Clinical trial NCT00745615
Conditions: Relapsing Remitting Multiple Sclerosis
Sponsor: Teva Pharmaceutical Industries, Ltd.
Start date: 2005-12-07; Completion date: 2017-07-23
Enrollment: 257 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multinational, multicenter, randomized, double-blind, parallel-group active extension of LAQ/5062 study (NCT00349193), assessing the tolerability, safety and efficacy of two doses (0.3 mg and 0.6 mg) of laquinimod, orally administered in participants with relapsing remitting multiple sclerosis (RRMS), followed by an open-label phase of laquinimod 0.6 mg daily. This study is LAQ/5063 (i.e., double-blind extension) and LAQ/5063 OL (i.e., subsequent open-label extension). - The first period of the extension study is an active, double-blind period. Participants from the active treatment arms in LAQ/5062 continue their assigned treatment in blinded fashion. Participants who were assigned to placebo treatment in LAQ/5062 are equally randomized in blinded-fashion to laquinimod 0.6 mg or laquinimod 0.3 mg. - Once termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the Sponsor) is performed, all participants continue on laquinimod 0.6 mg daily as an open-label intervention. The open-label period continues as long as the Sponsor continues the development of laquinimod 0.6 mg for RRMS or early discontinuation.

Detailed description:

Arms: arm 1: Participants who will be receiving laquinimod 0.3 milligram (mg) tablet once daily orally in double-blind core study, will continue to receive laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36. arm 2: Participants who will be receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) once daily orally in double-blind core study, will continue to receive laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36. arm 3: Participants who will be receiving placebo matching to laquinimod 0.3 mg tablet once daily orally in double-blind core study, will receive laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36. arm 4: Participants who will be receiving placebo matching to laquinimod 0.6 mg (2 tablets of placebo) once daily orally in double-blind core study, will receive laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36. arm 5: Participants who will be receiving laquinimod 0.3 mg tablet once daily orally either in double-blind core study or double-blind extension period, will receive laquinimod 0.6 mg capsule once daily orally in open-label extension period of this study until termination (as long as the Sponsor will continue the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years). arm 6: Participants who will be receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) once daily orally either in double-blind core study or double-blind extension period, will receive laquinimod 0.6 mg capsule once daily orally in open-label extension period of this study until termination (as long as the Sponsor will continue the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years).
Interventions: intervention 1: Laquinimod intervention 2: Placebo
Intervention descriptions: intervention 1: Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms. intervention 2: Placebo matching to laquinimod will be administered as per the dose and schedule specified in the respective arms.

Protocol documents:
Prot_SAP_000.pdf: 
Amended Protocol following Global Amendments 01 to 10
(including Statistical Analysis Plan)
An Active Extension of LAQ/5062 Study. a Multinational, Multi-Center,
Randomized, Double-Blind, Parallel-Group Study, to Evaluate the Safety,
Tolerability and Efficacy of Two Doses (0.3 mg and 0.6 mg) of
Laquinimod, Orally Administered in Relapsing Remitting (R-R) Multiple
Sclerosis (MS) Subjects (Study LAQ/5063 Active Double-Blind Phase)
Followed by an Open Label Phase of Laquinimod 0.6 mg Daily
(LAQ/5063 OL)
LAQ/5063 OL
NCT00745615
Amended Protocol following Global Amendments 01 to 10 Approval Date:
25 February 2016


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
1
 
TEVA PHARMACEUTICAL INDUSTRIES LTD., ISRAEL
CLINICAL STUDY PROTOCOL
Study Title:
An Active Extension of LAQ/5062 Study. a Multinational, Multi-Center, 
Randomized, Double-Blind, Parallel-Group Study, to Evaluate the Safety, 
Tolerability and Efficacy of Two Doses (0.3 mg and 0.6 mg) of 
Laquinimod, Orally Administered in Relapsing Remitting (R-R) Multiple 
Sclerosis (MS) Subjects Study LAQ/5063 Active Double-Blind Phase) 
Followed by an Open Label Phase of Laquinimod 0.6 mg Daily 
(LAQ/5063 OL).
Protocol No.:
LAQ/5063
EUDRACT number:
2005-004334-41
Clinical Phase:
Phase IIb
Protocol Version and Date: 
Final - September 11, 2005
Global Amendment # 1:
November 24, 2005
Global Amendment # 2:
October 23, 2006
Global Amendment # 3:
June 19, 2007
Global Amendment # 4:
November 22, 2007
Global Amendment # 5:
July, 30, 2008
Global Amendment # 6:
August, 28, 2008
Global Amendment # 7:
November 9, 2009
Global Amendment # 8:
September 15, 2011
Global Amendment # 9:
17 July 2014
Global Amendment # 10:
25 February 2016
Principal Investigator:
 Italy
MRI Principal Investigator
and MRI Analysis Center:
 
 Italy
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 Harmonisation) 
Guidelines and Directive 2001/20/EC of the European Parliament and the Council of the European Union.
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 opinions, patient informed 
consent and the approval of local regulatory authorities as required by local law.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
2
PROTOCOL APPROVAL PAGE


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
PROTOCOL APPROVAL PAGE...................................................................................................2
1.
SYNOPSIS .................................................................................................................11
2.
LIST OF ABBREVIATIONS.....................................................................................20
3.
INTRODUCTION......................................................................................................23
3.1.
Background.................................................................................................................23
3.1.1.
General........................................................................................................................23
3.1.2.
Study Drug..................................................................................................................23
3.2.
Nonclinical Experience...............................................................................................24
3.2.1.
Pharmacology .............................................................................................................24
3.2.2.
Metabolism and Pharmacokinetics.............................................................................24
3.2.3.
Toxicology..................................................................................................................25
3.3.1.
Clinical Pharmacology Studies...................................................................................26
3.3.2.
Clinical Safety and Efficacy Studies ..........................................................................27
3.4.
Known and Potential Risks and Benefits to Human Subjects....................................29
3.4.1.
Details of Important Adverse Drug Reactions............................................................31
3.4.1.1.
Liver Enzyme Elevations............................................................................................31
3.4.1.2.
Elevated Blood Fibrinogen Level...............................................................................32
3.4.1.3.
Elevated Blood C-Reactive Protein Level..................................................................32
3.4.1.4.
Back and Neck Pain....................................................................................................32
3.4.1.5.
Appendicitis................................................................................................................32
3.4.1.6.
Hematological Changes..............................................................................................32
3.4.1.7.
Cardiovascular Events (Laquinimod 1.2 and 1.5 mg) ................................................33
3.4.2.
Potential Safety Issues with Laquinimod ...................................................................33
3.4.2.1.
Pregnancy ...................................................................................................................33
3.4.2.2.
Cancer.........................................................................................................................34
3.4.2.3.
Cardiotoxicity and Systemic Inflammation................................................................34
3.5.
Rationale For Study Design And Dosages .................................................................35
3.5.1.
Study Design Rationale ..............................................................................................35
3.5.2.
Study Drug Dose Rationale ........................................................................................35
4.
STUDY OBJECTIVES ..............................................................................................36


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Protocol LAQ/5063 Open-Label
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4.1.
Safety And Tolerability ..............................................................................................36
4.1.1.
Safety..........................................................................................................................36
4.1.2.
Tolerability .................................................................................................................36
4.1.3.
Efficacy.......................................................................................................................36
4.1.4.
Ancillary Studies ........................................................................................................37
5.
STUDY DESIGN .......................................................................................................38
5.1.
Overview and Plan......................................................................................................38
5.2.
Number of Subjects ....................................................................................................42
5.3.
Inclusion Criteria ........................................................................................................42
5.4.
Exclusion Criteria.......................................................................................................43
6.
CONCOMITANT MEDICATIONS ..........................................................................45
6.1.
Allowed Concomitant Medications............................................................................45
6.2.
Disallowed Medications (During Study)....................................................................45
7.
STUDY CONDUCT...................................................................................................48
7.1.
Study Period................................................................................................................48
7.2.
Study Task Flow Sheets..............................................................................................49
7.3.
Detailed Study Plan ....................................................................................................55
7.3.1.
Baseline Visit (Week 0)..............................................................................................55
7.3.1.1.
Baseline Visit Procedures...........................................................................................55
7.3.1.2.
Randomization............................................................................................................57
7.3.1.3.
Post Randomization....................................................................................................57
7.3.1.4.
Day 1 PK Visit............................................................................................................58
7.3.2.
Scheduled Treatment Visits........................................................................................58
7.3.2.1.
Additional Pregnancy Detection Measures ................................................................60
7.3.3.
Termination Visit........................................................................................................60
7.3.4.
Criteria for Early Termination....................................................................................63
7.3.4.1.
Safety Stopping Rules.................................................................................................64
7.3.5.
Temporary Discontinuation of IMP............................................................................66
7.3.5.1.
Rescheduling of Missed Dose ....................................................................................66
7.3.6.
Unscheduled Visit.......................................................................................................66
7.3.6.1.
Unscheduled Samples.................................................................................................68
7.3.7.
Visits during Relapses (Scheduled and Unscheduled) ...............................................68
7.3.7.1.
Blinding ......................................................................................................................69


Amended Protocol following Global Amendments 01 to 10
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7.3.7.2.
Emergency Code Breaking.........................................................................................69
8.
ASSESSMENT METHODS ......................................................................................70
8.1.
Efficacy Assessment Methods....................................................................................70
8.1.1.
MRI Evaluations.........................................................................................................70
8.1.2.
Neurological Evaluations............................................................................................70
8.1.3.
MSFC..........................................................................................................................71
8.1.4.
On-Study Relapse Evaluation Procedures..................................................................71
8.2.
Safety Assessment Methods .......................................................................................71
8.2.1.
Physical Examination .................................................................................................71
8.2.2.
Emphasis on Physical Examination............................................................................72
8.2.3.
Vital Signs and Weight...............................................................................................72
8.2.4.
ECG ............................................................................................................................72
8.2.5.
Safety Laboratory Evaluations ...................................................................................73
8.2.5.1.
Urgent Safety Laboratory Panel .................................................................................75
8.2.6.
Adverse Events ...........................................................................................................75
8.2.7.
Abdominal Computed Tomography Scan ..................................................................76
8.2.8.
Glomerular Filtration Rate Estimation .......................................................................76
8.2.9.
Cardiovascular Risk Assessment and Management ...................................................76
8.3.
Assessment of Subject Compliance............................................................................76
8.4.
Ancillary Studies ........................................................................................................76
8.4.1.
Pharmacokinetic Sub-Study........................................................................................77
8.4.2.
Population Pharmacokinetic (PPK) Study..................................................................77
8.4.3.
Samples Handling for PK and PPK studies................................................................77
8.4.4.
Bioanalysis..................................................................................................................77
8.4.5.
Pharmacokinetic Calculation......................................................................................78
9.
INVESTIGATIONAL MEDICINAL PRODUCT.....................................................79
9.1.
Description..................................................................................................................79
9.2.
Assignment of Treatment ...........................................................................................79
9.3.
Investigational Medicinal Product Manufacturing.....................................................79
9.4.
Packaging And Labeling.............................................................................................80
9.5.
Distribution and Shipment..........................................................................................81
9.6.
Storage, Dispensing and Return .................................................................................81
9.7.
Route And Dosage Form ............................................................................................82


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9.8.
Verification of Compliance With Treatment Regimen ..............................................82
9.9.
Accountability.............................................................................................................83
10.
SAFETY AND PHARMACOVIGILANCE..............................................................84
10.1.
Protocol-Defined Adverse Events for Expedited Reporting ......................................89
11.
STATISTICAL METHODOLOGY...........................................................................90
11.1.
Sample Size Rationale................................................................................................90
11.2.
Randomization Procedure...........................................................................................90
11.3.
Subjects Cohorts.........................................................................................................91
11.4.
Efficacy Assessment...................................................................................................91
11.4.1.
Number of enhancing lesions on T1-weighted images taken on Week 36 .................91
11.4.2.
The number of new T2 lesions on scan taken on Week 36.........................................91
11.4.3.
The volume of T2 lesions on scan taken on Week 36.................................................91
11.4.4.
The number of new hypointense lesions on enhanced T1 scans taken on  
Week 36......................................................................................................................91
11.4.5.
The proportion of subjects with no enhancing lesions on Week 36...........................91
11.4.6.
The total number of confirmed relapses .....................................................................92
11.4.7.
The proportion of relapse-free subjects ......................................................................92
11.4.8.
EDSS scores................................................................................................................92
11.4.9.
Categorical change from baseline in EDSS Score......................................................92
11.5.
Safety And Tolerability Assessments.........................................................................92
11.5.1.
Adverse Events ...........................................................................................................92
11.5.2.
Laboratory Data..........................................................................................................92
11.5.3.
ECG ............................................................................................................................93
11.5.4.
Vital Signs ..................................................................................................................93
11.5.5.
Drug Tolerability & Drop-Out Assessment................................................................93
12.
REGULATORY AND ETHICAL ISSUES...............................................................94
12.1.
Compliance With Regulations Applicable To Clinical Trials....................................94
12.2.
Informed Consent .......................................................................................................94
12.3.
Ethics Committee........................................................................................................94
12.4.
Protocol Amendments ................................................................................................95
12.5.
Declaration Of The End Of The Clinical Trial...........................................................95
12.6.
Subject Confidentiality...............................................................................................95
12.7.
Liability And Insurance ..............................................................................................95


Amended Protocol following Global Amendments 01 to 10
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13.
DOCUMENTATION .................................................................................................96
13.1.
Study File And Site Documents .................................................................................96
13.2.
Site Documents/Equipment Supplied By The Sponsor..............................................96
13.3.
Maintenance And Retention Of Records....................................................................97
13.4.
Data Handling.............................................................................................................97
13.4.1.
Electronic Case Report Form......................................................................................97
13.4.2.
Coding.........................................................................................................................98
13.4.3.
Discrepancy Handling ................................................................................................98
13.4.4.
Data Correction...........................................................................................................98
13.4.5.
Data Extract ................................................................................................................99
13.4.6.
Source Documents......................................................................................................99
13.5.
Additional Documents And Records..........................................................................99
13.6.
Protocol Modification.................................................................................................99
14.
QUALITY ASSURANCE AUDITS/INSPECTIONS .............................................100
14.1.
Good Clinical Practice..............................................................................................100
14.2.
Quality Assurance Program......................................................................................100
14.3.
Regulatory Inspections .............................................................................................100
15.
STUDY MONITORING ..........................................................................................101
15.1.
Monitors And Monitoring Visits ..............................................................................101
15.2.
Primary Source Documents......................................................................................101
16.
CLINICAL PRODUCT COMPLAINTS .................................................................103
16.1.
Product Complaint Information Needed from the Investigational Center................103
16.2.
Handling of Study Drug at the Investigational Center .............................................104
16.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................104
16.4.
Documenting a Product Complaint ..........................................................................104
17.
USE OF INFORMATION AND PUBLICATIONS................................................106
17.1.
Confidential Information ..........................................................................................106
18.
STUDY PERSONNEL.............................................................................................107
18.1.
Study Principal Investigator .....................................................................................107
18.2.
Country Principal Investigator..................................................................................107
18.3.
Investigative Site Personnel......................................................................................107
18.3.1.
Principal Site Investigator.........................................................................................107


Amended Protocol following Global Amendments 01 to 10
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18.3.2.
The Neurologist/Physician........................................................................................107
18.3.3.
The MRI Radiologist and Technician.......................................................................107
18.3.4.
The Clinical Coordinator..........................................................................................108
18.4.
The Sponsor..............................................................................................................108
18.4.1.
Corporate Clinical Study Leader ..............................................................................108
18.4.2.
BioStatistics and BioMedical Informatics................................................................108
18.4.3.
Clinical Operations (Corporate Coordination Center)..............................................108
18.4.4.
Local Clinical Management (LCM) .........................................................................108
18.4.5.
Clinical Research Associate (CRA)..........................................................................109
18.4.6.
Global Drug Safety and Pharmacovigilance.............................................................109
18.4.7.
Medical Monitor.......................................................................................................109
18.4.8.
Global Operations Manager......................................................................................109
19.
STUDY COMMITTEES..........................................................................................110
19.1.
Clinical Advisory Board (CAB) ...............................................................................110
19.2.
Clinical Steering Committee (CSC) .........................................................................110
19.3.
Data Safety Monitoring Board (DSMB)...................................................................110
20.
INVESTIGATOR’S AGREEMENT........................................................................111
21.
RATIONALE FOR PROTOCOL AMENDMENT AND SUMMARY OF 
CHANGES ...............................................................................................................112
21.1.
Global Amendment #10............................................................................................112
21.2.
Global Amendment #9..............................................................................................129
22.
CHANGES TO PATIENT ENTRY CRITERIA......................................................139
APPENDIX 1.
DEFINITIONS .................................................................................................140
APPENDIX 2.
NEUROSTATUS .............................................................................................142
APPENDIX 3.
MRI PROTOCOL ............................................................................................161
APPENDIX 4.
MSFC ADMINISTRATION INSTRUCTIONS..............................................170
APPENDIX 5.
MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 
INDUCERS ..............................................................................................................177
APPENDIX 6.
LIST OF MEDICATIONS THAT SHOULD BE USED WITH 
CAUTION ................................................................................................................179
APPENDIX 7.
LIST OF STEERING COMMITTEE MEMBERS..........................................181
APPENDIX 8.
LIST OF DATA SAFETY MONITORING BOARD (DSMB) 
MEMBERS...............................................................................................................182
APPENDIX 9.
LIST OF CLINICAL ADVISORY BOARD (CAB) MEMBERS...................183


Amended Protocol following Global Amendments 01 to 10
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APPENDIX 10.
GUIDANCE ON SAFETY MONITORING..................................................184
23.
REFERENCES .........................................................................................................196


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
10
LIST OF TABLES
Table 1:
ALLEGRO: Summary of Efficacy Results ................................................................28
Table 2:
BRAVO: Summary of Efficacy Results.....................................................................28
Table 3:
Tabulated List of Adverse Reactions..........................................................................30
Table 4:
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for Alanine Aminotransferase, Aspartate Aminotransferase and 
Gamma Glutamyl Transpeptidase Tests.....................................................................31
Table 5:
Study Task Flow Sheet for Study 5063 (Double-Blind Active Extension 
Phase)..........................................................................................................................49
Table 6:
Study Task Flow Sheet for Study 5063 OL (up to Month 24) ...................................51
Table 7:
Study Task Flow Sheet for Study 5063 OL (Months 24 onwards) ............................53
Table 8:
A Partial List of Moderate/Strong CYP3A4 Inhibitors Disallowed 2 Weeks 
Prior to and During the Treatment Period and 30 Days After Last Dose.................177
Table 9:
A Partial List of CYP3A4 Inducers..........................................................................178
Table 10:
A Partial List of of CYP3A4 Substrates with a Narrow Therapeutic Index.............179
Table 11:
A Partial List of Drugs that are Mainly Metabolized by 
Cytochrome P450 1A2 .............................................................................................180
Table 12:
Study Task Flow Chart for Returning Subjects (Month 24 onwards)......................193
LIST OF FIGURES
Figure 1:
Treatment Groups in MS-LAQ/5062 (Core Study) and the Double-Blind and 
Open-Label Phases of LAQ/5063 (Extension Study).................................................39
Figure 2:
Study Flowchart for MS-LAQ/5062 Core Study........................................................40
Figure 3:
Study Flowchart for Open-Label Phase of LAQ/5063 Extension Study....................41


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
11
1.
SYNOPSIS 
Protocol Number
LAQ/5063
EudraCT Number
2005-004334-41
Protocol Title
An Active Extension of LAQ/5062 Study. a Multinational, Multicenter, Randomized, 
Double-Blind, Parallel-Group Study, to Evaluate the Safety, Tolerability and 
Efficacy of Two Doses (0.3 mg and 0.6 mg) of Laquinimod, Orally Administered in 
Relapsing Remitting (R-R) Multiple Sclerosis (MS) Subjects (Study LAQ/5063 
Active Double-Blind Phase) Followed by an Open Label Phase of Laquinimod 
0.6 mg Daily (LAQ/5063 OL).
Participating 
Countries
Europe (Italy, Germany, Spain, Czech Republic, Russia, Poland, U.K., Hungary) and 
Israel
Clinical Phase
IIb
Investigational 
Medicinal Product 
(IMP) & Dosage
For the initial extension phase (double-blind active extension phase):

0.3 mg arm: one white to off-white round biconvex tablet of 0.3 mg of 
laquinimod and one matching placebo tablet to be administered orally 
once daily.

0.6 mg arm: two white to off-white round biconvex tablets each of 
0.3 mg of laquinimod to be administered orally once daily.
Following approval of the Global Amendment # 4 to Protocol LAQ/5063 all subjects 
were switched to receive one white opaque cap and body, hard gelatin capsule 
containing laquinimod sodium equivalent to 0.6 mg laquinimod, to be administered 
orally once daily.
Study Duration
LAQ/5063 active double-blind phase (either completion of the full 36 weeks or as 
requested by the Sponsor) and an additional 24 months for the open label (OL) phase 
followed by further extension for a period of 36 months. Upon completion of this 
extension phase, subjects may continue to participate in the study as long as the 
Sponsor continues the development of laquinimod 0.6 mg for relapsing-remitting 
multiple sclerosis (RRMS).
Study Population
Subjects completing 36 weeks of the LAQ/5062 study in compliance with the 
protocol and meeting all inclusion/exclusion criteria will be eligible to be included in 
the extension study (LAQ/5063 active double-blind phase).
Following the termination of LAQ/5063 active double-blind phase (completion of the 
full 36 weeks or as requested by the Sponsor), subjects will be eligible to be enrolled 
in the open label phase (LAQ/5063 OL) if all inclusion/exclusion criteria are met.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
12
Study Objectives
To make treatment with laquinimod available to all subjects who previously 
participated in both the LAQ/5062 study and the LAQ/5063 active double-blind 
phase (completion of the full 36 weeks or as requested by the Sponsor).
To assess the long-term safety, and tolerability in the group that received active 
treatment in LAQ/5062 protocol and additional short term safety and tolerability in 
the group who received placebo treatment. The LAQ/5063 OL phase will assess 
long-term safety and tolerability of 0.6 mg laquinimod administered once daily.
Further efficacy data will be obtained by comparing baseline to termination in the 
group who received placebo treatment in LAQ/5062 (core study) protocol.
Study Design
This is a continuation of the LAQ/5062 study as a multinational, multicenter, 
randomized, double-blind, parallel group study, assessing the safety, tolerability and 
efficacy of two doses of laquinimod in subjects with RRMS followed by an open 
label phase of laquinimod 0.6 mg daily (LAQ/5063 OL).
Subjects will enter this randomized, two active arms study immediately after 
completion of the LAQ/5062 core study. The blinding in both, core study
(LAQ/5062) and its active double-blind extension phase (LAQ/5063), will be 
maintained. 
Subjects will enter the open-label phase (LAQ/5063 OL) upon the termination visit 
of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as 
requested by the Sponsor). 
Subjects previously treated with placebo in the LAQ/5062 study will be equally 
randomized to one of the active treatment groups:

0.6 mg of laquinimod per os (p.o.) once daily

0.3 mg of laquinimod p.o. once daily
Subjects previously treated with laquinimod 0.6 mg or laquinimod 0.3 mg will 
continue on their original treatment assignment. 
Upon the termination visit of LAQ/5063 active double-blind phase (completion of 
the full 36 weeks or as requested by the Sponsor) and after meeting the eligibility 
criteria of the open-label phase, all subjects will be treated with laquinimod 0.6 mg
once daily. 
Study Design
During the active double-blind phase subjects will be evaluated at study sites for 
7 scheduled visits or until Sponsor’s request:
Baseline (Week 0 / Termination (Week 36) of Core Study LAQ/5062), Week 4, 
Week 8, Week 12, Week 16, Week 24 and Week 36 (completion of the full 36 weeks 
of LAQ/5063 active double-blind phase or as requested by the Sponsor).
During the open label phase, the visits will be performed at monthly intervals for the 


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
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first 3 months and at three-month intervals for the period of 24 months. Upon 
completion of the 24-month treatment period, visits will be performed at 6 months 
intervals thereafter, where, for the purpose of this study, a month is 30 days and a 
visit is defined as X months ± 7 days.
During the open label phase subjects will be evaluated at study sites for the following
scheduled visits:
Baseline (Month 0 / Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor)), Month 1, Month 2, 
Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21, Month 24, 
Month 30, Month 36, Month 42, Month 48, Month 54, Month 60 and every 6 months 
thereafter, until termination (may continue to participate in the study as long as the 
Sponsor continues the development of laquinimod 0.6 mg for RRMS) or early 
discontinuation.
Subjects who discontinue treatment for any reason will continue follow-up according 
to scheduled visits.
Magnetic resonance imaging (MRI) scans: this section is relevant only for the 
LAQ/5063 double-blind phase and the first 24 months of the LAQ/5063 Open-Label 
phase. During the active double-blind phase MRI will be performed at Baseline 
(Week 0 / Termination (Week 36) of Core Study LAQ/5062), and Week 36 
(completion of the full 36 weeks of LAQ/5063 active double-blind phase or as 
requested by the Sponsor). For the open label phase MRI will be performed at 
baseline (Month 0 / Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor), Month 12 and 
Month 24. Subjects who performed the MRI scan within a window of ≤ 14 days, as 
part of the termination visit of LAQ/5063 active double-blind phase (completion of 
the full 36 weeks or as requested by the Sponsor), will not need to undergo another 
MRI scan for baseline visit of the open-label phase.
Neurological evaluations: during the active double-blind phase will be performed at 
Baseline (Week 0 / Termination (Week 36) of Core Study LAQ/5062), Week 12, 
Week 24 and Week 36 (completion of the full 36 weeks of LAQ/5063 active double-
blind phase or as requested by the Sponsor). For the open label phase Neurological 
evaluations will be performed at Baseline (Month 0 / Termination visit of LAQ/5063 
active double-blind phase (completion of the full 36 weeks or as requested by the 
Sponsor), Month 3, Month 6, Month 12, Month 18 and Month 24. Following 
Month 24 visit, neurological evaluations will be performed every 6 months 
thereafter. Subjects who performed the Neurological evaluations within a window of 
≤ 30 days, as part of the Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor) will not need to 
undergo a Neurological evaluation for the baseline visit of the open-label phase. 
Multiple Sclerosis Functional Composite (MSFC) will be assessed at Baseline 
(Week 0 / Termination (Week 36) of Core Study LAQ/5062), and Week 36 


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
14
(completion of the full 36 weeks of LAQ/5063 active double-blind phase or as 
requested by the Sponsor). For the open label phase MSFC will not be performed.
Adverse Events (AEs) will be monitored throughout the study.
Vital signs will be measured at each study visit throughout the study.
Physical examination will be performed at each study visit throughout the study. 
Subjects who performed the physical examination within a window of ≤ 30 days, as 
part of the Termination visit of LAQ/5063 active double-blind phase (completion of 
the full 36 weeks or as requested by the Sponsor), will not need to undergo another 
physical examination.
Clinical laboratory testing (including hematology, serum chemistry including liver 
enzymes and serum β-human chorionic gonadotropin (β-hCG) in women of 
child-bearing potential) will be performed at all visits during the active double-blind 
phase and the open-label phase. Subjects who performed the clinical laboratory 
testing within a window of ≤ 14 days, as part of the Termination visit of LAQ/5063 
active double-blind phase (completion of the full 36 weeks or as requested by the 
Sponsor), will not need to undergo another clinical laboratory testing at baseline visit 
of the open-label phase. 
A rapid urine β-hCG test will be performed in women of child-bearing potential at 
each scheduled study visit (at site). A rapid urine β-hCG test will be performed 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 asked 
specific questions regarding the test (see Appendix 10). 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. (see Appendix 10)
Electrocardiogram (ECG) will be performed at all visits during the active 
double-blind phase. For the open label phase ECG will be performed at Baseline 
(Month 0) / Termination visit of LAQ/5063 active double-blind phase (completion of 
the full 36 weeks or as requested by the Sponsor), Month 1, Month 2, Month 3, 
Month 6, Month 12, Month 18 and Month 24. After Month 24 visit, ECG will be 
performed every 6 months. Subjects who performed the ECG within a window of 
≤30 days, as part of the Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor), will not need to 
undergo another ECG at baseline visit of the open-label phase.
Testing for Factor V Leiden Mutation will be performed within scheduled or 
unscheduled visits during the open label phase, but will not be measured throughout 
the extension open label phase period. Carriers of the mutation will be discontinued 
from the study.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
15
Relapses will be monitored throughout the study.
Ancillary Studies (For LAQ/5063 active double-blind phase only):

Pharmacokinetic Study (PK): blood samples for PK analysis will be 
collected from a sub-group of subjects (the same subjects who 
participated in the LAQ/5062 PK study) at Baseline (Week 0 / 
Termination (Week 36) of Core Study LAQ/5062) and at Week 36 and 
post treatment period.

Population Pharmacokinetic Study (PPK): blood samples for PPK 
analysis will be collected from all subjects at Week 36 (termination visit 
of LAQ/5063 active double-blind phase (completion of the full 36 weeks 
or as requested by the Sponsor).
For subjects participating in the PK sub-study of LAQ/5063 active double-blind 
phase, will enter the open-label phase following a gap of at least 14 days from the 
Termination visit of LAQ/5063 active double-blind phase (completion of the full 
36 weeks or as requested by the Sponsor), in order to complete PK sample collection.
Number of Subjects
Subjects who successfully completed the LAQ/5062 study and wished to continue to 
the extension study (approximately 264 subjects)
Following the Termination visit of LAQ/5063 active double-blind phase (completion 
of the full 36 weeks or as requested by the Sponsor), subjects will be enrolled in the 
open-label phase (LAQ/5063 OL) phase if all inclusion/exclusion criteria are met.
Inclusion/Exclusion 
Criteria
Inclusion Criteria for LAQ/5063 active double-blind phase
1.
Subjects must have completed 36 weeks of treatment in the LAQ/5062 study 
and all its activities in accordance with the 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 give signed, written informed consent prior to entering this 
extension study.
Inclusion Criteria for the LAQ/5063 OL open-label phase


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
16
1.
Subjects must have completed the 36 weeks of treatment (completion of the 
full 36 weeks or as requested by the Sponsor), of the active double-blind 
phase
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 open-label phase (LAQ/5063 OL).
4.
Subjects must give signed, written informed consent prior to entering the 
open-label phase (LAQ/5063 OL).
Inclusion Criteria for the LAQ/5063 OL open-label phase - further extension (after 
visit Month 24):
1.
Subjects must have completed the 24 months of treatment of the first period 
of the open label phase. 
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)].
Inclusion/Exclusion 
Criteria
Exclusion Criteria for LAQ/5063 active double-blind phase
1.
Premature discontinuation from core study LAQ/5062 for any reason.
1.
Pregnancy or breastfeeding.
2.
Subjects with clinically significant or unstable medical or surgical condition 
detected or worsened during the core study, which would preclude safe and 
complete study participation. 
Exclusion Criteria for the LAQ/5063 OL open-label phase
1.
Premature discontinuation from LAQ/5063 active double-blind phase for any 


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
17
reason other than sponsor’s request.
2.
Pregnancy or breastfeeding.
3.
Subjects with clinically significant or unstable medical or surgical condition, 
detected or worsened during the active double-blind phase of LAQ/5063, 
which would preclude safe and complete study participation
4.
Use of experimental drugs, immunosuppressive drugs, and/or participation in 
clinical studies within the period from termination of LAQ/5063 active 
double-blind phase to the open-label phase (LAQ/5063 OL).
5.
Previous treatment with immunomodulators with the exception of 
laquinimod (including [IFN] 1a and 1b, Glatiramer Acetate and intravenous 
[IV] immunoglobulin) within 2 months prior to entering the open-label phase 
for those subjects who have a time gap between termination of LAQ/5063 
active double-blind phase to the open-label phase (LAQ/5063 OL).
6.
Use of corticosteroids within 30 days prior to entering the open-label phase, 
except for IV methylprednisolone 1 g/day for a maximum of 3 days, in the 
period from termination of LAQ/5063 active double-blind phase to the open-
label phase (LAQ/5063 OL).
7.
Use of potent inhibitors of CYP3A4 within 2 weeks prior to open label phase 
(LAQ/5063 OL) and/or use of fluoxetine one month prior entering the open 
label phase (LAQ/5063 OL), in the period from termination of LAQ/5063 
active double-blind phase to the open-label phase (LAQ/5063 OL) (see list in 
Appendix 5).
8.
Use of the following substrates of CYP1A2: theophylline and/or warfarin 
within 2 weeks prior to entering the open-label phase (LAQ/5063 OL), in the 
period from termination of LAQ/5063 active double-blind phase to the open-
label phase (LAQ/5063 OL)
9.
Use of amiodarone in the period from termination of LAQ/5063 active 
double-blind phase to the open-label phase (LAQ/5063 OL).
10. Following the switch to new formulation (capsules), hypersensitivity to: 
mannitol, meglumine or sodium stearyl fumarate
Exclusion Criteria for the LAQ/5063 OL open-label phase- further extension (after 
visit Month 24):
1.
Premature discontinuation from LAQ/5063 OL phase prior to completion of 
24 months of treatment period.
2.
Pregnancy or breastfeeding


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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.
Relapse Treatment
Allowed treatment for relapse is a fixed dose of 1 g/day IV methylprednisolone or 
oral steroids for a maximum of 5 consecutive days.
Outcome Measures
Safety 

AEs

Physical examinations

Vital signs and ECG 

Clinical laboratory parameters 
Tolerability

Number and percentage of subjects who prematurely discontinued from 
the study

Number and percentage of subjects who prematurely discontinued from 
the study due to AEs 
Efficacy 

Relapse Rate 

The proportion of relapse free subjects

Number of enhancing lesions on T1-weighted images

Number of new T2 lesions 

Volume of T2 lesions 

Number of new hypointense T1 lesions 

EDSS score


Amended Protocol following Global Amendments 01 to 10
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Outcome Measures
Ancillary Studies

Pharmacokinetic Study (PK): maximum plasma concentration (Cmax), 
time to Cmax (tmax), area under the concentration by time curve (AUC)
and elimination rate constant (λ) will be calculated.

PPK: Fitness of a population model to different covariates will be 
evaluated.
A separate PK and PPK protocol will be prepared for PK/PPK analysis.
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.


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2.
LIST OF ABBREVIATIONS
ABR-215062
laquinimod
ACTH
Adrenocorticotrophic Hormone
AE
Adverse Event
AhR
Aryl Hydrocarbon Receptor
AI
Ambulation Index
ALT
Alanine Aminotransferase (SGPT)
AST
Aspartate Aminotransferase (SGOT)
AUC
area under the concentration by time curve
CA
Competent Authority
CAB
Clinical Advisory Board
CDQC
Clinical Data Quality Control
CHMP
Committee for Medicinal Products for Human Use
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organization
CRP
C-reactive Protein
CSC
Clinical Steering Committee
CSU
Clinical Supplies Unit
CT
Computed Tomography
CYP
Cytochrome P
DLC
Dioxin-like Compound
DLT
Digital Linear Tape
DM
Data Management
DMC
Data Monitoring Committee
EAE
Experimental Autoimmune Encephalomyelitis
EC
Ethics Committee
ECG
Electrocardiogram
EDSS
Kurtzke's Expanded Disability Status Scale
EU
European Union
FS
Functional Systems
g
Gram
GCP
Good Clinical Practice
Gd
Gadolinium


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Gd-DTPA
Gadolinium-Gadopentetic Acid
GdE
Gadolinium Enhancing
GFR
Glomerular filtration rate
GTT
Gamma Glutamyl Transferase
HDL
High Density Lipoprotein
hs-CRP
High-sensitivity C-reactive Protein
I3C
Indole-3-Carbinol
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IFN
Interferons
IFN-β
Interferon β
IG
Immunoglobulin
IL
Interleukin
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ITT
Intent-to-Treat
IV
Intravenous
IVIG
Intravenous Immunoglobulin
IVRS
Interactive Voice Response System
kg
Kilogram
LCM
Local Clinical Management
LDL
Low Density Lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
ml
Milliliter
mm
Millimeter
MOA
Mode of Action
MRI
Magnetic Resonance Imaging
MRI-AC
Magnetic Resonance Imaging Analysis Center
MS
Multiple Sclerosis
MSFC
Multiple Sclerosis Functional Composite
PASAT
Paced Auditory Serial Addition Task
PCS
Potentially Clinically Significant
PK
Pharmacokinetics
PO
Per Os
PPK
Population Pharmacokinetics
PSI
Principal Site Investigator
QA
Quality Assurance


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RDC
Remote Data Capture
R-R
Relapsing-Remitting
RRMS
Relapsing-Remitting Multiple Sclerosis
SAE
Serious Adverse Event
SGOT
Serum Glutamate Oxaloacetic Transaminase
SGPT
Serum Glutamate Pyruvic Transaminase
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1
Relaxation Time T1
T2
Relaxation Time T2
TCDD
2,3,7,8-tetrachloro-p-dibenzodioxin
tmax
Time to Maximum Plasma Concentration
λ
elimination rate constant
-hCG
human Chorionic Gonadotropin


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23
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 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 (IFN)-β 1a (Avonex®a, Rebif®b), IFN-β
1b (Betaseron®c, Extavia®d), glatiramer acetate (Copaxone®e), mitoxantrone (Novantrone®f), and 
natalizumab (Tysabri®g; for patients non-responsive to other medications). Oral disease 
modifying treatments for RRMS include fingolimod (Gilenya®h), teriflunomide (Aubagio®i), and 
dimethyl fumarate (Tecfidera®j).Oral symptomatic treatment with dalfampridine (Ampyra®k) 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, 
pericarditis and pleuritis) occurring during Phase 3 studies led to early termination of these 
studies.
                                                
a Avonex is a registered trademark of Biogen Idec
b Rebif is a registered trademark of EMD Serono, Inc
c Betaseron is a registered trademark of Bayer
d Extavia is a registered trademark of Novartis Pharmaceuticals
e Copaxone® is a registered trademark of Teva Pharmaceutical Industries Ltd.
f Novantrone is a registered tradfemark of Serono Inc.
g Tysabri is a registered trademark of Biogen Idec.
h Gilenya is a registered trademark of Novartis Pharmaceuticals
i Aubagio is a registered trademark of Genzyme corporation
j Tecfidera is a registered trademark of Biogen Idec
k Ampyra is a registered trademark of Acorda therapeutics


Amended Protocol following Global Amendments 01 to 10
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24
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 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 (MOA) 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 P450 CYP 3A4-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 Hydrocarbon Receptor (AhR) transcription factor; activation of this
pathway by laquinimod has been demonstrated.
For a complete overview of the ADME-PK program of laquinimod, please refer to the 
laquinimod Investigator’s Brochure (IB).


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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 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 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 


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26
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 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.
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 
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 


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increase in laquinimod systemic exposure, respectively) and strong CYP3A4 inducers. At doses 
of 0.6 and 1.2 mg, laquinimod 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).
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


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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=0.04l]. In addition, treatment with laquinimod 
demonstrated reduction in brain atrophy: ALLEGRO: 32.8% [p<0.0001], BRAVOl : 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 
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 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)
                                                
l 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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
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.
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


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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.
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
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%)
The percentages listed in the table refer to all patients with normal values at baseline.
ULN = Upper limit of normal range; AST = aspartate aminotransferase; ALT = alanine aminotransferase ; GGT=
Gamma Glutamil Transpeptidase ; IU/L = international units/L


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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.
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
3.4.1.6.1. 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.
3.4.1.6.2. Decreased Platelets
Treatment with laquinimod has been associated with a generally mild decrease of the platelet 
count, without clinical manifestations.


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3.4.1.6.3. Increased White Blood Cells
Treatment with laquinimod has been associated with a generally mild increase of the total white 
blood cell count that was consistent across white blood cell 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.
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. 


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To prevent such exposure, women of childbearing potential (for example women who are not 
postmenopausal or surgically sterilized) must practice an acceptable method of birth control
(Section 5.3) 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 
will 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. 
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 2-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.


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3.5.
Rationale For Study Design And Dosages
3.5.1.
Study Design Rationale
This double-blind active extension study makes laquinimod available to subjects who 
successfully completed the double-blind placebo-controlled LAQ/5062, and enables the 
exploration of the long term safety, tolerability and clinical effect parameters during the disease.
LAQ/5062 study results analysis demonstrated that the 0.6 mg dose of laquinimod reached its 
primary endpoint, namely, reduction in the cumulative number of enhancing lesions. 
Accordingly, the open-label phase makes laquinimod 0.6 mg available to subjects who have 
completed the Termination visit of LAQ/5063 active double-blind phase (completion of the full 
36 weeks or as requested by the Sponsor), and enables the exploration of the long-term safety, 
tolerability and clinical effect parameters during the disease. 
3.5.2.
Study Drug Dose Rationale
The doses of 0.3 mg and 0.6 mg laquinimod per day that were chosen for the placebo-controlled 
protocol LAQ/5062 will be used in the active extension study.
Laquinimod has shown to have biological activity in animal models, PK studies, four phase I 
studies and two phase II clinical studies. The results of the phase II study demonstrated that 
administration of laquinimod (0.3 mg/day) to subjects with RRMS results in decreased numbers 
of active lesions in the brain.
Considering that the beneficial effects of laquinimod, as demonstrated in animal models and in 
the phase II study, are dose-dependent, this led to the assumption that a higher dose than that 
used in the phase II study may lead to increased efficacy, and strongly supports investigation of a 
higher but safe and tolerable dose. The core study, LAQ/5062 was designed to investigate
0.3 mg, as well as, 0.6 mg. The open-label safety clinical trial of laquinimod (0.9 mg/day) in 
RRMS patients has shown a reasonable safety profile. Therefore, it was decided to continue 
exploration of laquinimod doses of 0.3 mg and 0.6 mg in this extension study.
The data from the core LAQ/5062 study showed that oral formulation of laquinimod 
administered in a daily dose of 0.6 mg significantly reduced the mean cumulative number of 
Gd-enhancing lesions as compared to placebo. The 0.6 mg dose was well tolerated, and had a 
safety profile that was comparable to that of the 0.3 mg dose. Based on these positive results, all 
subjects participating in the open-label phase will receive laquinimod tablets (switched to 
capsules upon approval of Amendment # 4) in a daily dose of 0.6 mg.


Amended Protocol following Global Amendments 01 to 10
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36
4.
STUDY OBJECTIVES

To make treatment with laquinimod available to all subjects who previously 
participated in LAQ/5062 study and those who completed the Termination visit of 
LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested 
by the Sponsor).

To assess the long-term safety, and tolerability in the group that received active 
treatment in LAQ/5062 protocol and additional short term safety and tolerability in 
the group who received placebo treatment. LAQ/5063 OL phase will assess long-term 
safety and tolerability of 0.6 mg laquinimod once daily.
Further efficacy data will be obtained by comparing baseline to termination in the group who 
received placebo treatment in LAQ/5062 core study protocol.
4.1.
Safety And Tolerability
4.1.1.
Safety

Adverse Events (AEs)

Physical examinations

Vital signs and electrocardiogram (ECG)

Clinical laboratory parameters 
4.1.2.
Tolerability

Number and percentage of subjects who prematurely discontinued from the study

Number and percentage of subjects who prematurely discontinued from the study due 
to AEs
4.1.3.
Efficacy

Relapse Rate 

The proportion of relapse free subjects

Number of enhancing lesions on T1-weighted images

Number of new T2 lesions 

Volume of T2 lesions 


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37

Number of new hypointense T1 lesion

EDSS Score
4.1.4.
Ancillary Studies
PK assessments and population pharmacokinetics (PPK) evaluation.


Amended Protocol following Global Amendments 01 to 10
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5.
STUDY DESIGN
5.1.
Overview and Plan
This is a multinational, multicenter, randomized, double-blind, parallel-group active extension of 
LAQ/5062 study, assessing the tolerability, safety and efficacy of two doses (0.3 mg and 0.6 mg) 
of laquinimod, orally administered, in RRMS subjects, followed by an open-label phase of 
laquinimod 0.6 mg daily (LAQ/5063 OL).
For the double-blind phase seven planned study visits or until the Sponsor’s request (see Study 
Task Flow Sheet, Table 5) will be conducted at Baseline (Week 0 / Termination (Week 36) of 
Core Study LAQ/5062), Week 4, Week 8, Week 12, Week 16, Week 24 and Week 36. For the 
open-label phase the following study visits (see Study Task Flow Sheet, Table 6 and Table 7) 
will be conducted at Baseline (Month 0) / Termination visit of LAQ/5063 active double-blind 
phase (completion of the full 36 weeks or as requested by the Sponsor), Month 1, Month 2, 
Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21 and Month 24.
Additional visits during the further extension of the study will be at Months 30, 36, 42, 48, 54,
60 and every 6 months thereafter, until termination (as long as the Sponsor continues the 
development of laquinimod 0.6 mg for RRMS) or early discontinuation.
Subjects previously treated with placebo in the LAQ/5062 study will be equally randomized to 
one of the two active treatment groups:

0.6 mg of laquinimod per os (p.o.) once daily

0.3 mg of laquinimod p.o. once daily
Subjects previously treated with laquinimod 0.6 mg or laquinimod 0.3 mg will continue on their 
original treatment assignment. Once Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor) is performed, all subjects will 
continue on 0.6 mg daily.
Subjects will undergo MRI scans at Baseline (Week 0 / Termination (Week 36) of Core Study 
LAQ/5062), and Week 36 (Termination visit of LAQ/5063 active double-blind phase 
[completion of the full 36 weeks or as requested by the Sponsor]). For the open-label phase MRI 
will be performed at baseline (Month 0 / Termination visit of LAQ/5063 active double-blind 
phase (completion of the full 36 weeks or as requested by the Sponsor), Month 12 and Month 24. 
Subjects who performed the MRI scan within the past 14 days as part of the Termination visit of 
LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the 
Sponsor), will not need to undergo another MRI scan for baseline visit of LAQ/5063 OL.
Subjects who discontinue treatment for any reason will continue follow-up according to
scheduled visits.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
39
Unscheduled visits may be conducted whenever required due to various reasons, for example, 
AEs, or possible exacerbation.
Figure 1:
Treatment Groups in MS-LAQ/5062 (Core Study) and the Double-Blind and 
Open-Label Phases of LAQ/5063 (Extension Study)
Placebo
Laq 0.3 mg
Laq 0.6 mg
Laq 0.3 mg
Laq 0.6 mg
Laq 0.6 mg
Placebo
Laq 0.3 mg
Laq 0.6 mg
Laq 0.3 mg
Laq 0.6 mg
Laq 0.6 mg
MS-LAQ-5062 
Core Study
MS-LAQ-5063 (DB)
Extension
MS-LAQ-5063 (OL)
Extension
36 weeks
36 weeks
as long as the Sponsor 
continues the development of 
laquinimod 0.6 mg for RRMS 
(or early discontinuation)
MS-LAQ-5062 
Core Study
MS-LAQ-5063 (DB)
Extension
MS-LAQ-5063 (OL)
Extension
36 weeks
36 weeks
as long as the Sponsor 
continues the development of 
laquinimod 0.6 mg for RRMS 
(or early discontinuation)


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Protocol LAQ/5063 Open-Label
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Figure 2:
Study Flowchart for MS-LAQ/5062 Core Study


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
41
Figure 3:
Study Flowchart for Open-Label Phase of LAQ/5063 Extension Study


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
42
5.2.
Number of Subjects
Subjects who successfully completed the LAQ/5062 study and wished to continue to the 
extension study (approximately 264 subjects).
Subjects who completed LAQ/5063 phase double-blind phase (completion of the full 36 weeks 
or as requested by the Sponsor), will be invited to continue to the open-label phase (LAQ/5063 
OL).
5.3.
Inclusion Criteria
Subjects must meet all inclusion criteria in order to be eligible for Study 5063:
1. Subjects must have completed 36 weeks of treatment in the LAQ/5062 study and all 
termination visit activities in accordance with the 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 give signed, written informed consent prior to entering this extension 
study.
Inclusion Criteria For The Open-Label Phase
1. Subjects must have completed the 36 weeks of treatment (completion of the full 36 weeks 
or as requested by the Sponsor), of the active double-blind phase.
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 open-label phase (LAQ/5063 OL).
4. Subjects must give signed, written informed consent prior to entering the open-label 
phase (LAQ/5063 OL).


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
43
Inclusion Criteria for the LAQ/5063 OL open-label phase - further extension (after visit 
Month 24)
1. Subjects must have completed the 24 months of treatment of the first period of the open 
label phase 
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)]. 
5.4.
Exclusion Criteria
Any of the following conditions will exclude the subject from entering the study:
1. Premature discontinuation from core study LAQ/5062 for any reason.
2. Pregnancy or breastfeeding.
3. Subjects with clinically significant or unstable medical or surgical condition detected or 
worsened during the core study, which would preclude safe and complete study 
participation.
Exclusion Criteria For The Open-Label Phase
1. Premature discontinuation from LAQ/5063 active double-blind phase for any reason 
other than sponsor’s request.
2. Pregnancy or breastfeeding.
3. Subjects with clinically significant or unstable medical or surgical condition, detected or 
worsened during the active double-blind phase of LAQ/5063, which would preclude safe 
and complete study participation.
4. Use of experimental drugs, immunosuppressive drugs, and/or participation in clinical 
studies within the period from termination of LAQ/5063 active double-blind phase to the 
open-label phase (LAQ/5063 OL).
5. Previous treatment with immunomodulators with the exception of laquinimod (including 
IFN 1a and 1b, Glatiramer Acetate and intravenous [IV] immunoglobulin [IG]) within 2 
months prior to entering the open-label phase for those subjects who have a time gap 
between termination of LAQ/5063 active double-blind phase to the open-label phase 
(LAQ/5063 OL).


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
44
6. Use of corticosteroids within 30 days prior to entering the open-label phase, except for IV 
methylprednisolone 1 g/day for a maximum of 3 days, in the period from termination of 
LAQ/5063 active double-blind phase to the open-label phase (LAQ/5063 OL).
7. Use of potent inhibitors of CYP3A4 within 2 weeks prior to open label phase (LAQ/5063 
OL) and/or use of fluoxetine one month prior entering the open label phase (LAQ/5063 
OL), in the period from termination of LAQ/5063 active double-blind phase to the open-
label phase (LAQ/5063 OL) (see list in Appendix 5).
8. Use of the following substrates of CYP1A2: theophylline and/or warfarin within 2 weeks 
prior to entering the open-label phase (LAQ/5063 OL), in the period from termination of 
LAQ/5063 active double-blind phase to the open-label phase (LAQ/5063 OL).
9. Use of amiodarone in the period from termination of LAQ/5063 active double-blind 
phase to the open-label phase (LAQ/5063 OL).
10. Following the switch to new formulation (capsules), hypersensitivity to: mannitol, 
meglumine or sodium stearyl fumarate.
Exclusion Criteria for the LAQ/5063 OL open-label phase- further extension (after visit 
Month 24)
1. Premature discontinuation from LAQ/5063 OL phase prior to completion of 24 months of 
treatment period.
2. Pregnancy or breastfeeding
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 (see 
Appendix 10). 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 10).


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
45
6.
CONCOMITANT MEDICATIONS
6.1.
Allowed Concomitant Medications
Symptomatic MS agents, such as anti-cholinergic and anti-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 IV methylprednisolone 1 g/day or oral steroids 
for a maximum of 5 consecutive days. No tapering off is allowed.
Other medications, excluding those mentioned in Section 6.2, may be given concomitantly as 
needed for the subject’s welfare.
Topical and inhaled steroids are allowed at the discretion of the Investigator 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 case report form 
(CRF).
Unless clinically indicated, any concomitant therapy should remain stable during the study; 
changes to the concomitant therapy must be recorded in the source document file as well as in 
the CRF.
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 6) 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 6) should be advised that plasma levels of these drugs 
could increase when combined with laquinimod.
6.2.
Disallowed Medications (During Study)

Natalizumab (Tysabri®)

Fingolimod (Gilenya)


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
46

IFN-β 1a or 1b

Dimethyl fumarate (Tecfidera)

Glatiramer Acetate

Teriflunomide (Aubagio)

Alemtuzumab (Lemtrada)

Cladribine

Rituximab

Ocrelizumab

Atacicept

Belimumab

Ofatumumab

Inducers of CYP3A4 such as rifampin and carbamadizepine (for more examples see
Appendix 5). Use of CYP3A4 inducers may result in reduced laquinimod plasma 
concentrations and may reduce its effectiveness.

Moderate/strong inhibitors of CYP3A4; for example, ketoconazole and erythromyicin 
(see full list in Appendix 5) 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 relapse; see 
Section 6.1)

Adrenocorticotrophic hormone (ACTH)

Chemotherapeutic agents

Cytotoxic agents

Cyclophosphamide

IV immunoglobulin (IVIG)


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
47

Plasmapheresis

Any other experimental agents

Other immunosuppressive or immunomodulating agents


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
48
7.
STUDY CONDUCT
The study assessments will be performed according to the summary of the Study Task Flow 
Sheet (see Table 5). For the open-label phase the study assessments will be performed according 
to the summary of the Study Task Flow Sheet (see Table 6 and Table 7).
7.1.
Study Period
This is a continuation of the LAQ/5062 study as a multinational, multicenter, randomized, 
double-blind, parallel group study, assessing the safety, tolerability and efficacy of two doses of 
laquinimod in subjects with RRMS, followed by an open-label phase of laquinimod 0.6 mg daily 
(LAQ/5063 OL).
Subjects will enter this randomized, two active arms study immediately after completion of the 
LAQ/5062 core study. The blinding in both, core study (LAQ/5062) and its extension, will be 
maintained. Subjects will enter the open-label phase after completion of the Termination visit of 
LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the 
Sponsor).
The study duration is 36 weeks of double blind treatment (Week 0 [baseline] to Week 36 
[termination]) or until the Sponsor’s request. The duration of the open-label phase is as long as 
the Sponsor continues the development of laquinimod 0.6 mg for RRMS.
Subjects will be evaluated at study sites at Baseline (Week 0 / Termination (Week 36) of Core 
Study LAQ/5062), at Weeks 4, 8, 12, 16, 24, and 36 (Termination visit of LAQ/5063 active 
double-blind phase (completion of the full 36 weeks or as requested by the Sponsor). 
For the Study 5063 open label extension phase, the visits will be at monthly intervals for the first 
3 months and at three months intervals for the period of 24 months. Upon completion of the 
24 month treatment period visits will be performed at 6 months intervals thereafter, where, for 
the purpose of this study, a month is 30 days and a visit is defined as X months ± 7 days.
During the open label phase subjects will be evaluated at study sites for the following scheduled 
visits:
Baseline (Month 0 / Termination visit of LAQ/5063 active double-blind phase [completion of the 
full 36 weeks or as requested by the Sponsor]), Month 1, Month 2, Month 3, Month 6, Month 9, 
Month 12, Month 15, Month 18, Month 21, Month 24, Month 30, Month 36, Month 42, Month 
48, Month 54, Month 60 and every 6 months thereafter, until termination (as long as the Sponsor 
continues the development of laquinimod 0.6 mg for RRMS) or early discontinuation.
Subjects who discontinue treatment for any reason will continue follow-up according to 
scheduled visits.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
49
7.2.
Study Task Flow Sheets
Table 5:
Study Task Flow Sheet for Study 5063 (Double-Blind Active Extension
Phase)
Procedure/Visit Number
Baselinea
V0
V1
V2
V3
V4
V5
Termination / 
V4
Unscheduled 
Visitb
Weeks
0
4
8
12
16
24
36 / Early 
Discontinuatio
n
Informed Consent Signature
X
Eligibility Criteria
X
Concomitant Medications
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
X
X
X
Neurological Examinationc
X
X
X
X
X
MSFC
X
X
Evaluation of Relapsed
X
X
X
X
X
X
X
X
Serum β-hCGe
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
MRI (T1, T2)
X
Xf
X
Vital Signsg
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
Safety Laboratory Tests 
X
X
X
X
X
X
X
X
Samples for inflammatory markers
X
X
X
X
X
X
X
X
First IMP Administrationh
Xi
PK sampling (sub-group)
X
j
Xk
PPK Sampling (Ancillary study)
X
Laquinimod Dispensing, & 
Accountability
X
X
X
X
X
X
Xl
X
Subject Compliance
X
X
X
X
X
X
X
Termination Documentation & 
Notification of Early Termination 
X
a At Baseline of this extension study only Eligibility, Informed Consent and Drug Dispensing are performed. All 
other tasks are part of the activities of Termination of the Core study.
b Assessments during an unscheduled visit will be performed as deemed necessary by the Investigator, except for 
vital signs and adverse events, which are mandatory at each visit. Relapse evaluation will be conducted when the 
visit is due to subject’s complaint of possible relapse.
c 25-foot walk is performed with each neurological evaluation
d Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the 
Investigator/Coordinator.
e For women of child-bearing potential
f MRI scan will be performed within 4 days prior to the visit date.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
50
g Weight will be measured at baseline and termination visits only. 
h At home except for subjects participating in PK sub-study.
i One day post-baseline visit.
j One day post-baseline visit
k PK sampling will be performed in a sub-group of subjects following the last dose of treatment period on days: 1, 3, 
6, 10, 14 after visit 6 (Termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks 
or as requested by the Sponsor))
l Accountability only
Subjects participating in the PK sub-study will have a gap of at least 14 days between 
Termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as 
requested by the Sponsor), and Baseline Visit of the open-label phase (LAQ/5063 OL) in order 
to complete with the required assessments.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
51
Table 6:
Study Task Flow Sheet for Study 5063 OL (up to Month 24)
Procedure/Visit Number
Baseline
a V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
Termination / 
V10
Unschedule
d Visitb
Months
0
1
2
3
6
9
12
15
18
21
24/Early 
Discontinuati
on
Informed Consent Signature
X
Eligibility Criteria
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
ECG 
Xc
X
X
X
X
X
X
X
X
Neurological Examinationd
Xc
X
X
X
X
X
X
Evaluation of Relapsed
X
X
X
X
X
X
X
X
X
X
X
X
Serum and urine β-hCG e(on site)
Xf
X
X
X
X
X
X
X
X
X
X
X
Urine β-hCGe (self check, at home); Pregnancy 
tests mandatory phone callsg
EVERY 1 MONTH BETWEEN VISITS
Ascertaining use of effective contraception
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
MRI (T1, T2)
Xh
X
Xi
X
Vital Signsj
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
Xc
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory Testsk
Xf
X
X
X
X
X
X
X
X
X
X
X
Samples for inflammatory markers 
Xf
X
X
X
X
X
X
X
X
X
X
X
First IMP Administration
Xl
Laquinimod Dispensing, & Accountability
X
X
X
X
X
X
X
X
X
Xm
X
Subject Compliance
X
X
X
X
X
X
X
X
X
X
X


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
52
Procedure/Visit Number
Baseline
a V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
Termination / 
V10
Unschedule
d Visitb
Months
0
1
2
3
6
9
12
15
18
21
24/Early 
Discontinuati
on
Termination Documentation & Notification of 
Early Termination 
X
a At Baseline of the open label phase only Eligibility, Informed Consent and Drug Dispensing are performed. For most of the subjects all other tasks are part of 
the activities of Termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the Sponsor). For subjects who 
have a gap from termination of LAQ/5063 active double-blind phase and open-label phase the baseline visit should include all the assessments as stated in the 
above Task Flow Sheet
b Assessments during an unscheduled visit will be performed as deemed necessary by the Investigator, except for vital signs, which are mandatory at each visit. 
Relapse evaluation will be conducted when the visit is due to subject’s complaint of possible relapse.
c Subjects who performed the test evaluation within a window of ≤ 30 days, as part of the Termination visit of LAQ/5063 active double-blind phase (completion 
of the full 36 weeks or as requested by the Sponsor), will not need to undergo another test evaluation
d Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator. 25-foot walk is 
performed with each neurological evaluation
e For women of child-bearing potential
f Subjects who performed the test evaluation within a window of ≤ 14 days, as part of the Termination visit of LAQ/5063 active double-blind phase (completion 
of the full 36 weeks or as requested by the Sponsor), will not need to undergo another test evaluation
g Mandatory phone calls will be performed within 72 hours of the scheduled home pregnancy test
h A MRI performed within 14 days as part of the termination visit of LAQ/5063 active double-blind phase (completion of full 36 weeks or as requested by the 
Sponsor) will not need to undergo another MRI scan for Baseline visit of LAQ/5063 OL.
i MRI scan will be performed within 4 days prior to the visit date. 
j Weight will be measured at baseline and termination visits only. 
k Testing for Factor V Leiden Mutation will be performed within scheduled or unscheduled visits during the open label phase. Carriers. of the mutation will be 
discontinued from the study 
l All subjects will take the first IMP administration one day post-baseline visit. 
m Accountability only


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
53
Table 7:
Study Task Flow Sheet for Study 5063 OL (Months 24 onwards)
Procedure/Visit Number
V10
V11
V12
V13
V14
V15
V16
Every 6 
months
Termination
Unscheduled Visit
Months
24
30
36
42
48
54
60
Early Discontinuation
Unscheduled visita
Informed Consent b Signature
X
X
Inclusion/Exclusion criteria
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Cardiovascular risk factor assessment 
and managementc
X
X
X
X
Every 
12 months 
from Month 72
ECG 
X
X
X
X
X
X
X
X
X
X
Neurological Examination 
X
X
X
X
X
X
X
X
X
X
Evaluation of Relapsed
X
X
X
X
X
X
X
X
X
X
Ascertaining the use of Effective 
contraception
X
X
X
X
X
X
X
X
X
X
Serum and urine β-hCGe (on site)
X
X
X
X
X
X
X
X
Serum test only
X
Urine β-hCGc (self check, at home);
Pregnancy tests mandatory phone callsf
EVERY 1 MONTH BETWEEN VISITS
Adverse Events
X
X
X
X
X
X
X
X
X
X
MRI (T1, T2)
X
Vital Signs g
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
Safety Laboratory Tests (including 
inflammatory markers, GFR 
estimation) 
X
X
X
X
X
X
Xh
Xh
Xh
Xh
Laquinimod Dispensing, & 
Accountability
X
X
X
X
X
X
Xi
X
Xi
X
Subject Compliance
X
X
X
X
X
X
X
X
X
X
Termination Documentation & 
Notification of Early Termination 
X


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
54
Procedure/Visit Number
V10
V11
V12
V13
V14
V15
V16
Every 6 
months
Termination
Unscheduled Visit
Months
24
30
36
42
48
54
60
Early Discontinuation
Unscheduled visita
Unscheduled samples
Xj
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 Assessments during an unscheduled visit will be performed as deemed necessary by the Investigator, except for vital signs and adverse events, which are 
mandatory at each visit
b At Month 24 (visit 10) of the open label phase Informed Consent will be signed for the extended open label period of 36 months. At Month 60 (visit 16) of the 
open label phase an Informed Consent will be signed for the additional extension as long as the Sponsor continues the development of laquinimod 0.6 mg for 
RRMS
c In addition, an evaluation should take place as soon as possible for subjects already in the study, following approval of Amendment #10
d Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator
e For women of child-bearing potential
f Mandatory phone calls will be performed within 72 hours of the scheduled home pregnancy test
g Weight will be measured at all visits
h Inflammatory markers will not be collected from Month 60 and onwards
i Only drug retrieval
j 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.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
55
7.3.
Detailed Study Plan
The subject will attend the study site at scheduled visits as follows: Week 0 (baseline); and at 
Weeks 4, 8, 12, 16, 24 and 36 (Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor), the subject will attend the 
study site at scheduled visits as follow: Month 0 (baseline / Termination visit of LAQ/5063 
active double-blind phase (completion of the full 36 weeks or as requested by the Sponsor), and 
at Months 1, 2, 3, 6, 9, 12, 15, 18, 21 24, 30, 36, 42, 48, 54, 60 and every 6 months thereafter, 
until termination (as long as the Sponsor continues the development of laquinimod 0.6 mg for 
RRMS) or early discontinuation.
Two different neurologists/physicians will assess the subjects. 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 (Section 6). For 
the open-label phase there is no requirement to have two different neurologists/physicians to 
perform the neurological examination.
7.3.1.
Baseline Visit (Week 0)
The baseline (Week 0) visit will occur on Week 36 (termination) of the core study LAQ/5062.
For the open-label phase the baseline visit (Month 0) will occur at the Termination visit of 
LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the 
Sponsor). In case of a time gap between both phases, the baseline procedures carried out for 
LAQ/5063 OL open-label phase will be the same as for the LAQ/5063 active double-blind unless 
it is specified otherwise.
7.3.1.1.
Baseline Visit Procedures
After completion of all procedures and activities of the termination visit of the core study
(LAQ/5062), and placing a call to the IVRS to notify the subject’s termination from the core 
study, the investigator will establish eligibility of subjects willing to continue in the extension 
study. For the open-label phase, after completion of all procedures of the Termination visit of 
LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the 
Sponsor), and placing a call to the IVRS to notify the subject’s termination of the LAQ/5063 
active double-blind phase, the investigator will establish the eligibility of subjects willing to 
continue in the open-label phase (LAQ/5063 OL). Eligible subjects will be informed about all 
aspects of the study, including scheduled study visits and activities, and must sign and date the 
informed consent. Same procedure should be performed, separately for the open-label phase. A 
copy of the informed consent must be given to the subject. Same procedure should be performed, 
separately for the open-label phase. A call to the IVRS will be made in order to allocate the 
subjects to their treatment group according to a computer-generated randomization list produced 
by Teva Global BioStatistics and Global BioMedical Informatics units. For the open-label phase 
the IVRS will not be used as all subjects will be on the same treatment group.


Amended Protocol following Global Amendments 01 to 10
Protocol LAQ/5063 Open-Label
56
The IVRS will assign a pack number and the subject will be supplied and treated with the 
medication labeled with the same pack number. This is for LAQ/5063 active double-blind phase 
only.
For the open-label phase subjects who participate in the PK sub-study and/or have a time gap 
between Termination visit of LAQ/5063 active double-blind phase (completion of the full 
36 weeks or as requested by the Sponsor) and baseline visit of the open-label phase the first 
administration of the IMP will be taken at the site.
The following activities are part of termination visit of core study (LAQ/5062) and Termination 
visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by 
the Sponsor). 
The following activities will be performed as part of the baseline visit for the open-label phase 
(LAQ/5063 OL) unless it is specified otherwise.

Vital signs (temperature, pulse, blood pressure and weight)

ECG

Complete physical examination

Neurological evaluation including Functional System (FS) score, Ambulation Index 
(AI) score and EDSS, and 25 foot walk test

Multiple Sclerosis Functional Composite (MSFC) (This is relevant for LAQ/5063 
active double-blind phase only)

MRI

T1-weighted scan after administration of gadolinium-gadopentetic acid 
(Gd-DTPA)

T2-weighted scan

Laboratory tests including:

Urinalysis

Hematology

Serum chemistry

Serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) for women of 
child-bearing potential

Samples for inflammatory markers (e.g. CRP, fibrinogen)


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
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 potential teratogenicity and 
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)

Evaluation of a relapse (if relevant)

Review concomitant medications (ensuring no disallowed medication is being used).

Record of AEs
7.3.1.2.
Randomization
Assignment of subject to treatment group (randomization) will be performed at baseline visit of 
the extension study for eligible subjects. Randomization will be determined according to a 
computer-generated randomization list produced by Teva Global BioStatistics and Global 
BioMedical Informatics units, and the IVRS procedure will be used to allocate the subject to the 
treatment group. The IVRS will assign a pack number and the subject will be supplied and 
treated with the medication labeled with the same pack number. This is relevant for LAQ/5063 
active double-blind phase only.
7.3.1.3.
Post Randomization
The following procedures will be performed:

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.

Subjects will be instructed to administer the IMP once daily at approximately the 
same time of the day. The first administration of IMP in the extension study 
(LAQ/5063 active double-blind phase) and the open-label phase (LAQ/5063 OL), 
including subjects participating in the PK sub-study and/or have a time gap as well
between termination of the active double-blind phase and baseline visit of the open-
label phase will be the following day at the subject’s home. However, subjects 
participating in PK sub-study will come for a visit on the next day, and will 
administer the IMP at the site following the blood drawing.


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
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 or a 
relapse.
7.3.1.4.
Day 1 PK Visit
Subjects participating in the PK sub-study will come for a visit one day following randomization,
which was performed on Visit 0, for blood sampling before first administration of IMP at the 
site. This is relevant for LAQ/5063 active double-blind phase only.
7.3.2.
Scheduled Treatment Visits
Following the baseline visit, subjects will return to the study center for 5 treatment visits at 
Weeks 4, 8, 12, 16 and 24 ± 3 days unless decided otherwise by the Sponsor. For the open-label 
phase following the baseline visit, subjects will return to the study center for additional 16 visits 
at Months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54 and 60 ± 7 days. For the additional 
extension period (i.e., as long as the Sponsor continues the development of laquinimod 0.6 mg
for RRMS), visits will be performed every 6 months thereafter. Subjects who discontinue 
treatment for any reason will continue follow-up according to scheduled visits.
Following approval of Global Amendment #10, 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 these visits:

Call IVRS to obtain kit number(s). This is relevant for LAQ/5063 active double-blind 
phase only.

Reviewing inclusion/ exclusion criteria

Signing appendix to informed consent

Vital signs (temperature, pulse, blood pressure weight will be measured at all visits)

Complete physical examination 

Laboratory tests including:

Hematology

Serum chemistry (including glomerular filtration rate [GFR] estimation)

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 


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test is available (see Appendix 10). The rest of the visit activities should be 
performed

Samples for inflammatory markers– e.g. high-sensitivity C-reactive protein 
[hs-CRP] and fibrinogen-

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 potential teratogenicity and 
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)

The following actions will be taken for female subjects of child-bearing potential:
o
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. 
o
In order to verify whether the test has been performed and to record the result 
of the test (see Appendix 10), a mandatory phone call will be performed by 
the Treating 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 (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 stopped and the subject will be instructed to arrive to the 
study site as soon as possible to return all study drugs.

Complete neurological examinations including FS, AI, EDSS (Weeks 12 and 24 
only) and 25 foot walk test. For the open-label phase LAQ/5063 OL) this 
examination will be performed at Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and
60 and every 6 months thereafter for the additional extension period (i.e., as long 
as the Sponsor continues the development of laquinimod 0.6 mg for RRMS).

ECG. For the open-label phase (LAQ/5063 OL) ECG will be performed at Months 1, 
2, 3, 6, 12 ,18, and every 6 months thereafter

Evaluation of relapses (if applicable)

Review concomitant medication (ensuring no disallowed medication is being used)


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
Record of AEs

IMP capsules accountability and dispensing Subject compliance

Review instructions on IMP capsules administration (following the switch from 
tablets to capsules).

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 #10.
7.3.2.1.
Additional Pregnancy Detection Measures

All female subjects of child bearing potential will be invited to the site for an 
unscheduled visit as soon as the site's Principal Investigator receives and signs 
Amendment #5. 

The subject should be informed of the new safety issue regarding pregnancy. The 
issue of contraception should be reminded and emphasized. 

The Appendix to the Informed Consent should be signed. 

All female subjects of child bearing potential will be provided with home urine 
pregnancy test kits.
7.3.3.
Termination Visit 
Termination Visit (6) / (Week 36 ± 3 days) of LAQ/5063 Active Double-Blind Phase 
(Completion of the full 36 weeks or as requested by the sponsor), or any Termination or Early 
Discontinuation visit occurring as long as the Sponsor continues the development of laquinimod 
0.6 mg for RRMS.
In the event of early discontinuation, standard termination procedures will be followed.
Early discontinuation is defined as withdrawal from the study prior to the completion of the full 
study period:

Withdrawal prior to completion of 24 months of the first period of open label phase.

Subjects that chose to continue to the second period of open label phase (additional 
36 months), and did not complete this period.

Subjects that chose to continue treatment from Month 60 as long as the Sponsor 
continues the development of laquinimod 0.6 mg for RRMS and did not complete this 
period.


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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]).
Subjects who have completed 24 months of open label phase and chose not to continue to further 
extension of open label phase will be regarded as completers.
Subjects who have completed 60 months of the extension open label phase and chose not to 
continue to further extension of open label phase (as long as the Sponsor continues the 
development of laquinimod 0.6 mg for RRMS) will be regarded as completers.
The reason for discontinuation of therapy will be documented in the source documents and 
captured on the CRF. If there are several reasons for early discontinuation, the more severe will 
be chosen as the primary reason. In the event that laquinimod is discontinued early, an early 
termination visit should be completed as close to the last dosing date as possible.
Subjects who did not complete the 36 weeks of treatment of LAQ/5063 active double-blind 
phase until approval of amendment No 2 will be called for an a termination visit of the active 
double-blind phase as requested by the Sponsor to be switched to the open-label phase 
(LAQ/5063 OL)
In case a subject completed the 60 months OL period, but decided not to proceed with the further 
extension, he/she will be considered as completer.
The following will be performed at the Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor), and/or at any early 
discontinuation visit occurring as long as the Sponsor continues the development of laquinimod 
0.6 mg for RRMS:

Vital signs, including weight

Complete physical examination

Record of AEs: If an AE is still ongoing, or a new AE is present at the termination 
visit, it will be followed according to the discretion of the Investigator and recorded 
in the subject's source documents and in the CRF (see Section 7.3.4).

IMP accountability

Subject compliance

Review concomitant medication. 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.


Amended Protocol following Global Amendments 01 to 10
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
ECG

Complete neurological examination, including FS, AI, and EDSS, and 25 foot walk 
test

MSFC (this is relevant for LAQ/5063 active double-blind phase only)

Evaluation of relapses (if applicable). If a relapse is confirmed or ongoing at the 
termination visit, it will be followed until relapse stabilization. All follow-up 
evaluations must be documented in the source documents and the CRF.

Laboratory tests

Hematology

Serum chemistry (including GFR estimation)

Serum pregnancy test (β-hCG) for women of child-bearing potential

Blood sampling for PK study (ancillary study in sub-group of subjects. For 
subjects participating in this study, the IMP will be administered at the site. This 
is relevant for LAQ/5063 active double-blind phase only)

Blood sampling for PPK study (ancillary study in all subjects). (This is relevant 
for LAQ/5063 active double-blind phase only)

For a detailed sampling plan for PK and PPK studies refer to Section 8.4. (This is 
relevant for LAQ/5063 active double-blind phase only)

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 potential teratogenicity and 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) 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)

Call IVRS for update on subject’s termination (This is relevant for LAQ/5063 active 
double-blind phase only)


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63
Notification of the Sponsor in the event of early discontinuation including the reason for 
termination (see Section 7.3.4)
7.3.4.
Criteria for Early Termination
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 LAQ-5063 OL study.
Every attempt should be made to follow the early discontinued subjects. Subjects who 
prematurely discontinue the study should be followed and treated by the Site Investigator in a 
customary manner. For subjects who decide not to continue with any further visits, termination 
visit evaluations/procedures should be performed and completed before discontinuation. A 
subject may withdraw or be withdrawn from the study for the following reasons:
1. Subject withdrew consent (specify)
2. Teva requested that subject be withdrawn (specify)
3. Request of Investigator or Primary Care Physician (specify)
4. Non-compliance
5. Protocol violation
6. Loss to follow-up/failure to return
7. AE (specify primary AE)
8. Death
9. Pregnancy
10. Planned pregnancy
11. Lack of efficacy
12. Other (specify)
If a subject is withdrawn due to AEs, the appropriate AE sections of the CRF should be fully 
completed. The local clinical management (LCM)/Monitor should immediately be informed of 
any withdrawal. The primary AE that caused early discontinuation should be specified in the 
appropriate section in the CRF.


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If an AE is present at the last visit, it will be followed until the medical condition returns to 
baseline or is considered stable or chronic.
All efforts should be made to follow a subject who prematurely discontinues the study due to 
ongoing AE. In case of manifestation of a severe degree of intolerance to IMP and/or ongoing 
exacerbation, the subject may be prematurely discontinued at the discretion of the Investigator. 
Laboratory tests demonstrating clinically significant changes should be repeated and followed up 
until they return to normal or baseline levels, or are stabilized.
7.3.4.1.
Safety Stopping Rules
7.3.4.1.1. Liver Enzymes
In any increase of ALT or AST to ≥ 2 times ULN the “Guidance on Safety Monitoring” (see 
Appendix 10) 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 10:

Any increase in ALT or AST to ≥3 times ULN, combined with 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 (see Appendix 10)
7.3.4.1.2. Pregnancy
To further emphasize the importance of use of effective contraception and avoidance of 
pregnancy under laquinimod exposure, 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 potential teratogenicity and 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 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 


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65
pregnancy is suspected (positive urine β-hCG test result, delay of menstruation or any other 
reason suggesting pregnancy). 
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 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 10). 
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.
7.3.4.1.3. Cancer
Subjects who are diagnosed with a malignant solid or liquid tumor while participating in the 
study should stop study drug.


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66
7.3.4.1.4. 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.
7.3.4.1.5. 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.
7.3.5.
Temporary Discontinuation of IMP
Temporary discontinuation is defined as a missing of more than three consecutive doses.
IMP may be temporarily discontinued for either of the following reasons:

The subject develops an intolerable AE, which is perceived by the Site Investigator to 
be potentially related to IMP.

The subject is temporarily unable to take IMP due to a medical condition (concurrent 
illness or surgery, etc.).

The reasons for IMP temporary discontinuation should be recorded in the appropriate 
section of the IMP dispensing and compliance log in the CRF and the LCM should be 
notified.

The subject will report any discontinuation/delay to the Investigator and will be 
instructed by the Investigator regarding continuation of treatment.
7.3.5.1.
Rescheduling of Missed Dose
In the event of up to 3 consecutive days of missed doses of the once-daily IMP treatment, the 
subject will administer IMP immediately and continue with the previous treatment scheduling. 
This is not defined as temporary discontinuation.
In the event of more than 3 consecutive days of missed doses of the once-daily IMP treatment, 
the subject will administer IMP on the following day. This is defined as temporary 
discontinuation.
7.3.6.
Unscheduled Visit
An unscheduled visit may be performed at any time during the study as deemed necessary by the 
Investigator. The date and reason for an unscheduled visit will be recorded.


Amended Protocol following Global Amendments 01 to 10
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67
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

IMP dispensing, accountability and/or replacement

Subject compliance

Other, specify
Should the visit be related to a relapse, this will be clearly indicated on the CRF and the Study
Neurologist/Physician will carry out a complete neurological evaluation (FS/ AI/ EDSS) and 25 
foot walk test.
Additional analyses may be performed by the investigator and stated in the source 
documentation.
Mandatory Unscheduled Visit Procedures

Vital signs

Evaluation of AEs

Evaluation of a suspected relapse/follow-up

Ascertain use of effective contraception
Optional Unscheduled Visit Procedures

ECG

Physical examination

Neurological examination (by the Study Neurologist/Physician)

Laboratory tests (including estimation of GFR)

IMP accountability

Subject compliance


Amended Protocol following Global Amendments 01 to 10
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
Review of concomitant medications

For women of child bearing potential, serum or urine β-hCG test may be performed
7.3.6.1.
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 8.2.5.1)

pharmacokinetic blood sample

sample for potential biomarker analysis
7.3.6.1.1. 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.
7.3.6.1.2. 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.
7.3.7.
Visits during Relapses (Scheduled and Unscheduled)
Subjects will be instructed to contact their study site immediately should any symptoms 
suggestive of a relapse occur (see Section 8.1.4).
The Study Neurologist/Physician will evaluate the subject within 7 days of the telephone contact, 
conditional upon a symptomatic period of ≥48 hours.


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69
The relapse assessment will be documented in the source documents and in the CRF accordingly. 
A complete neurological assessment, including FS, AI and EDSS, 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 1.
Corticosteroids therapy (as described in Section 6.1) may be given for a confirmed relapse at the 
discretion of the Treating Neurologist/Physician and must be recorded in the CRF.
7.3.7.1.
Blinding
The randomization code for each subject will be delivered to the investigator via the IVRS. The 
subjects, investigators and site personnel, MRI personnel, and the personnel involved in subject 
assessment, monitoring, analysis and data management (excluding the Clinical Supplies Unit 
[CSU] personnel), are blinded to the subject assignment. In order to ensure that information, 
which could potentially bias handling, is not disclosed, the following precautions will be 
practiced:

Subjects’ general medical evaluations will be assessed separately from their 
neurological assessment evaluations by two 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.

MRI scan evaluation will be performed at a central reading center by staff that does 
not have access to the clinical data.
This section is relevant for LAQ/5063 active double-blind phase only.
7.3.7.2.
Emergency Code Breaking
Only in case of a serious adverse event (SAE), when the blinded information is urgently needed 
for the treatment of the subject, should the investigator reveal the relevant subject’s treatment 
allocation. The sponsor Local Clinical Trial Manager should be notified of the event prior to 
breaking of the code or immediately afterwards, without revealing the subject’s group 
assignment.
On completion of the study, record of un-blinding events of the emergency code breaking system 
will be generated and checked by the sponsor or by the sponsor’s authorized representative
This section is relevant for LAQ/5063 active double-blind phase only


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8.
ASSESSMENT METHODS
8.1.
Efficacy Assessment Methods
8.1.1.
MRI Evaluations
The subjects will undergo MRI at Baseline (Week 0 / Termination (Week 36) of Core Study), 
and at Week 36 (termination)/early discontinuation visit.
The following parameters will be assessed:

Number of T1 GdE lesions

Number of new T2 lesions

Volume of T2 lesions

Number of new hypointense T1 lesions on enhanced T1 scans ("black holes")
Steroid treatment for relapse (see Section 6.1) will not affect the schedule of MRI scans.
All MRI data will be interpreted by the MRI-Analysis Center (MRI-AC).
MRI scans can be performed within 4 days of each visit except for Week 36/ (termination) where 
the MRI scans are performed 4 days prior to this visit. For the MRI Protocol, see Appendix 3.
This section is relevant only for the LAQ/5063 double-blind phase and the first 24 months of the 
LAQ/5063 Open-Label phase.
8.1.2.
Neurological Evaluations
A complete neurological assessment will be performed at Baseline (Week 0 / Termination (Week 
36) of Core Study LAQ/5062), and at Weeks 12, 24 and 36 (Termination visit of LAQ/5063 
active double-blind phase (completion of the full 36 weeks or as requested by the Sponsor)/early 
discontinuation visit. For the open-label phase a complete neurological assessment will be 
performed at baseline (Month 0 / Termination visit of LAQ/5063 active double-blind phase 
(completion of the full 36 weeks or as requested by the Sponsor), Months 3, 6, 12, 18 and 24. 
Following completion of month 24, the neurological evaluations will be performed every 
6 months thereafter. Every effort should be made to ensure that the same Study
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 
10/2002). The results will be recorded on standardized and validated examination forms (see 
Appendix 2) as well as in the CRF.


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The footnote in Appendix 2 page 75 should be disregarded for this study in cases where 
Functional System Score for fatigue is 1 (“Mental Functions grade 1 does not contribute to 
EDSS – step definition”.). That is, when fatigue score=1, it does contribute both to Functional 
System Score and to the converted EDSS score (page 74, Appendix 2).
8.1.3.
MSFC
The MSFC consists of 3 clinical examinations, the results of which are combined using z-scores. 
The three clinical examinations include the Paced Auditory Serial Addition Task (PASAT), 
Timed 25 foot walk and 9-Hole Peg Test.
The tests will be performed at Baseline (Week 0 / Termination (Week 36) of Core Study), and 
Week 36 (termination)/early discontinuation visit.
Appendix 4 presents the instructions for administering the MSFC.
The 25 foot walk test will be performed each time neurological evaluation is performed 
(baseline, Weeks 12, 24 and 36).
This section is relevant for LAQ/5063 active double-blind phase only
8.1.4.
On-Study Relapse Evaluation Procedures
The subject will be examined within 7 days of the telephone contact, conditional upon a 
symptomatic period of ≥48 hours. 
For the open-label phase (LAQ/5063 OL) only one neurologist/physician is required (Study 
Neurologist/Physician) to perform a neurological examination and treat the subject as needed.
Relapse Determination
The Study Neurologist/Physician will make the decision as to whether the neurological change is 
considered a relapse, based on EDSS/FS scores (see Relapse Definition, Appendix 1).
Follow-up visits to monitor the course of the relapse will be made at the Study
Neurologist/Physician discretion, in addition to the assessment at the next scheduled visit.
In the case of an ongoing or just-started relapse at the study termination visit (Week 36)/early 
discontinuation visit, subjects will be followed up until the end of the relapse, wherever possible 
(see Section 7.3.3).
8.2.
Safety Assessment Methods
8.2.1.
Physical Examination
The Study Neurologist/Physician will perform a full examination at every visit.


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8.2.2.
Emphasis on Physical Examination
In light of the potential proinflammatory effect of laquinimod, and to appropriately monitor its 
early manifestations, physical examinations will be conducted on a regular basis with emphasis 
on clinical clues of proinflammatory manifestations. 
8.2.3.
Vital Signs and Weight
Vital signs (temperature, pulse and blood pressure) will be completed at all scheduled and 
unscheduled visits.
Blood pressure and pulse will be recorded in a sitting position after resting for 5 minutes. If the 
result appears not to be logical, the measurement will be repeated after an additional 5 minutes of 
resting and the result will be recorded in the CRF.
All measurements and times of measurements will be recorded on the source document.
Body weight will be measured at baseline (termination visit of core study LAQ/5062) and at 
Termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as 
requested by the Sponsor) /early discontinuation visit. For the open-label phase weight will be 
measured at all visits, and as long as the subject continues study drug treatment.
8.2.4.
ECG
ECGs will be performed at each study visit. For the open-label phase (LAQ/5063 OL) ECG will 
be performed at Months 1, 2, 3, 6, 12, 18 and 24. Following completion of Month 24, ECGs will 
be performed every 6 months.
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 
(PCS) 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.


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73
8.2.5.
Safety Laboratory Evaluations
Unless specified otherwise all laboratory testing will be performed by a central laboratory 
facility. In cases in which close-follow-up is required, as described in Appendix 10, certain tests 
may be performed in a local laboratory.
Laboratory tests (including pregnancy test for women of child bearing potential) will be 
performed at each scheduled study visit (in unscheduled visit upon need).
The following tests will be performed:
* Those tests may also be performed in a local lab according to the Safety Monitoring Guideline.

Serum Chemistry

Glucose

Creatinine (including GFR estimation)

Bilirubin (direct and total)*

Urea

AST (SGOT)*

ALT (SGPT)*

GGT*

Lipid profile (total cholesterol, high density lipoprotein [HDL], low density 
lipoprotein [LDL], triglycerides) under fasting conditions.

Pancreatic Amylase

Lipase will be tested in case of abnormal pancreatic amylase result (see 
Appendix 10 for guidance on monitoring subjects with elevated pancreatic 
amylase levels)

Total Protein*

Albumin*

Alkaline Phosphatase*

hs-CRP

CPK


Amended Protocol following Global Amendments 01 to 10
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74
o
In case of abnormal CPK result: troponin and CPK-MB will be tested
o
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

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. 
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.

Electrolytes

Sodium

Potassium

Phosphorous

Calcium

Coagulation

Fibrinogen

INR (to be performed in local laboratory, only if required according to Safety 
Monitoring Guidance, in Appendix 10

Hematology

Hemoglobin

MCH

MCV

MCHC

Hematocrit

Red Blood Cells (RBC)


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75

White Blood Cells + differential count*

Platelets count

Serology (to be performed only in a confirmed abnormality of liver enzymes, 
according to Appendix 10):

Anti-HAV IgM antibodies

Hepatitis B Surface antigen

Anti-HBc IgM antibodies

Anti- HCV IgG antibodies

Anti-nuclear antibodies

Anti-Smooth Muscle (Sm) antibodies

Anti-Liver-Kidney Microsomal (LKM)-1 antibodies
Same laboratory evaluations will be performed for LAQ/5063 OL phase.
8.2.5.1.
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
8.2.6.
Adverse Events
At each study visit, all AEs will be identified and documented as detailed in Section 10 of this 
protocol.


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8.2.7.
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.
8.2.8.
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 
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 7.3.4.1.5).
8.2.9.
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 7. In addition, an evaluation should take place as soon as possible for subjects already in 
the study, following approval of Amendment #10.
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.
8.3.
Assessment of Subject Compliance
At each study visit, the Investigator, Site Coordinator and/or pharmacist will assess the subject’s 
compliance with the study requirements. This will include checks of protocol compliance and 
use of laquinimod.
The subject will return all unused tablets and/or capsules (following the switch to capsules) in 
their original packages, blisters/bottles and all used partially empty and empty blisters/bottles 
and unused IMP at each visit to the study. Compliance with the dosing regimen will be 
determined by performing IMP accountability of returned blisters/bottles of the IMP used and 
unused. The number of unused tablets/capsules will be recorded on the CRF by site personnel. 
Percent compliance will be calculated as the number of used tablets/capsules divided by the 
number of total tablets/capsules expected to be used, multiplied by 100.
Subjects with less than 75% overall compliance during the entire study will be considered non-
compliant, although they will continue to be followed-up and included in the intent-to-treat (ITT)
cohort. Subjects who fail to comply with the study requirements may be withdrawn from the 
study, following consultation with the Sponsor.
8.4.
Ancillary Studies
The Ancillary studies are relevant for LAQ/5063 active double-blind phase only.


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77
8.4.1.
Pharmacokinetic Sub-Study 
Blood samples for of PK evaluation will be performed in a sub-set of countries and sites.
For PK evaluation blood sample (2 mL/each) will be collected from subjects at one time point 
prior to first administration of the IMP (one day after randomization into LAQ/5063), and on 
Week 36 at the following time points: pre-dose and at 10, 30, 45, 90 minutes, 3, 6, 24 hours and 
72 hours (day 3 post-study termination), 144 hours (day 6 post-study termination), 240 hours 
(day 10 post-study termination) and at 336 hours (day 14 post-study termination). The blood 
samples will be collected into tubes containing sodium heparin. All participants in this study 
should administer the IMP dose at the same time in the morning.
8.4.2.
Population Pharmacokinetic (PPK) Study
Blood samples for PPK study will be collected in all study sites. Subjects participating in PPK 
study are not necessarily participating in PK sub-study.
For PPK evaluation, 1 blood sample (2 mL/each) will be collected from subjects Week 36/Early 
Termination. The date and time of the blood sample, as well as the date and time of the last dose 
prior to the sample will be recorded on the CRF. A review of the treatment compliance will 
include information on the last week compliance regarding tablets intake. The blood samples will 
be collected into tubes containing sodium heparin.
8.4.3.
Samples Handling for PK and PPK studies
Plasma will be separated by centrifugation at nominally +4°C. Deviations from the blood 
sampling times will be recorded in the appropriate CRFs. Samples will be prepared by the site 
and sent frozen to the central laboratory for storage at -70°C. Samples for PK evaluation will be 
sent periodically to an analytical facility for analysis. The analytical facility is:
Teva Pharmaceutical Works Co. Ltd.
Innovative R&D
Bioanalytical Laboratory
Pallagi St. 13
Debrecen
4042 Hungary
8.4.4.
Bioanalysis
The concentrations of laquinimod will be determined in blood plasma using LC-MS/MS (Liquid 
Chromotography Tandem Mass Spectrometry) in accordance with the ABR-method M-0085A. 
Quantitation will be based on an internal standard, a stable isotope of laquinimod containing six 
13C atoms. The plasma will be prepared for injection onto the LC-MS/MS system by protein 
precipitation.


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78
8.4.5.
Pharmacokinetic Calculation
For calculation of the PK parameters, WinNonlin professional will be used. The PK parameters 
for each individual will be determined. The maximum plasma concentration (Cmax) and the time 
to maximum plasma concentration (tmax) values will be determined from the observed plasma 
concentration-time curve as the maximum concentration and the corresponding time after each 
sampling period. The elimination rate constant (λ) at steady rate will be estimated by linear 
regression analysis of the terminal slope of the logarithmic plasma concentration-time curve. The 
area under the plasma concentration-time curve will be calculated by using the linear/logarithmic 
trapezoidal rule. Time dependency will be evaluated by fitting a compartmental model to the 
data for each subject. An additional analysis will be performed by fitting a population model to 
the data and possible time, dose and sex dependencies will be investigated.


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79
9.
INVESTIGATIONAL MEDICINAL PRODUCT
9.1.
Description 
Laquinimod 0.3 mg tablets and/or matching placebo tablets will be administered to the subjects.
Laquinimod 0.3 mg tablets are white to off-white round biconvex tablets.
The active tablets contain laquinimod sodium salt equivalent to 0.3 mg laquinimod. All inactive 
ingredients (excipients) are pharmaceutically acceptable. Matching placebo tablets contain no 
active ingredients. The matching placebo tablets will be identical in color and appearance to the 
tablets containing 0.3 mg of laquinimod.
Study drugs will be supplied to the study sites by Teva Pharmaceutical Industries, Ltd., through a 
distribution center.
The placebo paragraph is relevant for LAQ/5063 active double-blind phase only.
Upon approval of the Global Amendment # 4 to Protocol LAQ/5063 the IMP were switched 
from laquinimod tablets 0.3 mg, administered as two tablets once daily, to laquinimod capsules 
0.6 mg. The clinical dosage remains unchanged at 0.6 mg of laquinimod, administered orally 
once a day.
9.2.
Assignment of Treatment
At baseline (termination visit of core study), after meeting the inclusion/exclusion criteria, 
assignment of a subject to a treatment group will be performed by the Interactive Voice 
Response system (IVRS) according to the randomization scheme produced by Teva Global 
BioStatistics and Global BioMedical Informatics units. The subject number remains as in the 
core study.
The assignment of treatment is relevant for LAQ/5063 active double-blind phase only.
9.3.
Investigational Medicinal Product Manufacturing
Siegfried Ltd., is the manufacturer of laquinimod tablets. Manufacturing was carried out in 
accordance with GMP applicable to IMPs.
The new study drug, laquinimod capsules 0.6 mg, which will be introduced during the open label 
phase of LAQ/5063 OL upon approval of Amendment # 4, is manufactured in compliance with 
current GMP standards by Teva Pharmaceutical Industries Ltd. Israel. 


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80
9.4.
Packaging And Labeling
Laquinimod 0.3 mg tablets and their matching placebo will be packaged into PVC-PVDC 
blisters. The blisters will be packed into monthly packs which will be assigned to subjects by 
using an IVRS.
The CSU at Teva Pharmaceutical Industries, Ltd., Israel, will be responsible for secondary
packaging, labeling and distributing of study drugs, according to EU regulations. These activities 
will be carried out by a sub-contracted company (Clinical Research Organization [CRO]).
Study drugs will be packed and labeled in a way that meets the regulatory requirements and 
maintains the blinded nature of the study.
The label of the monthly pack will include fixed information section to include for example the 
product name, storage conditions, instructions etc…) and variable information section. The 
variable information section will include 3 parts: one detachable part, which will be attached to 
the source document upon pack dispensing, 1 part will be attached to the prescription form 
(where applicable) and 1 part to remain on the pack. The variable information section will 
include the following variable data: batch code, pack number, and expiration date (all to be pre-
printed) and blank fields for investigator name, visit number and subject number. These blank 
fields will be manually filled-in by the Investigator upon provision of pack to the subject.
At each scheduled visit (except for termination visit), the subject will receive one or more 
monthly pack/s (according to visit duration). The amount of study drugs dispensed will suffice 
until the following dispensing visit.
The placebo, IVRS and blinding paragraphs are relevant for LAQ/5063 active double-blind 
phase only. For the open-label phase (LAQ/5063 OL) a batch number will be allocated instead of 
a batch code number.
The replacement of the current drug supply, laquinimod tablets 0.3 mg, with laquinimod capsules 
0.6 mg during the open label phase of LAQ/5063 OL, the process of packaging and labeling will 
be changed to the following:
The study drugs will be 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 at a Teva Pharmaceutical Industries Ltd. plant. The 
secondary packaging and labeling for subjects is performed under the responsibility of the 
Clinical Supply Unit of Teva Pharmaceutical Industries Ltd, according to European Union (EU) 
regulations and International Conference on Harmonization (ICH) guidelines as adopted by the 
FDA – Good Clinical Practice (GCP) (E6).
Each bottle will be identified by a unique bottle number that will be defined by sequential lists 
produced by Teva. 


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81
The label on the bottles will include a fixed information section (to include the product name, 
storage conditions, instructions etc.) and variable information section. The variable information 
section will include 3 parts: 2 detachable parts, which will be attached to the subject’s file upon 
bottle dispensing and 1 part to remain on the bottle. 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 investigator 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
Export and import of IMPs will be carried out according to the provisions of Directive 
2001/20/EC, Article 13.
Distribution and shipment of IMPs will be performed by a sub-contracted distribution CRO in 
appropriate shippers to maintain the required storage conditions of the study drugs. For the 
laquinimod capsules, bottles will be packed and shipped at room temperature in appropriate 
storage boxes.
Each shipment of IMPs supplies for the study will contain a shipment form describing the 
contact of shipment. This form will assist in maintaining current and accurate inventory records. 
When a shipment is received, the Investigator/Coordinator/pharmacist will acknowledge receipt 
of the IMPs supply by making ‘Shipment Activation Call’ (via the IVRS) and by signing on the 
shipment form and faxing it back to the distribution center (where applicable). For the open-label 
phase (LAQ/5063 OL) IVRS will not be used. Laquinimod 0.6 mg daily dose will be available at 
the sites.
If, upon arrival at the investigational site, the IMPs supplies appear to be damaged, the CSU 
should be contacted immediately.
9.6.
Storage, Dispensing and Return
IMP supplies must be kept in a secure, limited-access, refrigerated (2° -8°C) and controlled 
storage area. 
Only authorized personnel will have access to the IMP supplies.
The study site personnel at each site will be responsible for correct storage and handling of the 
study products. The IMPs supplies will be stored safely and properly in a temperature-controlled 
refrigerator (2°- 8°C), and must be kept under the prescribed conditions. The subjects should be 
instructed to store the IMPs (in their original package) in a refrigerator.
The IMP pack/s will be dispensed to the subject at the study site at each study visit starting at 
baseline visit (except for termination visit). The subjects will be instructed to administrate the 
study drugs once daily at approximately the same time of the day. The packs will be assigned to 
subjects by using an IVRS (this is relevant for LAQ/5063 active double-blind phase only). After 
assigning a pack number to the subject, the Investigator/Pharmacist/Coordinator should fill in 
manually the subject's number and investigator’s name on the label of the dispensed monthly 


Amended Protocol following Global Amendments 01 to 10
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pack, as well as on the detachable parts, which will be attached to the source document and 
prescription form (where applicable).
Subjects will be instructed to return all the empty blisters and unused study drugs in their original 
packs.
Upon approval of the Amendment #4 to LAQ/5063 the process will be changed to the following:
The IMP supplies which will be supplied in bottles must be stored at room temperature (15-
25ºC) in a limited access secured storage area.
The IMP bottles will be dispensed to the subject at the study site at each study visit following the 
approval of this amendment and the supply process which will follow the approval. The bottles 
will be assigned to subjects by the site personnel. 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 the subject will receive the amount of bottles of IMP according to visit interval, 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.
Route And Dosage Form
The following will be administered for each treatment group during the double blind phase:

0.3 mg group one white to off-white round biconvex tablet of 0.3 mg of laquinimod 
and one matching placebo tablet to be administered orally once daily.

0.6 mg group: two white to off-white round biconvex tablets of 0.3 mg of laquinimod 
tablets to be administered orally once daily.
For the open label phase (LAQ/5063 OL) all subjects will receive 0.6 mg of laquinimod: two 
white to off-white round biconvex tablets each of 0.3 mg of laquinimod to be administered orally 
once daily. Upon approval of Amendment # 4 for (LAQ/5063 OL) 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. 
9.8.
Verification of Compliance With Treatment Regimen
The subject will be requested to return all IMPs unused tablets/capsules (upon the switch to 
capsules following Amendment # 4 to LAQ/5063 protocol) in the original packages (blisters or 
bottles) to the study site at every visit.


Amended Protocol following Global Amendments 01 to 10
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83
Compliance with the dosing regimen will be determined by performing accountability of 
returned IMPs. The number of returned tablets (until the switch to capsules will occur)/capsules 
will be counted and recorded in the CRF by site personnel.
The subject number, pack number, batch code number, quantity of IMPs returned by the subject 
and visit date will be recorded by the site personnel. After the switch to the capsule formulation, 
batch number will be allocated instead of a batch code number.
The IMPs accountability records must be maintained at the site at all times.
Compliance will be calculated as a percentage by calculating the number of used capsules/tablets 
(tablets compliance will be calculated until the last tablets will be returned) divided by the 
number of total capsules/tablets(tablets compliance will be calculated until the last tablets will be 
returned) multiplied by 100.
Subjects with less than 75% overall compliance during the entire study will be considered 
non-compliant (see Section 8.3).
9.9.
Accountability
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, pack number, batch code 
number, quantity of IMPs returned by the subject and the date of accountability should be 
recorded on the appropriate accountability forms, to be provided by the CSU.
The IMPs accountability records must be maintained at the site at all times.
After accountability of returned study drugs is performed and recorded, all IMPs unused tablets
(all tablets should be returned upon the switch to capsules) /capsules must be returned by the 
monitor to the Sponsor or Sponsor’s designee for destruction.
Accountability forms, filled in by the Study Monitor, must be sent with the returned IMPs for 
verification and a copy is left at the site in the Investigator’s file.


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84
10.
SAFETY AND PHARMACOVIGILANCE
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 evaluation of conditions suggestive of 
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 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 labeling reference of this study is the IB.


Amended Protocol following Global Amendments 01 to 10
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85
The relationship to study treatment is characterized as in the below table until Month 60, 
inclusive:
TERM
DEFINITION
CLARIFICATION
Unrelated
This category applies to those AEs 
which, after careful consideration, 
are clearly and incontrovertibly due 
to extraneous causes (disease, 
environment, etc.)
Unlikely
In general, this category can be 
considered applicable to those AEs, 
which, after careful medical 
consideration at the time they are 
evaluated, are judged to be 
unrelated to the IMP.
An AE may be considered unlikely related if or when at least 
2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP.

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 
IMP.

It does not reappear or worsen when the IMP is re-
administered.
Possibly
This category applies to those AEs 
for which, after careful medical 
consideration at the time they are 
evaluated, a connection with the 
IMP administration appears 
unlikely but cannot be ruled out 
with certainty.
An AE may be considered possibly related if or when at least 
2 of the following apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

It could not readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the 
subject.

It follows a known pattern of response to the IMP.
Probably
This category applies to those AEs 
which, after careful medical 
consideration at the time they are 
evaluated, are felt with a high 
degree of certainty to be related to 
the IMP.
An AE may be considered probably related if or when at least 
3 of the following apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

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 AE 
does not disappear upon discontinuation of the IMP, 
yet IMP-relatedness clearly exists.

It follows a known pattern of response to the IMP.


Amended Protocol following Global Amendments 01 to 10
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86
The relationship to study treatment from Month 60 and thereafter is characterized as in the below 
table:
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 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 Reasonable Possibility 
related 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.
Serious Adverse Event
A SAE is defined as an AE that results in any of the following:

death

life-threatening

requires hospitalization or prolongs existing inpatients’ hospitalization


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
results in persistent or significant disability or incapacity

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.
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 should be recorded and reported immediately 
(cross reference to the Pharmacovigilance section). 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 last dose).
SAE Reporting
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 Local Safety 
Officer who will forward the SAE report to the Global Pharmacovigilance Unit:
SAEs originating in Europe and rest of the world should be sent to:
Global Drug Safety and Pharmacovigilance Unit (Israel)


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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
SAEs originating in Germany will be sent to:
Teva Germany safety mailbox
Only in the event of difficulty transmitting the form via email send the form to 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 contract 
research organization. 
For both initial and follow-up SAE reports the contract research organization forwards this 
information to the appropriate Pharmacovigilance unit at Teva or Local Safety Officer 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 contract research organization / Local Safety Officer 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 site number
2. Subject number
3. Clinical event:
a.
description
b. date of onset
c.
severity
d. treatment (including hospitalization)
e.
relationship to IMP (causality)
f.
action taken regarding IMP
4. If the AE was fatal:


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a.
cause of death (whether or not the death was related to the IMP)
b. autopsy findings (if available)
5. Medical History (copy)
6. Concomitant Medication (copy)
7. Any relevant reports (laboratory, discharge, x-Ray, etc) 
This information should be sent to the LCM/ Local Safety Officer 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. 
Pregnancy reports: Pregnancies should be reported throughout the study. This includes also 
normal pregnancies without AE. The pregnancy should be followed up 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. The pregnancies 
reporting procedure should be the same as the SAE reporting procedure.
Pregnancy follow-up should be recorded on a specific CRF provided by CRO.
10.1.
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.


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11.
STATISTICAL METHODOLOGY
A total of up to 264 subjects, randomized to treatment with 0.3 mg or 0.6 mg of laquinimod, are 
expected to be recruited into this double-blind, multi-national trial. The trial is planned for 36 
weeks of double-blind treatment.
All data summaries in this trial will be presented by treatment group.
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.
11.1.
Sample Size Rationale
Subjects that completed protocol LAQ/5062 will be eligible for inclusion in this trial. LAQ/5062 
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 264 subjects. 
11.2.
Randomization Procedure
The randomization scheme for this trial is based on the randomization scheme of protocol
LAQ/5062, where each subject was allocated to one of the 3 treatment groups: Laquinimod 
0.6 mg, Laquinimod 0.3 mg or placebo.
In this trial the subjects allocated to Laquinimod 0.6 mg and Laquinimod 0.3 mg groups will 
continue to receive the same treatment, while the subjects allocated to the placebo group will be 
randomized to receive either Laquinimod 0.6 mg or Laquinimod 0.3 mg.
The randomization scheme for LAQ/5062 placebo group, employing a 1:1 treatment assignment 
ratio, using blocks stratified by centers, will be prepared by Teva Global BioStatistics and Global 
BioMedical Informatics units. The scheme will be generated using SAS® PLAN procedure. The 
randomization list and the seed used to generate it will be kept sealed in a fire-protected safe. 
This randomization process generates a new 2:2:1:1 treatment assignment ratio, where the 
assignments are:

Subjects who were treated by Laquinimod 0.6 mg in both LAQ/5062 and LAQ/5063 
studies.

Subjects who were treated by Laquinimod 0.3 mg in both LAQ/5062 and LAQ/5063 
studies.

Subjects who were treated by placebo in study LAQ/5062 and by Laquinimod 0.6 mg
in study LAQ/5063.


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
Subjects who were treated by placebo in study LAQ/5062 and by Laquinimod 0.3 mg
in study LAQ/5063.
Because there is no obligation of LAQ/5062 subjects to enter this study, there is no guaranty that 
the 2:2:1:1 randomization scheme will be kept.
In the open-label phase, all subjects will receive laquinimod 0.6 mg daily
11.3.
Subjects Cohorts
A single data cohort is defined for this clinical trial. This cohort is:
ITT: Consists of all subjects who have been randomized 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.
11.4.
Efficacy Assessment
11.4.1.
Number of enhancing lesions on T1-weighted images taken on Week 36
Descriptive statistics of the number of enhancing lesions on T1-weighted images taken on 
Week 36 and change from LAQ/5062 baseline and LAQ/5063 baseline to Week 36 will be 
presented by treatment group. 
11.4.2.
The number of new T2 lesions on scan taken on Week 36
Descriptive statistics of new T2 lesions measured on Week 36, with reference to the previous 
visit performed under LAQ/5062 protocol, will be presented by treatment group.
11.4.3.
The volume of T2 lesions on scan taken on Week 36
This endpoint will be analyzed using the same methodology outlined for the number of 
enhancing lesions on T1-weighted images taken on Week 36 (see Section 11.4.1).
11.4.4.
The number of new hypointense lesions on enhanced T1 scans taken on 
Week 36
Descriptive statistics of the number of new hypointense lesions on enhanced T1 scans taken on 
Week 36, with reference to the previous visit performed under LAQ/5062 protocol will be 
presented by treatment group. 
11.4.5.
The proportion of subjects with no enhancing lesions on Week 36
The counts and percentages of subjects with no enhancing lesions on Week 36 will be presented 
by treatment group.


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11.4.6.
The total number of confirmed relapses 
Descriptive statistics of the total number of confirmed relapses will be presented by treatment 
group. 
11.4.7.
The proportion of relapse-free subjects
A subject that did not experience any relapse during the treatment period will be considered as a 
responder for the purpose of this analysis.
The counts and percentages of relapse-free subjects will be presented by treatment group.
11.4.8.
EDSS scores
Descriptive statistics of the EDSS scores, will be presented by treatment group and visit.
11.4.9.
Categorical change from baseline in EDSS Score
A subject's EDSS change is defined as the difference between the subject's EDSS score at 
Baseline, and his or her last non-Baseline recorded EDSS score. EDSS changes will be classified 
as "Worsening", "Unchanged" or "Improvement".
The counts and percentages of subjects in each category will be presented by treatment group 
and visit.
In addition, counts and percentages of the categorical change from study LAQ/5062 baseline will 
be presented.
11.5.
Safety And Tolerability Assessments
11.5.1.
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 treatment group, gender, age, maximal severity, maximal outcome, 
maximal action taken and maximal relationship to the tested drug. 
SAEs and seriousness criteria will be listed and discussed on a case by case basis.
11.5.2.
Laboratory Data
The incidence of laboratory tests outside the normal range and the incidence of measurements of 
potential clinical significance will be presented by treatment group. Shift analysis of these counts 
from LAQ/5062 baseline and LAQ/5063 baseline will also be provided. Descriptive statistics as 
well as their changes from LAQ/5062 baseline and LAQ/5063 baseline, will also be presented by 
study group.


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11.5.3.
ECG
The incidence of abnormal measurements will be presented by treatment group. Shift analysis 
from LAQ/5062 baseline and LAQ/5063 baseline will be provided as well. Descriptive statistics, 
as well as, their changes from LAQ/5062 baseline and LAQ/5063 baseline, will also be presented 
by study group. 
11.5.4.
Vital Signs 
Incidence of measurements of potential clinical significance will be presented by study group. 
Shift analysis from LAQ/5062 baseline and LAQ/5063 baseline will be provided as well. 
Descriptive statistics of vital signs, as well as, their changes from LAQ /5062 baseline and 
LAQ/5063 baseline, will be presented by study group.
11.5.5.
Drug Tolerability & Drop-Out Assessment
The number and percentage of subjects who failed to complete the study will be presented by 
treatment groups. 
The number and percentage of subjects who prematurely discontinued from the study due to AEs 
will be presented by treatment groups.


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12.
REGULATORY AND ETHICAL ISSUES
12.1.
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 GCP in the conduct of clinical trials on medicinal products for 
human use, as applicable by national legislation and directives, including Directive 2001/20/EC 
of the European Parliament and the Council of the EU.
12.2.
Informed Consent
The principles of Informed Consent, according to the ICH step 5 guidelines on GCP, and/or EU 
Directives, will be followed. A subject should not enter a clinical study or perform any study-
related procedures 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 approved 
informed consent form.
A signed copy of the consent form will be given to the subject and the original will be 
maintained at the site following the signing and dating by the person administering the consent 
and witness (where appropriate).
A copy of the proposed consent form must be submitted to the EC, together with the protocol, 
and approved prior to study start.
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).
12.3.
Ethics Committee
The EC has to issue a favorable opinion in order to allow the start of the clinical trial. Teva must 
receive, prior to site initiation, a copy of the written EC opinion which contains specific 
identification of the documents approved.
Any substantialm 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 sent 
to the EC and written opinion has to be provided to Teva. Records of the EC review and opinion 
of all documents pertaining to this study must be kept on file by the Investigator and are subject 
to regulatory authority and/or Sponsor inspection during or after completion of the study. SAEs 
must be reported to the EC by the Sponsor.
                                                
m as defined in the EU in the “Detailed guidance for the request for authorization of a clinical trial on a medicinal 
product for human use to the competent authorities, notification of substantial amendments and declaration of the 
end of the trial” (ENTR/CT April 2004)


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Periodic status reports must be submitted to the EC 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 must be sent to the Sponsor.
12.4.
Protocol Amendments
For clinical trial sites located in EU member states, the procedures outlined in Directive 
2001/20/EC, Article 10(a), are applicable. Elsewhere, the country regulations apply.
12.5.
Declaration Of The End Of The Clinical Trial
For clinical trial sites located in EU member states, 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). 
Elsewhere, the country regulations apply.
12.6.
Subject Confidentiality
The Sponsor is concerned about the individual subject’s privacy; therefore, all subject data will 
be identified by a subject identification number. The data will be blinded correspondingly in all 
data analyses. However, after receiving the subject’s approval (by signing the Informed 
Consent), it is required that the Investigator permit the Study Monitor, independent auditor or 
regulatory agency personnel (with or without the Investigator) 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 test result 
reports; admission/ discharge summaries for hospital admissions occurring while the subject is in 
the study; and autopsy reports for deaths occurring during the study (where applicable).
The subject's authorization allows Teva to receive and review the subject’s protected health 
information which may be re-disclosed to any authorized representative of Teva or central 
laboratory facility for review of subject medical records in the context of the study.
12.7.
Liability And Insurance
A Certificate of Clinical Trials Insurance will be provided to the study sites by Teva
Pharmaceutical Industries, Ltd in addition to the local certificate, as per local regulations. 


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13.
DOCUMENTATION
13.1.
Study File And Site Documents
Prior to the initiation of the study, the following documents must be provided to Teva 
Pharmaceutical Industries, Ltd.:
1. Confidentiality Agreement signed by Principal Site Investigator (PSI)
2. Copy of the protocol, amendments and notifications (if applicable), signed by the PSI
3. The PSI's curriculum vitae
4. Signed Clinical Study Agreement with site
5. EC written opinion for the protocol, amendments, informed consent, subject information 
sheet (if applicable), advertisements (if applicable) and membership list 
6. CA written opinion (if applicable)
7. Hospital Management opinion (if applicable)
8. PSI’s financial disclosure information
13.2.
Site Documents/Equipment Supplied By The Sponsor
Prior to the initiation of the study, the Sponsor will supply the Site Investigator with the 
following items, in addition to the protocol:

Current version of the IB

Central Laboratory certification and normal range values

Portable Computer for Data Capturing (including Oracle Clinical Remote Data 
Capture [RDC®] application; see Section 13.4)

A hard copy of the electronic CRF in PDF format

User Manual for the RDC®

Regulatory Binder

Informed Consent Template

Insurance Certificate


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
Subjects study binder, including source pages to be used during the study if hospital 
clinic office records are not used.
13.3.
Maintenance And Retention Of Records
It is the responsibility of the Site Investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation.
Site 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:

at least 2 years from the last marketing approval worldwide, or for at least 15 years, 
whichever is the greater; or

longer if required by local regulations
The Site Investigator will be instructed to consult with Teva before disposal of any study records 
and to notify Teva of any change in the location, disposition or custody of the study files.
At the end of the study, the sponsor will supply the site investigator a copy of the site's subjects 
electronic CRF in PDF format.
13.4.
Data Handling
13.4.1.
Electronic Case Report Form
Teva will provide each study site with one hard copy of the reference template for data collection 
tools.
Data will be entered at the site by the Site Investigator, Study Coordinator or the Site 
Coordinator, using the validated Oracle Clinical RDC® application, which provides a framework 
for entering clinical data on a CRF. The RDC® application is integrated with the Teva clinical 
data management validated system that is 21 CFR part 11 compliant (Oracle Clinical®).
The electronic CRFs 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 subject screened or enrolled 
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 and addresses (i.e., Subject 
Identification Record, see Section 13.5).
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 Clinical Research Associate (CRA)/monitor. Each 
entry will be monitored by the CRAs, Clinical Data Quality Control (CDQC) and the Data 
Management (DM) personnel. Once all the CRFs for a subject have been approved, verified, 


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reviewed and cleaned, the subject's CRFs will be locked. Site Investigators, Site Coordinators, 
CRAs, CDQC personnel, 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.

CDQC and DMs: data updating, discrepancy handling, data locking

QA: read only for data audit
13.4.2.
Coding
AEs and Medical History that are entered into the clinical data management systems will be 
coded using MedDRA. Medications that are entered into the clinical data management systems
will be coded using the World Health Organization Drug Dictionary (WHO Drug).
13.4.3.
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 data management 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.
13.4.4.
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. 


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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.
13.4.5.
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 data management 
and data analysis purposes.
13.4.6.
Source Documents
Prescription forms, label logs, laboratory test results, ECG strips and all other source documents 
should be maintained and kept at the study site in the subject study binder.
13.5.
Additional Documents And Records
Subject Screening and Assignment Log – reflects any subject who has signed the informed 
consent.
Subject Identification Record – allows linking of subject's study number, name and date of birth
for those subjects who were randomized to the study - to be kept only at the Site Investigator’s 
site.
IMP Inventory/Shipment Form – reflects the total amount of IMP shipped to the site and 
received and acknowledged by the Site Investigator, pharmacist or designee.
IMP Accountability Log – reflects the total amount of IMP dispensed to and returned by each 
subject.
Informed Consent Forms – must be available for each subject and verified for proper 
documentation.
13.6.
Protocol Modification
The procedures defined in the protocol and in the CRF will be carefully reviewed to ensure that 
all parties involved with the study fully understand the protocol. In order to ensure the validity of 
the data, with minimal exceptions, no deviations from the protocol may be made unless the issue 
is broad enough to warrant changes in writing from the Sponsor and the EC/IRB prior to 
implementation.


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14.
QUALITY ASSURANCE AUDITS/INSPECTIONS
14.1.
Good Clinical Practice
The study described in this protocol will be carried out according to internationally accepted 
standards of GCP. 
Laboratory tests/evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards.
14.2.
Quality Assurance Program
This clinical trial may be audited according to the Teva QA audit program.
The purpose of these audits is to determine whether or not the study is being conducted and 
monitored in compliance with the protocol as well as recognized GCP guidelines and 
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 arranged and conducted within a reasonable time frame.
14.3.
Regulatory Inspections
The study site may be inspected by regulatory agencies. These inspections may take place at any 
time during or after the study and are based on the local regulations, as well as ICH guidelines.
The CA of the EU member states concerned may request verification of compliance with GCP 
and GMP. In accordance with the provisions of Directive 2001/20/EC, Article 15, inspections by 
the CA may be conducted at the trial sites, the manufacturing site of the IMP, any laboratory 
used for analyses and/or the Sponsor's premises.


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15.
STUDY MONITORING
15.1.
Monitors And Monitoring Visits
The Study Monitor/CRA will be responsible for ensuring adherence to local regulations, EU 
Directives (where applicable), ICH guidelines and the Sponsor’s SOPs. Study Monitors for this 
trial will be provided by the Sponsor or Sponsor’s designee (in Germany, Spain, Czech Republic 
and Russia). The Monitors will operate according to the EU Directives and in compliance with 
ICH guidelines, as well as local regulations and Sponsor’s SOPs.
Sponsor Monitors and/or Monitors from CROs will be trained to monitor the study. They will be 
trained on ICH GCP guidelines, the Sponsor’s SOPs, study protocol, the use of RDC® and the 
study monitoring conventions.
Regular monitoring of study data at each site will be performed in accordance with applicable 
regulations. Individual sites will be monitored to ascertain that enrollment rate, data recording 
and protocol adherence are satisfactory. The frequency of monitoring individual sites may 
fluctuate depending upon enrollment rate and the quantity of data collected and will be 
documented in the monitoring plan.
These monitoring visits will be performed for the purposes of verifying adherence to the protocol 
and the completeness and exactness of data entered on the CRFs. 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 IMP accountability. The Monitor will review the 
progress of the study with the Site 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 or 
resolve data clarifications. Adequate time and space for these visits will be made available by the 
Site Investigator.
15.2.
Primary Source Documents
The Site Investigator must maintain primary source documents supporting CRF data entries. 
These documents, which are considered “source data,” should include documentation of:

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 Site 
Investigator(s); occurrence (or lack) of AEs; and changes in medication usage, 
including the date the IMP was commenced and completed

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 Site Investigator must also retain all subject-specific printouts, reports of tests and 
procedures performed as a requirement of the study. During monitoring visits, the Monitor will 
need to verify data in the CRFs against these source data.


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16.
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.
16.1.
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


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
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.
16.2.
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.
16.3.
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 10).
16.4.
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


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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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17.
USE OF INFORMATION AND PUBLICATIONS
17.1.
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 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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18.
STUDY PERSONNEL
A complete list of contact details of all study personnel and sites will be supplied to the Sponsor.
18.1.
Study Principal Investigator
The Study Principal Investigator is the head of the Clinical Steering Committee (CSC) and, as 
such, acts as the primary consultant on issues of safety, protocol adherence, study conduct and 
special cases regarding subject eligibility. He/she also motivates sites regarding recruitment.
18.2.
Country Principal Investigator
The Country Principal Investigator fulfills the same functions as the Study Principal Investigator, 
for his/her particular country.
18.3.
Investigative Site Personnel
At each study site, the staff will consist of a minimum of two neurologists/physicians, MRI 
radiologist, MRI technician and a Clinical Coordinator (who can be a nurse or a physician). One 
of the neurologists will serve as the PSI. His/her responsibilities are described below. For the 
open-label phase (LAQ/5063 OL) only one neurologist/physician is required and the other 
neurologist/physician will serve as back-up. 
18.3.1.
Principal Site Investigator
At each investigation site, a neurologist will be appointed to serve as the PSI 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 PSI will 
oversee the accrual of appropriate subjects, the conduct of the study according to the trial 
protocol, communication with the EC and collection of required data. The PSI may function as 
either the Treating or Examining Neurologist (see below).
18.3.2.
The Neurologist/Physician
For the open-label phase (LAQ/5063 OL) only one neurologist/physician is required (Study 
Neurologist/Physician).
18.3.3.
The MRI Radiologist and Technician
Applicable only for the LAQ/5063 study and the first 24 months of the open-label phase of the 
LAQ/5063 study.
The radiologist will be responsible for determining the subject’s capability to undergo MRI 
scans; the performance of the MRI scan according to the protocol guidelines for the entire 
duration of the study; and the preparation of adequate hard copies and electronic material. He/she 
will also be responsible for the quality of such material as well as for providing adequate storage 


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and back-ups of the primary data at the site. The MRI scans will be transferred in electronic 
format only to the MRI-AC.
The MRI technician is responsible for performing the MRI scans according to the protocol; 
preparing the hard and electronic copies; and performing the required back-ups and 
documentation of such procedures.
18.3.4.
The Clinical Coordinator
A nurse or physician will be responsible for subject scheduling. He/she will instruct the subject 
on proper laquinimod administration; collect and forward blood samples and requests to the 
appropriate laboratories; obtain and forward laboratory results; and assist all site study staff.
18.4.
The Sponsor
The list of Sponsor Personnel and Sponsor Representatives is no longer applicable see Section 21
and Appendix 8.
18.4.1.
Corporate Clinical Study Leader
The Corporate Clinical Study Leader is responsible for the day-to-day study activities at a 
corporate level; for ensuring good conduct and adequate resources; and for providing high-
quality study management and data management.
18.4.2.
BioStatistics and BioMedical Informatics 
Global BioStatistics and Global BioMedical Informatics Units are responsible for the 
randomization scheme, adequate performance of the data management application (RDC); the 
conduct of the routine data management 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.
18.4.3.
Clinical Operations (Corporate Coordination Center)
Teva Clinical Operations will manage the day-to-day operations of the trial at a corporate level. 
Teva will also be responsible for, among other things, 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.
18.4.4.
Local Clinical Management (LCM)
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 
data management.


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18.4.5.
Clinical Research Associate (CRA)
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 15.1 in this protocol for detailed monitoring activities.
18.4.6.
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.
18.4.7.
Medical Monitor
The Medical Monitor is responsible for periodically reviewing the safety data to include AEs and 
laboratory values.
18.4.8.
Global Operations Manager
Will manage the day-to-day operations of the trial and will also be responsible 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. 


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19.
STUDY COMMITTEES
19.1.
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 Appendix 9. 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
19.2.
Clinical Steering Committee (CSC)
The CSC members (see Appendix 7) will consist of all Country Principal Investigators and will 
be responsible for day-to-day study conduct issues in their relevant countries:

Assist in selection of qualified and experienced sites

Assist in design of protocol, CRF and other documents

Review subject eligibility criteria if needed

Follow-up enrollment rate

Assist sites for protocol adherence

Assist in regulatory submissions

Assist in review of publication
19.3.
Data Safety Monitoring Board (DSMB)
This section is no longer applicable - see Section 21.


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20.
INVESTIGATOR’S AGREEMENT
I have read this clinical protocol, number LAQ-5063 and the Amendments 1 to 10:
An active extension of LAQ/5062 study- multinational, multi-center, randomized, double-blind, 
parallel-group study, to evaluate the safety, tolerability and efficacy of two doses (0.3 mg and 
0.6 mg) of laquinimod, orally administered in relapsing remitting (R-R) MS subjects, followed 
by an open-label phase of laquinimod 0.6 mg daily (LAQ/5063 OL).
I agree that it contains all the necessary details for conducting this study.
I will conduct the study as outlined therein. I will provide copies of the protocol and all 
information regarding LAQ-5063 active double-blind phase and open-label phase as stated in the 
Investigator's Brochure, furnished to me by the Sponsor, to all relevant staff/members. I will 
discuss this material with them to ensure they are fully informed regarding LAQ-5063 active 
double-blind phase and open-label phase and the conduct of the study. I agree to keep records on 
all subject information (Case Report Forms and subject’s Informed Consent statement), LAQ-
5063 active double-blind phase and open-label phase shipment and return forms, and all other 
information collected during the study for a minimum period of 2 years or otherwise as 
instructed by Teva or local regulatory authorities.
Investigator's Name : _____________________
(printed)
Date : __________________ Signature : _________________
(dd/mm/yy)
On behalf of Teva:
Name : _____________________
Title : ____________________
Date : _____________________ 
Signature :__________________
(dd/mm/yy)


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21.
RATIONALE FOR PROTOCOL AMENDMENT AND SUMMARY 
OF CHANGES
21.1.
Global Amendment #10
This is the 10th amendment to protocol LAQ/5063. At the time of issuance of this amendment 
there are 110 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, urine HCG test at termination/early discontinuation has been 
removed to make consistent with the text
These changes do not alter the study population or endpoints.
Rationales for the major changes are given below 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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Original text with changes shown
New wording
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 3.1.2. 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 enzymes
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 
IB
Section 3.2.3. Toxicology
In addition, an Finally, a small 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 
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
Updated for consistency 
with the IB


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Original text with changes shown
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Reason/Justification for 
change
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 IBwith 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 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.
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.
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. At doses of 0.6 and 1.2 mg, 
laquinimod is a weak inhibitor of CYP3A4 and a strong inducer of 
CYP1A2. For additional information, please refer to the IB.
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. At doses of 
0.6 and 1.2 mg, laquinimod is a weak inhibitor of CYP3A4 and a 
strong inducer of CYP1A2. For additional information, please 
refer to the IB.
Updated for consistency 
with the IB


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Original text with changes shown
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Reason/Justification for 
change
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.
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.
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 
Information regarding 
safety findings in the 
CONCERTO and 
ARPEGGIO studies


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Reason/Justification for 
change
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.
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 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 
Information regarding 
safety findings in the 
CONCERTO and 
ARPEGGIO studies


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Original text with changes shown
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Reason/Justification for 
change
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.
Section 3.4.2.2. Cancer
It is the Sponsor’s position that these findings are likely related to 
the administration procedure or tospecies-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
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, 
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, 
Information added on 
safety of 0.6 mg dose


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Reason/Justification for 
change
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. 
laquinimod manifested clinical evidence of myocardial 
infarction. 
Section 5.1. Overview and Plan
(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 6.1. Allowed Concomitant Medications
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 6) 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.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.
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 6) 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.
Wording made consistent 
with IB
Section 6.2. Disallowed Medications (During Study) (Other sections affected by this change: Section 7.3.3. Termination Visit)

IFNs IFN-β 1a or 1b
...

Moderate/strong inhibitors of CYP3A4; for example, 
ketoconazole and erythromyicin (see full list in 
Appendix 5) 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 

IFN-β 1a or 1b
...

Moderate/strong inhibitors of CYP3A4; for 
example, ketoconazole and erythromyicin (see full 
list in Appendix 5) 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 
Clarification


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New wording
Reason/Justification for 
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laquinimod exposure, respectively.
in laquinimod exposure, respectively.
Section 7.1. Study Period (Other sections affected by this change: Section 7.3.2. Scheduled Treatment Visits; Section 7.3.4.1.1. 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 7.3.3. Termination Visit
(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

Female subjects of child-bearing potential 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)

Female subjects of child-bearing potential 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.
Section 7.3.4. Criteria for Early Termination
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 LAQ-5063 OL 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 LAQ-5063 OL study.
Clarification
Section 7.3.4.1.2. 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


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Reason/Justification for 
change
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 7.3.4.1.3.Invasive Cancer (Other sections affected by this change: APPENDIX 10. GUIDANCE ON SAFETY MONITORING)
Subjects who are diagnosed with a malignant solid or liquid tumor
invasive cancer while participating in the study should stop study 
medication and discontinue their participation in the study drug.
Subjects who are diagnosed with a malignant solid or liquid 
tumor while participating in the study should stop drug.
Correction of 
terminology
Section 7.3.4.1.4.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 7.3.4.1.5.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 7.3.6. Unscheduled Visit
(new text)

For women of child bearing potential, serum or 
urine β-hCG test may be performed
Added to make 
consistent with study 
flow chart
Section 7.3.6.1. 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 8.2.5.1)

pharmacokinetic blood sample
Additional samples can 
be collected


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Original text with changes shown
New wording
Reason/Justification for 
change

sample for potential biomarker analysis
Section 7.3.6.1.1.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 7.3.6.1.2. 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 8.2.3. Vital Signs and Weight (Other sections affected by this change: Section 7.3.2. Scheduled Treatment Visits)
Body weight will be measured at baseline (termination visit of 
core study LAQ/5062) and at Termination visit of LAQ/5063 
active double-blind phase (completion of the full 36 weeks or as 
requested by the Sponsor) /early discontinuation visit. For the 
open-label phase weight will be measured at all visits, and as long 
as the subject continues study drug treatment.
Body weight will be measured at baseline (termination visit of 
core study LAQ/5062) and at Termination visit of LAQ/5063 
active double-blind phase (completion of the full 36 weeks or as 
requested by the Sponsor) /early discontinuation visit. For the 
open-label phase weight will be measured at all visits, and as 
long as the subject continues study drug treatment.
Weight will be measured 
at all visits
Section 8.2.5. Safety Laboratory Evaluations (Other sections affected by this change: Section 7.3.2. Scheduled Treatment Visits; Section 7.3.3. 
Termination Visit)

hs-CRP

hs-CRP
It is specifically hs-CRP 
that should be measured


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Reason/Justification for 
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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, 
subject will be re tested to ascertain true 
decrease. If true decrease, a thorough anemia 
work up will be done including:
o
Directed medical history and physical 
examination
o
Blood smear, serum iron, ferritin, total iron 
binding capacity, folic acid, B12, 
haptoglobin, interleukin (IL) 1, IL 6, IFN γ, 
TNF α, and hepcidin
o
Additional investigations and follow up per 
the 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

Glucose

Ketones

Blood, Erythrocytes, Leukocytes

Protein

Nitrite
(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 8.2.5.1. 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:

serum chemistry panel, including fibrinogen and 
hs-CRP

hematology panel

CPK-MB
Unscheduled samples can 
be collected for further 
investigation of clinical 
events of interest


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Reason/Justification for 
change

troponin I
Section 8.2.7. 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
Section 8.2.8. Glomerular Filtration Rate Estimation (Other sections affected by this change: Section 7.3.2. Scheduled Treatment Visits; Section 8.2.5. 
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 
7.3.4.1.5).
GFR estimation added to 
monitor renal function
Section 8.2.9. Cardiovascular Risk Assessment and Management (Other sections affected by this change: Section 7.3.2. Scheduled Treatment Visits)
(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 7. In addition, an evaluation should take place as soon as 
possible for subjects already in the study, following approval of 
Amendment #10.
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
Section 10.
SAFETY AND PHARMACOVIGILANCE (Other sections affected by this change: Section 12.6. Subject Confidentiality; Section 13.4.1.
Electronic Case Report Form; APPENDIX 3. MRI PROTOCOL)
The following information should be provided to accurately and 
completely record the event:
1.
Investigator name and site number
2.
Subject number
3.
Subject initials
The following information should be provided to accurately and 
completely record the event:
1.
Investigator name and site number
2.
Subject number
Subject initials and 
demographics should no 
longer be recorded


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Original text with changes shown
New wording
Reason/Justification for 
change
4.
Subject demographics
Section 10.1. 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 12.2. Informed Consent (Other sections affected by this change: Section 7.3.2. Scheduled Treatment Visits)
(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 16. 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.
For complaints involving a device or other retrievable item, it is 
Section added for 
consistency with 
sponsor’s current 
protocol template


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Reason/Justification for 
change
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 16.1. 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 16.2. 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 
Section added for 
consistency with 


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Original text with changes shown
New wording
Reason/Justification for 
change
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.
sponsor’s current 
protocol template
Section 16.3. 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 10).
Section added for 
consistency with 
sponsor’s current 
protocol template
Section 16.4. 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 3. MRI PROTOCOL

Check that the subject can successfully undergo MRI 
examination, including GFR estimation.

Check that the subject can successfully undergo 
MRI examination, including GFR estimation.
Added requirement for 
GFR estimation
APPENDIX 5. MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 INDUCERS
(section, including tables, updated to make consistent with current 
IB)
(see Appendix 5 for new wording)
Updated for consistency 
with current IB
APPENDIX 6.
LIST OF MEDICATIONS THAT SHOULD BE USED WITH CAUTION
(section, including tables, updated to make consistent with current 
IB)
(see Appendix 6 for new wording)
Updated for consistency 
with current IB
APPENDIX 10. GUIDANCE ON SAFETY MONITORING
(new text)
4. Guidance on Monitoring Subjects with Elevated Pancreatic 
Amylase Levels
Guidance updated for 
consistency with body of 


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New wording
Reason/Justification for 
change
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.
the protocol


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129
21.2.
Global Amendment #9
This was the ninth amendment to protocol LAQ/5063. At the time of issuance of this amendment 
117 subjects had taken part 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 given below 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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Previous approved wording
Amended or new wording
Reason/Justification for change
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 5.1: Overview and plan AND Section 7.1: Study Period AND Section 7.3: Detailed Study Plan
… until laquinimod 0.6 mg is commercially available 
for the treatment of MS or until the development of 
laquinimod 0.6 mg for MS is stopped by the Sponsor.
…. 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 0.6 mg.
Section 5.1: Overview and plan
Figure 4:
Study Flowchart 
Figure 5:
Study Flowchart For Open_Label Phase
Addition of Figure 1:
Treatment Groups in MS-
LAQ/5062 (Core Study) and the Double Blind 
and Open Label Phases of LAQ/5063 
(Extension Study)
Table 5:
Study Task Flow Sheet for Study 5063 
(Double-Blind Active Extension Phase) 
Table 6:
Study Task Flow Sheet for Study 5063 OL (up 
to Month 24) 
Study Task Flow Sheet for Study 5063 OL (Months 24 
onwards)
Figure 1 was added to clarify the 
relationship between the core study 
(MS-LAQ/5062) and the extension 
study (LAQ/5063).
The titles of Tables 5-7 were changed
to clarify which study phase they 
correspond to.
Section 7.3: Detailed Study Plan
None

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 potential 
teratogenicity and delayed risks for a child exposed 
Teva considers the prevention of 
exposure to laquinimod during 
pregnancy to be of great importance, 
and following consultation with the 
CHMP and Monitoring Committee 
(DMC) has decided to introduce 
additional language and measures for 
pregnancy prevention in this 
amendment and in a revised informed 
consent form. 


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Previous approved wording
Amended or new wording
Reason/Justification for change
in uterus to laquinimod
Female subjects of child-bearing potential 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)
To strengthen the preventative 
measures, the amended protocol now 
includes: 
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 serum 
beta hCG test prior to randomization.
In addition a new Section 
(Section 11.5.6 – Pregnancy) was 
added to include more data on the 
potential delayed risks following in 
utero exposure to laquinimod, subjects' 
counselling and assuring of subjects' 
understanding and ability to follow the 
required preventive pregnancy 
measures.
Table 6 AND Table 7 AND Section 7.3: Detailed Study Plan
None.
Activity added to all study visits: 
- Ascertaining the use of effective contraception
Section 7.3.4.1.2: Pregnancy
None.
See Section 7.3.4.1.2.
Synopsis AND Section 7.3.2: Scheduled treatment visits AND Appendix 10: Guidance on safety monitoring
In case of suspected pregnancy (positive urine β-hCG 
test result) 
In case of suspected pregnancy (positive urine β-hCG test 
result, delay of menstruation or any other reason 
suggesting pregnancy) 
Synopsis AND Section 2: Exclusion Criteria AND Appendix 10: Guidance on safety monitoring
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. A new informed consent form should 
be signed before re-enrollment
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.
Synopsis AND Section 6.1: Allowed concomitant medications
….IV methylprednisolone for 3 days…..
…..IV methylprednisolone 1 g/day or oral steroids for 3 a 
maximum of 5 consecutive days…..
In order to comply with Standard of 
Care, the protocol now states that 
treatment for acute relapse may include 


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short term treatment with oral steroids.
Section 6.1: Allowed concomitant medications
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 6) 
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 Appendix 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 DDI 
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 
6) has been added to present partial lists 
of CYP3A4 substrates with a narrow 
therapeutic index and of drugs known 
to be metabolized by CYP1A2.
Laquinimod is mainly metabolized by 
the CYP3A4 P450 isoenzyme. 
Following 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 Wort) have 
been added as disallowed medications 
in all clinical studies with Laquinimod. 
Use of CYP3A4 inducers may result in 
reduced laquinimod plasma 
concentrations and reduced 
effectiveness. The Laquinimod 
Investigator's Brochure has been 
updated with the above information in 
Section 6.2: Disallowed medications (during the study)

Interferons

Natalizumab (Tysabri®)

Mitoxantrone (Novantrone®)

Glatiramer Acetate

Inhibitors of CYP3A4; for example, 
ketoconazole and erythromyicin (see full list in 
Appendix 5) 

Parenteral steroids (except if given as defined 
by protocol for acute relapse; see Section 6.1)

Oral steroids

Chemotherapeutic agents

Immunosuppressive or immunomodulating 
agents

Experimental agents (including aminopyridine)
IV Immunoglobulin (Ig) and any other IV experimental 
agents

Natalizumab (Tysabri®)

Fingolimod (Gilenya)

IFNs

Dimethyl fumarate (Tecfidera)

Glatiramer Acetate 

Teriflunomide (Aubagio)

Alemtuzumab (Lemtrada)

Cladribine

Rituximab

Ocrelizumab

Atacicept

Belimumab

Ofatumumab

Inducers of CYP3A4 such as rifampin and 
carbamadizepine (for more examples see Appendix 
5). Use of CYP3A4 inducers may result in reduced 


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Amended or new wording
Reason/Justification for change
laquinimod plasma concentrations and may reduce 
its effectiveness.

Moderate/strong inhibitors of CYP3A4; for 
example, ketoconazole and erythromyicin (see full 
list in Appendix 5)

Mitoxantrone (Novantrone®)

Oral steroids

Parenteral steroids (except if given as defined by 
protocol for acute relapse; see Section 6.1)

Adrenocorticotrophic hormone (ACTH)

Chemotherapeutic agents

Cytotoxic agents

Cyclophosphamide

IV immunoglobulin (IVIG)

Plasmapheresis

Any other experimental agents

Other immunosuppressive or immunomodulating 
agents
Section 6.7.1.
The disallowed use of CYP3A4 
inducers has been added to Section 6.2 
(Disallowed concomitant medications 
during the study) and Appendix 5 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 6.2 Disallowed concomitant 
medications during the study):
Fingolimod (Gilenya)
Dimethyl fumarate (Tecfidera)
Teriflunomide (Aubagio)
Alemtuzumab (Lemtrada)
The medication 4-amino pyridine 
(Ampyra, Fampyra) 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).
Appendix 5 – List* of systematically administered** CYP3A4 inhibitors which are disallowed prior and during 
the study
Cardiac drugs/antiarrhythmic agents
amiodarone
diltiazem
nifedipine
verapamil
mibefradil
Antimicrobial agents
Erythromycin
Clarithromycin
Troleandomycin
Telithromycin
Antifungals/Imidazoles
Fluconazole
Itraconazole
Ketoconazole
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


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Miconazole
Voriconazole
HIV drugs: 
Protease Inhibitors, such as indinavir, ritonavir and 
others
Delavirdine
Antidepressants
fluvoxamine
nefazodone
Others/antituberculosis and antimalarial
isoniazid
aprepitant
Antiemetics
Aprepitant
Diuretics
Conivaptan
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
Section 7.3.4: Criteria for early termination 
None
10. Planned pregnancy
11. Lack of efficacy
Two new criteria for early termination 
were added and new stopping rules 
were 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)
Section 7.3.4.1: Safety Stopping Rules AND Appendix 10: Guidance for Safety Monitoring
None
New subsections added: see Section 7.3.4.1.2and Section 
7.3.4.1.3for full text.
Section 8.1.4: On-study Relapse Evaluation Procedures
None
For the open-label phase (LAQ/5063 OL) only one 
neurologist/physician is required (Study 
Neurologist/Physician) to perform a neurological 
examination and treat the subject as needed.
In the open label extension there is no 
need for distinction between the 
Treating and the Examining Physicians/ 
Neurologists.
Section 7.3: Detailed Study Plan AND Section 8: Assessment Methods
…Examining neurologist/ physician…..
….Study neurologist/ physician……


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Section 17.3 Investigative Site Personnel AND Section 7.3: Detailed Study Plan
The Treating Neurologist/Physician
Will be responsible for subject eligibility evaluation, the 
supervision of the study drug administration, the 
recording and treating of adverse experiences, the 
monitoring of safety assessments, including routine 
laboratory parameters, and coordinating MRI 
performance. He will determine if a subject experiences 
a relapse (based on the evaluation performed by the 
Examining Neurologist/Physician) and whether to treat 
the relapse or not.
The Examining Neurologist/Physician
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.
Note: It is particularly important that the Treating 
Neurologist/Physician and the 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.
For the open label phase (LAQ/5063 OL) only one 
neurologist/physician is required.
The Neurologist/Physician 
For the open-label phase (LAQ/5063 OL) only one 
neurologist/physician is required (Study 
Neurologist/Physician).
Section 8.2.5: Safety Laboratory Evaluations

Cholesterol
[…]

CPK
[…]

Lipid profile (total cholesterol, high density 
lipoprotein [HDL], low density lipoprotein 
[LDL], triglycerides) under fasting conditions. 
Only at baseline and every 12 months during 
Periods 1 and 2.
[…]

CPK

In case of abnormal CPK result: troponin or 
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 


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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 > 1 g/dL from the subject’s 
hemoglobin level at Baseline, subject will be 
re-tested to ascertain true decrease. If true 
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 and 
haptoglobin

Additional investigations and follow-up per the 
Investigator’s discretion or Sponsor’s request.
requirement for testing urine myoglobin 
in case of CPK>2000 U/L, was added.
In addition, lipase will be tested in case 
of abnormal pancreatic amylase results.
In case of new hemoglobin decrease of 
> 1 g/dL, a thorough anemia work-up 
will be done.
Lipid profile added to align with other 
similar protocols.
Appendix 10: Guidance on Safety Monitoring
-
See section
The section has been greatly revised to 
bring in line with current experience. 
Please see section for full details.
Section 10: Safety and Pharmacovigilance
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 
In order to satisfy regulatory requirements, any Serious 
Adverse Event, 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 


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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:
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 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:
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 to fax, or contact the sponsor’s study 
personnel identified above for further instruction.
SYNOPSIS AND Section 5.3 Inclusion Criteria
2.
Women of child- bearing potential must 
practice a reliable method of birth control. (Acceptable 
methods of birth control in this study include: double 
barrier methods such as diaphragms with spermicide, 
condoms and spermicide. Also intrauterine devices; 
hormonal contraception must be accompanied by an 
additional method of birth control.).
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)].
Teva considers the prevention of 
exposure to laquinimod during 
pregnancy to be of great importance, 
and following consultation with the 
CHMP and Data Monitoring 
Committee (DMC) has decided to 
introduce additional language and 
measures for pregnancy prevention in 
this amendment.
Section 10 SAFETY AND PHARMACOVIGILANCE
Pregnancy reports: Pregnancy reports should be forward
to the Pharmacovigilance for data-entry to the global 
Pregnancy reports: Pregnancies should be reported 
throughout the study. This includes also normal 
Text brought up to date with current 
procedures.


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safety database. This includes also normal pregnancies 
without AE. 
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 CRF provided by Local 
Clinical Management.
The pregnancies reporting procedure should be the same 
as the SAE reporting procedure.
pregnancies without AE. The pregnancy should be 
followed up 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. The pregnancies 
reporting procedure should be the same as the SAE 
reporting procedure.
Section 11.2 Randomization Procedure
-
In the open-label phase, all subjects will receive 
laquinimod 0.6 mg daily
Clarification added.
Section 17.4.6 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 data monitoring 
committee (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.
Entire Document
-
Numbering of Appendices from has been changed 
throughout the text and are now numbered from 1 to 10
Updated cross-references to appendices 
(due to addition of a newAppendix 6).
In addition, literature references have 
been changed to reflect the changes in 
the protocol


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22.
CHANGES TO PATIENT ENTRY CRITERIA
Not applicable.


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APPENDIX 1.
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 
symptomsn". 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 are in the LAQ/5063 open label 
phase).
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 confirmation of a relapse.
                                                
n Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis (McDonald, Ann. 
Neurol. 2001;50:121-127)


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APPENDIX 2.
NEUROSTATUS
Standardized Neurological Examination and Assessment of Kurtzke’s Functional Systems and 
Expanded Disability Status


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APPENDIX 3.
MRI PROTOCOL
Applicable only for the LAQ/5063 study and the first 24 months of the open-label phase of the 
LAQ/5063 study.
Post-Gd T1-weighted and dual-echo MRI scans of the brain will be performed.
For each subject, on-treatment MRIs scans will be performed within 4 days prior to the visit at 
Week 36 (termination).
The same scanner, used in the core study LAQ/5062 must be used for each subject for the entire 
duration of the study; scanners should have at least 1.0 Tesla magnetic field strength. The MRI-
AC in 
will conduct the entire MRI analysis.
Scanning Requirements:
Given the importance of careful repositioning for serial MRI lesion counting and load 
assessments, great care should be taken when positioning the subjects in the scanner and head 
holder. The following rules apply to all the sites:

Check that the subject can successfully undergo MRI examination, including GFR 
estimation.

Enter the subject data into the scanner console, using:

study number (protocol number, site number, subject number)

date of birth/sex

weight

scan number 

Explain the scanning procedure to the subject and position her/him in the scanner in 
the most comfortable position.

Insert an intravenous needle in the subject’s arm and connect it with a long-line 
catheter to a drip-infusion of saline; for contrast injection the operator will be able to 
use the long-line without moving the subject table from the scanner.

Position the subject’s head and align it in the machine using land-marking devices 
provided with most of the equipment.

Position the subject’s eyebrows at the center of the coil and make sure that the 
horizontal light beam runs over the eyebrows and as close as possible to the line 
marking the coil center.


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
Position the nose along the Z axis of the scanner, i.e., make sure that the vertical light 
beam runs over the nose.

To avoid subject’s head movement, fix it with foam cushions and strips.

Move the subject into the scanner.
IMAGING
The following order for sequences will be kept:

T1-weighted axial scout

T1-weighted coronal scout

T1-weighted sagittal scout

Rapid T1-weighted SE or T2-weighted FSE/TSE axial (this is for repositioning 
check)

T2-weighted FSE/TSE

T1-weighted SE post gadolinium
Sequences from 1 to 4 will be done to obtain reference images for subject repositioning.
Sequence parameters:
T1-weighted axial scout:

TR: 100

TE: 10-20

Slice number: 3

Slice thickness: 5mm

Orientation: axial

Field of view (FOV): 210-230 mm

Matrix: 128 x 256

Inter-slice gap: 5 mm


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
Number of acquisitions: 1

Phase encoding: L > R
Using sequence 1 as a reference, make a coronal scout, parallel to the brain transverse diameter 
and depicting the midline of the brain best (i.e., at the level of the brainstem); the acquisition 
parameters will be the following:

TR: 100

TE: 10-20

Slice number: 1

Slice thickness: 5 mm

Orientation: coronal

Field of view (FOV): 210-230 mm

Matrix: 128 x 256

Number of acquisitions: 1

Phase encoding: L > R
From the coronal scout make a sagittal scout image, aligned with the falx cerebri and other 
midline structures, following these parameters:

TR: 500-650

TE: 10-20

Slice number: 1

Slice thickness: 5 mm

Orientation: sagittal

Field of view (FOV): 210-230 mm

Matrix: 128 x 256

Number of acquisitions: 1-3

Phase encoding: A > P


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On the sagittal scout image previously obtained, position the axial image group, placing the 
center of the slice group at the inferior borders of the corpus callosum genu and splenium. The 
slice group will be positioned to include the whole brain from the vertex to the level of the 
foramen magnum. Save the localizer image with the slices shown on it, to achieve the same slice 
positioning on subsequent scans; then make a rapid series of either T1-weighted or T2-weighted 
images (according to the site preference) in order to check the correct positioning of the slices.
For T1-weighted images, the following parameters should be used:

TR-600

TE: 10-20

Slice number: 22

Slice thickness: 3 mm

Orientation: axial

Field of view (FOV): 250 mm

Matrix: 140 x 256

Inter-slice gap: 3 mm

Series: interleaved

Number of acquisitions:1

Phase encoding: L > R
For T2-weighted images, a fast spin echo (or turbo spin echo) sequence should be used with the 
following parameters:

TR: 2200-3000

TE: either single-echo or dual-echo (according to site preference):

TE first echo: 30-50; TE second echo: 60-100

ETL: according to site preference

Slice number: 22

Slice thickness: 3 mm

Orientation: axial


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
FOV: 250 mm

Matrix: approximately 140 x 256. The number of phase-encode lines will depend on 
the exact sequence used

Inter-slice gap: 3 mm

Series: interleaved

Number of acquisitions: 1

Phase-encoding: L > R
Please note that the hardcopies of this first series of T1 or T2 axial images should be one only for 
the baseline scan and used as reference for repositioning the subsequent serial scans.
Write the slice positioning parameters (shift and rotation angle) of this series and use them for 
the subsequent series of the same scan (this is not necessary if the scanner has a repeat or history 
function).
If possible, to speed up the examination, use a rectangular 3/4 FOV (i.e., reduce the phase-
encoding matrix by 25%) when doing all the subsequent series of axial images. When using 3/4 
FOV, the FOV is 187.5 in L > R direction and 250 mm in A > P direction; matrix is 256 (read) x 
192 (phase).
The scanning procedure is resumed by doing two interleaved series of fast or turbo spin-echo 
dual echo sequence. Conventional spin-echo sequences are allowed in case fast imaging is not 
available. Image parameters will be the following:

TR: 2200-3000

TE: 15-50/80-120

ETL: 4-6

Slice number: 22

Slice thickness: 3 mm

Orientation: axial

Field of view (FOV): 250 mm

Matrix: 256 x 256 (192 x 256 if RECFOV)

Inter-slice gap: 3 mm

Series: interleaved


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
Number of acquisitions: 1

Phase encoding: L > R

Resaturation slab/flow compensation: Yes
The axial presaturation slab (50-80 mm) will be positioned inferior to the slice group to suppress 
flow-related artifacts.
The second series will have a slice position shifted 3 mm caudally compared with the first one, 
so that when both series are combined, the whole brain is covered.
Some General Electric and Philips scanners allow all the two separate acquisitions (each of 22 
slices) to be performed sequentially and automatically from a single prescription. If the scanner 
used allows the acquisitions to be split automatically in this way, then this should be done.
Perform a bolus injection of Gd-DPTA using the intravenous long-line and without moving the 
subject from the scanner. Use contrast at a standard dose of 0.1 mmol/kg (i.e., 0.2 ml/kg). During 
the post-injection delay interval the acquisition of additional sequences is allowed by negotiation 
with the MRI-AC (
). After a post-injection delay of 5 minutes, complete the 
scanning with post-Gd T1-weighted SE images.
The following parameters should be used:

TR: 600-650 (Keep the TR within the range and optimize the signal to noise ratio, 
i.e., the maximum echo time and the lowest bandwidth consistent with the TR range.)

TE: 10-20

Slice number: 22

Slice thickness: 3 mm

Orientation: axial

Field of view (FOV): 250 mm

Matrix: 256 x 256 (192 x 256 if RECFOV)

Inter-slice gap: 3 mm

Series: interleaved

Number of acquisitions: 2

Phase encoding: L > R

Presaturation slab/flow compensation: yes


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The second series of images will be positioned to fill the gaps of the first one. Once the two 
acquisitions are completed, check the image consistency in terms of both correct repositioning 
(when compared with “fast” T1) and covering the whole brain as indicated above. In case of 
spoiled post-contrast T1-weighted images due either to subject movement artifacts, or to a change 
in slice position of 6 mm or more (i.e., > 2 slice thickness compared to baseline scan), post-
contrast T1-weighted sequence should be repeated within 20 minutes after Gd-DTPA injection.
Scans should be evaluated by the center radiologist and any pathological, non-MS findings 
should be reported to the Treating Investigator.
ELECTRONIC BACKUP PROCEDURES
Electronic backups (CD) should be prepared and archived within the sites. 
Preparation of Scans:
A CD containing all sequences per visit should be prepared. All sheets should be divided into 20 
images, starting in the upper left corner with the most caudal slice; use the same format for all 
series.
For each scan, sheets should be the following:

One sheet divided into 4 with the axial and coronal localizers and two sagittal 
localizers (showing clearly how the axial slices were positioned, one with the position 
line alone and one with the whole slice group).

Two sheets for T1-weighted SE after contrast (20+20 images)

Four sheets for PD/T2-weighted FSE/TSE (20+20 images x 2)

One sheet for the last 4 cranial images of all sequences (4 images per row)

Total number of sheets for MRI scan: 8
In the event that machine constraints do not allow such image printing, the MRI-AC should be 
contacted and the image format negotiated on a site-by-site basis.
The site will keep its own hard copy backups only for the repositioning images of the screening 
(Week 4) MRI.
Electronic Data 
One set of scans will be sent by courier to the MRI-AC within 3 working days from the scan 
date.
The center will send a copy of MRI digital images to the MRI-AC.


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Different options are available as were discussed with the center prior to start of the core study to 
solve in advance any problem arising from the use of different media and data formats.
As a general guideline the following is a list, ordered by preference, of the acceptable media:

Electronic tapes: 4mm DAT or 8mm video 1/4” tape digital linear tape (DLT)

CD-ROM

5 1/4" Optical disks WORM or rewritable's depending on the scanner used

Network transfer ftp
Data sent by network transfer should respect the same time schedule and the transfer should be 
immediately notified to the MRI-AC with a detailed list of the data transferred, at the following 
e-mail address:
In any case, all electronic data of the scan, including scout images should be sent.
The site will keep electronic backups for all MRI data.
As subjects are entered, a planned time for the following scans will be provided to the MRI-AC 
by each participating site study coordinator. The MRI-AC will call each site on failure to log 
anticipated films and/or electronic data at the MRI-AC.
Steroid Treatment and MRI Scan Schedule
It is recognized that steroid therapy strongly reduces the effect of gadolinium-enhancement and 
to a minor degree, the size of lesion of T2-weighted images. However, moderate and severe MS 
relapses may warrant treatment with IV methylprednisolone (IVMP), as described in Section 6.1. 
In this study, subjects treated with IVMP will be scanned at pre-planned times, rather than to 
arbitrarily adjust for recent steroid use.
MRI Scan Analysis
The following analyses will be performed:

Count of total contrast-enhancing T1-weighted lesions 

T2 lesions load (volume) 

Count of number of new T2 lesions 

Count of new hypointense T1 lesions on enhanced T1 scans ("black holes")


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The quantification of lesion load will be performed using a semi-automated segmentation 
technique based on local threshold.
MRI Scan Quality Control
The quality of scans will be reviewed by the MRI-AC when received. Within 3 working days of 
receiving the scan, the MRI-AC will fax the MRI scan acceptance form to participating sites, the 
local clinical management and to the Corporate Coordination Center.
In case of unsatisfactory image quality, the scans will be rejected and repeated. Rejected scans 
will be repeated within 2 weeks from the date of the first assessment. Repositioning will be 
considered acceptable when less than a 2-slice thickness difference exists for recognizable 
landmarks on the axial slices between MRI sessions. 


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APPENDIX 4.
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:
1. Trial 1, Timed 25-Foot Walk
2. Trial 2, Timed 25-Foot Walk
3. Trial 1, Dominant Hand, 9-HPT
4. Trial 2, Dominant Hand, 9-HPT
5. Trial 1, Non-Dominant Hand, 9-HPT
6. Trial 2, Non-Dominant Hand, 9-HPT
7. 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 > .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. 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 treating 
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.
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:


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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.
Administration
Dominant Hand---Trial 1


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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, ask, "Are you right 
or left-handed?" 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.
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:


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
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.
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 audiotape 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
Audiocassette tape player, audiocassette tape with PASAT stimuli, clipboard, PASAT Record 
Forms
Discontinue Rules


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If the subject cannot get at least two answers correct (consecutive or not) on any one of the three 
3" practice sequences.
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 audiocassette (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 tape 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 tape 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.
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, 


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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. Write "NR" 
(for "no response") 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.).
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 5.
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 8).
Table 8:
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 9).
Table 9:
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 6.
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 10) should be advised that plasma 
levels of these drugs could increase when combined with laquinimod.
Table 10:
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 11 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 11:
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 7.
LIST OF STEERING COMMITTEE MEMBERS


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APPENDIX 8.
LIST OF DATA SAFETY MONITORING BOARD (DSMB) 
MEMBERS
It should be noted that as the study is in open label phase, the originally assigned DSMB is not 
operating any further.
The study is supervised by Teva’s internal safety committee as well as by an external Data 
Monitoring Committees (DMC) of the ongoing Phase III studies MS-LAQ-301 (ALLEGRO) and 
MS-LAQ-302 (BRAVO).


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APPENDIX 9.
LIST OF CLINICAL ADVISORY BOARD (CAB) 
MEMBERS


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APPENDIX 10. GUIDANCE ON SAFETY MONITORING
1. Guidance on Monitoring Subjects with Elevated Liver Function Tests
Liver enzymes (ALT, AST, GGT, ALP), as well as total bilirubino 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 
undertakenp. 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
                                                
o In case total bilirubin is >ULN, than direct bilirubin will be checked
p 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".


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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 
4 weeks and will include measurement of liver enzymes at least QW (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.
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 5. 


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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. 
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).


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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 Section 7.2).
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. 
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.


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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 LAQ/5063 OL phase (completion 
of all Termination visit activities) according to the LAQ/5063 OL 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 during the study 
and up to 30 days after the last dose of the study treatment was administered. 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, long-acting injectable 
contraceptive). 
5. Subjects must be willing and able to comply with the protocol requirements for the 
duration of the study. 
6. Subjects must be able to comprehend, sign and date a written informed consent prior to 
re-enrolling into the LAQ/5063 OL study.
Exclusion Criteria for returning subjects
Any of the following conditions will exclude the subject from re-enrolling into the study:


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1. Premature discontinuation from the LAQ/5063 OL study, for any reason, except planned 
pregnancy. 
2. Subjects with progressive forms of MS or other non RRMS 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®), IFN-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 subjects 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 test 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 LAQ/5063 OL study, which preclude safe participation and 
completion of the LAQ/5063 OL 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 12:
Study Task Flow Chart for Returning Subjects (Month 24 onwards)
Visit
V10E1 V11E1 V12E1 V13E1 V14E1
V15E1
V16E1
Every 6
months
Termination/Early 
Discontinuation
Unscheduled 
Visita
Month
24E1
30E1
36E1
42E1
48E1
54E1
60E1
Informed consentb
X
X
Inclusion/exclusion criteria
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Cardiovascular risk factor 
assessment and managementc
X
X
X
X
Every 
12 months 
from 
Month 72
ECG
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
X
X
X
X
X
X
X
X
Evaluation of relapsed
X
X
X
X
X
X
X
X
X
X
Ascertaining the use of effective
contraception
X
X
X
X
X
X
X
X
X
X
Serum and urine βhCGe (on site)
X
X
X
X
X
X
X
X
X
X
Urine hCG (self check, at home); 
pregnancy tests mandatory phone 
callsf
EVERY 1 MONTH BETWEEN VISITS
Adverse events
X
X
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
Safety laboratory evaluation 
(CBC, chemistry, GFR estimation, 
markers of inflammation)
X
X
X
X
X
X
Xh
Xh
Xh
Xh
Laquinimod dispensing and 
accountability
X
X
X
X
X
X
Xi
X
Xi
X
Subject compliance
X
X
X
X
X
X
X
X
X
X


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Visit
V10E1 V11E1 V12E1 V13E1 V14E1
V15E1
V16E1
Every 6
months
Termination/Early 
Discontinuation
Unscheduled 
Visita
Month
24E1
30E1
36E1
42E1
48E1
54E1
60E1
Termination documentation and 
notification of early termination
X
Unscheduled samples
Xj
Subjects who are discontinued from study treatment will be encouraged to continue all scheduled visits and procedures until completion of both study periods 
(with the exception of procedures associated with drug dispensing and accountability, pregnancy testing, and GFR estimation [including body weight 
measurement]).
a Assessments during an unscheduled visit will be performed as deemed necessary by the Investigator, except for vital signs and adverse events, which are 
mandatory at each visit
b At Month 24 (visit 10) of the open label phase Informed Consent will be signed for the extended open label period of 36 months. At Month 60 (visit 16) of the 
open label phase an Informed Consent will be signed for the additional extension as long as the Sponsor continues the development of laquinimod 0.6 mg for 
RRMS
c In addition, an evaluation should take place as soon as possible for subjects already in the study, following approval of Amendment #10
d Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator
e For women of child-bearing potential
f Mandatory phone calls will be performed within 72 hours of the scheduled home pregnancy test
g Weight will be measured at all visits
h Inflammatory markers will not be collected from Month 60 and onwards
i Only drug retrieval
j 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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23.
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Sormani MP, Bonzano L, Roccatagliata L, Mancardi GL, Uccelli A, Bruzzi P. Surrogate 
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