justification for 
change
Section 8.2.9.1.1. Unscheduled Pharmacokinetic Samples
(new section)
Unscheduled pharmacokinetic blood samples may be collected at the 
discretion of the investigator or medical monitor at any time to assist 
with further investigations of cardiovascular events or other clinical 
event of interest. The samples should be collected as soon as possible 
in association with the event.
Details of sample collection and processing are provided in the 
Laboratory Manual.
Additional samples can 
be collected
Section 8.2.9.1.2. Unscheduled Biomarker Samples
(new section)
Unscheduled samples for potential biomarker assessments may be 
collected at the discretion of the investigator or medical monitor at 
any time to assist with further investigations of cardiovascular events 
or other clinical event of interest. The samples should be collected as 
soon as possible in association with the event.
Potential biomarker assessments to better understand laquinimod 
MoA, as well as to explore response predictive markers for efficacy 
or safety, may include 1) cytokines and other soluble marker levels; 
2) RNA analysis; 3) proteomic profile; and/or 4) other relevant 
biomarkers.
Details of sample collection and processing are provided in the
Laboratory Manual. Since new biomarker techniques continue to be 
developed, the method and laboratory that will be recommended 
cannot be anticipated.
Additional samples can 
be collected
Section 10.2.1.1. Protocol Defined Adverse Events for Expedited Reporting
(new section)
Ischemic cardiac events (such as myocardial infarction, unstable 
angina, acute coronary syndrome etc), and cerebrovascular events 
(such as cerebral arterial occlusion, cerebral ischemia, etc) should be 
reported to the sponsor within 48 hours, including completion of the 
corresponding dedicated CRF.
Due to cardiovascular 
findings at higher dose 
levels, adverse events for 
expedited reporting have 
been identified.
Section 10.2.2. Abdominal Computed Tomography Scan
(new section)
In case of pancreatitis or suspected pancreatitis, an abdominal 
computed tomography (CT) scan should be performed as soon as 
possible in order to clarify the diagnosis and enable assessment of 
severity of this condition. An MRI may be performed as an alternative 
to the CT scan.
Added for consistency 
with other laquinimod 
protocols


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New wording
Reason/Justification for 
change
Section 10.2.3. Safety Laboratory Evaluations (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E (Visits 1E) 
and Onwards]; Section 8.2.3. Termination/ Early Discontinuation)

hs-CRP

hs-CRP
It is specifically hs-CRP 
that should be measured
o
In case of abnormal CPK result: 
troponin or and CPK-MB will be tested
o
In case of abnormal CPK result: troponin and 
CPK-MB will be tested
Both troponin and (not 
or) CPK MB will be 
measured
In case of new hemoglobin decrease of 
> 1g/dL from the subject’s hemoglobin level 
at Baseline, subjects will be re tested to 
ascertain true decrease. If true decrease, a 
thorough anemia work up will be done 
including:
o
direct medical history and physical 
examination
o
blood smear, serum iron, ferritin, total 
iron binding capacity, folic acid, B12, 
haptoglobin, IL 1, IL 6, IFN γ, TNF α, 
and hepcidin. 
o
additional investigations and follow up 
per Investigator’s discretion or 
Sponsor’s request
(text deleted)
Anemia panel will no 
longer be performed (this 
assessment was included 
to help understand the 
mode of action of 
laquinimod, with any 
changes expected to 
occur in the first few 
months of treatment, and 
was not pertinent to 
subject’s direct safety)

Urinalysis
pH
Glucose 
Ketones
Erythrocytes, Leukocytes
Protein
(text deleted)
Urinalysis will no longer 
be performed for 
consistency with other 
laquinimod studies and 
because the clinical 
information gained from 
such a test would be 
minimal in this study.
Section 10.2.3.1. Urgent Safety Laboratory Panel
(new section)
Unscheduled urgent safety laboratory samples may be collected at the 
discretion of the investigator or medical monitor at any time to assist 
with further investigations of cardiovascular events or other clinical 
event of interest. The samples should be collected as soon as possible 
in association with the event.
The following tests (and others, if required) will be performed on 
these samples:
Unscheduled samples can 
be collected for further 
investigation of clinical 
events of interest


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New wording
Reason/Justification for 
change

serum chemistry panel, including fibrinogen and hs-CRP

hematology panel

CPK-MB

troponin I
Section 10.2.4. Vital Signs and Weight (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E (Visits 1E) and 
Onwards])
Body weight will be measured at Month 0E [Baseline 
(Termination visit of the MS LAQ 302 study)] and every 12 
months thereafter, all visits until Termination/Early 
discontinuation, and as long as the subject continues study 
drug treatment. 
Body weight will be measured at all visits until Termination/Early 
discontinuation, and as long as the subject continues study drug 
treatment. 
Weight will now be 
measured at all visits
Section 10.2.7. Glomerular Filtration Rate Estimation (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E 
(Visits 1E) and Onwards]; Section 10.2.3. Safety Laboratory Evaluations)
(new section)
Significant changes in laquinimod exposure, in particular in terms of 
unbound drug fraction, are predicted in patients with moderate and 
severe renal impairment (see Section 3.3.1). Consequently, GFR will 
be estimated at all visits to monitor renal function in the study in order 
to identify subjects with potentially impaired laquinimod clearance. 
Subjects with a confirmed GFR ≤60 mL/min/1.73 m2 should stop 
study medication temporarily and the GFR assessment should be 
repeated. If the renal impairment is confirmed (GFR ≤60 
mL/min/1.73 m2), the subject should stop study medication 
permanently (see Section 8.2.6.5).
GFR estimation added to 
monitor renal function
Section 10.2.8. Cardiovascular Risk Assessment and Management (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits 
[Months 1E (Visits 1E) and Onwards])
(new section)
Evaluation and management of major modifiable cardiac risk factors 
(eg, diabetes, high blood pressure, hyperlipidemia, tobacco smoking) 
will be performed at the time points indicated in Table 5. In addition, 
an evaluation should take place as soon as possible for subjects 
already in the study, following approval of Amendment #2.
Cardiovascular risk management should be conducted according to 
evidence-based, local standard-of-care procedures. Subjects will 
undergo referral to a suitable clinic if needed.
Additional safety
precautions for 
cardiovascular risks


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New wording
Reason/Justification for 
change
Section 11.2.1. SAE Reporting (Other sections affected by this change: Section 13.3. Subject Confidentiality; Section 15.1. Data Collection via Remote Data 
Capture (RDC))
The following information should be provided to accurately 
and completely record the event:
1.
Investigator Name and Center Number
2.
Subject Number
3.
Subject initials
4.
Subject Demographics
The following information should be provided to accurately and 
completely record the event:
1.
Investigator Name and Center Number
2.
Subject Number
Subject initials and 
demographics should no 
longer be recorded
Section 13.2. Informed Consent (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E (Visits 1E) and Onwards])
(new text)
Subjects continuing on laquinimod 0.6 mg will be re consented with 
information about the cardiovascular risk seen in higher doses (see 
Section 3.4.1.7).
Subjects continuing on 
the study with this 
amendment will be re 
consented.
Section 18. CLINICAL PRODUCT COMPLAINTS
(new section)
A clinical product complaint is defined as a problem or potential 
problem with the physical quality or characteristics of clinical drug 
supplies or clinical device supplies used in a clinical research study 
sponsored by Teva. Examples of a product complaint include but are 
not limited to:

suspected contamination

questionable stability (eg, color change, flaking, 
crumbling, etc)

defective components

missing or extra units (eg, primary container is received 
at the investigational center with more or less than the 
designated number of units inside)

incorrect packaging, or incorrect or missing 
labeling/labels

unexpected or unanticipated taste or odor, or both

device not working correctly or appears defective in 
some manner
Each investigational center will be responsible for reporting a possible 
clinical product complaint by completing the product complaint form 
provided by Teva and emailing it to 
 within 48 hours of 
becoming aware of the issue.
Section added for 
consistency with 
sponsor’s current protocol 
template


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New wording
Reason/Justification for 
change
For complaints involving a device or other retrievable item, it is 
required that the device (or item) be sent back to the sponsor for 
investigative testing whenever possible. For complaints involving a 
drug product, all relevant samples (eg, the remainder of the subject’s 
drug supply) should be sent back to the sponsor for investigative 
testing whenever possible.
Section 18.1. Product Complaint Information Needed from the Investigational Center
(new section)
In the event that the product complaint form cannot be completed, the 
investigator will obtain the following information, as available:

investigational center number and principal investigator 
name

name, phone number, and address of the source of the 
complaint

clinical protocol number

subject identifier (subject study number) and 
corresponding visit numbers, if applicable

product name and strength for open-label studies

subject number, bottle, and kit numbers (if applicable) 
for double-blind or open-label studies

product available for return Yes/No

product was taken or used according to protocol Yes/No

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not 
all the required information can be obtained immediately. Known 
information must be reported immediately. The sponsor will 
collaborate with the investigator to obtain any outstanding 
information.
Section added for 
consistency with 
sponsor’s current protocol 
template
Section 18.2. Handling of Study Drug at the Investigational Center
(new section)
The investigator is responsible for retaining the product in question in 
a location separate from the investigator’s clinical study supplies. The 
sponsor may request that the investigator return the product for 
further evaluation and/or analysis. If this is necessary, the clinical 
Section added for 
consistency with 
sponsor’s current protocol 
template


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New wording
Reason/Justification for 
change
study monitor or designee will provide the information needed for 
returning the study drug.
If it is determined that the investigational center must return all study 
drug, the sponsor will provide the information needed to handle the 
return.
The integrity of the randomization code and corresponding blinded 
clinical supplies will be maintained whenever possible. A serious 
adverse event or the potential for a product quality problem existing 
beyond the scope of the complaint may be a reason to unblind the 
clinical supplies for an affected subject.
Section 18.3. Adverse Events or Serious Adverse Events Associated with a Product Complaint
(new section)
If there is an adverse event or serious adverse event due to product 
complaint, the protocol should be followed for recording and 
reporting (Section 11).
Section added for 
consistency with 
sponsor’s current protocol 
template
Section 18.4. Documenting a Product Complaint
(new section)
The investigator will record in the source documentation a description 
of the product complaint, and any actions taken to resolve the 
complaint and to preserve the safety of the subject. Once the 
complaint has been investigated by the sponsor and the investigator, if 
necessary, an event closure letter may be sent to the investigational 
center where the complaint originated or to all investigational centers 
using the product.
Section added for 
consistency with 
sponsor’s current protocol 
template
APPENDIX C. MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 INDUCERS
(section, including tables, updated to make consistent with 
current IB)
(see Appendix C for new wording)
Updated for consistency 
with current IB
APPENDIX D. LIST OF MEDICATIONS THAT SHOULD BE USED WITH CAUTION
(section, including tables, updated to make consistent with 
current IB)
(see Appendix D for new wording)
Updated for consistency 
with current IB
APPENDIX E. GUIDANCE ON SAFETY MONITORING
(new text)
4. Guidance on Monitoring Subjects with Elevated Pancreatic 
Amylase Levels
Pancreatic amylase will be measured at each study visit. Lipase will 
be tested in case of abnormal pancreatic amylase results and on all 
follow up visits until normalization of pancreatic amylase level. In 
case of suspected pancreatitis, the subject should undergo a thorough 
clinical evaluation including an abdominal CT scan as soon as 
possible in order to clarify the diagnosis and enable assessment of 
Guidance updated for 
consistency with body of 
the protocol


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Reason/Justification for 
change
severity of this condition. An MRI may be performed as an alternative 
to the CT scan.
5. Liver Impairment
Subjects who develop any chronic liver disease associated with liver 
functional impairment while participating in the study should stop 
study medication.
6. Renal Impairment
Subjects who develop renal disease associated with moderate or 
severe functional impairment, defined as glomerular filtration rate 
(GFR) ≤60 mL/min/1.73 m2, while participating in the study should 
stop study medication temporarily and the GFR assessment should be 
repeated. If the renal impairment is confirmed (GFR ≤60 
mL/min/1.73 m2), the subject should stop study medication 
permanently.


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24.2.
Global Amendment #1
At the time of issuance of this amendment there were 822 ongoing subjects in this study.
This amendment included: updates to the introduction and safety sections based on accumulating 
data with laquinimod; and more stringent pregnancy prevention measures.
In addition to the major revisions this amended protocol included updates, modifications and 
clarifications in sections related to stopping rules, disallowed medication, and study duration.
These changes did not alter the study population, study design, or endpoints.
Rationales for the major changes are listed in the summary table below.
Deletions are indicated with a strikethrough, additions with an underline.


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Previous approved wording
Amended or new wording
Rationale
Section 3 INTRODUCTION
-
See section
The section has been greatly 
revised to bring in line with 
current experience. Please see 
section for full details.
Synopsis AND Section 4: Study objectives AND Section 5.1: Overview and plan AND Section 5.3: Rationale for study design, dose and 
population AND Section 8.1: Study period
…..until laquinimod 0.6 mg is commercially available 
for the treatment of MS patients or until its 
development for MS has been stopped
……. as long as the Sponsor continues the development 
of laquinimod 0.6 mg for RRMS.
The Sponsor reasoned that the 
long term follow-up for safety 
and efficacy is of utmost 
importance and would like to 
maintain the subjects under 
this clinical protocol. The 
Sponsor would like to prolong 
the study as long as the 
Sponsor continues the 
development of laquinimod 
0.6 mg for RMMS patients. 
Therefore, the duration of the 
study will no longer be 
dependent on commercial 
availability of laquinimod 
0.6mg.
Synopsis
For purposes of neurological/medical assessments, 
the study will be divided into 2 periods:
Period 1: in which all subjects will continue to be 
evaluated by 2 distinct physicians 
a Treating and 
an Examining Neurologists/ Physician (as in the 
MS LAQ 302 study).
Period 2: in which all subjects will be assessed by a 
single Study Physician/ Neurologist.
The Sponsor will inform the sites when to change 
from Period 1 to Period 2
As of the implementation of Protocol Amendment #1, 
all neurological/medical assessments may be performed 
by a single Study Physician/Neurologist since all the 
sites are now in Period 2 of the study.
Distinction of Period 1/2 –
there is no longer need to 
distinguish between study 
period 1 and 2 since all the 
subjects are now in the study 
period 2. Similarly there is no 
need for distinction between 
the Treating and the 
Examining Physicians/ 
Neurologists.


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Amended or new wording
Rationale
Section 5.1: Overview and plan
5.2 Study Periods
The medical/neurological assessments of the subjects 
at each clinical site will be performed differently in 
each of the following study periods. 
Period 1: 
In this period, either two separate Neurologists or two 
Physicians will continue to assess the subjects in the 
MS LAQ 302E study (as in the MS LAQ 302 study). 
An Examining Neurologist/Physician will assess the 
subject’s neurological status, unaware of subject’s 
well being and a Treating Neurologist/Physician will 
decide whether a subject experienced a relapse and 
will treat the subject as needed (in addition to his/her 
responsibility for subject eligibility evaluation, the 
supervision of the study drug administration, the 
recording and treating of adverse events and the 
monitoring of safety assessments, including routine 
laboratory parameters).
In order to maintain reliable evaluation and reduce the 
potential for bias the following actions will be 
undertaken:
The Examining Neurologist/Physician will be the only 
one to evaluate the subject neurologically. 
The Examining Neurologist/ Physician will have no 
access to the subject's file, including previous 
neurostatus forms, RDC system and adverse events. 
A decision as per treatment of a relapse will be under 
the sole responsibility of the Treating Neurologist/ 
Physician.
Period 2: 
In this period, there will be no need for 2 separate 
physicians to assess the subjects in the MS-LAQ-
302E study. From that moment, subjects participating 
in the MS-LAQ-302E study will be assessed by a 
The medical/neurological assessments of the subjects at 
each clinical site will no longer be performed differently 
since all the sites are now in study period 2. In each of 
the following study periods. In this period, there will be 
no need for 2 separate physicians to assess the subjects 
in the MS-LAQ-302E study. From that moment,
sSubjects participating in the MS-LAQ-302E study will 
be assessed by a single physician/Neurologist ("Study 
Physician/ Neurologist").


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Amended or new wording
Rationale
single physician/Neurologist ("Study Physician/ 
Neurologist").
The study will begin with medical/neurological 
assessments which will be performed as described in 
Period 1 (identical to the assessment methods in the 
MS LAQ 302 study)
The sponsor will inform the sites when to change the 
method of medical/neurological assessments from 
Period 1 to Period 2
Section 8.2.1 Baseline Visit (Month 0E) (Visit 0E) (Termination visit of the MS-LAQ-302 study) 
Procedures
Serum pregnancy test (β-hCG) for women of child-
bearing potential.
. Serum pregnancy test (β-hCG) for women of child-
bearing potential. In case of positive result, the subject 
will not be eligible to participate in the extension and 
will be considered a screening failure for the extension 
phase.
Section 10.1.2 Neurological Evaluations
At each of the study Periods, every effort should be 
made to ensure that the same Neurologist/Physician 
performs the neurological assessment at all visits for a 
particular subject.
At each of the study Periods. Every effort should be 
made to ensure that the same Neurologist/Physician 
performs the neurological assessment at all visits for a 
particular subject.
Section 8.2.9.1: Visits during relapses (scheduled and unscheduled)
The Examining Neurologist/Physician (or Study 
Physician/ Neurologist, where applicable, see 
Section 5.1.1)
the Treating Neurologist/Physician [or by the Study 
Physician, where applicable (see Section 5.1.1),
The Examining Study Neurologist/Physician (or Study 
Physician/ Neurologist, where applicable, see 
Section 5.1.1)
the Treating Study Neurologist/Physician [or by the 
Study Physician, where applicable (see Section 5.1.1)
Section 10.1.1: On-study Relapse Evaluation and Determination

Subjects will be instructed to telephone their 
study site within 48 hours should any symptoms 
suggestive of a relapse appear.

The Treating Neurologist/Physician (or the 
Study Physician/Neurologist, where applicable) 
(see Section 5.1.1 and Section 18.1.2) will 

Subjects will be instructed to telephone their study 
site within 48 hours should any symptoms 
suggestive of a relapse appear.

The Study Neurologist/Physician will evaluate the 
subject once any symptom suggestive of a relapse 
occurs.


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Rationale
evaluate the subject once any symptom 
suggestive of a relapse occurs.

In case of a suggestive relapse during a 
scheduled or unscheduled visit in 
Period 1 (see Section 5.1.1):

The Treating Neurologist/Physician 
will refer the subject to the 
Examining Neurologist/Physician for 
performance of neurological 
evaluations and obtain EDSS score 
(see Section 18.1.3). 

An Examining Neurologist/Physician 
will assess the subject’s neurological 
status, unaware of subject’s well 
being and a Treating Neurologist/ 
Physician will decide whether a 
subject experienced a relapse and will 
treat the subject as needed.

In case of a suggestive relapse during a 
scheduled or unscheduled visit in 
Period 2 (see Section 5.1.1):

The evaluation of symptoms as well as the 
neurological evaluations/ EDSS will be made by 
the Study Physician (see Section 19.1.2). 

Based on the assessment of symptoms and the 
EDSS/FS evaluation, the Study Physician will 
decide whether a subject experienced a relapse 
and will treat the subject as needed. 

In any case, the neurological evaluation of the 
subject (by The Examining Neurologist in 
Period 1 or by the Study Physician/Neurologist 
in Period 2) will be performed within 7 days of 
symptoms onset, conditional upon a 
symptomatic period of ≥ 48 hours.

In case of a suggestive relapse during a scheduled 
or unscheduled visit:

The evaluation of symptoms as well as 
the neurological evaluations/ EDSS will 
be made by the Study 
Physician/Neurologist. 

Based on the assessment of symptoms 
and the EDSS/FS evaluation, the Study 
Physician/Neurologist will decide 
whether a subject experienced a relapse 
and will treat the subject as needed. 

In any case, the neurological evaluation of the 
subject by the Study Physician/Neurologist will be 
performed within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥ 48 
hours.

In the case of an ongoing or just-started relapse at 
the study Termination/Early discontinuation visit, 
subjects will be followed up until relapse 
stabilization 


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
In the case of an ongoing or just-started relapse 
at the study termination/early discontinuation 
visit, subjects will be followed up until relapse 
stabilization 
Section 11.2.1: SAE Reporting
In order to satisfy regulatory requirements, any 
Serious Adverse Event, whether deemed IMP-related 
or not, must be reported to the Local Clinical 
Management as soon as possible after the investigator 
or coordinator has become aware of its occurrence.
The SAE form completion and reporting must not be 
delayed even if all of the information is not available 
at the time of the initial contact.
The SAE should be submitted within 24 hours of 
becoming aware of the event to the Local Clinical 
Management. The local Clinical Management will 
forward the report to the Local Safety Officer who 
will forward the SAE report to the Global
Pharmacovigilance Unit:
SAE originated in Europe and rest of the world should 
be sent to:
Global Drug Safety and Pharmacovigilance Unit 
(Israel)
SAE originated in USA will be sent to:
In order to satisfy regulatory requirements, any SAE, 
whether deemed IMP-related or not, must be reported to 
the Contract Research Organization (CRO) as soon as 
possible after the investigator or coordinator has 
become aware of its occurrence. The SAE form 
completion and reporting must not be delayed even if 
all of the information is not available at the time of the 
initial contact.
The SAE should be submitted within 24 hours of 
becoming aware of the event to the CRO. The CRO will 
forward the report to the appropriate Pharmacovigilance 
unit at Teva or the Local Safety Officer (LSO) who will 
forward the SAE report to the appropriate
Pharmacovigilance unit at Teva:
SAE originated in Europe and rest of the world 
should be sent to:
Global Drug Safety and Pharmacovigilance Unit (Israel)
SAE originated in USA will be sent to:
Teva USA clinical safety mailbox
SAE originated in Canada will be sent to:
Teva Canada safety mailbox
SAE originated in Germany will be sent to:
Teva Germany safety mailbox


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Only in the event of difficulty transmitting the form via 
email, send the form via fax, or contact the sponsor’s 
study personnel identified above for further instruction.
In Period 1, blinding will be maintained for the people 
who are involved directly in the study, therefore in 
case of a SUSAR case only the Local Safety Officer 
will receive the un blinded report for regulatory 
submission, while the others will receive a blinded 
report (Teva S.O.P 50.11.16). This precaution is not 
relevant for Period 2.
None
Section 19.1.1: The Principal Investigator
The Treating Neurologist/Physician (applicable in 
Period 1)
The Treating Neurologist/Physician will be 
responsible for subject eligibility evaluation, the 
supervision of the study drug administration, the 
recording and treating of adverse events, the 
monitoring of safety assessments, including routine 
laboratory parameters, and coordinating MRI 
performance. He/she will determine if a subject 
experiences a relapse and whether to treat the relapse 
or not and he/she will decide whether to treat the 
subject as needed. 
The Examining Neurologist/Physician (applicable in 
Period 1) 
The Examining Neurologist will be responsible for all 
neurological examinations. Throughout the study, the 
Examining Neurologist/Physician will remain 
unaware of the safety profile. For each subject, the 
same Examining Physician should be used for all 
neurological exams performed throughout the study.
It is particularly important that:

The Treating Neurologist/Physician and the 
None


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Examining Neurologist/Physician do not discuss 
safety issues with each other. The Examining 
Neurologist/Physician will not ask the subject 
any questions regarding his well being.

The Treating Neurologist/Physician will inform 
the subject of the importance of not discussing 
safety issues with the Examining 
Neurologist/Physician.
Section 19.1.2: The Study Physician/Neurologist
Section 18.1.2 The Study Physician/ Neurologist 
(applicable in Period 2)
In case where there is no need for distinction between 
the Treating and the Examining Physicians/ 
Neurologists (Period 2) (to be communicated to the 
clinical sites by the Sponsor, or Sponsor's designee),
the Study Physician/ Neurologist will be responsible 
for the general medical evaluations as well as the 
neurological assessments. The Study Physician will 
make the decision as to whether the neurological 
change is considered a relapse, based on EDSS/FS 
scores obtained by him/her.
Section 19.1.2 The Study Physician/Neurologist 
The Study Physician/Neurologist will be responsible for 
the general medical evaluations as well as the 
neurological assessments. The Study Physician will
make the decision as to whether the neurological change 
is considered a relapse, based on EDSS/FS scores 
obtained by him/her.
Section 20.2: Data Monitoring Committee
During Period 1, the DMC Chairperson will interact 
with the Sponsor’s statistician. Within this work
frame, the study un blinded statistician, will produce 
and distribute reports to the DMC members. The 
statistician of the DMC will address any statistical 
question raised by the DMC during data review, and 
will perform data analyses according to the DMC’s 
request. During Period 2, this interaction may be done 
via the Global Clinical Leader. 
None
Appendix B: Definitions
In Period 1 (see Section 5.1.1), the subjects’ general 
medical evaluations will be assessed separately from 
their neurological assessment evaluations by two 
In Period 2, there will be no distinction between the 
Treating Neurologist/ Physician and the Examining 
Neurologist/ Physician. In such cases, a single Study 


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different Neurologists/ Physicians. An Examining 
Neurologist/Physician will assess the subject’s 
neurological examination, unaware of subject’s well 
being and a Treating Neurologist/ Physician will 
decide whether a subject experienced a relapse and 
will prescribe steroids or other concomitant 
medications as needed.
The Treating Neurologist/Physician will make the 
decision as to whether the neurological change is 
considered a relapse, based on EDSS/FS scores as 
assessed by the Examining Neurologist/ Physician 
(see Relapse Definition, above).
Follow up visits to monitor the course of the relapse 
until stabilization will be made at the Treating 
Neurologist/Physician discretion, in addition to the 
assessment at the next scheduled visit.
In Period 2 (see Section 5.1.1), there will be no 
distinction between the Treating Neurologist/ 
Physician and the Examining Neurologist/ Physician. 
In such cases, a single Study Physician will be 
responsible for the general medical evaluations as 
well as the neurological assessments. The Study 
Physician will make the decision as to whether the 
neurological change is considered a relapse, based on 
EDSS/FS scores obtained by him/her. The Study 
Neurologist/ Physician will follow-up on the subject 
during the course of a relapse, until stabilization. 
Relapse Evaluation Procedures
Subjects will be instructed to telephone their study site 
within 48 hours should any symptoms suggestive of a 
relapse appear.
In Period 1, the Examining Neurologist/ Physician 
will evaluate the subject within 7 days of symptoms 
onset, conditional upon a symptomatic period of ≥ 48 
hours:
Physician/Neurologist will be responsible for the 
general medical evaluations as well as the neurological 
assessments. The Study Physician/Neurologist will 
make the decision as to whether the neurological change 
is considered a relapse, based on EDSS/FS scores 
obtained by him/her. The Study Neurologist/ Physician 
will follow-up on the subject during the course of a 
relapse, until stabilization. 
Relapse Evaluation Procedures
Subjects will be instructed to telephone their study site 
within 48 hours should any symptoms suggestive of a 
relapse appear.
The Study Neurologist/ Physician will evaluate the 
subject within 7 days of symptoms onset, conditional 
upon a symptomatic period of ≥ 48 hours:
•
The Study Neurologist/Physician will evaluate 
and treat the subject once any symptom suggestive of a 
relapse occurs.
In Period 2, all of the above mentioned relapse 
evaluation activities will be performed by the Study 
Neurologist/ Physician.


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
The Treating Neurologist/Physician will evaluate 
the subject once any symptom suggestive of a 
relapse occurs.

In case of a suggestive relapse during a scheduled 
or unscheduled visit, the Treating 
Neurologist/Physician will refer the subject to the 
Examining Neurologist/Physician.
In Period 2, all of the above mentioned relapse 
evaluation activities will be performed by the Study 
Neurologist/ Physician.
Synopsis AND Section 8.2: Detailed Study Plan
In case of suspected pregnancy, …..
In case of suspected pregnancy (positive urine β-hCG 
test result, delay of menstruation or any other reason 
suggesting pregnancy), ….
Teva considers the prevention 
of exposure to laquinimod 
during pregnancy to be of 
great importance, and 
following consultation with 
the CHMP and Data Safety 
Committee (DMC) has 
decided to introduce additional 
language and measures for 
pregnancy prevention in this 
amendment and in a revised 
informed consent form. 
To strengthen the preventative 
measures, the measures for 
pregnancy prevention now 
include: 
a requirement for two 
contraception methods (as 
recommended by the DMC) 
and a requirement for using a 
contraception method 30 days 
prior to 
randomization.Furthermore a 
Table 5Study Task Flow Chart AND Section 8.2: Detailed Study Plan AND Appendix E (Study task flow 
chart for returning subjects)
None.
Section 8.2: Detailed Study Plan
Female subjects of child-bearing potential will 
be reminded about (should be recorded in the 
source documents) the importance of stopping 
the study drug and informing the site in any 
case of suspected pregnancy (positive home 
urine test result, absence of menstruation or 
any other reason suggesting pregnancy)

For all subjects who are female of child-
bearing potential:

The use of effective contraception will 
be ascertained at each study visit 
(should be recorded in the source 
documents).

Subjects will be instructed during each 
visit about the teratogenicity and 
potential delayed risks for a child 
exposed in uterus to laquinimod

Female subjects of child bearing 
potential will be reminded about 
(should be recorded in the source 
documents) the importance of stopping 
the study drug and informing the site in 


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any case of suspected pregnancy 
(positive home urine test result, delay 
of menstruation or any other reason 
suggesting pregnancy)
serum beta HCG test prior to 
enrollment and additional 
follow up measures and 
clarifications are added.
Section 8.2.3: Termination/ early discontinuation
Female subjects of child-bearing potential will be 
reminded to continue using an acceptable method of 
contraception up to 30 days from the date of the last 
dose of the IMP
The use of effective contraception will be ascertained 
(should be recorded in the source documents) and all 
subjects will be reminded to continue using two 
acceptable methods of contraception up to 30 days from 
the date of the last dose of the IMP
Synopsis AND Section 6.2 Exclusion Criteria
The Sponsor realizes that there 
might be female subjects of 
childbearing potential who are 
participating in this long-term 
study that might want to get 
pregnant in the future, and 
might be interested in 
continuing taking Laquinimod 
after giving birth. The Sponsor 
would like to assure that these 
women do not conceive during 
treatment with laquinimod and 
are given the opportunity to 
return to the study, if they 
wish, following childbirth and 
lactation. Therefore, the 
protocol has been amended to 
say that these subjects may be 
re-enrolled after meeting 
inclusion/exclusion criteria.
None
Female subjects of childbearing potential who may 
want to get pregnant in the future, and are interested in 
re-starting laquinimod treatment following delivery and 
cessation of breastfeeding may be able to re-enroll in 
the study after meeting inclusion/exclusion criteria 
below. Re-enrollment will be permitted on a case-by-
case basis. Notwithstanding, Teva is under no 
obligation to re-enroll such subjects and reserves the 
right to re-enroll or reject enrolment of such returning 
subjects for no reason and on its sole discretion. A new 
informed consent form should be signed before re-
enrollment (see Appendix E).
Section 7.1: Allowed Concomitant Medication/Therapies
Short-term treatment with IV corticosteroids will be 
allowed during acute relapses; Allowed treatment for 
relapses is a fixed dose of IV methylprednisolone 1 
g/day or oral steroids for a maximum of five 
Short-term treatment with IV corticosteroids will be 
allowed during acute relapses; Allowed treatment for 
relapses is a fixed dose of IV methylprednisolone 1 
g/day or oral steroids for a maximum of five 
In order to align the protocol 
with more recent clinical study 
protocols with laquinimod, 
allowed treatment for relapses 


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consecutive days. No tapering off is allowed.
Other medications, excluding those mentioned in 
Section 7.2 may be given concomitantly as needed for 
the subject’s welfare.
Topical and inhaled steroids are allowed at the 
discretion of the Treating Physician/Neurologist for 
indications other than MS.
Administration of all medications, including 
indication, dose, frequency, and route of 
administration will be recorded in the source 
documentation file and in the electronic Case Report 
Form (eCRF).
consecutive days. No tapering off is allowed.
Other medications, excluding those mentioned in 
Section 7.2 may be given concomitantly as needed for 
the subject’s welfare.
Topical and inhaled steroids are allowed at the 
discretion of the Study Physician/Neurologist (or the 
Study Physician, were applicable, see Section 5.1.1) for 
indications other than MS.
Administration of all medications, including indication, 
dose, frequency, and route of administration will be 
recorded in the source documentation file and in the 
electronic Case Report Form (eCRF).
include a short course of 
glucocorticosteroids (e.g., IV 
methylprednisolone 1g/day for 
up to 5 consecutive days or 
oral steroids). Extended 
courses of steroids beyond 5 
days constitute a protocol 
violation. No tapering off is 
allowed.
Section 7.1: Allowed Concomitant Medication/ Therapies
The use of CYP1A2 substrates (e.g. theophylline, 
warfarin) during the treatment period is permitted. 
However, due to the fact that laquinimod is an inducer
of CYP1A2 in vitro, subjects who are treated with 
these medications should be monitored for a possible 
reduction in their effect or blood level and their 
(CYP1A2 substrates) dose should be adjusted 
accordingly.
Clinical studies have shown laquinimod 0.6 mg to be a 
potent inducer of CYP1A2. Subjects taking drugs that 
are metabolized by CYP1A2 (examples listed in 
Appendix F) should be advised that plasma levels of 
these drugs could decrease when combined with 
laquinimod. Physicians should consider increasing the 
dose of such medications upon initiation of laquinimod 
treatment; in this case, dose reduction of the CYP1A2 
inhibitor should be considered if laquinimod is stopped.
Drug-Drug interaction studies have been performed 
with laquinimod doses of 0.6 mg and 1.2 mg. These 
studies show that laquinimod at both doses is a weak 
inhibitor of CYP3A4. Subjects taking drugs that are 
metabolized by CYP3A4 (specifically those with a 
Narrow Therapeutic Index listed in Table 6) should be 
advised that plasma levels of these drugs could increase 
when combined with laquinimod.
Laquinimod is a potent 
inducer of CYP1A2. A 
recently completed drug-drug 
interaction study confirmed 
that laquinimod at the dose of 
1.2 mg is also a weak 
CYP3A4 inhibitor. Therefore, 
these paragraphs were 
included to emphasize the risk 
related to the concomitant use 
of laquinimod and drugs that 
are metabolized by CYP1A2 
or CYP3A4.
In addition, a new appendix 
(Appendix D) has been added 
to present partial lists of 
CYP3A4 substrates with a 
narrow therapeutic index and 
of drugs known to be 
metabolized by CYP1A2.
Appendix D: List of Allowed Medications During the Study That Should Be Used with Caution
None
A partial list Of CYP3A4 substrates with a narrow 
therapeutic index
alfentanil
cyclosporine


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diergotamine
ergotamine
fentanyl
pimozide
quinidine
sirolimus
tacrolimus
A partial list of drugs known to be metabolized by 
CYP1A2:
clozapine
duloxetine
theophylline
tizanidine
alosetron
ramelteon
tacrine
Section 7.2: Disallowed Concomitant Medications During Study

Interferons

Glatiramer Acetate (Copaxone®)

Natalizumab (Tysabri®)

Inhibitors of CYP3A4; for example, 
ketoconazole and erythromyicin (as listed in 
Appendix C)

Mitoxantrone (Novantrone®)

Oral steroids

Parenteral steroids (except if given as defined 
by protocol for treatment of an acute relapse 
as specified in Section 7.1) 

Chemotherapeutic agents

4-amino pyridine or 3,4 diaminopyridine

IV Immunoglobulin (Ig) and any other 
experimental agents 

Other Immunosuppressive or 
immunomodulating agents

Natalizumab (Tysabri®)

Fingolimod (Gilenya)

Interferons

Dimethyl fumarate (Tecfidera)

Glatiramer Acetate (Copaxone®)

Teriflunomide (Aubagio)

Alemtuzumab (Lemtrada)

Cladribine

Rituximab 

Ocrelizumab

Atacicept

Belimumab

Ofatumumab

Inducers of CYP3A4 such as rifampin and 
carbamazepine (for more examples 
seeAppendix C). Use of CYP3A4 inducers may 
result in reduced laquinimod plasma 
Laquinimod is mainly 
metabolized by the CYP3A4 
P450 isoenzyme. Following an 
in vivo study in healthy 
volunteers (LAQ DDI-125 
study), rifampin, a strong 
inducer of CYP3A4 was found 
to significantly enhance the 
metabolism of laquinimod and 
leads to an approximately 80% 
reduction in the plasma levels 
of laquinimod, as measured by 
the area under the plasma 
concentration-time curve 
(AUC). Therefore, strong 
inducers of CYP3A4 
(Carbamazepine, Phenytoin, 
Phenobarbital, St. John's 


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concentrations and may reduce its effectiveness.

Moderate or strong inhibitors of CYP3A4; for 
example, ketoconazole and erythromycin (as 
listed in Appendix C)

Mitoxantrone (Novantrone®)

Oral steroids

Parenteral steroids (except if given as defined 
by protocol for treatment of an acute relapse as 
specified in Section 7.1)

Adrenocorticotrophic hormone (ACTH)

Chemotherapeutic agents

Cytotoxic agents

Cyclophosphamide

IV Immunoglobulin (Ig)

Plasmapheresis

Any other experimental agents

Other Immunosuppressive or 
immunomodulating agents
Wort) may result in reduced 
laquinimod plasma 
concentrations and reduced 
effectiveness. Therefore 
CYP3A4 inducers have been 
added as disallowed 
medications in all clinical 
studies with laquinimod. The
Laquinimod Investigator's 
Brochure Edition 7 has been 
updated with the above 
information in Section 6.7.1.
The disallowed use of 
CYP3A4 inducers has been 
added to Section 7.2 
(Disallowed concomitant 
medications during the study) 
and Appendix C has been 
updated with the list of 
disallowed medications.
Recently several drugs have 
been approved for use in 
RRMS. The amended protocol 
has been updated to include 
the following drugs in the 
disallowed medication during 
study (Section 7.2 Disallowed 
concomitant 
medications 
during the study):
Fingolimod (Gilenya)
Dimethyl fumarate (Tecfidera)
Teriflunomide (Aubagio)
Alemtuzumab (Lemtrada)
The medication 4-amino 
pyridine (Ampyra, Fampyra) 


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is now allowed during the 
study since it is no longer an 
experimental drug (has 
received FDA approval and 
indicated to improve walking 
in adult patients with multiple 
sclerosis (MS) who have 
walking disability).
Section 8.2.5: Post Early Discontinuation Follow-Up Visit
In case of early termination of the study due to an AE 
for which the relationship with the study drug is 
characterized as ‘Reasonable Possibility’, CYP3A4 
inhibitors are disallowed during the 30 days after the 
last dose has been administered.
In case of early termination of the study due to an AE 
for which the relationship with the study drug is 
characterized as ‘Reasonable Possibility’, moderate and 
strong CYP3A4 inhibitors are disallowed during the 30 
days after the last dose has been administered.
Appendix C List of Systemically-administered CYP3A4 Inhibitors which are Disallowed Prior and During Study
Cardiac drugs/antiarrhythmic agents
amiodarone
diltiazem
nifedipine
verapamil
mibefradil
Antimicrobial agents
Erythromycin
Clarithromycin
Troleandomycin
Telithromycin
Antifungals/Imidazoles
Fluconazole
Itraconazole
Ketoconazole
Miconazole
Voriconazole
A partial list of moderate/strong CYP3A4 inhibitors:
Medication class
Drug name
Protease inhibitors
indinavir, saquinavir, 
lopinavir, nelfinavir, 
amprenavir, atazanavir, 
darunavir, ritonavir
Antivirals:
boceprevir, telaprevir
Antifungals:
Ketoconazole, Itraconazole, 
voriconazole, posaconazole, 
fluconazole
Antibiotics
troleandomycin, 
clarithromycin, telithromycin, 
ciprofloxacin, erythromycin
Antidepressant
nefazodone
Calcium channel 
blocker
Diltazem, verapamil, 
mibefradil
Antiemetics
Aprepitant
Diuretics
Conivaptan


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HIV drugs: 
Protease Inhibitors, such as indinavir, ritonavir and 
others
Delavirdine
Antidepressants
fluoxetine
fluvoxamine
nefazodone
Others/antituberculosis and antimalarial
isoniazid
quinine
cimetidine
zileuton
aprepitant 
*
This is a partial list only
** Systemic drugs only. Topical preparations (vaginal 
preparations, creams, etc) are allowed. 
*** In case of early termination of the study due to 
AE which is considered as 
'Reasonable Possibility
' 
related to the study drug, CYP3A4 inhibitors are 
disallowed during 30 days after the last dose of the 
study drug was taken. 
Antineoplastic 
agents
Imatinib
Note:
Interactions between drugs and grapefruit juice are 
documented for drugs with low bioavailability due to 
pre-systemic gut-wall metabolism. Based on the 
suggested high oral bioavailability of laquinimod in 
humans, we do not predict that such interactions are
expected with laquinimod.
Moderate/strong CYP3A4 inhibitors are disallowed 
during the 30 days after the last dose has been 
administered.
A partial list of CYP3A4 inducers:
carbamazepine
phenobarbital
phenytoin 
rifabutin
rifampin
St. John
's Wort
* This isa partial list only
** Systemic drugs only. Topical preparations (vaginal 
preparations, creams, etc) are allowed.
Synopsis AND Table 5: Study Flow Chart AND Section 8.2.1: Baseline visit AND Section 8.2.2: Scheduled Treatment Visits [Months 1E 
(Visits1E) and onwards] AND Section 8.2.3: Termination/ early discontinuation
Safety laboratory test: serum levels of TSH, T3 and 
free T4
Monitoring of thyroid function 
tests was relevant during the 
core study treatment with 
Avonex. Currently, there are 
no subjects in the open label 
extension phase treated with 
Avonex. No safety signal for 
Section 10.2.2: Safety Laboratory Evaluations
T3, Free T4, TSH only at months 0E 
[Baseline (Termination visit of the MSLAQ302 
study)], 6E and then at every scheduled study visit 
thereafter, until Termination/Early discontinuation 


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visit.
hypo-and hyperthyroidism, or 
abnormal thyroid function 
tests has been detected with 
laquinimod use. If a diagnosis 
of hypo-or hyperthyroidism is 
established, the subject should 
be treated according to best 
medical practice.
Section 8.2.4.1: Criteria for Early Treatment Discontinuation
None
8). 
Planned pregnancy
9). 
Lack of efficacy (according to the Investigator’s 
decision).
Two additional criteria for 
early treatment 
discontinuation have been 
included: pregnancy (due to 
fact that laquinimod is 
contraindicated in pregnancy) 
and lack of efficacy.
Section 10.2.2: Safety laboratory evaluations
Laboratory tests to be 
performed in case of abnormal 
CPK were added to the 
relevant sections dealing with 
safety laboratory evaluations.
In case of abnormal CPK 
results, testing of troponin or 
CPK MB (which was formally 
only specified as reflex testing 
in the laboratory manual) are 
currently specified in the 
protocol. A requirement for 
testing urinemyoglobin in 
case of CPK>2000U/Lwas 
added.
In addition, lipase will be 
tested in case of abnormal 
pancreatic amylase results.
In case of low hemoglobin 
[…]
CPK
[…]
[…]

CPK

In case of abnormal CPK result: 
troponin or CPK-MB will be tested

In case of CPK > 2000 U/L urine 
myoglobin will be tested and the following tests 
will be repeated: CPK, CPK MB, blood urea 
nitrogen, creatinine, electrolytes including 
potassium, calcium, phosphate, CRP and 
fibrinogen 
[…]

Lipase will be tested in case of 
abnormal pancreatic amylase results
[…]

Hemoglobin. In case of new 
hemoglobin decrease of >1g/dL from the 
subject’s hemoglobin level at Baseline, subject will 
be re-tested to ascertain true decrease. If true 


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decrease, a thorough anemia work-up will be done 
including:
Directed medical history and physical 
examination
Blood smear, serum iron, ferritin, total iron 
binding capacity, folic acid, B12, 
haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, and 
hepcidin.
Additional investigations and follow-up per 
the Investigator’s discretion or Sponsor’s 
request.
levels, a thorough anemia 
work-up will be done.
Section 8.2.6: Safety Stopping rules
Inflammatory Events:
The subject
's participation in the study will be 
discontinued immediately upon meeting either one of 
the following criteria:
A combination of elevated CRP (≥3xULN) or 
WBC (≥2xULN) or fibrinogen (≥ 3x ULN) with 
significant signs/symptoms suggestive of 
inflammation of noninfectious origin (e.g. arthralgia, 
chest pain, chest discomfort or edema).
An established diagnosis of either of the 
following: pericarditis, pleuritis, pleural effusion, 
newlydiagnosed non infectious arthritis or primary 
peritonitis.
Thromboembolic events:
In any suspicion for thrombotic events, all measures 
should be taken in order to establish or to exclude the 
diagnosis. The decision as per the continuation of the 
study drug will be made on a case by case basis. 
Pancreatitis:
Any subject with an established diagnosis 
(radiographically/sonographicallybased) of acute 
pancreatitis will be immediately withdrawn from the 
study.
New subsections added; seeSection 8.2.6.2 andSection 
8.2.6.3 for full text
The Sponsor has decided to 
remove the stopping rules of 
monitoring of inflammatory 
conditions, monitoring the 
potential of developing 
thrombosis and monitoring of 
serum pancreatic amylase 
based on the updated safety 
analysesand to align the 
protocol with more recent 
clinical study protocols with 
laquinimod.
Complete blood count, 
amylase, CRP and fibrinogen 
are routinely monitored during 
scheduled visits. The subjects 
with these laboratory 
abnormalities should be 
managed and treated 
according to best medical 
practice. 
In addition: A new serum 
chemistry evaluation should 


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be performed in case of CPK 
> 2000 U/L (i.e. urine
myoglobin and troponin) to 
complete safety assessments in 
case of abnormally high CPK 
levels. In addition, in case of 
abnormal pancreatic amylase 
results, lipase will be tested.
Laboratory tests to be 
performed in case of abnormal 
CPK, and elevated p-amylase 
were added to the relevant 
sections dealing with safety 
laboratory evaluations.
Implemented following 
CHMP opinion, two new 
conditions were included 
among the stopping rules 
(women who become pregnant 
during the study and subjects 
diagnosed with invasive 
cancer) 
Synopsis AND Section 10.1.7: Economic Impact
Section deleted
None
The Sponsor has decided not 
to perform Termination/Early 
discontinuation visit MRI 
assessments for all subjects in 
the study. No change in the 
MRI assessments for the MRI 
ancillary study.
Section 19.1.2: The Study Physician/ Neurologist
Section deleted
None
Section 19.2.2: Clinical Operations Manager
The Global Operations Manager is responsible for 
day-to-day operations of the study…..
The Global Clinical Operations Manager is responsible 
for day-to-day operations of the study…..


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Previous approved wording
Amended or new wording
Rationale
Section 19.2.6: Global Drug Safety and Pharmacovigilance
Global Drug Safety & Pharmacovigilance is 
responsible for: reviewing any safety issues that arise 
during the study, assessing and evaluating the SAEs 
occurring during the study and submission of relevant 
SAEs to health authorities/CA as per regulations. The 
Global Clinical Safety Director is responsible for all 
safety aspects of the study. He/she will ensure that the 
safety of the subjects is appropriately assessed and 
maintained according to the study protocol, objectives 
and goals. He/she will assist in the approval and 
preparation of safety data as required by the external 
DMC (see details below).
Global Drug Safety & Pharmacovigilance is responsible 
for: reviewing safety issues that arise during the study, 
assessing and evaluating the causality of SAEs 
occurring during the study and submission of relevant 
SAEs to health authorities/CA as per regulations.
Text amended to bring up to 
date with current process.
Appendix E: Guidance on Safety Monitoring
-
See Appendix E
The section has been greatly 
revised to bring in line with 
current experience. Please see 
section for full details.
Appendix K: The SF-36v2™ Health Survey
None
None
A typo was corrected in 
Question 9 of the survey
Entire Document
-
Numbering of Appendices from 6 to 11 has been 
changed throughout the text.
In addition, appendices are now numbered from A to K.
Updated cross-references to 
appendices (due to addition of 
a new Appendix D).
In addition, literature 
references have been changed 
to reflect the changes in the 
protocol


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25.
CHANGES TO PATIENT ENTRY CRITERIA
Not applicable.


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APPENDIX A. DEFINITIONS
Relapse (attack)
A relapse will be defined as the appearance of one or more new neurological abnormalities or the 
reappearance of one or more previously observed neurological abnormalities.
This change in clinical state must last at least 48 hours and be immediately preceded by an 
improving neurological state of at least thirty (30) days from onset of previous relapse. 
This criterion is different from the clinical definition of relapse: "at least 24 hours duration of 
symptomsa". Since "in study" relapse definition must be supported by an objective neurological 
evaluation (see next paragraph), a neurological deficit must sustain long enough to eliminate 
pseudo-relapses.
An event will be counted as a relapse only when the subject's symptoms are accompanied by 
observed objective neurological changes, consistent with at least one of the following:

an increase of at least 0.5 in the EDSS score as compared to previous evaluation.

an increase of one grade in the score of 2 or more of the 7 FS as compared to previous 
evaluation.

an increase of 2 grades in the score of one FS as compared to the previous evaluation.
The EDSS/FS/AI (in the first visit indicative for a relapse, as well as in follow up visits) will be a 
part of a complete neurological assessment performed by the Examining Neurologist/ Physician 
(or the Study's Neurologist/ Physician, in case all subjects in the MS-LAQ-302 double-blind 
placebo-controlled study have completed (or early terminated) their treatment period).
The subject must not be undergoing any acute metabolic changes such as fever or other medical 
abnormality. A change in bowel/bladder function or in cognitive function must not be entirely 
responsible for the changes in EDSS or FS scores.
                                                
a Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis (McDonald, Ann. 
Neurol. 2001;50:121-127)


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In Period 2, there will be no distinction between the Treating Neurologist/ Physician and the 
Examining Neurologist/ Physician. In such cases, a single Study Physician/Neurologist will be 
responsible for the general medical evaluations as well as the neurological assessments. The 
Study Physician/Neurologist will make the decision as to whether the neurological change is
considered a relapse, based on EDSS/FS scores obtained by him/her. The Study Neurologist/ 
Physician will follow-up on the subject during the course of a relapse, until stabilization. 
Relapse Evaluation Procedures
Subjects will be instructed to telephone their study site within 48 hours should any symptoms 
suggestive of a relapse appear.
The Study Neurologist/ Physician will evaluate the subject within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥48 hours:

The Study Neurologist/Physician will evaluate and treat the subject once any 
symptom suggestive of a relapse occurs.
In Period 2, all of the above mentioned relapse evaluation activities will be performed by the 
Study Neurologist/ Physician.
Relapsing-Remitting (R-R) Multiple Sclerosis (MS)
R-R MS is characterized by clearly defined acute attacks with full recovery or with sequelae and 
residual deficit upon recovery, periods between disease relapses characterized by a lack of 
disease progression (Lublin 1996)a.
                                                
a Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis. Neurol 1996;46:907-911.


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APPENDIX B. NEUROSTATUS
Standardized Neurological Examination and Assessment of Kurtzke’s Functional Systems and 
Expanded Disability Status (EDSS).


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APPENDIX C. MODERATE/STRONG CYP3A4 INHIBITORS AND 
CYP3A4 INDUCERS
Laquinimod pharmacokinetics are affected by moderate and strong CYP3A4 inhibitors; 
moderate/strong CYP3A4 inhibitors are disallowed within 2 weeks of baseline until 30 days after 
the last dose has been administered.
Moderate and strong CYP3A4 inhibitors are prohibited because concomitant administration is 
predicted to increase laquinimod exposure and may increase the likelihood of adverse events
(Table 6).
Table 6:
A Partial List of Moderate/Strong CYP3A4 Inhibitors Disallowed 2 Weeks 
Prior to and During the Treatment Period and 30 Days After Last Dose
Medication class
Drug name
Protease inhibitors
indinavir, saquinavir, lopinavir, nelfinavir, amprenavir, atazanavir, 
darunavir, ritonavir
Antivirals:
boceprevir, telaprevir, danoprevir, ledipasvir, elvitegravir
Antifungals:
Ketoconazole, Itraconazole, voriconazole, posaconazole, fluconazole
Antibiotics
troleandomycin, clarithromycin, telithromycin, ciprofloxacin, 
erythromycin
Antidepressant
nefazodone
Calcium channel blocker
Diltazem, verapamil, mibefradil
Antiemetics
Aprepitant, casopitant, netupitant
Diuretics
Conivaptan
Antineoplastic agents
Imatinib
Antiarrhythmics
dronedarone
Note:

This is a partial list only

Systemic drugs only. Topical preparations (vaginal preparations, creams, etc) are 
allowed. 


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Inducers of CYP3A4 are also disallowed during the study (Table 7).
Table 7:
A Partial List of CYP3A4 Inducers
Medication class
Drug name
Antibiotics 
rifampin, rifabutin, nafcillin
Anticonvulsants
phenytoin, carbamazepine, phenobarbital, oxcarbazepine
Antineoplastic agents 
mitotane
Anti-retroviral
efavirenz, talviraline, etravirine, lersivirine
Protease inhibitors
lopinavir, tipranavir, ritonavir
Antilipemics agents
avasimibe
Antiandrogens
enzalutamide
Endothelin Receptor 
Antagonists
bosentan
Antipsychotics
thioridazine
Psychostimulants
modafinil, armodafinil
Herbal Medications
St. John's wort


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APPENDIX D. LIST OF MEDICATIONS THAT SHOULD BE USED 
WITH CAUTION
Laquinimod 0.6 mg/day increases the systemic exposure of midazolam (a sensitive CYP3A4 
substrate) 1.5-fold. Therefore, plasma levels of drugs that are CYP3A4 substrates may increase 
when combined with laquinimod. Subjects taking drugs that are metabolized by CYP3A4 
(specifically those with a Narrow Therapeutic Index) (Table 8) should be advised that plasma 
levels of these drugs could increase when combined with laquinimod.
Table 8:
A Partial List of of CYP3A4 Substrates with a Narrow Therapeutic Index
alfentanil
cyclosporine
diergotamine
ergotamine
fentanyl
pimozide
quinidine
sirolimus
tacrolimus
Laquinimod 0.6 mg/day reduces the systemic exposure of caffeine (a sensitive CYP1A2 
substrate) 5-fold. Laquinimod doses higher than 0.6 mg/day may further increase CYP1A2 
induction and decrease exposure of CYP1A2 substrates. Plasma levels of drugs that are CYP1A2 
substrates may decrease when combined with laquinimod. Also, during a period of 30 days 
following the last laquinimod dose these CYP1A2 substrates are potentially less effective due to 
decreased plasma levels. Table 9 presents a partial list of drugs that are mainly metabolized by 
CYP1A2, ie, CYP1A2 plays a major role in their biotransformation. The systemic exposure of 
these drugs is expected to be significantly reduced by laquinimod coadministration. Drugs that 
are mainly metabolized by CYP1A2 and have a narrow therapeutic index are of special concern 
and appear in bolded text.
In general, as a precautionary measure, it is recommended to avoid the use of CYP1A2 
substrates in clinical trials of laquinimod. Therapeutic alternatives may be considered in the 
appropriate clinical context.


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Table 9:
A Partial List of Drugs that are Mainly Metabolized by 
Cytochrome P450 1A2
Medication class
Drug name
Antidepressant
Agomelatine, Duloxetine, Mirtazapine, Nortriptyline, Fluvoxamine
Antipsychotics
Chlorpromazine, Clozapine, Olanzapine, Thiothixene, 
Trifluoperazine
Migraine Treatments
Frovatriptan, Zolmitriptan
Anesthetics
Lidocaine (systemic use)
Antineoplastic agents
Erlotinib
Muscle relaxants
Cyclobenzaprine, Tizanidine
Sleep disorders
Melatonin, Ramelteon
Respiratory Agents
Aminophylline, Theophylline
Benzodiazepines
Chlordiazepoxide
Alpha adrenergic agonist
Guanabenz
Beta blockers
Propranolol
Parkinson's treatment
Rasagiline, Ropinirole
Alzheimer's Treatments
Tacrine
Diuretics
Triamterene
Miscellaneous agents
Alosetron (irritable bowel syndrome treatment), Riluzole 
(amyotrophic lateral sclerosis treatment), Methadone
Drugs with a narrow therapeutic index appear in bolded text


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APPENDIX E. GUIDANCE ON SAFETY MONITORING
1. Guidance on Monitoring Subjects with Elevated Liver Function Tests
Liver enzymes (ALT, AST, GGT, ALP), as well as total bilirubin1 will be measured at each 
study visit.
In any case of elevated ALT or AST to a level exceeding of ≥2xULN (including subjects whose 
Baseline ALT or AST levels are ≥2x and ≤3x the ULN, who may be enrolled in the study), a 
thorough medical history and physical examination with a focus on liver disease should be 
undertaken2. In addition, the subject should be instructed to refrain from alcoholic beverages. 
In case of symptoms compatible with drug-induced liver injury, the subject should be invited for 
an unscheduled visit to measure liver enzymes as soon as possible.
Solitary elevations of total bilirubin, not accompanied by elevations of ALT or AST should be 
managed according to the discretion of the Study Physician/Neurologist.
1.1 Elevation of Either ALT or AST to ≥3 x ULN:
Confirmation of the abnormality (in case the abnormality is of ALT or AST ≥ 8 times the ULN, 
no confirmation is required prior to study drug discontinuation, but the assessments below should 
be performed):

The day in which the abnormal value is received from the laboratory will be 
considered as Day 0.

The Investigator should repeat the test before Day 2, for confirmation purposes (this 
may be performed in a local laboratory along with CBC and differential to assess for 
eosinophilia. In general, in case a blood sample is sent to a local laboratory, the 
following assessments [and reference ranges] are mandatory: ALT [serum glutamic 
pyruvic transaminase; SGPT], AST [serum glutamic oxaloacetic transaminase; 
SGOT], ALP, total bilirubin, CBC [with differential for eosinophil count, separate 
tube], and INR [separate tube; not to be sent in a confirmatory test]). The investigator 
should also question the subject regarding symptoms.
The abnormality will be regarded as confirmed in each of the following scenarios:
1. In case Baseline value was within normal range and ALT or AST is still ≥3xULN
                                                
1 In case total bilirubin is >ULN, than direct bilirubin will be checked
2 Thorough medical history with a focus on liver disease: Personal or family history of liver disease; personal 
history of a systemic disease with potential liver involvement; exposure to alcohol, medications (prescription or 
OTC), herbal preparations, dietary supplements, recreational drugs, special diets or environmental chemical agents; 
potential exposure to infectious agents (eg, travel to developing countries, history of potential exposure to blood or 
blood products, high-risk sexual relations) and any additional information deemed relevant by the investigator.
Physical examination – including signs of chronic liver disease


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2. In case Baseline value was above ULN and ALT or AST is ≥2 times the Baseline value.
Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the eCRF.
Additional Tests/Evaluations

Serology for Hepatitis A, B, and C viruses (central laboratory). 

Serology for autoimmune hepatitis: anti-nuclear antibodies, ASMA (Anti Smooth 
Muscle Antibodies), anti-LKM (Liver Kidney Microsomal) antibodies (central 
laboratory).

An ultrasound examination of the liver and biliary tract.

Other diagnostic tests/consultations, as deemed necessary by the investigator e.g. 
serology for hepatitis E virus in case of travel to endemic geography) 
Observation and Follow-Up (to be performed after the abnormality was confirmed as above)
1.1.1 ALT or AST ≥3× and ≤5×ULN (if Baseline value is ≥2.5×ULN, ALT or AST 
≥3.5×ULN and ≤5×ULN)
In addition to the above procedures required for any elevation to levels >3xULN:

ALT, AST, GGT, ALP, total and direct bilirubin, CBC and differential (to assess for 
eosinophilia) and INR should be monitored on days 5 (±2), 8 (±2), 14 (±2), and 28 
(±2). On at least 1 of these days, the test should be performed centrally. (INR should 
be sent to a local laboratory only.)

In cases where a local laboratory is used, the results should be recorded in the eCRF, 
accompanied by the reference range of the relevant measurements.

Should the abnormality (≥3xULN in case Baseline within normal range or ≥2xULN 
in case the Baseline value was above ULN, but still <5xULN) persist further, the 
subject will be followed according to the investigator's discretion, but at least once a 
month a blood sample for ALT, AST, GGT, ALP, and total and direct bilirubin 
should be sent to the central laboratory.
1.1.2 ALT or AST ≥5x but less than 8xULN
In addition to the above procedures required for any elevation to levels >3xULN:

ALT, AST, GGT, ALP, total and direct bilirubin, CBC and differential count (to 
assess for eosinophilia), and INR should be monitored twice a week.


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
At least for every other measurement, the tests should be sent to the central 
laboratory. The rest of the tests may be sent to a local laboratory. INR should always 
be sent to a local laboratory.
1.1.3 ALT or AST ≥8xULN
In addition to the above procedures required for any elevation to levels >3xULN:

The study drug should be discontinued immediately and the early termination visit 
should be performed.

For follow-up guidance, please see below Section "Follow-up of Liver Enzymes after 
Stopping-Rules are met".
1.2 Stopping Rules:
In the following circumstances, the study drug will be discontinued immediately:

Any increase in ALT or AST to ≥3xULN, combined with INR >1.5 or total bilirubin 
>2xULN

Any increase in ALT or AST to ≥3xULN, which is accompanied by nausea, 
vomiting, fever, rash, or eosinophilia

Any increase in ALT or AST to levels ≥5x but <8xULN, which is persistent for 
≥2 weeks of repeated measurements

Any increase in ALT or AST to levels ≥8xULN

In any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
1.2.1 Follow-Up of Liver Enzymes After Stopping-Rules Are Met:

A subject who meets the above criteria for discontinuation of the study drug should 
be invited to the site to return the study drug. Early termination visit activities should 
be performed as soon as possible.

Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the investigator.

In any case, following early termination, the minimal follow-up period will be 
30 days and will include measurement of liver enzymes at least weekly (may be 
performed in a local laboratory, with at least 1 test being sent to the central 
laboratory).

Every effort should be made to complete the additional tests/ evaluations, as 
described above.


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2. Use of Moderate/Strong CYP3A4 Inhibitors
Laquinimod PK is affected by moderate and strong CYP3A4 inhibitors; therefore, 
moderate/strong CYP3A4 inhibitors are disallowed during study and 30 days after the last dose 
has been administered. A partial list of commonly used CYP3A4 inhibitors is presented in
Appendix C. 
3. Cancers diagnosed during the study
Subjects that are diagnosed with a malignant solid or liquid tumor while participating in the 
study should stop study drug.
4. Guidance on Monitoring Subjects with Elevated Pancreatic Amylase Levels
Pancreatic amylase will be measured at each study visit. Lipase will be tested in case of 
abnormal pancreatic amylase results and on all follow-up visits until normalization of pancreatic 
amylase level. In case of suspected pancreatitis, the subject should undergo a thorough clinical 
evaluation including an abdominal CT scan as soon as possible in order to clarify the diagnosis 
and enable assessment of severity of this condition. An MRI may be performed as an alternative 
to the CT scan.
5. Liver Impairment
Subjects who develop any chronic liver disease associated with liver functional impairment 
while participating in the study should stop study medication.
6. Renal Impairment
Subjects who develop renal disease associated with moderate or severe functional impairment, 
defined as glomerular filtration rate (GFR) ≤60 mL/min/1.73 m2, while participating in the study 
should stop study medication temporarily and the GFR assessment should be repeated. If the 
renal impairment is confirmed (GFR ≤60 mL/min/1.73 m2), the subject should stop study 
medication permanently.
7. Management of Pregnancy and Pregnancy Testing During the Study
Exposure to laquinimod during pregnancy should be avoided.
To further emphasize the importance of use of effective contraception and avoidance of 
pregnancy under laquinimod exposure (see Section 3.4), and to reduce as much as possible the 
exposure to laquinimod if a pregnancy occurs despite all recommended measures, all subjects 
who are women of childbearing potential will be instructed about the teratogenicity and potential 
delayed risks for a child exposed in uterus to laquinimod. These subjects will also be counseled 
about the importance of using two acceptable methods of birth control throughout the entire 
treatment duration and until 30 days after the last dose of treatment was administered and about 
the need to stop treatment immediately if pregnancy is suspected. 


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Women of child-bearing potential (for example women who are not postmenopausal or 
surgically sterilized) must practice an acceptable method of birth control for 30 days before 
taking the study drug and two acceptable methods of birth control for the duration of the study 
and until 30 days after the last dose of study medication. Acceptable methods of birth control 
include: intrauterine devices, barrier method (condom or diaphragm with spermicide) and 
hormonal methods of birth control (e.g. oral contraceptive, contraceptive patch, long-acting 
injectable contraceptive).
The subjects' understanding of the importance of preventive pregnancy measures and their ability 
to follow the required instructions will be ascertained by the investigator and recorded in source 
documents at every visit. Any female subject who becomes pregnant during the study will 
discontinue her participation in the study and will not perform the activities described for 
scheduled follow-up visits.
At each scheduled visit, the subject will undergo a urine β-hCG test. In addition, a serum 
pregnancy β-hCG test will be performed at each visit to the site. Subjects who have discontinued 
study drug but are continuing to attend study visits for follow-up do not need to perform 
pregnancy tests.
1. In case the urine test is negative, study drugs will be dispensed according to planned visit 
tasks (see Table 5).
a.
If the blood test is positive, the subject will be contacted immediately and instructed 
to stop taking the study drug. The subject should be invited to attend an early 
termination visit.
b. If the blood test is negative – study procedures will be undertaken as planned.
2. In case the urine test is positive – the study drug will not be dispensed (if this occurs at 
Baseline visit, the subject will not be eligible to participate in the study and will be 
considered as a screening failure)
a.
If the blood test is positive, the subject will be invited to the site for an early 
termination visit 
b. If the blood test is negative, the subject will be contacted and informed about the test 
result and the study drugs will be sent to her by courier as soon as possible.
3. Starting from visit 3 (Month 3), the following actions will be taken:
a.
The subject will be provided with home pregnancy urine β-hCG test kits and will be 
guided how to perform the test. 
b. The subject will be instructed to perform the test in monthly intervals (every 28 (±2) 
days) from the visit date. These dates should be recorded by the study coordinator and
a telephone call, will be scheduled to be performed within 72 hours of the urine test 
date. 


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c.
A mandatory phone call will be performed by the Study Neurologist/ Physician or by 
the site’s nurse/ study coordinator every month in order to verify whether the test has 
been performed and to record the result of the test in the subject’s file. In case of a 
suspected pregnancy, the subject will be instructed to stop taking the study drug and 
arrive to the site as soon as possible for an unscheduled visit, with the remaining 
study medications. In the site, a quantitative urine β-hCG pregnancy test should be 
performed and the rest of the activities will be as in 2.
In case of an established diagnosis of pregnancy, the Study Physician/Neurologist should discuss 
with the subject the potential teratogenicity and delayed risks for a child exposed in utero to 
laquinimod. The possibility of termination of the pregnancy should be discussed. In case the 
subject decides to continue the pregnancy, she will be followed to determine outcome, including 
spontaneous or elective termination, details of birth, and presence or absence of any birth defect, 
congenital abnormalities or maternal and newborn complications.
Female subjects of child-bearing potential who might want to get pregnant in the future, and 
might be interested in continuing taking laquinimod after giving birth and have stopped 
breastfeeding may be able to re-enroll in the study after meeting inclusion/exclusion criteria 
below. Re-enrollment will be permitted on a case-by-case basis. Notwithstanding, Teva is under 
no obligation to re-enroll such subjects and reserves the right to re-enroll or reject enrolment of 
such returning subjects for no reason and on its sole discretion. A new informed consent form 
should be signed before re-enrollment.
Inclusion criteria for returning subjects
Subjects must meet all inclusion criteria in order to be eligible for the study:
1. Subjects must have completed the Termination visit of MS-LAQ-302E
(completion of all Termination visit activities) according to the MS-LAQ-302E 
protocol. 
2. Subjects must be ambulatory with Kurtzke’s EDSS score of 0-5.5 in 
re-enrollment visits. 
3. Subjects must be in a stable neurological condition, relapse-free and free of any 
corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os 
(PO)] or adrenocorticotrophic hormone (ACTH), 60 days prior to re-
enrollment.
4. Women of child-bearing potential (for example women who are not 
postmenopausal or surgically sterilized) must practice an acceptable method of 
birth control for 30 days before taking the study drug and two acceptable 
methods of birth control for the duration of the study and until 30 days after the 
last dose of study medication. Acceptable methods of birth control include: 
intrauterine devices, barrier method (condom or diaphragm with spermicide) 
and hormonal methods of birth control (e.g. oral contraceptive, contraceptive 
patch, long-acting injectable contraceptive). 
5. Subjects must be willing and able to comply with the protocol requirements for 
the duration of the study. 


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6. Subjects must be able to comprehend, sign and date a written informed consent 
prior to re-enrolling into the MS-LAQ-302E study.
Exclusion criteria for returning subjects
Any of the following conditions will exclude the subject from re-enrolling into the study:
1. Premature discontinuation from the MS-LAQ-302 study, for any reason except 
for planned pregnancy. 
2. Subjects with progressive forms of MS or other nonRRMS variant of 
neuroinflammatory or demyelinating diseases.
3. Use of experimental or investigational drugs and/or participation in drug 
clinical studies within 6 months prior to re-enrollment visit.
4. Use of immunosuppressive agents, or cytotoxic agents, including 
cyclophosphamide and azatioprine within 12 months prior to re-enrollment 
visit.
5. Use of either of the following within 2 years prior to re-enrollment: 
natalizumab (Tysabri®), rituximab, ocrelizumab, atacicept, belimumab, or 
ofatumumab. 
6. Previous treatment with glatiramer acetate (Copaxone®), Interferon-β (either 1a 
or 1b), fingolimod (Gilenya®), dimethyl fumarate (Tecfidera) or IV 
immunoglobulin (IVIG) within 2 months prior to re-enrollment visit.
7. Use of teriflunomde (Aubagio®) within- 2 years prior to re-enrollment, except 
if active washout (with either cholestyramine or activated charcoal) was done 2 
months or more prior to randomization.
8. Use of mitoxantrone (Novantrone) within 5 years prior to re-enrollment in 
patients with normal ejection fraction and who did not exceed the total lifetime 
maximal dose.
9. Previous use of cladribine and alemtuzumab (Lemtrada).
10. Previous total body irradiation or total lymphoid irradiation.
11. Previous stem cell treatment, autologous bone marrow transplantation, or 
allogenic bone marrow transplantation. 
12. Acute infection within 2 weeks prior to re-enrollment visit.
13. Major trauma or surgery within 2 weeks prior to re-enrollment visit.
14. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to re-
enrollment visit.
15. Use of inducers of CYP3A4 within 2 weeks prior to re-enrollment visit.
16. Pregnancy [according to serum β-hCG performed within 7 days prior to re-
initiation of treatment] or breastfeeding. 
17. Serum levels ≥3xULN of either ALT or AST at re-enrollment visit.
18. Serum direct bilirubin which is ≥2xULN at re-enrollment visit. 


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19. Subjects with clinically significant or unstable medical or surgical condition 
detected or worsened during the MS-LAQ-302E or MS-LAQ-302E study, 
which preclude safe participation and completion of the MS-LAQ-302E study. 
20. Any malignancies, excluding basal cell carcinoma, in the 5 years prior to 
re-enrollment.
21. Subjects who underwent endovascular treatment for Chronic Cerebrospinal 
Venous Insufficiency (CCSVI) within 3 months prior to re-enrollment.


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Table 10:
Study Task Flow Chart for Returning Subjects after Planned Pregnancy
Visit
V0E1
V1E1
V2E1
V3E1
V41
Every 6 
months
Every 12 
months
Every 24 
months
Termination /
Early 
Discontinuation
Unscheduled 
Visita, b
Month
0E1
1E1
2E1
3E1
6E1
Informed Consent for returning subjects
X
Eligibility Criteria for returning subjects
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Cardiovascular risk factor assessment and 
managementc
X
X
Physical Examination
X
X
X
X
X
X
Vital Signs
Xd
X
X
X
X
Xe
Xe
Xe
Xe
X
ECG
X
X
X
X
X
X
X
Safety Laboratory Evaluation (CBC,
Chemistry, markers of inflammation, GFR 
estimation)
X
X
X
X
X
X
X
X
X
X
Ascertaining use of effective contraception
X
X
X
X
X
X
X
X
X
X
Serum hCGf
X
X
X
X
X
X
X
X
X
X
Urine βhCGf(on site)
X
X
X
X
X
X
X
X
X
X
Discuss the importance of Contraceptionf
X
X
X
X
X
X
X
X
X
X
Urine hCGf(self check, at home)
EVERY 1 MONTH BETWEEN 
SCHEDULED VISITS
Adverse Events
X
X
X
X
X
X
X
X
X
X
Neurological examination (EDSS/FS/AI/ 25 
foot walk)
X
X
X
X
X
X
X
Evaluation of Relapseg
X
X
X
X
X
X
X
X
X
X
MSFCh
X
X
X
X
X
X


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Visit
V0E1
V1E1
V2E1
V3E1
V41
Every 6 
months
Every 12 
months
Every 24 
months
Termination /
Early 
Discontinuation
Unscheduled 
Visita, b
Month
0E1
1E1
2E1
3E1
6E1
Binocular Low-Contrast Visual Acuity
X
X
X
X
X
X
MFIS
X
X
X
X
X
X
Mandatory phone calls (pregnancy tests)i
EVERY 1 MONTH BETWEEN
SCHEDULED VISITS
Mandatory phone calls (general well-being, 
all subjects)j
EVERY 3 MONTHS 
BETWEEN SCHEDULED VISITS
Drug Compliance & Dispensing
X
X
X
X
X
X
X
X
Xk
X
Termination Documentation and 
Notification of Early Termination
X
Unscheduled samples
Xl
Subjects who are discontinued from study treatment will be encouraged to continue all scheduled visits and procedures until completion of the study (with the 
exception of procedures associated with drug dispensing and accountability, pregnancy testing, and GFR estimation [including body weight measurement]).
a Vital signs and AEs are mandatory activities in an unscheduled visit. All other activities are optional and may be performed as deemed necessary by the 
investigator. Chest X-ray may also be performed in this visit.
b Post treatment follow up visit in cases of early discontinuation (In which vital signs, review of AEs and concomitant medications, as well as pregnancy test are 
mandatory. All other marked activities are optional).
c In addition, an evaluation should take place as soon as possible for subjects already in the study, following approval of Amendment #2.
d Post-dose vital signs will be measured at Baseline and after 30 and 60 minutes.
e Weight will be measured at all visits until Termination/Early discontinuation.
f For women of childbearing potential. Serum pregnancy test (beta human chorionic gonadotropin [β-hCG]) for women of child-bearing potential within the 7 
days prior to re-initiation of treatment
g Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator
h Within the MSFC evaluation, the PASAT and 9-HOLE Peg tests will be performed at months 0E1, 6E1, and every 6 months, while the Timed 25-foot walk test 
will be performed each time a neurological evaluation is performed
i For women of child-bearing potential; to be performed within 72 hours of the scheduled home pregnancy test
j The call will be documented in the source documents. For women of child-bearing potential, there is no need to perform a separate call, as this question will be 
a part of the monthly pregnancy urine test call.
k Only drug retrieval
l Unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or samples for potential biomarker analyses may be collected at the 
discretion of the investigator or medical monitor at any time to assist with further investigations of cardiovascular events or other clinical event of interest. The 
samples should be collected as soon as possible in association with the event.


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AE = Adverse Event, AI = Ambulation Index, β-hCG = beta-human Chorionic Gonadotropin, CBC = Complete Blood Count, ECG = Electrocardiogram, EDSS 
= Kurtzkle’s Expanded Disability Status Scale, FS = Functional System, GFR = glomerular filtration rate, MFIS = Modified Fatigue Impact Scale, MSFC = 
Multiple Sclerosis Functional Composite


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APPENDIX F.
MODIFIED FATIGUE IMPACT SCALE (MFIS)
INSTRUCTIONS
Following is a list of statements that describe how fatigue may affect a person. Fatigue is a 
feeling of physical tiredness and lack of energy that many people experience from time to time. 
In medical conditions like MS, feelings of fatigue can occur more often and have a greater 
impact than usual. Please read each statement carefully, and then circle the one number (0, 1, 
2,…) that best indicates how often fatigue has affected you in this way during the past 4 weeks. 
Please answer every question. If you are not sure which answer to select, please choose the one 
answer that comes closest to describing you. 
Because of my fatigue
during the past 4 weeks…
Almost
Never
Rarely  Sometimes 
Often  Always
1. I have been less alert.
0
1
2
3
4
2. I have had difficulty 
paying attention for 
long periods of time.
0
1
2
3
4
3. I have been unable to 
think clearly 
0
1
2
3
4
4. I have been clumsy 
and uncoordinated 
0
1
2
3
4
5. I have been forgetful 
0
1
2
3
4
6. I have had to pace myself 
in my physical activities 
0
1
2
3
4


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Because of my fatigue
during the past 4 weeks…
Almost
Never Rarely  Sometimes 
Often  Always
7. I have been less motivated
to do anything that requires
physical effort
0
1
2
3
4
8. I have been less motivated
to participate in social 
activities.
0
1
2
3
4
9. I have been limited in my 
ability to do things away
from home. 
0
1
2
3
4
10. I have had trouble 
maintaining physical effort
for long periods. 
0
1
2
3
4
11. I have had difficulty 
making decisions
0
1
2
3
4
12. I have been less motivated
to do anything that requires
thinking
0
1
2
3
4
13. my muscles have felt weak 
0
1
2
3
4
14. I have been physically 
uncomfortable 
0
1
2
3
4
15. I have had trouble finishing
tasks that require thinking
0
1
2
3
4


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Because of my fatigue
during the past 4 weeks…
Almost
Never Rarely  Sometimes 
Often  Always
16. I have had difficulty 
organizing my thoughts
when doing things at home
or at work
0
1
2
3
4
17. I have been less able to 
complete tasks that require
physical effort. 
0
1
2
3
4
18. My thinking has been 
slowed down
0
1
2
3
4
19. I have had trouble
concentrating
0
1
2
3
4
20. I have limited my
physical activities. 
0
1
2
3
4
21. I have needed to rest more
often or for longer periods. 
0
1
2
3
4


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APPENDIX G. MSFC ADMINISTRATION INSTRUCTIONS
Multiple Sclerosis Functional Composite (MSFC)
The MS Functional Composite is an instrument assessing disability. It was developed by a 
special task force on clinical outcome assessments. It was the consensus of the task force that 
important clinical dimensions, not emphasized in existing rating scales, should be measured.
General Instructions
The MSFC should be administered as close to the beginning of a study visit as possible. The 
components of the MSFC should be administered in the following order:
Trial 1, Timed 25-Foot Walk
Trial 2, Timed 25-Foot Walk
Trial 1, Dominant Hand, 9-HPT
Trial 2, Dominant Hand, 9-HPT
Trial 1, Non-Dominant Hand, 9-HPT
Trial 2, Non-Dominant Hand, 9-HPT
PASAT-3"
Instructions for the Timed 25-Foot Walk
Description
The Timed 25-Foot Walk is a quantitative measure of lower extremity function. It is the first 
component of the MSFC administered at each visit. The subject is directed to one end of a 
clearly marked 25-Foot course and is instructed to walk 25 feet as quickly as possible, but safely. 
The task is immediately administered again by having the subject walk back the same distance. 
Subjects may use assistive devices when doing this task.
Materials Needed
Stopwatch, clipboard, Timed 25-Foot Walk Record Form, marked 25-Foot distance in an 
unobstructed hallway, assistive device (if needed)
Time Limit Per Trial
3 minutes (180 seconds) per trial.
Discontinue Rules


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If the subject cannot complete Trial 2 of the Timed Walk after a 5-minute rest period.
If the subject cannot complete a trial in 3 minutes.
Administration
Trial 1
Make sure that the stopwatch is set to 0:00. For the Timed 25-Foot Walk, the subject should be 
directed to one end of a clearly marked 25-Foot course (clearly defined on the floor or on the 
wall) and instructed to stand just behind the starting line. Point out where the 25-Foot course 
ends, then instruct the subject as follows: "I'd like you to walk 25 feet as quickly as possible, but 
safely. Do not slow down until after you've passed the finish line. Ready? Go."
Begin timing when the lead foot is lifted and crosses the starting line. The examiner should walk 
along with the subject as s/he completes the task. Stop timing when the lead foot crosses the 
finish line. The examiner should then record the subject's walk time to within 0.1 second, 
rounding as needed. Round up to the next tenth if hundredth's place is > (greater than or equal to) 
.05, round down if hundredth's place is <.05 (e.g., 32.45" would round to 32.5" but 32.44" would 
round to 32.4"). Once the time is recorded, be sure to reset the stopwatch.
Trial 2
After completing the first timed walk, position the subject just behind the line where s/he is not 
standing, repeat the same instructions, and have the subject complete the walk again.
Assistive Devices
The goal is to have the subject use the same assistive device at each study visit. The Study
Physician/Neurologist will select an assistive device at the beginning of the study for each 
subject that needs one, keeping in mind that the subject may deteriorate modestly during the trial.
In general, subjects should use their customary assistive device(s), NOT the least assistance 
possible to complete the test. For subjects with significant gait impairment, the Study
Neurologist/Physician should have the subject use a rolling walker even if this is not the subject's 
customary device. In general, non-wheeled walkers should not be used. If a subject does use an 
assistive device, this should be noted on the Record Form.
Completing the Record Form
Record any circumstances that you believe may have affected the subject's performance. These 
are factors that may have affected the trial but were not severe enough to necessitate repetition of 
the trial. Examples include, but are not limited to, the following:
The subject had a cold or reports not feeling well.
The subject tripped but did not fall.


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If a situation arises that necessitates the repetition of a trial, indicate the reason a trial had to be 
repeated on the Record Form. Examples of reasons to repeat a trial include, but are not limited 
to, the following:
The subject fell during the walk.
Examiner forgot to start or stop stopwatch.
Examiner forgot to reset stopwatch in between trials.
The subject stopped to talk to someone while walking, or another person/thing 
somehow interfered with walk.
Record only the times for the two successfully completed trials of the Timed 25-Foot Walk. If 
the subject could not complete one or both of the trials of the Timed 25-Foot Walk, record this in 
the appropriate Section of the Record Form. For example, if the subject's disease has progressed 
and/or physical limitations prohibit him or her from completing the trial, you should indicate 
"Unable to complete trial due to physical limitations" and record any specifics that you can 
observe (i.e., subject in a wheelchair now and unable to walk, etc.). If the subject did not 
complete a trial for any other reason, specify this as well (e.g., subject fell and was too fatigued 
to complete another trial, subject refused to complete trial).
Instructions for the 9-Hole Peg Test
Description
The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. The 9-HPT is 
the second component of the MSFC to be administered. Both the dominant and non-dominant 
hands are tested twice (two consecutive trials of the dominant hand, followed immediately by 
two consecutive trials of the non-dominant hand). It is important that the 9-HPT is administered 
on a solid table (not a rolling hospital bedside table) and that the 9-HPT apparatus be anchored.
Materials Needed
9-HPT Apparatus, Anchor, stopwatch, clipboard, 9-HPT Record Form
Time Limit per Trial
5 minutes (300 seconds) per trial
Discontinue Rules
If the subject cannot complete one trial of the 9-HPT in 5 minutes.
If the subject cannot complete a trial with his or her dominant hand within 5 minutes, move on to 
the trials with the non-dominant hand.
If the subject cannot complete a trial with his or her non-dominant hand, move on to the PASAT.


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Administration
Dominant Hand---Trial 1
Make sure that the stopwatch is set to "0:00." Introduce this Section by saying, "Now, we're 
going to be measuring your arm and hand function." If this is the first visit, determine the 
dominant hand, ask, "Are you right or left-handed?" If the subject is not sure, then the dominant 
hand is determined by asking the subject which hand he/she did or does write with. Make a note 
of the dominant hand for subsequent instructions. Place the 9-HPT apparatus on the table, 
directly in front of the subject. Arrange the apparatus so that the side with the pegs is in front of 
the hand being tested and the side with the empty pegboard is in front of the hand not being 
tested. Secure with anchor.
Read the following instructions to the subject: "On this test, I want you to pick up the pegs one 
at a time, using one hand only, and put them into the holes as quickly as you can in any order 
until all the holes are filled. Then, without pausing, remove the pegs one at a time and return 
them to the container as quickly as you can. We'll have you do this two (2) times with each 
hand. We'll start with your [DOMINANT] hand. You can hold the pegboard steady with your 
[NON-DOMINANT] hand. If a peg falls onto the table, please retrieve it and continue with the 
task. If a peg falls on the floor, keep working on the task and I will retrieve it for you. See how 
fast you can put all of the pegs in and take them out again. Are you ready? Begin."
Start timing as soon as the subject touches the first peg, and stop timing when the last peg hits 
the container. If a peg drops on the floor, the examiner may retrieve it and put it back in the peg 
box. However, if a peg drops onto the table, allow the subject to retrieve it.
Record the subject's time under "Dominant hand ---Trial 1." If the subject stops after having put 
all the pegs into the holes, prompt the subject to remove them as well by saying, "And now 
remove them all." If the subject begins to remove more than one peg at a time, correct him/her 
by saying, "Pick up one peg at a time."
Dominant Hand ---Trial 2
After the first trial with the dominant hand, say, "Good. Now, I'd like you to do the same thing 
again, once again using your [DOMINANT] hand. See how fast you can put all of the pegs in 
and take them out again. Ready? Begin." Again, start timing as soon as the subject touches the 
first peg, and stop timing when the last peg hits the container. Record the subject's time under 
"Dominant hand---Trial 2."
Non-Dominant Hand ---Trials 1 and 2
After the second trial with the dominant hand, rotate the apparatus 180 degrees such that the side 
with the pegs is now in front of the non-dominant hand and the empty pegboard is in front of the 
dominant hand. Then say, " OK. Now, I'd like you to switch and use your [NON-DOMINANT] 
hand. This time, you can use your [DOMINANT] hand to stabilize the pegboard. Ready? Begin." 
Administer, time and record the two non-dominant hand trials following the procedures 
described above for dominant hand trials.


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Completing the Record Form
Record any circumstances that you believe may have affected the subject's performance. These 
are factors that may have affected the trial but were not severe enough to necessitate repetition of 
the trial. Examples include, but are not limited to, the following:
The subject dropped a peg.
The subject has a cold.
The subject forgot eyeglasses and had difficulty seeing pegs.
The subject talked during the task.
The subject knocked entire apparatus on the floor
If a trial is repeated, indicate this and specify the reason it had to be repeated. Examples of 
reasons to repeat a trial include the following:
The subject knocked entire apparatus on the floor.
The examiner forgot to start or stop stopwatch.
The examiner forgot to reset the stopwatch in between trials.
Record only the times for the two successfully completed trials for each hand on the 9-HPT. If 
the subject could not complete one or both of the trials for either hand of the 9-HPT, record this 
in the appropriate Section of the Record Form. If the subject's disease has progressed and/or 
physical limitations prohibit him or her from completing the trial, the examiner should mark, 
"Unable to complete trial due to physical limitations." and then record any specifics that can be 
observed (e.g., subject unable to use right hand, subject could not complete within time limit, 
etc.). If the subject did not complete a trial for any other reason, describe the specific 
circumstances (e.g., subject refused).
Instructions for the Paced Auditory Serial Addition Test (PASAT)
Description
The PASAT is a measure of cognitive function that specifically assesses auditory information 
processing speed and flexibility, as well as calculation ability. The PASAT is the last measure 
administered at each visit. It is presented on CD player to control the rate of stimulus 
presentation. Single digits are presented every 3" and the subject must add each new digit to the 
one immediately prior to it. The test result is the number of correct sums given (out of 60 
possible). To minimize familiarity with stimulus items, two alternate forms have been developed; 
the order of these should be counterbalanced across testing sessions.
Materials Needed
CD player, CD with PASAT stimuli, clipboard, PASAT Record Forms
Discontinue Rules
If the subject cannot get at least two answers correct (consecutive or not) on any one of the three 
3" practice sequences.


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If the subject cannot get at least one answer correct on PASAT-3" test, this subject is considered 
unable to perform the test.
Administration
Verify that you have the correct Record Form and CD player (Form A or B) before you start 
reading the instructions for the 3" Practice Trial to the subject.
PASAT-3 Practice Trial
For Part 1 (stimuli every 3") say, "On this CD you are going to hear a series of single digit 
numbers that will be presented at the rate of one every 3 seconds. Listen for the first two 
numbers, add them up, and tell me your answer. When you hear the next number, add it to the 
one you heard on the tape right before it. Continue to add the next number to each preceding 
one. Remember, you are not being asked to give me a running total, but rather the sum of the last 
two numbers that were spoken on the tape."
Then give the following example: "For example, if the first two numbers were '5' and '7,' you 
would say '12.' If the next number were '3,' you would say '10.' Then if the next number were '2,' 
you would say '5.' If the subject is having difficulty understanding these instructions, write 5, 7, 3 
and 2 on a sheet of paper and repeat the instructions demonstrating how the task is done.
Then say, "This is a challenging task. If you lose your place, just jump right back in---listen for 
two numbers in a row and add them up and keep going. There are some practice items at the 
beginning of the tape. Let's try those first." Play the sample items, stopping the CD after the last 
practice item. Repeat the practice items, if necessary, until the subject understands the 
instructions (up to three times). You should always administer at least one practice trial before 
administering the actual test. If the subject begins to give you a running total, stop the practice 
immediately and explain the task again, emphasizing that he/she is not to give you a running 
total. Then start the practice items again from the beginning. If the subject begins adding each 
number to the number two previous to it, again stop the practice immediately, explain the correct 
way to do the task, and start the practice items from the beginning. If the subject merely makes a 
math error, do not stop the tape; continue with the practice items. After two consecutive 'no 
responses,' prompt him/her to resume by saying, "Jump back in with the next two numbers you 
hear."
Administer the practice sequence a maximum of three times. Record answers in the space 
provided on the back of the PASAT Record Form.


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PASAT-3
Once it is clear that the subject possesses sufficient understanding of the task, begin Part 1. 
Before starting Part 1, remind him/her: "Remember if you get lost, just jump back in because I 
can't stop the test once it has begun." Discourage talking and oral calculations during the test, 
only the subject's answers should be spoken out loud. The subject may need prompting to 
continue the test if she/he gets lost. After five consecutive 'no responses,' redirect the subject 
quickly by saying, "Jump back in," but do not stop the tape.
Completing the PASAT Record Form
Circle all correct answers. Write in any incorrect responses in the space provided. Place a dash 
when no response was given. If the subject corrects him/herself after giving a response, count the 
amended answer as the response. The amended response is the one that will be used in 
determining total correct, regardless of whether it was the correct or incorrect response. Slash 
through the old response and write in "SC" with a circle around it to indicate that the subject 
self-corrected.
Each Section of the PASAT has a maximum of 60 correct answers (i.e., 61 digits are presented 
for each part). Count the total number correct (number of circled answers) for PASAT-3 and 
record on both the PASAT Record Form and the Summary Score Sheet.
Finally record any circumstances that you believe may have affected the subject's performance. 
These are factors that may have affected the trial, but were not severe enough to necessitate 
repetition of the trial. Examples include, but are not limited to, the following:

Subtle noises outside of the testing room

Subject reports frustration or mild distress

Subject talked during test (other than to give answers)
If a trial must be repeated, indicate this and specify the reason why it had to be repeated. 
Examples of reasons to repeat a trial include, but are not limited to, the following:

Test interrupted (e.g. someone walked into the room or other major disturbance)

Examiner error, such as starting the tape in the wrong place or using the wrong form.
Record only totals for the successfully completed PASAT-3.
If the subject is unable to perform the PASAT (i.e., cannot get at least two correct on any 3" 
practice and at least one correct on the test portion), the examiner should indicate "Unable to 
complete due to cognitive limitations" and record any specific observations. If the subject did not 
complete a trial for any other reason, record the reasons for this as well (e.g., subject refused to 
complete test, etc.).


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Scores from the MSFC component test results will be computed by the Data Management 
Center. Instructions will be included in the analytical plan.


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APPENDIX H. LOW-CONTRAST SLOAN LETTER CHART TESTING 
FOR PATIENTS WITH MULTIPLE SCLEROSIS 
Low-Contrast Sloan Letter Chart Testing
For Patients with Multiple Sclerosis:
Testing Protocol Manual
(BINOCULAR TESTING)
Laura J. Balcer, M.D., M.S.C.E.
University of Pennsylvania
The following are instructions for testing patients using the front illuminated Low-Contrast 
Sloan Letter Charts (LCSLC - Precision Vision, LaSalle, IL). The inter-rater reliability of this 
testing protocol has been shown to be extremely high in patients with multiple sclerosis and in 
visually-asymptomatic volunteers. A standardized script with instructions to be read to the 
patient by the examiner is included below. The examiner should read through the following 
instructions and practice testing prior to examining study patients.
Preparation and Set-Up:
a)
Set room lighting level to 80-100 cd/m2 (equivalent is about 80-100 foot-
candles). This level illumination may be achieved in a bright exam room/hallway 
with fluorescent lighting. Having exact lighting is less important than using the 
same room/area for each patient/testing session. 
b)
Place the charts at 2 meters distance from the patient’s eyes. An 
artist’s easel or similar device may be used, as may a ledge, stand, 
or chair to prop the charts perpendicular to the floor. Use a pre-
measured string or tape to measure the distance from the patient’s 
eyes (bridge of nose) to the testing charts at the beginning of each 
testing session (each patient). 
c)
The 100%, 2.5%, and 1.25% charts will be used for testing.
d)
Patients should wear their usual distance correction for testing (glasses or contact 
lenses that are used for driving, etc.). The same glasses or contact lenses (same 
prescription) should be used for each testing session throughout the study. 
e)
Patients should be asked to read the charts with both eyes open. 
Vision Testing:
Instruct patient to read slowly, letters only, left to right, starting at the top of the chart. 


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Instruct the patient that they are not allowed to re-read any line.
The patient is allowed to correct a “mis-speak” of a single letter only if he/she does so before
reading the next letter---instruct the patient of this.
During the chart reading, PUSH (encourage) the patient until he/she cannot read any letters after 
being told to guess.
The patient must guess at each letter, even if he/she cannot easily read it, until he/she cannot or 
does not correctly identify any of the 5 letters on a particular line. 
Stopping Rule: Once the patient cannot or does not correctly identify any of the 5 letters on a line 
after attempting it, STOP. Go on to the next chart.
Test all 3 charts in the same order (100%, 2.5%, 1.25%) for each patient.
During testing, circle all letters read correctly on the data forms for each chart (with both eyes). 
Put an “X” through each incorrectly identified letter; leave unattempted letters unmarked. 
Fill in the number of letters correct at the end of each line of 5 letters. Record the total number of 
letters correct for each chart at the bottom of the column. The Snellen visual acuity equivalent 
(i.e., 20/20 or 6/6) for the patient corresponds to the lowest line on the 100% chart (black on 
white) for which the patient identifies 3 or more letters correctly.
If a patient is unable to identify any of the letters correctly on the first line of any of the 3 charts, 
please indicate this at the top of the data collection form.


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Script for Testing to be Read to Patient:
These instructions should be read to the patient once he/she is comfortably seated in front of the 
charts at 2 meters distance (see above for instructions on Preparation and Set-Up):
1. I am going to show you 3 different eye charts with letters on them. 
The letters will become increasingly lighter for each chart. 
2. For each chart, please begin at the very top of the chart and read each 
letter slowly, from left to right on each line.
3. If you miss-speak on a letter or feel you have identified it incorrectly, 
you may correct your response only before you read the next letter.
4. You are not allowed to re-read an entire line.
5. Please try not to lean forward in the chair while reading the letters.
After the first chart (100% chart) has been uncovered, say:
6. You may begin reading the letters. 
7. Please start at the top of the chart.
For each chart, allow the patient to continue reading letters until he/she either:
1) Does not identify any of the 5 letters on any given line correctly say: 
You may stop. We will go on to the next chart now.
OR
2) States that they are unable to read any more letters point to the line which is next for the 
patient to attempt (use the yellow-tipped pointer only) and say:
Can you read any of the letters on this line? 
a) 
If patient responds no say: Please guess if you can.
If patient responds that they cannot say: 
You may stop. We will go on to the next chart now.
b) If patient responds yes or begins reading, then continue to record responses until the patient 
cannot or does not correctly identify any of the 5 letters on a given line. 
Stopping Rule: For each chart, once the patient cannot or does not identify any of the 5 letters 
correctly on a given line, say: You may stop. We will go on to the next chart now.


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Please use the yellow-tipped pointer only to point to the charts (pens and fingers may leave 
marks). The examiner may point to the chart when requested by the patient to indicate the line 
that they are attempting/should attempt next.
Repeat the above procedure for each of the 3 charts (100%, 2.5%, and 1.25% in that order) with 
both eyes open.


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APPENDIX I.
LOW-CONTRAST TUMBLING-E CHART TESTING FOR 
PATIENTS WITH MULTIPLE SCLEROSIS 


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APPENDIX J.
WORK PRODUCTIVITY AND ACTIVITIES 
IMPAIRMENT – GENERAL HEALTH V2.0 (WPAI-GH) 
QUESTIONNAIRE
The following questions ask about the effect of your health problems on your ability to work and 
perform regular activities. By health problems we mean any physical or emotional problem or 
symptom. Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? 
____ NO
____ YES
If NO, check “NO” and skip to question 6.
The next questions are about the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of your 
health problems? Include hours you missed on sick days, times you went in late, left early, 
etc., because of your health problems. Do not include time you missed to participate in 
this study.
_____HOURS
3.
During the past seven days, how many hours did you miss from work because of any 
other reason, such as vacation, holidays, time off to participate in this study?
_____HOURS
4.
During the past seven days, how many hours did you actually work?
_____HOURS (If “0”, skip to question 6.)


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5.
During the past seven days, how much did your health problems affect your productivity 
while you were working? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual. If health problems affected your work only a little, choose a low number. 
Choose a high number if health problems affected your work a great deal. 
Consider only how much health problems affected 
productivity while you were working.
Health problems 
had no effect on 
my work
Health problems 
completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6.
During the past seven days, how much did your health problems affect your ability to do 
your regular daily activities, other than work at a job? 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were limited 
in the amount or kind of activities you could do and times you accomplished less than you 
would like. If health problems affected your activities only a little, choose a low number. 
Choose a high number if health problems affected your activities a great deal. 
Consider only how much health problems affected your ability 
to do your regular daily activities, other than work at a job.
Health problems 
had no effect on 
my daily activities
Health problems 
completely 
prevented me from 
doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER


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APPENDIX K. THE SF-36V2™ HEALTH SURVEY
The SF-36® Health Survey asks for your views about your health in general. This information 
will help keep track of how you feel and how well you are able to do your usual activities.
Please answer every question. Some questions may look like others, but each one is different. 
Please take the time to read and answer each question carefully, and circle the one number that 
best describes your answer to each question. Thank you for completing this survey!
1. In general, would you say your health is:
(circle one)
Excellent......................................................................
1
Very Good...................................................................
2
Good ...........................................................................
3
Fair ..............................................................................
4
Poor .............................................................................
5
1. Compared to one year ago, how would you rate your health in general now?
  (circle one)
Much better now than one year ago…………………..
1
Somewhat better now than one year ago.....................
2
About the same as one year ago..................................
3
Somewhat worse now than one year ago ....................
4
Much worse now than one year ago............................
5


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2. The following questions are about activities you might do during a typical day. 
Does your health now limit you in these activities? If so, how much?
(circle one number on each line)
Activities
Yes,
Limited
A Lot
Yes,
Limited
A Little
No, Not
Limited
At All
a. Vigorous activities, such as running, lifting
  heavy objects, participating in strenuous
  sports
1
2
3
b. Moderate activities, such as moving a table,
  pushing a vacuum cleaner, bowling, or playing
  golf
1
2
3
c. Lifting or carrying groceries
1
2
3
d. Climbing several flights of stairs
1
2
3
e. Climbing one flight of stairs
1
2
3
f. Bending, kneeling, or stooping
1
2
3
g. Walking more than a mile
1
2
3
h. Walking several hundred yards
1
2
3
i. Walking one hundred yards
1
2
3
j. Bathing or dressing yourself
1
2
3
3. During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of your physical 
health?
(circle one number on each line)
All of the 
time
Most 
of the 
time
Some 
of the 
time
A little 
of the 
time
None of 
the time.
a. Cut down on the amount of time you spent on
  work or other activities
1
2
3
4
5
b. Accomplished less than you would like
1
2
3
4
5
c. Were limited in the kind of work or other
  activities
1
2
3
4
5
d. Had difficulty performing the work or other
  activities (for example, it took extra effort)
1
2
3
4
5


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4. During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of any emotional problems
(such as feeling depressed or anxious)?
(circle one number on each line)
All of 
the 
Time
Most 
of the 
Time
Some 
of the 
Time
A Little 
of the 
Time
None of 
the 
Time
a. Cut down the amount of time you spent on work or other
  activities
1
2
3
4
5
b. Accomplished less than you would like
1
2
3
4
5
c. Did work or other activities less carefully than usual
1
2
3
4
5
5. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups?
(circle one)
Not at all ...........................................................................1
Slightly..............................................................................2
Moderately........................................................................3
Quite a bit .........................................................................4
Extremely..........................................................................5
6. How much bodily pain have you had during the past 4 weeks?
(circle one)
None .................................................................................1
Very mild..........................................................................2
Mild ..................................................................................3
Moderate...........................................................................4
Severe ...............................................................................5
Very Severe ......................................................................6


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7. During the past 4 weeks, how much did pain interfere with your normal work (including 
both work outside the home and housework)?
(circle one)
Not at all ........................................................ .............
1
A little bit.....................................................................
2
Moderately...................................................................
3
Quite a bit ....................................................................
4
Extremely ....................................................................
5
8. These questions are about how you feel and how things have been with you during the 
past 4 weeks: For each question, please give the one answer that comes closest to the way 
you have been feeling: How much of the time during the past 4 weeks -
..........(circle one number on each line)
All
of the
Time
Most
of the
Time
Some
of the
Time
A
little
of the Time
None
of the
Time
a. Did you feel full of life?
1
2
3
4
5
b. Have you been very nervous?
1
2
3
4
5
c. Have you felt so down
  in the dumps that
  nothing could cheer
  you up?
1
2
3
4
5
d. Have you felt calm and
  peaceful?
1
2
3
4
5
e. Did you have a lot of
  energy?
1
2
3
4
5
f. Have you felt down-hearted 
   and depressed?
1
2
3
4
5
g. Did you feel worn out?
1
2
3
4
5
h. Have you been happy?
1
2
3
4
5
i. Did you feel tired?
1
2
3
4
5


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9. During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)?
(circle one)
All of the time ............................................................1
Most of the time .........................................................2
Some of the time ........................................................3
A little of the time ......................................................4
None of the time.........................................................5
10. How TRUE or FALSE is each of the following statements for you?
(circle one number on each line)
Definitely
True
Mostly
True
Don't
Know
Mostly
False
Definitely
False
a. I seem to get sick
  a little easier than
  other people
1
2
3
4
5
b. I am as healthy as
  anybody I know
1
2
3
4
5
c. I expect my health
  to get worse
1
2
3
4
5
d. My health is
  excellent
1
2
3
4
5