Clinical trial NCT00988052
Conditions: Relapsing Multiple Sclerosis
Keywords: Relapsing Multiple Sclerosis
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2009-11-10; Completion date: 2017-07-01
Enrollment: 839 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to make laquinimod 0.6 mg available for all subjects who completed the placebo-controlled MS-LAQ-301 study according to the protocol and to evaluate the long-term safety, tolerability and effect on disease course of daily oral laquinimod 0.6 mg in subjects with relapsing multiple sclerosis.

Detailed description:

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

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol with Amendment 03
(including Statistical Analysis Plan)
A Multinational, Multicenter, Open-Label, Single-Assignment
Extension of the MS-LAQ-301 (ALLEGRO) Study, to Evaluate the
Long-Term Safety, Tolerability and Effect on Disease Course of Daily
Oral Laquinimod 0.6 mg in Subjects with Relapsing Multiple Sclerosis
Study Number MS-LAQ-301E
NCT00988052
Protocol with Amendment 03 Approval Date: 25 February 2016


Protocol No: MS-LAQ-301E
Amended Protocol 03
ALLEGRO Extension Study
1
 
TEVA PHARMACEUTICAL INDUSTRIES LTD., ISRAEL
CLINICAL STUDY PROTOCOL
Study Title:
A Multinational, Multicenter, Open-Label, Single-Assignment 
Extension of the MS-LAQ-301 (ALLEGRO) Study, to Evaluate the 
Long-Term Safety, Tolerability and Effect on Disease Course of Daily 
Oral Laquinimod 0.6 mg in Subjects with Relapsing Multiple Sclerosis
Protocol No:
MS-LAQ-301E
EudraCT/IND No:
2009-012989-30 / 071287
Clinical Phase:
III Open-Label Extension Study
Protocol Version Date:
June 04, 2009
Global Amendment # 1
November 1, 2009
Global Amendment # 2
17 July 2014
Global Amendment # 3
25 February 2016
Principal Investigator(s):
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 
Harmonization) Guidelines and EU Directives
CONFIDENTIAL
The information in this document is considered privileged and confidential, and may not be disclosed to 
others except to the extent necessary to obtain Institutional Review Board/Ethics Committee approval, 
informed consent and the approval of local regulatory authorities as required by local law.


Protocol No: MS-LAQ-301E
Amended Protocol 03
ALLEGRO Extension Study
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PROTOCOL REVIEW & APPROVAL


Protocol No: MS-LAQ-301E
Amended Protocol 03
ALLEGRO Extension Study
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
PROTOCOL REVIEW & APPROVAL..........................................................................................2
TABLE OF CONTENTS.................................................................................................................3
1.
SYNOPSIS .................................................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................15
3.
INTRODUCTION......................................................................................................18
3.1.
Background.................................................................................................................18
3.1.1.
General........................................................................................................................18
3.1.2.
Study Drug..................................................................................................................18
3.2.
Nonclinical Experience...............................................................................................19
3.2.1.
Pharmacology .............................................................................................................19
3.2.2.
Metabolism and Pharmacokinetics.............................................................................19
3.2.3.
Toxicology..................................................................................................................20
3.3.
Clinical Experience.....................................................................................................21
3.3.1.
Clinical Pharmacology Studies...................................................................................21
3.3.2.
Clinical Safety and Efficacy Studies ..........................................................................22
3.4.
Known and Potential Risks and Benefits to Human Subjects....................................24
3.4.1.
Known and Potential Risks and Benefits for Laquinimod .........................................24
3.4.1.1.
Details of Important Adverse Drug Reactions: ..........................................................26
3.4.1.2.
Potential Safety Issues with Laquinimod ...................................................................28
4.
STUDY OBJECTIVES ..............................................................................................30
4.1.
Ancillary Studies ........................................................................................................30
5.
STUDY DESIGN .......................................................................................................31
5.1.
Overview And Plan.....................................................................................................31
5.1.1.
Study Periods..............................................................................................................31
5.1.1.1.
Revealing the MS-LAQ-301 Study Treatment Assignment during the Open-
Label Study.................................................................................................................32
5.2.
Rationale for Study Design, Dose and Population .....................................................32
6.
STUDY POPULATION.............................................................................................33
6.1.
Inclusion Criteria ........................................................................................................33


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ALLEGRO Extension Study
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6.2.
Exclusion Criteria.......................................................................................................33
7.
MEDICATIONS/THERAPIES – ALLOWED AND DISALLOWED .....................35
7.1.
Allowed Concomitant Medications/Therapies ...........................................................35
7.2.
Disallowed Concomitant Medications During Study.................................................35
8.
STUDY CONDUCT...................................................................................................37
8.1.
Study Period................................................................................................................37
8.2.
Detailed Study Plan ....................................................................................................40
8.2.1.
Baseline Visit (Month 0E) (Visit 0E) (Termination Visit of the MS-LAQ-
301 Study) Procedures:...............................................................................................40
8.2.2.
Scheduled Treatment Visits [Months 1E (Visits 1E) and Onwards]..........................42
8.2.3.
Termination/ Early Discontinuation ...........................................................................45
8.3.
Early Treatment Discontinuation................................................................................47
8.3.1.
Criteria for Early Treatment Discontinuation.............................................................48
8.3.1.1.
Post Early Discontinuation Follow-Up Visit..............................................................48
8.3.2.
Safety Stopping Rules.................................................................................................49
8.3.2.1.
Liver Enzymes............................................................................................................49
8.3.2.2.
Pregnancy ...................................................................................................................50
8.3.2.3.
Cancer.........................................................................................................................51
8.3.2.4.
Liver Impairment........................................................................................................51
8.3.2.5.
Renal Impairment .......................................................................................................51
8.3.3.
Replacement of Withdrawn Subjects..........................................................................51
8.3.4.
Temporary Discontinuation of Study Drug Treatment...............................................51
8.3.5.
Unscheduled Visit.......................................................................................................52
8.3.5.1.
Unscheduled Samples.................................................................................................53
8.3.6.
Visits during Relapses (Scheduled and Unscheduled) ...............................................54
8.3.6.1.
Relapse Follow-up:.....................................................................................................55
9.
INVESTIGATIONAL MEDICINAL PRODUCTS/STUDY DRUGS......................56
9.1.
Treatment Administered .............................................................................................56
9.2.
Method of Assigning Subjects Numbers ....................................................................56
9.3.
Description of Investigational Medicinal Product/Study Drug ..................................56
9.4.
Packaging and Labeling..............................................................................................56
9.5.
Distribution and Shipment..........................................................................................57
9.6.
Storage, Dispensing and Return .................................................................................57


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9.7.
Verification of Compliance With Treatment Regimen ..............................................58
9.8.
Accountability and Compliance .................................................................................58
10.
ASSESSMENT METHODS ......................................................................................59
10.1.
Efficacy Assessment Methods....................................................................................59
10.1.1.
On-Study Relapse Evaluation & Determination.........................................................59
10.1.2.
Neurological Evaluations............................................................................................59
10.1.3.
MSFC..........................................................................................................................60
10.1.4.
Modified Fatigue Impact Scale (MFIS)......................................................................60
10.1.5.
Binocular Low- Contrast Visual Acuity.....................................................................60
10.1.6.
Ancillary Studies ........................................................................................................61
10.1.6.1.
MRI Ancillary Study: .................................................................................................61
10.1.6.2.
MT Ancillary Study:...................................................................................................61
10.1.6.3.
MRS Ancillary Study: ................................................................................................62
10.2.
Safety Parameters .......................................................................................................62
10.2.1.
Adverse Events ...........................................................................................................62
10.2.1.1.
Protocol-Defined Adverse Events for Expedited Reporting ......................................62
10.2.2.
Abdominal Computed Tomography Scan ..................................................................62
10.2.3.
Safety Laboratory Evaluations ...................................................................................62
10.2.3.1.
Urgent Safety Laboratory Panel .................................................................................65
10.2.4.
Vital Signs and Weight...............................................................................................65
10.2.5.
ECG ............................................................................................................................65
10.2.6.
Physical Examination .................................................................................................66
10.2.7.
Glomerular Filtration Rate Estimation .......................................................................66
10.2.8.
Cardiovascular Risk Assessment and Management ...................................................66
11.
SAFETY AND PHARMACOVIGILANCE..............................................................67
12.
STATISTICAL METHODOLOGY...........................................................................72
12.1.
Sample Size Rationale................................................................................................72
12.2.
Randomization Procedure...........................................................................................72
12.3.
Subjects Analysis Sets ................................................................................................72
12.4.
Definition of baseline values ......................................................................................72
12.5.
Efficacy Assessment...................................................................................................72
12.6.
Safety And Tolerability Assessments.........................................................................73
12.6.1.
Data presentation ........................................................................................................73


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12.6.2.
Adverse Events ...........................................................................................................73
12.6.3.
Laboratory Data..........................................................................................................73
12.6.4.
ECG ............................................................................................................................73
12.6.5.
Vital Signs ..................................................................................................................73
12.6.6.
Drug Tolerability & Drop-Out Assessment................................................................73
13.
REGULATORY AND ETHICAL ISSUES...............................................................74
13.1.
Compliance with Regulations Applicable to Clinical Trials......................................74
13.2.
Informed Consent .......................................................................................................74
13.3.
Subject Confidentiality...............................................................................................74
13.4.
Ethics Committee (EC) / Institutional Review Board (IRB)......................................74
13.5.
Protocol Amendments ................................................................................................75
13.6.
Declaration of the End of the Clinical Trial ...............................................................75
13.7.
Liability And Insurance ..............................................................................................75
14.
DOCUMENTATION .................................................................................................76
14.1.
Study File and Site Documents...................................................................................76
14.2.
Study Documents Supplied by the Sponsor................................................................76
14.3.
Maintenance and Retention of Records......................................................................77
14.4.
Data Handling.............................................................................................................77
14.4.1.
Data Collection via Remote Data Capture (RDC)......................................................77
14.4.1.1.
Data Collection...........................................................................................................77
14.4.1.2.
Discrepancy Handling ................................................................................................78
14.4.1.3.
Data Correction...........................................................................................................79
14.4.1.4.
Data Extract ................................................................................................................79
14.4.1.5.
Source Documents......................................................................................................79
14.4.1.6.
Electronic CRF ...........................................................................................................79
14.5.
Additional Documents and Records...........................................................................79
15.
QUALITY ASSURANCE AUDITS ..........................................................................80
15.1.
Good Clinical Practice................................................................................................80
15.2.
Quality Laboratory Standards.....................................................................................80
15.3.
Quality Assurance Program........................................................................................80
15.4.
Regulatory Inspections ...............................................................................................80
16.
STUDY MONITORING ............................................................................................81
16.1.
Monitors/CRAs and Monitoring Visits ......................................................................81


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16.2.
Primary Source Documents........................................................................................81
17.
CLINICAL PRODUCT COMPLAINTS ...................................................................83
17.1.
Product Complaint Information Needed from the Investigational Center..................83
17.2.
Handling of Study Drug at the Investigational Center ...............................................84
17.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................84
17.4.
Documenting a Product Complaint ............................................................................84
18.
USE OF INFORMATION AND PUBLICATION ....................................................85
18.1.
Confidential Information ............................................................................................85
19.
STUDY PERSONNEL...............................................................................................86
19.1.
Investigative Site ........................................................................................................86
19.1.1.
The Principal Investigator...........................................................................................86
19.1.2.
The Study Physician/ Neurologist ..............................................................................86
19.1.3.
The MRI Radiologist and Technician.........................................................................86
19.1.4.
Study Coordinator or Designee ..................................................................................86
19.2.
The Sponsor................................................................................................................87
19.2.1.
Global Clinical Leader................................................................................................87
19.2.2.
Global Operations Manager........................................................................................87
19.2.3.
Data Management & Biostatistics ..............................................................................87
19.2.4.
Local Clinical Management........................................................................................87
19.2.5.
Clinical Research Associate/Monitor .........................................................................87
19.2.6.
Global Drug Safety and Pharmacovigilance...............................................................87
19.2.7.
Medical Monitor.........................................................................................................87
20.
STUDY COMMITTEES............................................................................................89
20.1.
Steering Committee ....................................................................................................89
20.2.
Data Monitoring Committee (DMC)..........................................................................89
20.3.
Clinical Advisory Board (CAB) .................................................................................90
20.4.
Publication Committee ...............................................................................................90
INVESTIGATOR’S AGREEMENT.............................................................................................91
21.
REFERENCES ...........................................................................................................92
22.
RATIONALE FOR PROTOCOL AMENDMENT AND SUMMARY OF 
CHANGES .................................................................................................................93
22.1.
Global Amendment #3................................................................................................93


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22.2.
Global Amendment #2..............................................................................................110
23.
CHANGES TO PATIENT ENTRY CRITERIA......................................................134
APPENDIX A.
DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS: 2005 
REVISIONS TO THE “MCDONALD CRITERIA” ...............................................135
APPENDIX B.
DEFINITIONS.................................................................................................137
APPENDIX C.
NEUROSTATUS.............................................................................................140
APPENDIX D.
MRI PROTOCOLS (INCLUDING MT AND MRS) .....................................151
APPENDIX E.
MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 
INDUCERS ..............................................................................................................170
APPENDIX F.
LIST OF MEDICATIONS THAT SHOULD BE USED WITH 
CAUTION ................................................................................................................172
APPENDIX G.
GUIDANCE ON SAFETY MONITORING...................................................174
APPENDIX H.
MODIFIED FATIGUE IMPACT SCALE (MFIS).........................................185
APPENDIX I.
MSFC ADMINISTRATION INSTRUCTIONS ..............................................187
APPENDIX J.
LOW-CONTRAST SLOAN LETTER CHART TESTING FOR 
PATIENTS WITH MULTIPLE SCLEROSIS .........................................................194
APPENDIX K.
LOW-CONTRAST TUMBLING-E CHART TESTING FOR 
PATIENTS WITH MULTIPLE SCLEROSIS .........................................................197


Protocol No: MS-LAQ-301E
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ALLEGRO Extension Study
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LIST OF TABLES
Table 1:
ALLEGRO: Summary of Efficacy Results ................................................................23
Table 2:
BRAVO: Summary of Efficacy Results.....................................................................23
Table 3:
Tabulated List of Adverse Reactions..........................................................................25
Table 4:
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for Alanine Aminotransferase, Aspartate Aminotransferase and 
Gamma-Glutamyl Transpeptidase Tests.....................................................................26
Table 5.
Study Task Flow Chart for Extension Phase..............................................................38
Table 6:
A Partial List of Moderate/Strong CYP3A4 Inhibitors Disallowed 2 Weeks 
Prior to and During the Treatment Period and 30 Days After Last Dose.................170
Table 7:
A Partial List of CYP3A4 Inducers..........................................................................171
Table 8:
A Partial List of of CYP3A4 Substrates with a Narrow Therapeutic Index.............172
Table 9:
A Partial List of Drugs that are Mainly Metabolized by 
Cytochrome P450 1A2 .............................................................................................173
Table 10:
Study Task Flow Chart for Returning Subjects after Planned Pregnancy................182


Protocol No: MS-LAQ-301E
Amended Protocol 03
ALLEGRO Extension Study
10
1.
SYNOPSIS
Protocol Number:
MS-LAQ-301E
Eudract/IND Numbers:
2009-012989-30 / 071287
Study Title:
A Multinational, Multicenter, Open-Label, Single-Assignment Extension of 
the MS-LAQ-301 (ALLEGRO) Study, to Evaluate the Long-Term Safety, 
Tolerability and Effect on Disease Course of Daily Oral Laquinimod 0.6 mg 
in Subjects with Relapsing Multiple Sclerosis
Number of Centers:
All centers that randomized subjects in the MS-LAQ-301 study
Clinical Phase:
III, open-label extension study
Study Duration:
Treatment phase: starting from completion of the MS-LAQ-301 study
(Termination visit), as long as the Sponsor continues the development of 
laquinimod 0.6 mg for Relapsing Remitting Multiple Sclerosis (RMMS).
Study Population:
Subjects, who completed the Termination visit of the MS-LAQ-301 double-
blind treatment phase according to the MS-LAQ-301 protocol, signed an 
informed consent form for the open-label extension study and met all 
eligibility criteria for this study.
Study Objective(s):
To make laquinimod 0.6 mg available to all subjects who completed the 
placebo-controlled MS-LAQ-301 study according to the protocol and to 
evaluate the long-term safety, tolerability and effect on disease course of daily 
oral laquinimod 0.6 mg in subjects with relapsing multiple sclerosis.
Study Design:
This is a multinational, multicenter, open-label, single-assignment extension 
of the MS-LAQ-301 study, to evaluate the long-term safety, tolerability and 
effect on disease course of daily oral laquinimod 0.6 mg in subjects with 
relapsing multiple sclerosis.
Eligible subjects will be treated with laquinimod 0.6 mg capsules once daily.
Subjects completing the full-duration of the double-blind MS-LAQ-301 study 
(completion of Termination visit) according to the MS-LAQ-301 protocol
will be offered the opportunity to enter the MS-LAQ-301E study. In this 
open-label study, the subjects will be treated with laquinimod 0.6 mg
(regardless of their initial treatment assignment during the MS-LAQ-301 
study) as long as the Sponsor continues the development of laquinimod 
0.6 mg for RRMS.
Scheduled in-clinic visits will be conducted at Baseline (Month 0E) (the 
Termination visit of MS-LAQ-301 will serve as the baseline visit of MS-
LAQ-301E) and at months 1E, 2E, 3E, 6E and every 6 months thereafter, until 
Termination/Early discontinuation.
The following assessments will be performed at the specified time points:

Vital signs will be measured at each study visit. At month 0E 
[Baseline (Termination visit of the MS-LAQ-301 study)] vital 
signs will be measured also 30 and 60 minutes after the 
administration of the first dose of laquinimod 0.6 mg.


Protocol No: MS-LAQ-301E
Amended Protocol 03
ALLEGRO Extension Study
11

Weight will be measured at all visits until Termination/early 
discontinuation.

A physical examination will be performed at months 0E [Baseline
(Termination visit of the MS-LAQ-301 study)], 6E, 12E and then 
every 12 months (every other scheduled visit) thereafter, until 
Termination/Early discontinuation visit.
The following safety clinical laboratory tests will be performed:

Complete blood count (CBC) with differential – at all scheduled 
visits.

Serum chemistry (including electrolytes, liver enzymes, direct 
and total bilirubin, pancreatic amylase, creatine phosphokinase 
[CPK], and estimated glomerular filtration rate) – at all scheduled 
visits.

Hematology.

A urine dipstick beta human Chorionic Gonadotropin (β-hCG)
test will be performed in women of child-bearing potential (at 
site) - at all scheduled visits.

Serum β-hCG in women of child-bearing potential - at all
scheduled study visits.

Starting after visit Month 3E a urine dipstick β-hCG test will be 
performed at home in women of child-bearing potential every 28 
(±2) days. The subject will be contacted by telephone within 72 
hours after the test is scheduled to be performed and will be asked 
specific questions regarding the test. In any case of suspected 
pregnancy (positive urine β-hCG test result, delay of 
menstruation or any other reason suggesting pregnancy), the 
caller will make sure that the study drug has been discontinued 
and the subject will be instructed to arrive to the site as soon as 
possible with all study drugs.

Serum conventional high-sensitivity C-reactive protein (hs-CRP) 
and fibrinogen - at all scheduled visits.

In case of abnormal CPK result: troponin and CPK-MB will be 
tested. In case of CPK >2000 U/L urine myoglobin will be tested 
and the following tests will be repeated: CPK, CPK-MB, blood 
urea nitrogen, creatinine, electrolytes including potassium, 
calcium, phosphate, hs-CRP and fibrinogen

Lipase will be tested in case of abnormal pancreatic amylase 
results

The use of effective contraception will be ascertained at every 
visit.
Starting from Visit Month 6E, all subjects will be regularly contacted by 
telephone every 3 months between the scheduled visits and asked a general 
question regarding their well-being (for women of child-bearing potential, 
there is no need to perform a separate call, as this question will be a part of 
the monthly pregnancy urine test call).
Electrocardiogram (ECG), neurological evaluations, including Expanded 
Disability Status Scale (EDSS), 25 foot walk test/Ambulation Index (AI), 
Functional systems (FS), Multiple Sclerosis Functional Composite (MSFC), 


Protocol No: MS-LAQ-301E
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ALLEGRO Extension Study
12
subject-reported fatigue as assessed by the Modified Fatigue Impact Scale 
(MFIS) and Binocular low-contrast visual acuity using the 100%, 2.5% and 
1.25% contrast level charts [Sloan letter or Tumbling-E] will be performed at 
months 0E [Baseline (Termination visit of the MS-LAQ-301 study)], 6E and 
then at every scheduled study visit thereafter, until Termination/Early 
discontinuation visit.
Adverse events (AEs) will be monitored throughout the study.
Concomitant medications will be monitored throughout the study.
Relapses will be confirmed/monitored throughout the study.
The allowed treatment for a relapse will be intravenous methylprednisolone 
1 g/day or oral steroids for up to 5 consecutive days.
Magnetic Resonance Imaging (MRI) scan at Termination/Early 
discontinuation visit will be performed on subjects who participated in the 
MRI ancillary study only.
Subjects who discontinue treatment for any reason will continue follow-up 
according to scheduled visits.
Ancillary studies:
MRI: Subjects who participated in the Frequent MRI ancillary study during 
the MS-LAQ-301 study will be offered to continue to undergo MRI scans 
during the open-label extension study. During the MS-LAQ-301E study, these 
scans will be performed at Months 0E [Baseline (This is the Termination scan 
of the MS-LAQ-301 study)] and then every 12 months thereafter, until 
Termination/Early discontinuation.
Magnetization Transfer (MT): Subjects who participated in the MT ancillary 
study during the MS-LAQ-301 study will be offered to continue to undergo 
MT scans during the open-label extension study. During the MS-LAQ-301E 
study, these scans will be performed at Months 0E [Baseline (Termination 
visit of the MS-LAQ-301 study)] (this scan is a part of the MT ancillary study 
under the MS-LAQ-301 protocol) and then every 12 months thereafter until 
Termination/Early discontinuation.
Magnetization Resonance Spectroscopy (MRS): Subjects who participated in 
the MRS ancillary study during the MS-LAQ-301 study will be offered to 
continue to undergo MRS scans during the open-label extension study. 
During the MS-LAQ-301E study, these scans will be performed at Months 0E 
[Baseline (Termination visit of the MS-LAQ-301 study)] (this scan is a part of 
the MRS ancillary study under the MS-LAQ-301 protocol) and then every 24 
months thereafter, until Termination/Early discontinuation.
For purposes of neurological/medical assessments, the study will be divided 
into 2 periods:
Period 1: in which all subjects will continue to be evaluated by 2 distinct 
physicians - a Treating and an Examining Neurologists/ Physician (as in the 
MS-LAQ-301 study).
Period 2: in which all subjects will be assessed by a single Study Physician/ 
Neurologist.


Protocol No: MS-LAQ-301E
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All neurological/medical assessments may be performed by a single Study 
Physician/Neurologist since all the sites are now in Period 2 of the study.
Female subjects of childbearing potential who might want to get pregnant in 
the future, and are interested in re-starting laquinimod treatment following 
delivery and cessation of breastfeeding may be able to re-enroll in the study 
after meeting inclusion/exclusion criteria. Re-enrollment will be permitted on 
a case-by-case basis. Notwithstanding, Teva is under no obligation to re-
enroll such subjects and reserves the right to re-enroll or reject enrolment of 
such returning subjects for no reason and on its sole discretion. A new 
informed consent form should be signed before re-enrollment.
Number of Subjects:
A total of 1106 subjects were randomized to the MS-LAQ-301 study. A total 
of 839 subjects who completed the Termination visit of the MS-LAQ-301 
study according to the MS-LAQ-301 protocol, signed an informed consent 
form for the open-label extension study, and met all eligibility criteria for this 
study enrolled to the MS-LAQ-301E study. 
Inclusion/Exclusion
Criteria:
Inclusion Criteria:
1.
Subjects must have completed the Termination visit of MS-LAQ-301 
(completion of all Termination visit activities) according to the MS-
LAQ-301 protocol.
2.
Women of child-bearing potential (for example women who are not 
postmenopausal or surgically sterilized) must practice two acceptable 
methods of birth control for the duration of the study and until 30 
days after the last dose of study medication [acceptable methods of 
birth control in this open label extension phase include: intrauterine 
devices, barrier methods (condom or diaphragm with spermicide), and 
hormonal methods of birth control (e.g. oral contraceptive, 
contraceptive patch, and long-acting injectable contraceptive)].
3.
Subjects must be willing and able to comply with the protocol 
requirements for the duration of the study.
4.
Subjects must be able to comprehend, sign and date a written 
informed consent prior to entering the MS-LAQ-301E study.
Exclusion Criteria:
1.
Premature discontinuation from the MS-LAQ-301 study, for any 
reason.
2.
Pregnancy [according to urine dipstick β-hCG test performed at 
Baseline (Month 0E) visit] or breastfeeding.
3.
Subjects with clinically significant or unstable medical or surgical 
condition detected or worsened during the MS-LAQ-301 study, which 
preclude safe participation and completion of the MS-LAQ-301E 
study. Acute exacerbation of MS will not exclude participation in the 
MS-LAQ-301E study.
4.
Use of inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks 
prior to baseline visit (V0E, Month 0E).
Route and Dosage 
Form:
One capsule containing 0.6 mg laquinimod to be administered orally once 
daily.


Protocol No: MS-LAQ-301E
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14
Outcome Measures:
To assess the long-term safety and tolerability of daily oral laquinimod 
0.6 mg in subjects with relapsing multiple sclerosis.
Safety and Tolerability Outcome Measures:
Safety:

AE

Vital signs

ECG findings

Clinical laboratory parameters
Tolerability:

Proportion of subjects (%) who prematurely discontinued from 
the study, reason of discontinuation and the time to withdrawal.

Proportion of subjects (%) who prematurely discontinued from 
the study due to AEs and the time to withdrawal
Efficacy
To assess the long-term effect of laquinimod 0.6 mg on disease course, as 
assessed by several parameters:

Number of confirmed relapses

Progression of disability as measured by the EDSS score 
(including FS and AI)

Progression of disability as measured by the MSFC score

Binocular low-contrast visual acuity using the 100%, 2.5% and 
1.25% contrast level charts [Sloan letter or Tumbling-E]

Subject-reported fatigue as assessed by the MFIS
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
9-HPT
9-Hole Peg Test
ACTH
Adrenocorticotrophic Hormone
ADME
Absorption/Distribution/Metabolism/Elimination
AE
Adverse Event
AI
Ambulation Index
AhR
Aryl Hydrocarbon Receptor
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (SGPT)
AST
Aspartate Aminotransferase (SGOT)
ARR
Annualized Relapse Rate
ASMA
Anti-Smooth Muscle Antibodies
AUC
Area Under the Concentration by Time Curve
BP
Blood Pressure
ß-hCG
Beta-human Chorionic Gonadotropin
CA
Competent Authority
CAB
Clinical Advisory Board
CBC
Complete Blood Count
CCSVI
Chronic Cerebrospinal Venous Insufficiency
CHMP
Committee for Medicinal Products for Human Use
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
CPK
Creatine Phosphokinase
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C-reactive Protein
CSF
Cerebrospinal Fluid
CSU
Clinical Supplies Unit
CT
Computed Tomography
CYP
Cytochome P450
DLC
Dioxin-like Compound
DLT
Digital Linear Tape
DM
Data Management
DMC
Data Monitoring Committee
EAE
Experimental Autoimmune Encephalomyelitis


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EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDSS
Expanded Disability Status Scale
EU
European Union
FDA
Food and Drug Administration
FS
Functional Systems
FOV
Field of View
g
gram
GCP
Good Clinical Practice
Gd
Gadolinium
Gd-DTPA
Gadolinium-Gadopentetic Acid
GdE
Gadolinium Enhancing
GFR
Glomerular filtration rate
GGT
Gamma-Glutamyl Transpeptidase
GMP
Good Manufacturing Practice
HDL
High Density Lipoprotein
hs-CRP
High-sensitivity C-reactive Protein
I3C
Indole-3-Carbinol
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IFN-β
Interferon-beta
Ig
Immunoglobulin
IM
Intramuscular
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent-To-Treat
IV
Intravenous
IVIG
Intravenous Immunoglobulin
IVRS/ IWRS
Interactive Voice Response System
kg
kilogram
L
Liter
LCM
Local Clinical Management
LDL
Low Density Lipoprotein
LKM
Liver Kidney Microsomal
LSO
Local Safety Officer


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MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MFIS
Modified fatigue Impact Scale
mg
Milligram
ml
Milliliter
mm
Millimeter
MOA
Mechanism Of Action
MRI
Magnetic Resonance Imaging
MRI-AC
Magnetic Resonance Imaging Analysis Center
MRS
Magnetization Resonance Spectroscopy
MS
Multiple Sclerosis
MSFC
Multiple Sclerosis Functional Composite
MT
Magnetization Transfer
MTR
Magnetization Transfer Ratio
NAA
N-Acetyl Aspartate
PASAT
Paced Auditory Serial Addition Task
PO
Per Os
QA
Quality Assurance
RDC
Remote Data Capture
RRMS
Relapsing Remitting Multiple Sclerosis
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCDD
Tetrachloro-p-dibenzodioxin
Tmax
Time to Maximal Plasma Drug Concentration
ULN
Upper Limit of the Normal Range
VOI
Volume of Interest
WBC
White Blood Cell (Count)


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3.
INTRODUCTION
3.1.
Background
3.1.1.
General
Multiple Sclerosis (MS) is a chronic, relapsing or progressive, inflammatory demyelinating 
disease of the central nervous system (CNS), which leads to disability of various degrees and has 
different progression rates in different patients. Its prevalence rate varies between races and 
geographical latitude. MS is a common disease, affecting approximately 2,500,000 subjects 
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 for MS 2006). There is, as yet, 
no cure. Treatment has been aimed at controlling symptoms and slowing progression of disease
(Neuhaus et al 2003). Authorized disease-modifying drugs for Relapsing Remitting Multiple 
Sclerosis (RRMS) given by injection include interferon-beta (IFN-β) 1a (Avonex®a, Rebif®b) or
1b (Betaseron®c, Extavia®d), glatiramer acetate (Copaxone®e), mitoxantrone (Novantrone®f), 
natalizumab (Tysabri®g; for patients non-responsive to other medications), and alemtuzumab 
(Lemtrada®). 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 has demonstrated efficacy in various types of experimental autoimmune 
encephalomyelitis (EAE) models, as well as in cuprizone induced demyelination, all accepted 
models of MS.
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 
                                                
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


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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.
The precise mechanism of action (MOA) of laquinimod in MS is still under investigation. 
Available data support that laquinimod is an immunomodulator that acts in the periphery and 
within the CNS. The suggested mode of action of laquinimod includes modulation of peripheral 
inflammation and direct modulation of the CNS resident parenchymal cells, including down-
regulation of the astrocytic pro-inflammatory response (a process known as astrogliosis). By 
these suggested protective mechanisms, laquinimod restricts peripheral inflammation as well as 
tissue damage and neurodegeneration in MS.
Laquinimod demonstrates a predictable and linear pharmacokinetics (PK) profile 
(see Section 3.3.1) characterized by high plasma protein binding (>98%), high oral 
bioavailability (~90%), low oral clearance (~0.09 L/h), low apparent volume of distribution 
(~10 L) and long half-life (~80 h).
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 cytochrome 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.


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For a complete overview of the Absorption/Distribution/Metabolism/Elimination (ADME)-PK 
program of laquinimod, please refer to the laquinimod Investigator’s Brochure (IB).
3.2.3.
Toxicology
The nonclinical safety program of laquinimod has encompassed separate investigations on vital 
organ systems, single and repeat dose toxicity in mice (duration up to 13 weeks), rats (duration 
up to 26 weeks), and dogs (duration up to 52 weeks), genotoxicity, carcinogenicity studies in 
p53+/- transgenic mice and in rats, toxicity to reproduction, photosafety testing, immunotoxicity 
evaluation, and local tolerance.
Safety pharmacology studies in the rat and dog did not demonstrate significant effects of 
laquinimod on the function of cardiovascular, respiratory, central nervous, renal and 
gastrointestinal systems providing safety margins in the range of 100- to 810-fold above the 
intended clinical dose of 0.6 mg/day based on maximal plasma concentrations.
Overall, the non clinical safety program identified several safety issues. Specifically, the 
toxicities identified are pro-inflammatory effects (including thyroiditis), mild liver toxicity, and 
mild reductions of red blood cell 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 


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the US National Toxicology Program as irrelevant for I3C risk assessment (NTP TR-584 2014). 
No increased incidence of oral tumors was seen in humans exposed to TCDD, indicating a 
species specific response in rats. Therefore, oral cavity tumors induced by laquinimod in rats 
after a lifelong exposure do not imply an elevated carcinogenicity risk in humans. Humans, in 
general, also seem to be less sensitive to AhR activation by laquinimod than rats, as shown by 
the differential gene expression profiles discussed in the IB.
A standard pre- and post-natal toxicity study and a follow-up investigational study in rats 
demonstrated urogenital malformations in female rat offspring exposed in utero to laquinimod at 
doses similar to the clinical dose of 0.6 mg/day based on exposure. A slight delay in puberty and 
reduction in fertility were noted in rat offspring exposed in utero to laquinimod at doses slightly 
higher than the clinical dose of 0.6 mg/day in humans. The mechanism leading to the 
malformations in rats is unknown. Induction of urogenital malformations in rodents has been 
reported for a variety of agents including sex hormones and the AhR agonist TCDD. Several 
studies were performed to investigate the potential hormonal modulating activity of laquinimod, 
but no such effects were demonstrated at clinically relevant levels. An AhR mediated effect 
cannot be excluded since it plays a distinct role in developmental processes in many 
experimental animals. However, the relevance to humans of the teratogenic effects seen in 
rodents is questionable. In a pre- and post-natal toxicity study in monkeys, the high dose level 
was associated with higher incidence of prenatal loss which limited the number of monkeys that 
could be evaluated, but there were no treatment-related malformations at doses up to 28-fold the 
expected plasma exposure at intended clinical dose of 0.6 mg/day. 
Based on the above, humans should not be exposed to laquinimod during pregnancy.
A complete overview of the safety pharmacology and non clinical safety program of laquinimod 
is presented in the laquinimod IB.
In the planned clinical study, potential risks will be mitigated by careful screening of subjects, 
frequent and proactive monitoring of subjects and appropriate stopping rules. Furthermore, an 
independent data monitoring committee (DMC) is assigned to assess the data (see Section 20.2).
3.3.
Clinical Experience
Detailed information concerning all clinical studies with laquinimod is presented in the IB.
3.3.1.
Clinical Pharmacology Studies
Laquinimod is considered to have high oral bioavailability with linear, time independent and 
predictable pharmacokinetics, 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 


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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 pharmacokinetics are 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.
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
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: 


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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 3.4.1.1.7.
3.4.
Known and Potential Risks and Benefits to Human Subjects
3.4.1.
Known and Potential Risks and Benefits for Laquinimod
Unless noted otherwise, characterization of the safety profile (important risks and adverse drug 
reactions) of laquinimod is based on the pivotal MS studies, in which laquinimod was 
administered to a total of 983 MS patients at a dose of 0.6 mg/day for up to 2 years. Very 
common or important adverse reactions include headache, abdominal pain, back and neck pain 
and appendicitis. Mild liver enzyme elevations (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], and gamma-glutamyl transpeptidase [GGT]) have been reported 
commonly, but Hy’s law criteria have not been met and there have been no cases of liver failure. 
Treatment with laquinimod may be associated with some additional laboratory abnormalities, 
including hematological changes (hemoglobin decreased/anemia, white blood cell (WBC) count
increased, platelets decreased) and elevation of blood C-reactive protein (CRP) or fibrinogen 
levels; these laboratory changes are generally mild and asymptomatic.
The safety profile of laquinimod is provided in detail below:
Table 3 presents the list of possible adverse drug reactions.
The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10)

Common (≥1/100 to < 1/10)

Uncommon (≥1/1000 to < 1/100)

Rare (≥1/10000 to < 1/1000)

Very rare (< 1/10000)
                                                
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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
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
a For liver enzyme elevations and anemia - see below.
b Blood C‑ reactive protein increased was observed at doses higher than 0.6 mg.


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3.4.1.1.
Details of Important Adverse Drug Reactions:
3.4.1.1.1. 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
The percentages listed in the 
table below refer to all patients 
with normal values at baseline. 
Test:
Range of Increase
Placebo
Laquinimod 0.6 mg
AST (IU/L)
Patients with Normal Test 
at Baseline:
N = 977
Patients with Normal Test 
at Baseline:
N = 950
> 1 and ≤3 x ULN*
83 (8.5%)
159 (16.7%)
> 3 and ≤5 x ULN
6 (0.6%)
9 (0.9%)
> 5 and ≤8 x ULN
4 (0.4%)
1 (0.1%)
> 8 x ULN
2 (0.2%)
0 (0.0%)
ALT (IU/L)
Patients with Normal Test 
at Baseline:
N = 930
Patients with Normal Test 
at Baseline:
N = 888
> 1 and ≤3 x ULN
165 (17.7%)
262 (29.5%)
> 3 and ≤5 x ULN
5 (0.5%)
30 (3.4%)
> 5 and ≤8 x ULN
6 (0.6%)
5 (0.6%)
> 8 x ULN
7 (0.8%)
5 (0.6%)
GGT (IU/L)
Patients with Normal Test 
at Baseline: 
N =930
Patients with Normal Test 
at Baseline : 
N = 906
> 1 and < 3 x ULN
90 (9.7%)
147 (16.2%)
> 3 and < 5 x ULN
11 (1.2%)
22 (2.4%)
> 5 and < 8 x ULN
1 (0.1%)
6 (0.7%)
ULN = Upper limit of normal range; AST = aspartate aminotransferase; ALT = alanine aminotransferase; 
GGT = Gamma-Glutamyl Transpeptidase ; IU/L = international units/L


Protocol No: MS-LAQ-301E
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27
3.4.1.1.2. 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.
3.4.1.1.3. 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.
3.4.1.1.4. Back and Neck Pain
Treatment with laquinimod has been associated with an increased incidence of back and neck 
pain. Back and neck pain 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.
3.4.1.1.5. 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.
3.4.1.1.6. Hematological Changes

Hemoglobin decrease/Anemia: Treatment with laquinimod has been associated with a 
mild, asymptomatic, non-progressive decrease of the hemoglobin level, which 
occurred early after initiation of treatment and was usually transient without cessation 
of therapy or need for anti-anemic therapy.

Decreased platelets: Treatment with laquinimod has been associated with a generally 
mild decrease of the platelet count, without clinical manifestations.

Increased WBCs: Treatment with laquinimod has been associated with a generally 
mild increase of the total WBC count that was consistent across WBC subtypes, 
without clinical manifestations.
3.4.1.1.7. Cardiovascular Events (Laquinimod 1.2 and 1.5 mg)
On 30 December 2015, a DMC review of 8 unblinded cases from the LAQ-MS-305
(CONCERTO) and TV5600-CNS-20006 (ARPEGGIO) studies found an imbalance in serious 


Protocol No: MS-LAQ-301E
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28
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.
3.4.1.2.
Potential Safety Issues with Laquinimod
3.4.1.2.1. Pregnancy
Studies in rats have shown reproductive toxicity including teratogenicity (urogenital 
malformations) at doses similar to the clinical dose of 0.6 mg/day in humans. Delay in puberty 
and reduced fertility were noted in rat offspring exposed to laquinimod in utero at doses higher 
than the clinical dose of 0.6 mg/day in humans (Section 3.2.3). The relevance to humans of these 
findings is not known, but cannot be excluded.
Exposure to laquinimod during pregnancy must be avoided.
To prevent such exposure, women who are of childbearing potential (for example women who 
are not postmenopausal or surgically sterilized) must practice an acceptable method of birth 
control (Section Section 8.3.2.2) for 30 days before taking the study drug and two acceptable 
methods of birth control during all study 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 


Protocol No: MS-LAQ-301E
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29
contraceptive, contraceptive patch and long-acting injectable contraceptive). Use of acceptable
contraception should be ascertained at every study visit.
In addition, regular pregnancy testing is required during the study. If pregnancy is suspected 
despite all recommended precautions (e.g., positive urine beta-human chorionic gonadotropin 
[β-hCG] test result, delay of menstruation or any other reason suggesting pregnancy), treatment 
should be discontinued immediately. The subject should be reminded of the potential risk to the 
fetus, and all options, including termination of pregnancy, should be discussed.
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.
3.4.1.2.2. 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.
3.4.1.2.3. Cardiotoxicity and Systemic Inflammation
In clinical studies performed with laquinimod’s predecessor molecule, roquinimex, 
pericarditis/pleuritis and ischemic heart disorders were identified as important safety concerns. 
Serious toxicities that occurred during Phase 3 trials led to discontinuation of these trials. 
Roquinimex demonstrated serious toxicities including increased rates of myocardial infarction, 
pericarditis, and pleuritis that were observed in three Phase 3, placebo-controlled studies in MS 
patients. The mechanism by which roquinimex caused these events was not identified, but they 
were considered to be possible manifestations of a systemic inflammatory response, an 
assessment which was also supported by roquinimex nonclinical findings. A thorough analysis 
was done on the laquinimod safety data (which is mostly reflective of the 0.6 mg/day dose) to 
evaluate similar potential safety issues. Based on 2347 patients exposed to laquinimod 0.6 mg for 
over 10000 patient-years, as well as the patients exposed to 0.6 mg in the CONCERTO and 
ARPEGGIO studies, analyses showed that these safety issues do not constitute a clear signal for 
laquinimod in doses up to 0.6 mg/day. However, at doses of 1.2 and 1.5 mg, laquinimod 
manifested clinical evidence of myocardial infarction.


Protocol No: MS-LAQ-301E
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30
4.
STUDY OBJECTIVES
To make treatment with oral laquinimod 0.6 mg available to all subjects who participated in the 
double-blind, placebo-controlled MS-LAQ-301 study and who completed the Termination visit 
of this study according to the MS-LAQ-301 protocol as long as the Sponsor continues the 
development of laquinimod 0.6 mg for RMMS.
To assess the long-term safety and tolerability of laquinimod 0.6 mg once daily in subjects with 
relapsing MS.
To assess the long-term effects of laquinimod 0.6 mg on the disease course, as measured by 
clinical efficacy outcomes, which were evaluated in the double-blind treatment phase in this 
subject population.
4.1.
Ancillary Studies
The following ancillary studies will be performed in a subset of subjects:
MRI: Subjects who participated in the Frequent MRI ancillary study during the MS-LAQ-301 
study will be offered to continue to undergo MRI scans during the open-label extension study. 
During the MS-LAQ-301E study, these scans will be performed at Months 0E [Baseline (This is 
the Termination scan of the MS-LAQ-301 study)] and then every 12 months thereafter, until 
Termination/Early discontinuation.
Magnetization Transfer (MT): Subjects who participated in the MT ancillary study during the 
MS-LAQ-301 study will be offered to continue to undergo MT scans during the open-label 
extension study. During the MS-LAQ-301E study, these scans will be performed at Months 0E 
[Baseline (Termination visit of the MS-LAQ-301 study)] (this scan is a part of the MT ancillary 
study under the MS-LAQ-301 protocol) and then every 12 months thereafter until 
Termination/Early discontinuation.
Magnetic Resonance Spectroscopy (MRS): Subjects who participated in the MRS ancillary study 
during the MS-LAQ-301 study will be offered to continue to undergo MRS scans during the 
open-label extension study. During the MS-LAQ-301E study, these scans will be performed at 
Months 0E [Baseline (Termination visit of the MS-LAQ-301 study)] (this scan is a part of the 
MRS ancillary study under the MS-LAQ-301 protocol) and then every 24 months thereafter, 
until Termination/Early discontinuation.


Protocol No: MS-LAQ-301E
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31
5.
STUDY DESIGN
5.1.
Overview And Plan
This is a multinational, multicenter, open-label, single-assignment extension of the 
MS-LAQ-301 study, to evaluate the long-term safety, tolerability and effect on disease course of 
daily oral laquinimod 0.6 mg in subjects with relapsing MS.
Eligible subjects will be treated with laquinimod 0.6 mg capsules once daily.
Subjects completing the full duration of the double-blind MS-LAQ-301 study (completion of the 
Termination visit) according to the MS-LAQ-301 protocol will be offered the opportunity to 
enter into the open label extension MS-LAQ-301E study. In this open-label study they will be 
treated with laquinimod 0.6 mg once daily, regardless of their initial treatment assignment during 
the MS-LAQ-301 study.
Scheduled in-clinic visits will be conducted at Baseline (month 0E; the Termination visit of 
MS-LAQ-301 will serve as the baseline visit of MS-LAQ-301E) and at months 1E, 2E, 3E, 6E 
and every 6 months thereafter, as long as the Sponsor continues the development of laquinimod 
0.6 mg for RMMS. At this time point, subjects will be invited to attend a Termination visit.
Subjects who discontinue treatment for any reason will continue follow-up according to 
scheduled visits.
5.1.1.
Study Periods
As of the implementation of Protocol Amendment #2, the medical/neurological assessments of 
the subjects at each clinical site will no longer be performed differently since all the sites are 
now in study period 2.
Period 1:
In this period, either two separate Neurologists or two Physicians will continue to assess the 
subjects in the MS-LAQ-301E study (as in the MS-LAQ-301 study). An Examining 
Neurologist/Physician will assess the subject’s neurological status, unaware of subject’s 
well-being and a Treating Neurologist/Physician will decide whether a subject experienced a 
relapse and will treat the subject as needed.
In order to maintain reliable evaluation and reduce the potential for bias the following actions 
will be undertaken:
The Examining Neurologist/Physician will be the only one to evaluate the subject neurologically.
The Examining Neurologist/ Physician will have no access to the subject's file, including 
previous neurostatus forms, remote data capture (RDC) system and adverse events (AEs).


Protocol No: MS-LAQ-301E
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32
A decision as per treatment of a relapse will be under the sole responsibility of the Treating 
Neurologist/ Physician.
Period 2:
In this period, there will be no need for 2 separate physicians to assess the subjects in the MS-
LAQ-301E study. Subjects participating in the MS-LAQ-301E study will be assessed by a single 
physician/Neurologist ("Study Physician/ Neurologist").
5.1.1.1.
Revealing the MS-LAQ-301 Study Treatment Assignment during the Open-
Label Study
The investigator may request the Sponsor to provide the original treatment allocation of the 
subject in the MS-LAQ-301 study. This will be possible only after transition to Period 2.
5.2.
Rationale for Study Design, Dose and Population
The open-label extension MS-LAQ-301E study is designed to:
Provide laquinimod 0.6 mg once daily to all subjects who successfully complete the double-
blind, placebo-controlled MS-LAQ-301 study as long as the Sponsor continues the development 
of laquinimod 0.6 mg for RRMS.
Provide information on laquinimod's long-term safety, tolerability and effect on disease course in 
this subject population.
The 0.6 mg daily dose was selected, since this was the dose used in the double-blind, placebo-
controlled MS-LAQ-301 study.


Protocol No: MS-LAQ-301E
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33
6.
STUDY POPULATION
One thousand, one hundred and six (1106) subjects were randomized to the MS-LAQ-301 study. 
All subjects who complete the Termination visit of the MS-LAQ-301 study (according to the 
MS-LAQ-301 protocol), meet the eligibility criteria and sign an informed consent form will be 
enrolled to the MS-LAQ-301E study.
6.1.
Inclusion Criteria
Subjects must meet all inclusion criteria in order to be eligible for the study:
1. Subjects must have completed the Termination visit of MS-LAQ-301 (completion of all 
Termination visit activities) according to the MS-LAQ-301 protocol.
2. Women of child-bearing potential (for example women who are not postmenopausal or 
surgically sterilized) must practice two acceptable methods of birth control for the 
duration of the study and until 30 days after the last dose of study medication [acceptable 
methods of birth control in this open label extension phase include: intrauterine devices, 
barrier methods (condom or diaphragm with spermicide), and hormonal methods of birth 
control (e.g. oral contraceptive, contraceptive patch, and long-acting injectable 
contraceptive)].
3. Subjects must be willing and able to comply with the protocol requirements for the 
duration of the study.
4. Subjects must be able to comprehend, sign and date a written informed consent prior to 
entering the MS-LAQ-301E study.
6.2.
Exclusion Criteria
Any of the following conditions will exclude the subject from entering the study:
1. Premature discontinuation from the MS-LAQ-301 study, for any reason.
2. Pregnancy [according to urine dipstick β-hCG test performed at Baseline (Month 0E) 
visit] or breastfeeding.
3. Subjects with clinically significant or unstable medical or surgical condition detected or 
worsened during the MS-LAQ-301 study, which preclude safe participation and 
completion of the MS-LAQ-301E study. Acute exacerbation of MS will not exclude 
participation in the MS-LAQ-301E study.
4. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline visit (V0E, Month 0E).
Female subjects of childbearing potential who may want to get pregnant in the future, and are 
interested in re-starting laquinimod treatment following delivery and cessation of breastfeeding 


Protocol No: MS-LAQ-301E
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34
may be able to re-enroll in the study after meeting inclusion/exclusion criteria in Appendix G. 
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 (Appendix G).


Protocol No: MS-LAQ-301E
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35
7.
MEDICATIONS/THERAPIES – ALLOWED AND DISALLOWED
7.1.
Allowed Concomitant Medications/Therapies
Symptomatic MS agents, such as anti-cholinergic and spasmolytic drugs, are permitted at
clinically appropriate doses.
Short-term treatment with corticosteroids will be allowed during relapses. Allowed treatment for 
relapses is a fixed dose of intravenous (IV) methylprednisolone 1 g/day or oral steroids for a 
maximum of 5 consecutive days. No tapering off is allowed.
Other medications, excluding those mentioned in Section 7.2 may be given concomitantly as 
needed for the subject’s welfare.
Topical and inhaled steroids are allowed at the discretion of the Study Physician/Neurologist for 
indications other than MS.
Administration of all medications, including indication, dose, frequency, and route of 
administration will be recorded in the source documentation file and in the electronic Case 
Report Form (eCRF).
Clinical studies have shown laquinimod 0.6 mg to be a strong inducer of CYP1A2. Subjects 
taking drugs that are metabolized by CYP1A2 (examples listed in Appendix F) 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 F) should be advised that plasma levels of these drugs 
could increase when combined with laquinimod.
7.2.
Disallowed Concomitant Medications During Study

Natalizumab (Tysabri®)

Fingolimod (Gilenya)

IFN-β 1a or 1b

Dimethyl fumarate (Tecfidera)

Glatiramer Acetate (Copaxone®)


Protocol No: MS-LAQ-301E
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36

Teriflunomide (Aubagio)

Alemtuzumab (Lemtrada)

Cladribine

Rituximab

Ocrelizumab

Atacicept

Belimumab

Ofatumumab

Inducers of CYP3A4 such as rifampin or carbamazepine (more examples are 
provided in Appendix E). Use of CYP3A4 inducers may results in reduced 
laquinimod plasma concentrations and reduced effectiveness

Moderate/strong inhibitors of CYP3A4, for example, ketoconazole and erythromycin
(as listed in Appendix E) are disallowed for 2 weeks prior to the baseline visit 
through to 30 days after the final dose of laquinimod. Laquinimod is extensively 
metabolized predominantly by CYP3A4, and ketoconazole and fluconazole, strong 
and moderate inhibitors of CYP3A4, were found to inhibit the metabolism, leading to 
2.5- and 3.1-fold increases in laquinimod exposure, respectively.

Mitoxantrone (Novantrone®)

Oral and parenteral steroids (except if given as defined by protocol for treatment of a 
relapse as specified in Section 7.1)

Adrenocorticotrophic hormone (ACTH)

Chemotherapeutic agents

Cytotoxic agents

Cyclophosphamide

IV Immunoglobulin (Ig)

Plasmapheresis

Any other experimental agents

Other Immunosuppressive or immunomodulating agents


Protocol No: MS-LAQ-301E
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37
8.
STUDY CONDUCT
8.1.
Study Period
The study assessments will be performed according to the summary of the Study Task Flow 
Sheet (see Table 5 – Study Task Flow Chart.)
A month in the treatment period is defined as 30 days ± 4 days.
The study, in which all eligible subjects will be treated with daily laquinimod 0.6 mg, will last as 
long as the Sponsor continues the development of laquinimod 0.6 mg for RMMS. Subjects who 
discontinue treatment for any reason will continue follow-up according to scheduled visits.


Protocol No: MS-LAQ-301E
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38
Table 5.
Study Task Flow Chart for Extension Phase
Visit
V0Ea
V1E
V2E
V3E
V4E
Every 6 
months
Every 12 
months
Every 24 
months
Termination/
Early 
Discontinuation
Unscheduled 
Visitb,c
Month
0E
1E
2E
3E
6E
Informed Consent
X
Eligibility Criteria
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Cardiovascular risk factor assessment and 
managementd
X
X
First Dose at Site
X
Physical Examination
X
X
X
X
X
X
Vital Signs
Xe
X
X
X
X
Xf
Xf
Xf
Xf
X
ECG
X
X
X
X
X
X
X
Safety Laboratory Evaluation (CBC, 
Chemistry, GFR estimation, markers of 
inflammation)
X
X
X
X
X
X
X
X
X
X
Serum β-hCGg
X
X
X
X
X
X
X
X
X
X
Urine β-hCGg (on site)
X
X
X
X
X
X
X
X
X
Ascertaining use of effective contraception
X
X
X
X
X
X
X
X
X
X
Urine -hCGg (self check, at home)
EVERY 1 MONTH BETWEEN 
SCHEDULED VISITS
AE
X
X
X
X
X
X
X
X
X
X
Neurological examination (EDSS/FS/AI/ 25 
foot walk)
X
X
X
X
X
X
X
Evaluation of Relapseh
X
X
X
X
X
X
X
X
X
X
MSFCi
X
X
X
X
X
X
Binocular Low-Contrast Visual Acuity
X
X
X
X
X
X
MFIS
X
X
X
X
X
X
MRI (T1, T2) (Ancillary study, sub-group)
X
X
X
Xj
MT MRI (ancillary study, sub-group)
X
X
X
Xk
MRS (ancillary study, sub-group)
X
X
Xk
Mandatory phone calls (pregnancy tests)l
EVERY 1 MONTH BETWEEN 
SCHEDULED VISITS


Protocol No: MS-LAQ-301E
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39
Visit
V0Ea
V1E
V2E
V3E
V4E
Every 6 
months
Every 12 
months
Every 24 
months
Termination/
Early 
Discontinuation
Unscheduled 
Visitb,c
Month
0E
1E
2E
3E
6E
Mandatory phone calls (general well-being, 
all subjects)m
EVERY 3 MONTHS 
BETWEEN SCHEDULED VISITS
Drug Compliance & Dispensing
X
X
X
X
X
X
X
X
Xn
X
Termination Documentation and 
Notification of Early Termination
X
Unscheduled Samples
Xo
AE = adverse event, AI = ambulation index, β-hCG = beta-human chorionic gonadotropin, CBC = complete blood count, ECG = electrocardiogram, EDSS = 
Kurtzke’s expanded disability status scale, FS = functional systems, GFR = glomerular filtration rate, MFIS = modified fatigue impact scale, MRI = magnetic 
resonance imaging, MRS = magnetic resonance spectroscopy, MSFC = multiple sclerosis functional composite, MT = magnetization transfer
a The Termination visit of the MS-LAQ-301 study will serve as the Baseline visit of the MS-LAQ-301E study. Therefore, all activities, excluding Urine β-hCG 
(on site), informed consent, eligibility criteria and first dose at site are a part of the Termination visit of the MS-LAQ-301 study and therefore should not be 
repeated.
b Vital signs and AEs are mandatory activities in an unscheduled visit. All other activities are optional and may be performed as deemed necessary by the 
investigator. Chest X-ray may also be performed in this visit.
c Post treatment follow up visit in cases of early discontinuation (In which vital signs, review of AEs and concomitant medications, as well as pregnancy test are 
mandatory. All other marked activities are optional).
d In addition, an evaluation should take place as soon as possible for subjects already in the study, following approval of Amendment #3
e Post-dose vital signs will be measured at Baseline and after 30 and 60 minutes, whereas the pre-dose vital signs will be taken from the last measurement in the 
MS-LAQ-301 study.
f Weight will be measured at every visit until Termination/Early discontinuation.
g For women of childbearing potential
h Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator
i The PASAT and 9-HPT will be performed at Months 0E [Baseline (Termination visit of the MS-LAQ-301 study)], 6E and every 6 months (every scheduled 
visit) thereafter, until Termination/early discontinuation visit. The Timed 25 Foot walk test will be performed each time neurological evaluation is performed.
j In case Termination visit of the study is scheduled to less than 14 days after the performance of a scheduled scan – the scan should not be repeated.
k In case Termination visit of the study is scheduled to less than 30 days after the performance of a scheduled scan – the scan should not be repeated.
l For women of child-bearing potential; to be performed within 72 hours of the scheduled home pregnancy test
m The call will be documented in the source documents. For women of child-bearing potential, there is no need to perform a separate call, as this question will be 
a part of the monthly pregnancy urine test call.
n Only drug retrieval
o 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.
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]).


Protocol No: MS-LAQ-301E
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40
8.2.
Detailed Study Plan
8.2.1.
Baseline Visit (Month 0E) (Visit 0E) (Termination Visit of the MS-LAQ-301 
Study) Procedures:
After completion of all procedures of the Termination visit of the MS-LAQ-301 study according 
to the MS-LAQ-301 protocol, and placing a call to the interactive voice response system (IVRS)
to notify the subject's completion of the MS-LAQ-301 study, the subject will be offered to 
participate in the MS-LAQ-301E study. The subject will be informed about all aspects of the 
study, including scheduled study visits and activities, and must sign and date the informed 
consent form. A copy of the informed consent form must be given to the subject. Eligibility for 
participation in the MS-LAQ-301E study will be established by the investigator.
The Baseline visit of the MS-LAQ-301E open-label extension study will occur at the 
Termination visit of the MS-LAQ-301 study. Therefore, many of the activities/assessments of 
the Termination visit of the MS-LAQ-301 study will serve as the Baseline visit (Month 0E)
procedures of the MS-LAQ-301E study.
The following list includes all Baseline (Month 0E) activities. These activities were performed 
under the scope of the Termination visit of the MS-LAQ-301 study and therefore should not be 
repeated, unless otherwise specified.

Vital signs (temperature, pulse, blood pressure [BP] and weight)

Physical examination

Complete neurological examination including functional system (FS), ambulation 
index (AI), 25 foot walk, EDSS

MSFC

Evaluation of a relapse

Electrocardiogram (ECG)

Review of concomitant medications.

MRI: This activity is performed as a part of the Termination visit activities in the MS-
LAQ-301 study in all subjects. This scan will serve as the Baseline (Month 0E) 
assessment in those subjects who participated in the frequent-MRI ancillary study in
the MS-LAQ-301 study and signed a special informed consent form for this sub-study
in the MS-LAQ-301E study and will include:

T1-weighted, after administration of Gd-gadopentetic acid (Gd-DPTA)

T2-weighted


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
3D T1-weighted

MT: This activity is performed as a part of the Termination visit activities in the MS-
LAQ-301 study subjects who took part in the MT ancillary study. This scan will serve 
as the Baseline (Month 0E) assessment in those subjects who participated in the MT
ancillary study in the MS-LAQ-301 study and signed a special informed consent form 
for this sub-study in the MS-LAQ-301E study.

MRS: This activity is performed as a part of the Termination visit activities in the 
MS-LAQ-301 study subjects who took part in the MRS ancillary study. This scan will 
serve as the Baseline (Month 0E) assessment in those subjects who participated in the 
MRS ancillary study in the MS-LAQ-301 study and signed a special informed 
consent form for this sub-study in the MS-LAQ-301E study

AE recording

Safety laboratory tests including:

Serum pregnancy test (β-hCG) for women of child-bearing potential. In case of 
positive result, the subject will not be eligible to participate in the extension and 
will be considered a screening failure for the extension phase.

Urinalysis

Hematology (Complete blood count [CBC], including differential)

Serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin, 
pancreatic amylase and creatine phosphokinase [CPK]).

Markers of inflammation (serum conventional CRP and fibrinogen)

Subject-reported fatigue will be assessed by the Modified Fatigue Impact Scale 
(MFIS) (see Appendix H)

Binocular low-contrast visual acuity assessment, using 100%, 2.5% and 1.25% 
contrast charts [Sloan letter or Tumbling E (see Appendix J and Appendix K)].
New activities to be performed at Baseline visit (Month 0E, Visit 0E) (not part of the 
Termination visit) are:

Subjects will be given all the necessary supplies and detailed instructions for 
administration of IMP, which will be reviewed with the subject during the visit. In 
addition, subjects will be instructed to contact the study center if any questions or 
problems arise.

Urine pregnancy test (β-hCG) for all women of child-bearing potential. In case of 
positive result, the subject will not be eligible to participate in the study.


Protocol No: MS-LAQ-301E
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42

For all subjects who are female of child-bearing potential:

The use of effective contraception will be ascertained at each study visit (should 
be recorded in the source documents).

Subjects will be instructed during each visit about the teratogenicity and potential 
delayed risks for a child exposed in uterus to laquinimod.

Subjects will be reminded about (should be recorded in the source documents)
importance of stopping the study drug and informing the site in any case of 
suspected pregnancy (positive home urine test result, delay of menstruation or any 
other reason suggesting pregnancy).

A call to the IVRS will be made to allocate a pack number for the open-label 
extension phase.

First dose administration of the IMP.

Post-dose vital signs (30 & 60 minutes, pulse and BP only) (pre-dose vital signs will 
be taken from the Termination visit vital signs measurement).

AE recording will be performed upon any subjects’ complaint following study drug 
administration (if relevant) or staff observation.

Subjects will be instructed to contact the study site in the event of any change in their 
medical condition, the appearance of any AEs or any symptom suggestive of a 
relapse.
8.2.2.
Scheduled Treatment Visits [Months 1E (Visits 1E) and Onwards]
Subjects will visit the study center at months 1E, 2E, 3E, 6E (visits 1E, 2E, 3E, 4E, respectively) 
and then every 6 months thereafter. Subjects who discontinue treatment for any reason will 
continue follow-up according to scheduled visits.
Following approval of Global Amendment #3, subjects continuing on laquinimod 0.6 mg will be 
re-consented with information about the cardiovascular risk seen in higher doses (see 
Section 3.4.1.1.7).
The following procedures and evaluations will be performed at each scheduled visit:

Vital signs (temperature, pulse, BP).

Review concomitant medications (ensuring no disallowed medication is being used)

Record of AEs

Evaluation of relapse


Protocol No: MS-LAQ-301E
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
Subject compliance (IMP accountability)

Review instructions on IMP administration and dispensing

Ascertaining use of effective contraception (should be recorded in the source 
documents).

For all subjects who are female of child-bearing potential:

The use of effective contraception will be ascertained at each study visit (should 
be recorded in the source documents).

Subjects will be instructed during each visit about the teratogenicity and potential 
delayed risks for a child exposed in uterus to laquinimod.

Subjects will be reminded about (should be recorded in the source documents)
importance of stopping the study drug and informing the site in any case of 
suspected pregnancy (positive home urine test result, delay of menstruation or any 
other reason suggesting pregnancy) and importance of performing the home 
pregnancy urine tests every one month (starting after visit Month 3E).

Safety laboratory tests:

Serum pregnancy test (β-hCG) for women of child-bearing potential.

Urine pregnancy test (β-hCG) for women of child-bearing potential. In case of 
positive result, study drug should not be dispensed, until results of serum β-hCG 
test is available and pregnancy is either confirmed or excluded 
(see Appendix G). In case of suspected pregnancy, the rest of the visit activities 
should be performed as well.

Hematology (CBC with differential).

Serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin,
pancreatic amylase, CPK, and estimated GFR).

Markers of inflammation (serum conventional high-sensitivity C-reactive protein 
[hs-CRP] and fibrinogen).

IVRS call to obtain pack number.
The following procedures and evaluations will be performed at Month 6E (visit 4E) and at all 
scheduled visits thereafter:

Complete neurological examination including FS, EDSS, AI and Timed 25 Foot 
walk.


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
MSFC.

Binocular low-contrast visual acuity assessment, using 100%, 2.5% and 1.25% 
contrast charts [Sloan letter or Tumbling E (see Appendix J and Appendix K)].

Subject-reported fatigue will be assessed by the MFIS.
In addition, the following procedures/assessment will be performed:

Physical examination will be performed at months 6E (visit 4E), 12E (visit 5E) and 
then every 12 months thereafter (every other scheduled visit).

ECG will be performed at month 6E (visit 4E) and at every scheduled visit thereafter.

MRI Ancillary Study: The scan will be performed at Month 12E (Visit 5E) and every 
12 months thereafter and will include:

T1-weighted, after administration of Gd-DPTA.

T2-weighted.

3D T1-weighted.

MT Ancillary Study: The scan will be performed at Month 12E (Visit 5E) and every 
12 months thereafter.

MRS Ancillary Study: The scan will be performed at Month 24E (Visit 7E) and every 
24 months thereafter.

Weight will be measured at all visits.

Evaluation and management of major modifiable cardiac risk factors (eg, diabetes, 
high blood pressure, hyperlipidemia, tobacco smoking) will be performed every 
12 months, with referral to treatment and follow-up in a suitable clinic if needed. In 
addition, an evaluation should take place as soon as possible for subjects already in 
the study, following approval of Amendment #3.
Starting from Month 3E (Visit 3E), the following actions will be taken for female subjects of 
child-bearing potential:

The subject will be provided with home pregnancy urine β-hCG test kits and will be 
guided how to perform the test. The site staff will schedule the home test to be 
performed every 28 ± 2 days.

In order to verify whether the test has been performed and to record the result of the 
test (see Appendix G), a mandatory phone call will be performed by the Study 
Neurologist/ Physician or by the site’s nurse/ study coordinator within 72 hours after 


Protocol No: MS-LAQ-301E
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45
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.
Starting from Visit Month 6E, all subjects will be regularly contacted by telephone every 3 
months between the scheduled visits and asked a general question regarding their well-being (for 
women of child-bearing potential, there is no need to perform a separate call, as this question 
will be a part of the monthly pregnancy urine test call). Performance of this call will be 
documented in the source documents.
The sequence of assessments performed during the visits should be as follows:
1. MFIS (when applicable)
2. The 9-Hole Peg (9-HPT) and paced auditory serial additional task (PASAT) components 
of the MSFC (Timed 25 Foot walk may be performed later) (when applicable)
3. The rest of the visit activities, as described above
8.2.3.
Termination/ Early Discontinuation
The Termination visit date may be different in each country. Upon a decision of the Sponsor to 
stop the development of laquinimod 0.6 mg for RRMS patients, the local clinical trial 
management will notify the site teams when to invite the subjects to the site, in order to perform 
the Termination visit.
Subjects who have performed all Termination visit activities (in case the Sponsor decides to stop 
the development of laquinimod 0.6 mg for RMMS patients) will be regarded as completers.
Early discontinuation is defined as any withdrawal from the study prior to the completion of the 
treatment period. The treatment period is defined between Month 0E visit (Visit 0E, Baseline)
(Termination visit of the MS-LAQ-301 study) (after administration of the first dose) and 
Termination visit, included. Subjects who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures until completion of the study (with 
the exception of procedures associated with drug dispensing and accountability, pregnancy 
testing, and GFR estimation [including body weight measurement]).
All reasons for discontinuation of therapy will be documented in the source documents as well as 
the eCRF comment form. Only one reason (the most severe) for early discontinuation should be 
recorded in the eCRF Termination form.
In the event that the study IMP was discontinued early, the following forms should be completed 
as close to the last dosing date as possible:

Termination/ Early discontinuation visit form.


Protocol No: MS-LAQ-301E
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
Last visit that the subject attended.
The following procedures and evaluations will be performed at this visit:

Vital signs (temperature, pulse, BP, weight).

Physical examination.

Safety laboratory tests:

Serum pregnancy test (β-hCG) for women of child-bearing potential

Hematology (CBC with differential)

Serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin, 
pancreatic amylase, CPK, and estimated GFR)

Markers of inflammation (serum conventional hs-CRP and fibrinogen).

ECG.

Review concomitant medications. Note: moderate/strong CYP3A4 inhibitors are 
disallowed during the 30 days after the last dose has been administered. For 
information on the use of CYP1A2 substrates following laquinimod cessation, please 
refer to the laquinimod IB.

Record of AEs.

If an AE is still ongoing, or a new AE is present at the termination visit, it will be 
followed until resolution or until it is considered stable or chronic and will be 
recorded in the subject's source documents and in the eCRF.

Complete neurological examination including FS, AI, EDSS and Timed 25 Foot 
walk.

MSFC.

For all subjects who are female of child-bearing potential:

The use of effective contraception will be ascertained (should be recorded in the 
source documents) and they will be reminded to use two acceptable methods of 
contraception up to 30 days from the date of the last dose of the IMP.

Subjects will be instructed about the teratogenicity and potential delayed risks for 
a child exposed in uterus to laquinimod.

Female subjects of child-bearing potential will be reminded about (should be 
recorded in the source documents) importance of stopping the study drug and 


Protocol No: MS-LAQ-301E
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47
informing the site in any case of suspected pregnancy (positive home urine test 
result, delay of menstruation or any other reason suggesting pregnancy)

Binocular low-contrast visual acuity assessment, using 100%, 2.5%, and 1.25% 
contrast charts [Sloan letter or Tumbling E (see Appendix J and Appendix K)].

Evaluation of relapse.

MRI Ancillary Study: The scan will include:

T1-weighted, after administration of Gd-DPTA

T2-weighted

3D T1-weighted.
If Termination visit is scheduled/performed less than 14 days after the performance of 
a scheduled MRI scan – the scan should not be repeated.

MT Ancillary Study: An MT scan will be performed. If Termination/Early 
discontinuation visit is scheduled/performed less than 1 month after the performance 
of a scheduled MT scan – the scan should not be repeated.

MRS Ancillary Study: An MRS scan will be performed. If Termination/Early 
discontinuation visit is scheduled/performed less than 1 month after the performance 
of a scheduled MRS scan – the scan should not be repeated.

Subject-reported fatigue will be assessed by the MFIS (see Appendix H).

Subject compliance (IMP accountability).

IVRS call to report subject’s termination/early discontinuation.
The sequence of assessments performed during the visit should be as follows:
1. MFIS
2. The 9-Hole Peg and PASAT components of the MSFC (Timed 25 Foot walk may be 
performed later)
3. The rest of the visit activities, as described above
8.3.
Early Treatment Discontinuation
Subjects who are discontinued from study treatment will be encouraged to continue all scheduled 
visits and procedures until completion of the study (with the exception of procedures associated 
with drug dispensing and accountability, pregnancy testing, and GFR estimation [including body 
weight measurement]).


Protocol No: MS-LAQ-301E
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An early termination visit should be completed for all subjects who prematurely discontinue 
from the study and do not agree to or cannot continue all scheduled visits and procedures. It 
includes subjects who took at least one dose in the MS-LAQ-301E study.
Every attempt should be made to follow the early discontinued subjects. The subjects who 
prematurely discontinue the study should be treated by the investigator in a customary manner. 
In case of early discontinuation due to ongoing AE, manifestation of a severe degree of 
intolerance to IMP and/or ongoing MS relapse, the subject should remain under medical 
observation and followed until the medical condition returns to baseline or is considered stable or 
chronic.
8.3.1.
Criteria for Early Treatment Discontinuation
A subject may withdraw or be withdrawn from the study for the following reasons:
1. Subject withdrew consent
2. Sponsor requested subject to be withdrawn (this does not include declaration of study 
termination by the Sponsor)
3. Request of primary care physician or investigator
4. Protocol violation/ Non-compliance
5. Lost to follow-up/failure to return
6. AE (specify primary AE in the AE log)
7. Pregnancy
8. Planned pregnancy
9. Lack of efficacy (according to the Investigator’s decision)
10. Death
Any attempt should be made to clarify and to document the exact reason for discontinuation.
8.3.1.1.
Post Early Discontinuation Follow-Up Visit
Note: This section specifically pertains to subjects that discontinue treatment early but do not 
agree to continue follow up.
In case of early discontinuation due to AE, the subject should be invited to attend an unscheduled 
visit, which will serve as a post-treatment follow-up visit. The post treatment follow-up visit 
should occur at 30 +/- 4 days from the last dose taken in the study.


Protocol No: MS-LAQ-301E
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Women of child-bearing potential should continue using contraception methods up to 30 days 
after the last study drug dose was taken.
Moderate and strong CYP3A4 inhibitors are disallowed during the 30 days after the last dose has 
been administered.
The following procedures will be performed during this visit:
Mandatory procedures:

Vital signs

Review of concomitant medications

Evaluation of AEs

Pregnancy test (serum β-hCG test only; for women of child-bearing potential)
Optional procedures:

Evaluation of a suspected relapse/follow-up

ECG

Physical examination

Neurological examination

Safety laboratory tests

Chest X-ray
8.3.2.
Safety Stopping Rules
8.3.2.1.
Liver Enzymes
In any increase of ALT or AST to ≥ 2 times ULN the “Guidance on Safety Monitoring” (see
Appendix G) should be thoroughly followed.
In the following circumstances, study drug will be discontinued immediately and liver enzymes 
will be monitored until normalization or stabilization of the abnormality, according to the 
Guidance in Appendix G:

Any increase in ALT or AST to ≥3 times ULN, combined with International 
Normalized Ratio (INR) >1.5 or total bilirubin >2xULN.

Any increase in ALT or AST to ≥3 times ULN, which is accompanied by nausea, 
vomiting, fever, rash, or eosinophilia.


Protocol No: MS-LAQ-301E
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50

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 G).
8.3.2.2.
Pregnancy
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 child-bearing 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 effective contraception 
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
(positive home urine test result, delay of menstruation or any other reason suggesting 
pregnancy).
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 of stopping treatment immediately if 
pregnancy is suspected (positive home urine 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 Local Safety Officer (LSO)/CRO with the pregnancy form. 


Protocol No: MS-LAQ-301E
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The process for reporting a pregnancy is the same as that for reporting a serious adverse event 
(SAE see Section 11).
Any woman who becomes pregnant during the study will discontinue treatment. Subjects who 
become pregnant will be monitored for the outcome of the pregnancy (including spontaneous or 
voluntary termination. If the pregnancy continues to term, the outcome (health of the infant up to 
8 weeks of age), details of birth, and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the sponsor. Any 
complication of pregnancy during the study and any complication of pregnancy that the 
investigator becomes aware of after termination from the study will be reported as an AE or 
SAE, as appropriate.
If the pregnancy does not continue to term, one of the following actions will be taken:

For a spontaneous abortion, report as a SAE.

For an elective abortion due to developmental anomalies, report as a SAE.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form.
8.3.2.3.
Cancer
Subjects who are diagnosed with a malignant solid or liquid tumor while participating in the 
study should stop study drug.
8.3.2.4.
Liver Impairment
To avoid exposures to higher levels of laquinimod (see Section 3.3.1), a stopping rule related to 
liver impairment has been introduced. Subjects who develop any chronic liver disease associated 
with hepatic function impairment while participating in the study should stop study medication.
8.3.2.5.
Renal Impairment
To avoid exposures to higher levels of laquinimod (see Section 3.3.1), a stopping rule related to 
renal impairment has been introduced. Subjects who develop renal disease associated with 
moderate or severe functional impairment, defined as glomerular filtration rate (GFR) 
≤60 mL/min/1.73 m2, while participating in the study should stop study medication temporarily 
and the GFR assessment should be repeated. If the renal impairment is confirmed (GFR 
≤60 mL/min/1.73 m2), the subject should stop study medication permanently.
8.3.3.
Replacement of Withdrawn Subjects
Not applicable.
8.3.4.
Temporary Discontinuation of Study Drug Treatment
Temporary discontinuation is defined as missing of more than three consecutive doses. Skipping 
of 14 or more consecutive doses will be considered as a major protocol violation.


Protocol No: MS-LAQ-301E
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The reasons for temporary IMP/study drug discontinuation should be recorded in the appropriate 
section of the IMP/study drug dispensing and return form in the eCRF and the local clinical 
management (LCM) should be notified.
The subject will report any temporary discontinuation to the investigator and will be instructed 
by the investigator regarding continuation of treatment.
8.3.5.
Unscheduled Visit
An unscheduled visit may be performed at any time during the study at the subject's request or as 
deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded.
The reasons for the unscheduled visit may be:

Appearance of a new AE or an AE follow-up

Change in concomitant medications

Possible relapse

Relapse follow-up

Laboratory follow-up

Post early-discontinuation follow-up visit (see Section 8.3.1)

IMP dispensing, accountability and/or replacement

Subject compliance

Other (should be specified)
Should the visit be related to a relapse, this will be clearly indicated on the eCRF and the Study 
Neurologist/Physician will carry out a complete neurological evaluation (FS/AI/EDSS/ Timed 25 
Foot walk).
Additional analyses may be performed by the investigator and stated in the source 
documentation.
Mandatory Unscheduled Visit Procedures

Vital signs

Evaluation of AEs


Protocol No: MS-LAQ-301E
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Optional Unscheduled Visit Procedures

Evaluation of a suspected relapse/follow-up

ECG

Physical examination

Neurological examination

Safety laboratory tests (including estimation of GFR)

In case of drug dispensing/replacement call IVRS to obtain a pack number

IMP accountability

Subject compliance

Review of concomitant medications

For all subjects who are female of child-bearing potential:

Serum or urine β-hCG test may be performed

The use of effective contraception will be ascertained (should be recorded in the 
source documents) and they will be reminded to use two acceptable methods of 
contraception up to 30 days from the date of the last dose of the IMP.

Subjects will be instructed about the teratogenicity and potential delayed risks for 
a child exposed in uterus to laquinimod.

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).
8.3.5.1.
Unscheduled Samples 
According to the judgment of the investigator or medical monitor, the following unscheduled 
samples may be collected to assist with further investigations of cardiovascular events or other 
clinical event of interest:

urgent safety laboratory test panel (see Section 10.2.3.1)

pharmacokinetic blood sample


Protocol No: MS-LAQ-301E
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54

sample for potential biomarker analysis
8.3.5.1.1. Unscheduled Pharmacokinetic Samples
Unscheduled pharmacokinetic blood samples may be collected at the discretion of the 
investigator or medical monitor at any time to assist with further investigations of cardiovascular 
events or other clinical event of interest. The samples should be collected as soon as possible in 
association with the event.
Details of sample collection and processing are provided in the Laboratory Manual.
8.3.5.1.2. 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.
8.3.6.
Visits during Relapses (Scheduled and Unscheduled)
Subjects will be instructed to contact their study site within 48 hours should any symptoms 
suggestive of a relapse occur (see Appendix B).
The Study Physician/ Neurologist, will evaluate the subject within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥48 hours.
The relapse assessment will be documented in the source documents and in the eCRF 
accordingly. A complete neurological assessment, including FS, AI, EDSS and Timed 25 Foot 
walk, will be performed by the Study Neurologist/Physician.
The decision as to whether the neurological change is considered a relapse will be made by the 
Study Neurologist/Physician, based on the criteria listed in Appendix B].
Corticosteroids therapy (as described in Section 7.1) may be given for a confirmed relapse at the 
discretion of the Study Neurologist/Physician and must be recorded in the source documents and 
eCRF.


Protocol No: MS-LAQ-301E
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55
8.3.6.1.
Relapse Follow-up:
Upon a confirmed relapse, subject’s neurological condition must be followed up closely within 
scheduled or unscheduled visits. The stabilization of a relapse date/ approximate date should be 
indicated in the source document and the eCRF.
Every attempt should be made to document the resolution of relapses.
At all the follow up visits for a confirmed relapse a full neurological examination (EDSS 
including FS and AI and 25 foot walk) must be performed. This should be done at a visit that is 
close to stabilization or no later than 2 weeks after stabilization date.


Protocol No: MS-LAQ-301E
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56
9.
INVESTIGATIONAL MEDICINAL PRODUCTS/STUDY DRUGS
9.1.
Treatment Administered
All subjects will be administered one capsule of laquinimod 0.6 mg to be taken orally at the same 
hour every day.
Capsules should be swallowed with a glass of water.
Subjects are allowed to omit study drug up to 3 consecutive days.
9.2.
Method of Assigning Subjects Numbers
The same randomization number which was used to identify a certain subject in the MS-LAQ-
301 study will serve this purpose in the MS-LAQ-301E study as well. At baseline (month 0E, 
visit 0E) (Termination visit of the MS-LAQ-301 study), the investigator will enter the subject's 
number (the same as was used in the MS-LAQ-301 study) to the IVRS in order to dispense the 
study drug.
The IVRS will keep track of subjects' visits and status.
9.3.
Description of Investigational Medicinal Product/Study Drug
Laquinimod 0.6 mg capsules are manufactured in compliance with current Good Manufacturing 
Practice (GMP) standards and guidelines applicable to IMPs by Teva Pharmaceutical Industries 
Ltd. Israel. Laquinimod 0.6 mg capsules are white opaque cap and body; hard gelatin capsules 
filled with white to off-white granulate.
9.4.
Packaging and Labeling
The study drug is packaged in round 50 cc white high density polyethylene bottles containing 35 
capsules. The bottles are capped with child-resistant polypropylene caps, each equipped with a 
silica desiccant insert.
The primary packaging is performed under the responsibility of the Clinical Manufacturing Unit 
of Teva Pharmaceutical Industries Ltd. The secondary packaging and labeling for subjects is 
performed under the responsibility of the Clinical Supplies Unit (CSU) of Teva Pharmaceutical 
Industries Ltd, according to European Union (EU) regulations and International Conference on 
Harmonisation (ICH) guidelines as adopted by the Food and Drug Administration (FDA) – Good 
Clinical Practice (GCP) (E6).
Each bottle will be identified by a unique bottle number.
The label on the bottles will include a fixed information section (to include the product name, 
storage conditions, instructions etc.) and variable information section. The variable information 


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section will include 3 parts: One detachable part, which will be attached to the subject’s file upon 
bottle dispensing, one part to remain on the bottle and the third may be used according to local 
needs (pharmacy, prescription, etc). The variable information section will include the following 
variable data: batch number, bottle number, and expiration date (all to be pre-printed) and blank 
fields for the dispensing investigator's name, visit number and subject number. These blank 
fields will be manually filled-in by the Investigator upon provision of bottle to the subject.
9.5.
Distribution and Shipment
Distribution and shipment of IMPs will be performed by a Contract Research Organization 
(CRO), according to the distribution guidelines.
The IMP bottles will be packed and shipped at room temperature (15-25oC/59-77oF) in 
appropriate storage boxes. If the IMP supplies appear to be damaged/missing upon arrival at the 
investigational site, the Sponsor should be contacted immediately.
Each shipment of IMPs supplies for the study will contain a shipment form describing the 
content of shipment. This form will assist in maintaining current and accurate inventory records. 
When a shipment is received, the site investigator/ site coordinator/pharmacist will acknowledge 
receipt of the IMP supply by making "Confirm Shipment” call (via the IVRS/IWRS).
When a shipment is received in a depot, acknowledgement of receipt of the IMP supply will be 
received by the CSU.
Importing of the IMP by an EU member will be carried out according to the provisions of 
Directive 2001/20/EC, Article 13.
9.6.
Storage, Dispensing and Return
IMP supplies will be kept in a secure, limited-access, temperature-controlled storage area.
Only authorized personnel will have access to the IMP. The study site personnel at each site will 
be responsible for correct storage and handling of the IMP.
All IMP bottles must be stored at room temperature (15-25oC/59-77oF).
Apart of Termination visit, the IMP bottles will be dispensed to the subject at the study site at 
each study visit starting at baseline visit (Month 0E; Termination visit of the MS-LAQ-301 
study). The bottles will be assigned to subjects by using an IVRS/IWRS. After assigning a bottle 
number to the subject, the site personnel should fill in the subject’s number, the visit number and 
the dispensing investigator's name on the label of the dispensed bottle as well as on the 
detachable parts that would be attached to the subject’s file.
At each visit from baseline (Month 0E; Termination visit of the MS-LAQ-301 study) to Month 
3E visit the subject will receive 1 bottle of IMP (baseline, Month 1E and Month 2E). At visit 
month 3 the subject will receive 3 bottles of IMP. From visit month 6 onward the subject will 


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receive 6 IMP bottles according to visit duration, an amount that will suffice until the following 
scheduled dispensing visit.
Subjects will be instructed to return all used empty bottles and unused IMP at each visit. The Site 
Investigator/site coordinator is responsible for performing IMP accountability at the site. The 
Monitor is responsible for the accountability of the returned IMPs.
9.7.
Verification of Compliance With Treatment Regimen
At each study visit the investigator /site coordinator will assess the subject’s compliance with the 
prescribed regimen for the study medication. This will include checks of protocol compliance 
and use of study drug in order to assess the reliability of subject-generated data. Subjects who 
fail to comply with the study requirements may be withdrawn from the study, following 
consultation with the Sponsor.
Compliance with the dosing regimen will be determined by performing IMP accountability of 
returned bottles of the used and unused IMP. The number of used and unused capsules will be 
recorded on the eCRF by site personnel. Percent compliance will be calculated as the number of 
used capsules divided by the number of total capsules expected to be used, multiplied by 100. 
Subjects with less than 75% overall compliance during the entire study will be considered non-
compliant.
9.8.
Accountability and Compliance
IMP accountability records must be maintained at the site at all times.
Upon Teva's (or Teva's designee) monitor visit at the site, accountability of the returned IMPs 
should be performed and recorded by the monitor. The subject number, the date, batch code, 
bottle number and quantity of IMP returned by the subject will be checked for correctness and 
recorded via the IVRS or on the appropriate accountability forms, to be provided by the CSU.
During the study, all IMPs (used and unused bottles) and the corresponding accountability forms
(if applicable) must be returned by the monitor to the Sponsor or Sponsor’s designee (CRO) on 
an on-going basis for reconciliation and destruction. A photocopy of these records must be kept 
at the study sites.


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10.
ASSESSMENT METHODS
10.1.
Efficacy Assessment Methods
10.1.1.
On-Study Relapse Evaluation & Determination
Subjects will be instructed to telephone their study site within 48 hours should any symptoms 
suggestive of a relapse appear.
The Study Physician/Neurologist will evaluate the subject once any symptom suggestive of a 
relapse occurs.
In case of a suggestive relapse during a scheduled or unscheduled visit:

The evaluation of symptoms as well as the neurological evaluations/EDSS will be 
made by the Study Physician/Neurologist.

Based on the assessment of symptoms and the EDSS/FS evaluation, the Study 
Physician/Neurologist will decide whether a subject experienced a relapse and will 
treat the subject as needed.
In any case, the neurological evaluation of the subject by the Study Physician/Neurologist will be 
performed within 7 days of symptoms onset, conditional upon a symptomatic period of ≥ 48 
hours.
In the case of an ongoing or just-started relapse at the study termination/early discontinuation 
visit, subjects will be followed up until relapse stabilization (see Section 8.3.6.1).
10.1.2.
Neurological Evaluations
A complete neurological assessment will be performed at Months 0E [Baseline (Termination 
visit of the MS-LAQ-301 study)], 6E and every 6 months thereafter until termination/early 
discontinuation of the study. At each of the study Periods, every effort should be made to ensure 
that the same Neurologist/Physician performs the neurological assessment at all visits for a 
particular subject.
FS and EDSS will be assessed based on a slightly modified neurological examination 
(Neurostatus: L. Kappos, Dept. of Neurology, University Hospital, CH-4031/Basel. Version 
12/05). The results will be recorded on standardized and validated examination forms (see 
Appendix C) as well as in the eCRF.
Mental Functional System Score 1b (due to mild fatigue) will contribute to the EDSS score while 
mental Functional System Score 1a will not contribute to the EDSS score.


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10.1.3.
MSFC
The MS Functional Composite consists of 3 clinical examinations, the results of which are 
combined using z-scores. The three clinical examinations include the PASAT, Timed 25 Foot 
walk and 9-HPT.
The PASAT and 9-HPT will be performed at Months 0E [Baseline (Termination visit of the MS-
LAQ-301 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/early discontinuation visit.
The Timed 25 Foot walk test will be performed each time neurological evaluation is performed.
Appendix I presents the instructions for administering the MSFC.
10.1.4.
Modified Fatigue Impact Scale (MFIS)
Subject-reported fatigue will be assessed by the MFIS at months 0E [Baseline (Termination visit 
of the MS-LAQ-301 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/early discontinuation visit.
The MFIS is a validated specific subject-reported outcome measure that was developed to 
evaluate the impact of fatigue on the lives of people with MS. The instrument will be self-
administrated during the visit and consists of total score and 3 subscales to assess the impact of 
fatigue on:
1. Cognitive function (10 items)
2. Physical function (10 items)
3. Psychosocial function (20 items)
The subject is asked to circle the appropriate response on a Likert scale: 0 – no problem; 1 –
small problem; 2 - moderate problem; 3 – big problem; 4 – extreme problem. The MFIS takes
approximately 10 minutes to complete and has good internal consistency as measured by
Cronbach’s alpha (0.98 for full sample analysis of the entire questionnaire and >0.87 for all
subscale items by group) and has been shown to be able to discriminate between different subject
populations as well as between groups with different severity levels in MS (see Appendix G).
10.1.5.
Binocular Low- Contrast Visual Acuity
It has been demonstrated that low-contrast visual acuity, as measured using the Sloan Charts has 
a substantial capacity to capture visual dysfunction in subjects with MS.
The low-contrast visual acuity will be assessed binocularly at Months 0E [Baseline (Termination 
visit of the MS-LAQ-301 study)], 6E and every 6 months (every scheduled visit) thereafter, until 
Termination/early discontinuation visit, along with the MSFC assessments. At each visit, the 
letter acuity will be captured using 100%, 2.5% and 1.25% contrast charts, from a distance of 2 


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meters, with the subject’s usual distance correction. In case the subject is not familiar with the 
English/Roman alphabet, the Tumbling E charts will be used.
Appendix J and Appendix K present the instructions for administering the binocular low-contrast 
visual acuity test.
10.1.6.
Ancillary Studies
10.1.6.1.
MRI Ancillary Study:
The scan will be performed only for those subjects who participated in the frequent MRI 
ancillary study (in the MS-LAQ-301 study) and signed a separate informed consent form at 
Baseline visit (Termination visit of the MS-LAQ-301 study) of the MS-LAQ-301E study. The 
scan will be performed at Month 0E [Baseline; this is the same scan as the Termination scan
of the MS-LAQ-301 study (there is no need to repeat it) and should be performed prior to the 
first dose administration in the MS-LAQ-301E study] and every 12 months thereafter and will 
include:

T1-weighted, after administration of Gd-DPTA

T2-weighted

3D T1-weighted
MRI scans can be performed within ±4 days of the scheduled visits except for Termination/early 
discontinuation visit where the MRI should be performed within 4 days prior to the visit day.
Steroid treatment for relapse (see Section 7.1) will not affect the schedule of this optional 
MRI scan. Where possible, the scan should be performed prior to steroid treatment.
All MRI data will be interpreted by the MRI analysis center (MRI-AC).
For the MRI Protocol, see Appendix D.
10.1.6.2.
MT Ancillary Study:
MT Ancillary Study: In contrast to conventional MRI techniques, which acquire their signal 
from the free water protons, MT contrast is based on the saturation of the macromolecular 
protons and the subsequent exchange of magnetization into the free proton pool. This study 
provides values that strongly correlate with axonal integrity in MS lesions (for protocol see
Appendix D). The scan will be performed only for those subjects who participated in the MT 
ancillary study in the MS-LAQ-301 study and signed a separate informed consent form at 
Baseline visit of the MS-LAQ-301E study (Termination visit of the MS-LAQ-301 study).
The scan will be performed again at Months 12E and every 12 months thereafter. MT scans can 
be performed within ±4 days of the scheduled visits except for Month 0E (which is the 
Termination of the MS-LAQ-301 study) and Termination/early discontinuation visit where the
scan should be performed within 4 days prior to the visit day.


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10.1.6.3.
MRS Ancillary Study:
Magnetic resonance spectroscopy (MRS) provides an in vivo method for characterization of 
tissue metabolites, including N-acetyl aspartate (NAA), choline-containing compounds, 
creatinine plus phosphocreatine, lactate and inositol in localized areas of the brain. NAA is 
present in high concentration in neurons and oligodendrocyte-type 2 astrocyte (O-2A) 
progenitors but absent in other cells (NAA is undetectable in mature oligodendrocytes). 
Decreased levels of NAA may therefore be used as marker for axonal loss (for protocol see
Appendix D). The scan will be performed only for those subjects who participated in the MRS 
ancillary study in the MS-LAQ-301 study and signed a separate informed consent form at 
Baseline visit of the MS-LAQ-301E study (Termination visit of the MS-LAQ-301 study).
The scan will be performed again at Months 24E and every 24 months thereafter. MRS scans can 
be performed within ±4 days of the scheduled visits except for Month 0E (which is the 
Termination of the MS-LAQ-301 study) and Termination/early discontinuation visit where the
scan should be performed within 4 days prior to the visit day.
10.2.
Safety Parameters
10.2.1.
Adverse Events
AEs will be recorded from when a subject has signed the Informed Consent Form and 
throughout the study, including the follow-up period. They should be reviewed and updated at 
each subsequent visit and during any phone contact with the subject.
10.2.1.1.
Protocol-Defined Adverse Events for Expedited Reporting
Ischemic cardiac events (such as myocardial infarction, unstable angina, acute coronary 
syndrome etc), and cerebrovascular events (such as cerebral arterial occlusion, cerebral ischemia, 
etc) should be reported to the sponsor within 48 hours, including completion of the 
corresponding dedicated CRF.
10.2.2.
Abdominal Computed Tomography Scan
In case of pancreatitis or suspected pancreatitis, an abdominal computed tomography (CT) scan 
should be performed as soon as possible in order to clarify the diagnosis and enable assessment 
of severity of this condition. An MRI may be performed as an alternative to the CT scan.
10.2.3.
Safety Laboratory Evaluations
Unless specified otherwise all laboratory testing will be performed by a central laboratory
facility.
In cases in which close follow-up is required, as described in Section 8.3.2 and Safety 
Monitoring Guidance, Appendix G, 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).


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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 estimation of GFR)

Bilirubin (direct and total)*

Urea

AST (SGOT)*

ALT (SGPT)*

GGT*

Total Protein*

Albumin*

hs-CRP

CPK

In case of abnormal CPK result: troponin and CPK-MB will be tested

In case of CPK > 2000 U/L urine myoglobin will be tested and the following tests 
will be repeated: CPK, CPK-MB, blood urea nitrogen, creatinine, electrolytes 
including potassium, calcium, phosphate, hs-CRP and fibrinogen

Alkaline Phosphatase (ALP)*

Pancreatic Amylase

Lipase will be tested in case of abnormal pancreatic amylase results (see Appendix G
for guidance on monitoring subjects with elevated pancreatic amylase levels)
Electrolytes

Sodium

Potassium

Calcium

Phosphorous


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Coagulation

Fibrinogen

INR (to be performed in local laboratory, only if required according to Safety 
Monitoring Guidance, Appendix G)
Pregnancy tests

Serum β-hCG pregnancy tests (to be performed in women of child-bearing potential, 
at all scheduled study visits)

Urine β-hCG pregnancy test (to be performed in women of child-bearing potential), at 
all scheduled study visits (excluding Termination) and every 28 ± 2 days, at home, 
starting from visit Month 3E.
Pregnancy tests do not need to be performed for women who have discontinued study treatment 
but are continuing to attend scheduled study visits for follow-up.
Hematology

Hemoglobin.

Mean Corpuscular Hemoglobin (MCH)

Mean Corpuscular Volume (MCV)

Mean Corpuscular Hemoglobin Concentration (MCHC)

Hematocrit

Red Blood Cells count (RBC)

WBC count + differential*

Platelet count
Serology (to be performed only for a confirmed abnormality of liver enzymes, according to
Appendix G):

Anti-Hepatitis A IgM antibodies

Hepatitis B Surface antigen

Anti-Hepatitis B Core IgM antibodies

Anti- Hepatitis C IgG antibodies

Anti-nuclear antibodies


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
Anti-Smooth Muscle antibodies (ASMA)

Anti-Liver-Kidney Microsomal (LKM)-1 antibodies
10.2.3.1.
Urgent Safety Laboratory Panel
Unscheduled urgent safety laboratory samples may be collected at the discretion of the 
investigator or medical monitor at any time to assist with further investigations of cardiovascular 
events or other clinical event of interest. The samples should be collected as soon as possible in 
association with the event.
The following tests (and others, if required) will be performed on these samples:

serum chemistry panel, including fibrinogen and hs-CRP

hematology panel

CPK-MB

troponin I
10.2.4.
Vital Signs and Weight
Vital signs (temperature, pulse and BP) will be completed at all scheduled and unscheduled 
visits.
BP and pulse will be recorded in a sitting position after resting for 5 minutes.
All measurements and time of measurements will be recorded in the source documents.
Body weight will be measured at all visits until Termination/early discontinuation, and as long as 
the subject continues study drug treatment.
10.2.5.
ECG
ECG will be performed at months 0E [Baseline (Termination visit of the MS-LAQ-301 study)]
and every 6 months thereafter, until Termination/Early discontinuation visit.
The subject should rest for at least 10 minutes before measurement is taken. Twelve-lead ECG 
should be performed following the subject being in a supine position for 5 minutes.
The interpretation of the ECG will be made only locally, by the investigator, and the clinical 
evaluation remains under the investigator’s/ local cardiologist responsibility. Therefore, the 
investigator/local cardiologist will be responsible to determine whether ECG findings are of 
clinical significance.
The ECG will be evaluated by the investigator at time of performance (signed and dated) and the 
printout should be kept in the source documentation file. When potentially clinically significant 
findings are detected by the Site Investigator, a cardiologist should be consulted for a definitive 


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interpretation. All communications and diagnoses should be filed in the source documentation 
file.
The investigator’s interpretation of the ECG will be recorded in the eCRF.
10.2.6.
Physical Examination
Physical examination will be performed at months 0E [Baseline (Termination visit of the MS-
LAQ-301 study)], 6E, 12E and then every 12 months thereafter, until Termination/early 
discontinuation visit.
Any finding on physical examination (whether a new condition or worsening of a pre-existing 
condition) should be recorded as an AE.
10.2.7.
Glomerular Filtration Rate Estimation
Significant changes in laquinimod exposure, in particular in terms of unbound drug fraction, are 
predicted in patients with moderate and severe renal impairment (see Section 3.3.1). 
Consequently, GFR will be estimated at all visits to monitor renal function in the study in order 
to identify subjects with potentially impaired laquinimod clearance. Subjects with a confirmed 
GFR ≤60 mL/min/1.73 m2 should stop study medication temporarily and the GFR assessment 
should be repeated. If the renal impairment is confirmed (GFR ≤60 mL/min/1.73 m2), the subject
should stop study medication permanently (see Section 8.3.2.5).
Following recent findings connecting Gd-based contrast agents and nephrogenic systemic 
sclerosis, GFR value should be evaluated prior to performing an MRI scan, where administration 
of Gd-based contrast agent is planned. The central laboratory will provide the GFR value prior to 
the scheduled MRI tests. In case GFR estimation is not provided by the central laboratory, 
calculation should be done at the site, prior to any MRI scan via the following web calculator:
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm
In case GFR is ≤60 mL/min, the MRI scan should be performed without contrast (Gd) and 
further evaluation of renal impairment is required (refer to Section 8.3.2.5)
10.2.8.
Cardiovascular Risk Assessment and Management
Evaluation and management of major modifiable cardiac risk factors (eg, diabetes, high blood 
pressure, hyperlipidemia, tobacco smoking) will be performed at the time points indicated in
Table 5. In addition, an evaluation should take place as soon as possible for subjects already in 
the study, following approval of Amendment #3.
Cardiovascular risk management should be conducted according to evidence-based, local 
standard-of-care procedures. Subjects will undergo referral to a suitable clinic if needed.


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


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


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for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
resulting in an AE will normally be considered serious by this criterion.
Inpatient hospitalization or prolongation of existing hospitalization means that hospital inpatient 
admission and/or prolongation of hospital stay were required for treatment of AE, or that they 
occurred as a consequence of the event. It does not refer to pre-planned elective hospital 
admission for treatment of a pre-existing condition that has not significantly worsened, or to 
diagnostic procedure. It does not refer either to hospitalization for iv steroid treatment of a 
relapse, unless it is a worsening of condition beyond expected disease progression (as described 
below).
The term "life-threatening" in the definition of "serious" refers to an event in which the subject
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.
Any new SAE that occurs after the study period and is considered to be related (reasonable 
possibility) to the IMP or study participation should be recorded and reported immediately. The 
study period for the purpose of SAE reporting is defined as the period from the subject's 
signature on the informed consent form until the end of the follow-up period (30 days following 
the last dose).
SAE Reporting
In order to satisfy regulatory requirements, any SAE, whether deemed IMP-related or not, must 
be reported to the CRO as soon as possible after the investigator or coordinator has become 
aware of its occurrence. The SAE form completion and reporting must not be delayed even if all 
of the information is not available at the time of the initial contact.
The SAE should be submitted within 24 hours of becoming aware of the event to the CRO. The 
CRO will forward the report to the appropriate Pharmacovigilance unit at Teva or the LSO who 
will forward the SAE report to the appropriate Pharmacovigilance unit at Teva:
SAE originated in Europe and rest of the world should be sent to:
Global Drug Safety and Pharmacovigilance Unit (Israel)
SAE originated in USA will be sent to:
Teva USA clinical safety mailbox


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SAE originated in Canada will be sent to:
Teva Canada clinical 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.
Additional information (follow-up) about any SAE unavailable at the initial reporting should be 
forwarded by the site within 24 hours of the information becoming available to the CRO.
For both initial and follow-up SAE reports the CRO forwards this information to the appropriate 
Pharmacovigilance unit at Teva or the LSO who forwards it to the appropriate 
Pharmacovigilance unit at Teva within 48 hours. The Pharmacovigilance units at Teva will 
submit a summary of the clinical course of the SAEs back to the CRO/LSO for local submission 
to the regulatory authorities (competent authorities [CA]) and Ethics Committee 
(EC)/Institutional Review Boards (IRBs) and investigators according to regulations.
The following information should be provided to accurately and completely record the event:
1. Investigator Name and Center Number
2. Subject Number
3. Clinical Event
a.
description
b. date of onset
c.
severity
d. treatment
e.
relationship to study drug (causality)
f.
action taken regarding study drug
4. If the AE results in Death


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


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12.
STATISTICAL METHODOLOGY
A total of up to 1106 subjects, who were enrolled in study MS-LAQ-301 are expected to be 
recruited into this study.
The statistical analyses of this study will be exploratory in nature. Continuous variables will be 
presented by descriptive statistics (mean, standard deviation, minimum, median and maximum 
values), by treatment group. For categorical variables, treatment group counts and percentage 
from total subject population will be tabulated.
12.1.
Sample Size Rationale
Subjects that completed the full double-blind treatment period of protocol MS-LAQ-301 will be 
eligible for inclusion in this trial. MS-LAQ-301 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 
1106 subjects.
12.2.
Randomization Procedure
As this is an open label single arm study, no randomization procedure is applied.
12.3.
Subjects Analysis Sets
A single analysis set is defined for this clinical trial. This analysis set is:
Intent-to-treat analysis set (ITT): Consists of all subjects who have been enrolled to the study and 
received at least one dose of IMP. In accordance with the ITT principle, all subjects randomized 
will be kept in their originally assigned treatment group.
12.4.
Definition of baseline values
The last observed values from study MS-LAQ-301 will serve as the baseline values for this 
study.
12.5.
Efficacy Assessment
The statistical analyses of this study will be exploratory in nature. Continuous variables will be 
presented by descriptive statistics (mean, standard deviation, minimum, median and maximum 
values), for the whole study population, as well as by original treatment group in study MS-
LAQ-301. For categorical variables, counts and percentage from total subject population will be 
tabulated, as well as counts and percentages by original treatment group in study MS-LAQ-301.


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12.6.
Safety And Tolerability Assessments
12.6.1.
Data presentation
All data summary tables will be presented for the whole study population, as well as by original 
treatment group in study MS-LAQ-301.
12.6.2.
Adverse Events
The incidence and frequency of AEs will be presented by System Organ Class and preferred 
terminology according to Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
AEs will also be presented by System Organ Class, High Level Term and preferred terminology.
Data will be tabulated by gender, maximal severity, maximal outcome and maximal relationship 
to the tested drug.
SAEs and seriousness criteria will be listed, tabulated and discussed on a case by case basis as 
well.
12.6.3.
Laboratory Data
Laboratory quantitative parameters will be summarized and presented by using descriptive 
statistics.
All laboratory values recorded during the study will be individually listed and flagged for values 
outside reference ranges and potential clinical significance.
12.6.4.
ECG
Distribution of Subjects by Investigators ECG Interpretation will be presented.
The ECG interpretation of the investigators will be individually listed.
12.6.5.
Vital Signs
Vital signs parameters will be summarized and presented by using descriptive statistics.
Incidence of measurements of potential clinical significance will be provided.
Vital signs parameters recorded during the study will be individually listed and flagged for 
potential clinical significance values.
12.6.6.
Drug Tolerability & Drop-Out Assessment
The number and percentage of subjects who failed to complete the study will be provided.
The number and percentage of subjects who prematurely discontinued from the study due to AEs
will be provided.


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13.
REGULATORY AND ETHICAL ISSUES
13.1.
Compliance with Regulations Applicable to Clinical Trials
The study will be conducted according to the laws, regulations and administrative provisions 
relating to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use, as applicable by national legislation and EU Directives and US 21 CFR Part 11, 50, 
54, 56, 312.
13.2.
Informed Consent
The principles of Informed Consent, according to the Declaration of Helsinki and its updates, 
ICH guidelines on GCP, 21 CFR part 50 of the FDA regulations and/or EU Directives, will be 
followed. A subject should not enter a clinical study until he/she has been properly informed, has 
been given time to contemplate participation, and has freely given his/her consent by signing and 
dating the EC/IRB approved informed consent form. This must be done prior to performing any 
study related procedures.
The proposed consent form and any other documents relevant to the consent process must be 
submitted to the EC/IRB, together with the protocol, and must be approved prior to study start.
A copy of the fully signed and dated Informed Consent Form and any other documents relevant 
to the consent process will be given to the subject and the original will be maintained at the site.
Subjects continuing on laquinimod 0.6 mg will be re-consented with information about the 
cardiovascular risk seen in higher doses (see Section 3.4.1.1.7).
13.3.
Subject Confidentiality
All subject data will be identified by a subject identification number.
After obtaining subject’s consent, the investigator will permit the study monitor, independent 
auditor or regulatory agency personnel to review that portion of the subject’s medical record that 
is directly related to the study. This shall include all study relevant documentation including 
subject medical history to verify eligibility, laboratory tests results, admission/discharge 
summaries for hospital admissions occurring while the subject is on study and autopsy reports 
for deaths occurring during the study (if applicable).
13.4.
Ethics Committee (EC) / Institutional Review Board (IRB)
The study must have unconditional approval in writing, by an appropriate EC/IRB. A copy of the 
Letter of Approval from the EC/IRB, which contains the list of the documents approved, must be 
received by Teva/CRO prior to site initiation.


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


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


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
Country Model Informed Consent Form

Central Laboratory Certification and Normal Ranges

Insurance Certificate

Operations Manual
14.3.
Maintenance and Retention of Records
It is the responsibility of the investigator to maintain a comprehensive and centralized filing
system of all relevant documentation.
Investigators will be instructed to retain all study records required by Teva and regulatory 
authorities in a secure and safe facility with limited access for one of the following time periods 
based on notification from Teva
A period of at least two years from last marketing authorization and notification from Sponsor
Or a period of at least two years after discontinuation of clinical development of the 
investigational product as confirmed by Teva
Or longer if required by local regulations.
The investigator will be instructed to consult with Teva before disposal of any study records and 
to provide written notification to Teva of any change in the location, disposition, or custody of 
the study files.
14.4.
Data Handling
14.4.1.
Data Collection via Remote Data Capture (RDC)
14.4.1.1.
Data Collection
The site teams should be trained to use the RDC® system. In any case of change in study teams, 
appropriate training will be given.
Teva will provide each study site with one hard copy of the reference template for data collection 
tools (Master CRF).
Data will be entered at the site by the Site Investigator, Study Coordinator, the Site Coordinator 
or other appropriately designated and trained study personnel, using the validated Oracle Clinical 
RDC® application, which provides a framework for entering clinical data on a CRF. The Oracle 
Clinical RDC® application is integrated with the Teva clinical data management (DM) validated 
system, conforms to 21 CFR part 11 requirements.


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The eCRFs are used to record study data and are an integral part of the study and subsequent 
reports. Therefore, the CRFs must be completed for each enrolled subject, according to the 
subject’s source data on a per-visit basis.
Subjects should not be identified by name. Appropriately coded identification must be used. The 
Site Investigator must keep a separate log of subject names, non-identifiable initials (if 
applicable) and addresses (i.e., Subject Identification Log).
Each entered CRF must be approved by the Site Investigator on a per-visit basis and verified 
against the subject’s source documents by the Clinical Research Associate (CRA)/monitor. Each 
entry will be monitored by the CRAs and the DM personnel. Once all the CRFs for a subject 
have been approved, verified, reviewed and cleaned, the subject's CRFs will be locked. Site 
Investigators, Site Coordinators, CRAs, DM personnel, Medical Monitors and quality assurance 
(QA) personnel will be trained by authorized Teva staff on the use of the RDC® application 
before receiving authorization to use the application. The assignment of user privileges will be 
according to the following user roles:

Site Coordinator: data entry

Study Coordinator: data entry and updating, discrepancy handling

Site Investigator: data entry and updating, discrepancy handling and CRF approval

CRA: discrepancy handling and CRF verification

Medical Monitor: discrepancy handling.

DM: data updating, discrepancy handling, data locking

QA: read only for data audit

Read Only: browsing of data only
14.4.1.2.
Discrepancy Handling
The internal consistency and data integrity of the study database are defined by a validated set of 
rules. A deviation from this set of pre-defined computerized rules creates a database discrepancy 
which can be handled using the RDC® application 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.


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Note that the RDC® application discrepancy management facility is fully supported by an 
accepted regulatory audit trail of procedures and logs.
14.4.1.3.
Data Correction
Data correction can also be performed using the validated RDC® application update facility. For 
each instance of data modification, the system requires the reason and justification for change. 
The system keeps a full audit trail of the data values, date and time of modification, and the 
electronic signature of the user who performed the change.
14.4.1.4.
Data Extract
The Oracle Clinical® system stores the data in generic tables. The data is extracted from Oracle 
Clinical® to SAS® on a per data collection module basis. Each extracted file contains all the 
visits of the corresponding form. The data is extracted on a scheduled basis for data management 
and data analysis purposes.
14.4.1.5.
Source Documents
Prescription forms, label logs, laboratory test results and ECG strips/interpretations, as well as all 
other source documents should be maintained and kept at the study site in the subject study 
binder.
14.4.1.6.
Electronic CRF
At the end of the study, the Sponsor will supply the site investigator a copy of the site's subject 
electronic CRF in PDF format.
14.5.
Additional Documents and Records
1. Subject Screening and Assignment Log – A listing of all subjects who signed the 
informed consent and entered the MS-LAQ-301E study.
2. Subject Identification Log – A listing of all randomized subjects. This allows linking of 
the enrolled subject to the study. Information should include, but is not limited to: 
subjects’ name, date of birth and contact information and subject non-identifiable initials
(if applicable). This confidential list will be maintained by the investigational site and 
should not be forwarded to the Sponsor.
3. Drug Accountability Log - This form documents the total amount of study drug 
dispensed to and returned by each subject (if applicable).


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15.
QUALITY ASSURANCE AUDITS
15.1.
Good Clinical Practice
The study described in this protocol will be carried out according to the local regulatory 
requirements and ICH accepted standards of GCP. All procedures described in this protocol will 
be performed according to approved written SOPs unless otherwise stated.
15.2.
Quality Laboratory Standards
Laboratory tests/evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards. See Central Laboratory Manual unless otherwise stated.
15.3.
Quality Assurance Program
This clinical trial may be audited according to the Teva QA program.
The purpose of these audits is to determine whether the study is being conducted and monitored 
in compliance with the protocol as well as recognized GCP guidelines and local regulations. 
These audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent inspection by any regulatory authority. Such audits, if 
necessary, will be pre-arranged with the site and conducted within a reasonable time frame.
15.4.
Regulatory Inspections
The study may be inspected by regulatory agencies. These inspections may take place at any 
time during or after the study and are based on the national regulations, as well as ICH 
guidelines.


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16.
STUDY MONITORING
16.1.
Monitors/CRAs and Monitoring Visits
The Study Monitor/CRA will be responsible for ensuring adherence to FDA, EU Directives, ICH 
guidelines and the Sponsor’s SOPs. Study Monitors for this trial will be provided by the 
Sponsor. The monitors will follow the current “Guideline for the Monitoring of Clinical 
Investigators” supplied by the FDA or will operate according to the EU Directives and in 
compliance with ICH guidelines.
Experienced independent monitors or monitors from CROs will also be trained in Teva’s SOPs, 
study protocol and the study monitoring conventions.
Regular monitoring of study data at each site will be performed as defined by the study specific 
monitoring plan. Individual sites will be monitored to verify that enrollment rate, data recording, 
and protocol adherence are satisfactory. The frequency of monitoring individual sites may 
fluctuate depending upon enrollment rate, quantity of data collected and the complexity of the 
study, and will be described in the monitoring plan.
These monitoring visits will be performed for the purposes of verifying adherence to the protocol 
and the completeness and accuracy of data entered on the CRF. The study monitor will verify 
CRF entries by comparing them with the primary source documents (hospital/clinic/office 
records), which will be made available for this purpose. The monitor will review the 
maintenance of regulatory documentation and drug accountability. The monitor will review the 
progress of the study with the investigator and other site personnel on a regular basis. At the end
of the study, a close-out monitoring visit will be performed. Monitoring visits will be arranged in 
advance with site personnel at a mutually acceptable time. Sufficient time must be allowed by 
the site personnel for the monitor to review CRFs and relevant source documents. The 
coordinator and/or investigator should be available to answer questions or resolve data 
clarifications. Adequate time and space for these visits will be made available by the 
investigator.
16.2.
Primary Source Documents
The investigator must maintain primary source documents to support CRF data entries. These 
documents, which are considered “source data”, may include but are not limited to:

Demographic information

Evidence supporting the diagnosis/condition for which the subject is being studied

General information supporting the subject’s participation in the study

Medical history and physical findings


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


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17.
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.
17.1.
Product Complaint Information Needed from the Investigational 
Center
In the event that the product complaint form cannot be completed, the investigator will obtain the 
following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

subject identifier (subject study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies


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
subject number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return Yes/No

product was taken or used according to protocol Yes/No

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
17.2.
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.
17.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 11).
17.4.
Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint,
and any actions taken to resolve the complaint and to preserve the safety of the subject. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product.


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18.
USE OF INFORMATION AND PUBLICATION
18.1.
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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19.
STUDY PERSONNEL
19.1.
Investigative Site
19.1.1.
The Principal Investigator
At each investigational center, a physician will be appointed to serve as a principal investigator 
and will have overall responsibility to lead the site study team (Neurologist, radiologists, 
technician and clinical coordinator as appropriate) and aspects of the study at the respective site. 
The Principal Investigator will oversee the accrual of appropriate subjects, the conduct of the 
study according to the trial protocol and the collection of required data.
19.1.2.
The Study Physician/ Neurologist
The Study Physician/Neurologist will be responsible for the general medical evaluations as well 
as the neurological assessments. The Study Physician/Neurologist will make the decision as to 
whether the neurological change is considered a relapse, based on EDSS/FS scores obtained by 
him/her.
19.1.3.
The MRI Radiologist and Technician
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 electronic material. He/she will also be 
responsible for the quality of such material as well as for providing adequate storage 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 radiologist is responsible for reviewing all MRI scans for non-MS related pathology.
The MRI technician is responsible for performing the MRI scans according to the protocol; 
preparing the electronic copies; and performing the required back-ups and documentation of such 
procedures.
19.1.4.
Study Coordinator or Designee
A study coordinator or other staff member designated by the Principal Investigator will be 
responsible for subject scheduling and completion of all subjects’ eCRFs and recording of AEs. 
He/she will instruct the subject on proper study drug administration. He/she will collect and 
forward blood samples and requests to the appropriate laboratories, will obtain and forward 
laboratory results and perform other duties delegated by the Principal Investigator as instructed.


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19.2.
The Sponsor
19.2.1.
Global Clinical Leader
The Global Clinical Leader maintains overall responsibility for the study and is responsible for 
ensuring good conduct and adequate resources; for providing high-quality study management 
and data management and for the coordination of all study committees.
19.2.2.
Global Operations Manager
The Global Operations Manager is responsible for day-to-day operations of the study, and also 
for coordinating and handling all subject study data from the investigational sites. This includes 
daily maintenance of all study aspects and study status on internal periodic reports.
19.2.3.
Data Management & Biostatistics
Global Biostatistics and Data Management units are responsible for the adequate performance of 
the data management application (Oracle Clinical); 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.
At the discretion of the Sponsor Data Management may be performed by a CRO.
19.2.4.
Local Clinical Management
The LCM is responsible for the local day-to-day activities of the study and to ensure that the 
Sponsor supplies adequate resources to provide high quality study management, monitoring and 
data management. The LCM is responsible for submitting safety reports to local regulatory 
authorities, EC/IRB and investigators, where required.
19.2.5.
Clinical Research Associate/Monitor
The CRA/monitor is responsible for monitoring the conduct of the study at the study centers. 
Monitoring visits will be arranged in advance, at a mutually acceptable time, with site personnel. 
Refer to Section 16.1 in this protocol for detailed monitoring activities.
19.2.6.
Global Drug Safety and Pharmacovigilance
Global Drug Safety & Pharmacovigilance is responsible for: reviewing safety issues that arise 
during the study, assessing and evaluating the causality of SAEs occurring during the study and 
submission of relevant SAEs to health authorities/CA as per regulations.
19.2.7.
Medical Monitor
The Medical Monitor is responsible for reviewing all safety clinical data in an ongoing basis 
through the course of the study. The medical monitor is reviewing individual safety subject’s 
safety data as well as listings and tabulated safety data.


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The medical monitor is responsible to evaluate any emerging data driven safety issues during the 
course of the study, and alert the clinical leader, responsible LCM/CRA, safety officer and notify 
the DMC.
The action plan of any safety emerged issues will be coordinated by the medical monitor and 
clinical leader. The narratives of any safety issues with medical importance will be prepared by 
the medical monitor.
The medical monitor is also responsible to follow up the safety emerged issues through the 
study, their capture within the eCRF, and SAE reports (if necessary), and the execution of the 
action plan/follow up of a subject as recommended by safety officer and DMC.
The medical monitor is responsible to prepare the safety information periodical reports for the 
DMC meetings and present the data during the open session of the DMC meetings.


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20.
STUDY COMMITTEES
20.1.
Steering Committee
The Steering Committee may offer expert opinion as to clinical aspects of the protocol design 
and may be consulted during the course of the study. Periodical teleconferences will be held to 
assess and discuss clinical and operative progress of the study. Protocol amendments, safety 
issues and potential publications will be discussed with the committee and recommendations 
may be made to the Sponsor as appropriate. The Steering Committee will include designees from 
the participating countries/regions Principal Investigators.
20.2.
Data Monitoring Committee (DMC)
The DMC will be composed of external independent physicians with expertise in MS, internal 
medicine, cardiology, as well as a specialist in hepatic diseases and a statistician. Ad-hoc 
consultations may be made with additional specialists as will be deemed necessary during the 
course of the study.
The DMC responsibilities are:
To review the progress of the trial and the accumulation of data, both periodically and on an ad-
hoc basis, in order to ensure subjects’ welfare.

To oversee the emerging safety data of the study.

To review efficacy data, as deemed necessary.

To assess whether there is any basis upon which to recommend modification or 
premature termination of the study.
The DMC Chairperson is responsible for all DMC interactions with the Sponsor, through the 
Global Clinical Leader. The Global Clinical Leader is responsible for addressing safety issues 
identified by the DMC. He/she will report to the DMC about the risk management plan 
established by the Sponsor.
A DMC plan/charter will be prepared in the first meetings of the DMC, and signed by the DMC 
members and Sponsor’s designees. The charter describes the function and manner of operation of 
the DMC.
DMC meetings will take place at a set schedule, according to study characteristics, needs, and 
progress.
Meetings may be in a teleconference or face to face, according to study needs.


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In case of need for an urgent discussion of a safety issue, the DMC chair or the Sponsor may call 
an unscheduled meeting.
Participants of the meetings are: DMC chair, DMC members, clinical leader, study medical 
monitor, and Sponsors’ DMC statistician.
DMC meeting minutes and conclusions are a part of the study’s documents and risk management 
plan.
All DMC reports should be available upon request to regulatory and ethical authorities.
The Sponsor will work closely with the committee to provide the necessary data for review. The 
list of DMC members will be detailed in the DMC plan/charter.
20.3.
Clinical Advisory Board (CAB)
The Clinical Advisory Board (CAB) will be responsible for the clinical development plan of the 
study including all clinical issues regarding study design and conduct. For a list of CAB 
members please refer to the Operation Manual.
The committee’s responsibilities will include involvement in:

design of the clinical development plan

design of study protocols

interpretation of results analysis upon study completion
20.4.
Publication Committee
The publication committee will be responsible for developing the publication plan consistent 
with the study end points and out comes, and the needs of the medical community and the 
Sponsor.
This committee will be composed of the chair of the steering committee, designees from the 
CAB, which are taking a pivotal role in the study, and also the Sponsor’s designee.
The publication plan will be prepared in the after completion of subject recruitment into the 
study.
This plan will determine the publication policy of the study outcomes and recommend on the 
main publishers. The plan will be consistent with Teva policy on use of confidential information 
(see Section 18.1).


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TEVA Pharmaceutical Industries, Ltd.
Protocol No. MS-LAQ-301E
INVESTIGATOR’S AGREEMENT
I have carefully read the foregoing protocol including all appendices and agree that it contains all 
the necessary information for conducting the study safely.
I will conduct this study in strict accordance with this protocol and according to the current GCP 
guidelines and will attempt to complete the study within the time designated.
I will provide copies of the protocol and all other information relating to pre-clinical and prior 
clinical experience submitted by the Sponsor to all personnel responsible to me who participate 
in the study. I will discuss this information with them to assure that they are adequately informed 
regarding the drug and conduct of the study.
I agree to keep records on all subject information (CRFs, shipment and drug return forms and all 
other information collected during the study) in accordance with the current GCP and local 
regulations.
Principal Investigator’s name
Teva Representative's name
Signature
Signature
Date
Date
Institution


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21.
REFERENCES
EMEA Guideline on Clinical Investigation of Medicinal Products for the Treatment of Multiple 
Sclerosis (CPMP/EWP/561/98 Rev. 1, Nov. 2006)
Neuhaus O, Archelos JJ, Hartung HP. Immunomodulation in multiple sclerosis: from 
immunosuppression to neuroprotection. Trends Pharmacol Sci 2003;24:131-8.
NTP TR-521: National Toxicology Program. NTP technical report on the toxicology and 
carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in 
female Harlan Sprague-Dawley rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser. 2006 
Apr;(521):4-232.
NTP TR-584: National Toxicology Program. NTP technical report on the toxicology studies of 
indole-3-carbinol (CAS No. 700-06-1) in F344/N rats and B6C3F1/N mice and toxicology and 
carcinogenesis studies of indole-3-carbinol in Harlan Sprague Dawley rats and B6C3F1/N mice 
(Gavage Studies). Draft - Scheduled Peer Review Date: May 22, 2014.
Sormani MP, Bonzano L, Roccatagliata L, Mancardi GL, Uccelli A, Bruzzi P. Surrogate 
endpoints for EDSS worsening in multiple sclerosis. A meta-analytic approach. Neurology. 2010 
Jul 27;75(4):302-9


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22.
RATIONALE FOR PROTOCOL AMENDMENT AND SUMMARY
OF CHANGES
22.1.
Global Amendment #3
At the time of issuance of this amendment there are 542 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 3.4.1.1.7). 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 did not alter the study population or endpoints.
Rationales for the major changes are given and all substantive changes are listed in the summary 
table below.
Deletions are indicated with a strikethrough, additions with an underline.


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


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


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Original text with changes shown
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Reason/Justification for change
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 is extensively metabolized, predominantly by 
CYP3A4. Laquinimod metabolites levels in plasma are very 
low and parent laquinimod is the main systemically 
circulating entity. Laquinimod pharmacokinetics are 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.
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 
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 pharmacokinetics are 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.
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 
Updated for consistency with the 
IB


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Reason/Justification for change
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.
hepatic impairment (mild to severe) and renal impairment 
(moderate to severe) across this dose range.
Section 3.3.2. Clinical Safety and Efficacy Studies
(new text)
On 30 December 2015 the DMC for the LAQ-MS-305 
(CONCERTO) and TV5600-CNS-20006 (ARPEGGIO) studies 
held an unscheduled meeting to review cardiovascular events. 
The DMC found an imbalance in serious cardiovascular events in 
the high dose treatment arms (1.2 mg in CONCERTO, 1.5 mg in 
ARPEGGIO). Due to these events and the DMC 
recommendation to stop all laquinimod treatment arms above 0.6 
mg in the MS trials, the 1.2 mg treatment arm in the 
CONCERTO study was discontinued as of 01 January 2016. The 
risk/benefit balance of this dose was considered negative at that 
point.
The DMC did not identify any overt cardiovascular risk in the 
0.6 mg treatment arm, but felt that long term monitoring for 
emergence of any signal is necessary. Therefore, the 0.6 mg 
treatment arms in the CONCERTO and ARPEGGIO studies will 
be continued while the sponsor closely monitors cardiovascular 
events in all laquinimod studies, such as this one. This is 
discussed further in Section 3.4.1.1.7.
Information regarding safety 
findings in the CONCERTO and 
ARPEGGIO studies
Section 3.4.1.
Known and Potential Risks and Benefits for Laquinimod
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


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Reason/Justification for change
Section 3.4.1.1.7.Cardiovascular Events (Laquinimod 1.2 and 1.5 mg)
(new section)
On 30 December 2015, a DMC review of 8 unblinded cases from 
the LAQ-MS-305 (CONCERTO) and TV5600-CNS-20006 
(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 
Information regarding safety 
findings in the CONCERTO and 
ARPEGGIO studies


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Reason/Justification for change
causality are ongoing.
Section 3.4.1.2.2. Cancer
It is the sponsor’s position that these findings are likely 
related to the administration procedure or to species-specific 
mechanisms
It is the sponsor’s position that these findings are likely related to 
species-specific mechanisms
Administration procedure no 
longer considered a factor
Section 3.4.1.2.3. 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 these 
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 
infarctionThis analysis showed that none of these safety 
issues constitute a signal of concern for laquinimod.
Serious toxicities that occurred during Phase 3 trials led to 
discontinuation of these trials. Roquinimex demonstrated serious 
toxicities including increased rates of myocardial infarction, 
pericarditis, and pleuritis that were observed in three Phase 3, 
placebo-controlled studies in MS patients. The mechanism by 
which roquinimex caused these events was not identified, but 
they were considered to be possible manifestations of a systemic 
inflammatory response, an assessment which was also supported 
by roquinimex nonclinical findings. A thorough analysis was 
done on the laquinimod safety data (which is mostly reflective of 
the 0.6 mg/day dose) to evaluate similar potential safety issues. 
Based on 2347 patients exposed to laquinimod 0.6 mg for over 
10000 patient-years, as well as the patients exposed to 0.6 mg in 
the CONCERTO and ARPEGGIO studies, analyses showed that 
these safety issues do not constitute a clear signal for laquinimod 
in doses up to 0.6 mg/day. However, at doses of 1.2 and 1.5 mg, 
laquinimod manifested clinical evidence of myocardial 
infarction.
Information added on safety of 
0.6 mg dose
Section 5.1. Overview And Plan (Other sections affected by this change: Section 8.1. Study Period; Section 8.2.2. Scheduled Treatment Visits [Months 1E 
(Visits 1E) and Onwards]; Section 8.3.2.1. Liver Enzymes)
(new text)
Subjects who discontinue treatment for any reason will continue 
follow-up according to scheduled visits.
Additional follow-up added for 
safety reasons
Section 7.1. Allowed Concomitant Medications/Therapies
Short-term treatment with corticosteroids will be allowed 
during acute relapses.
Short-term treatment with corticosteroids will be allowed during 
relapses.
Treatment can be used for any 
relapses (not just acute relapses)
Clinical studies have shown laquinimod 0.6 mg to be a potent 
strong inducer of CYP1A2. Subjects taking drugs that are 
Clinical studies have shown laquinimod 0.6 mg to be a strong 
inducer of CYP1A2. Subjects taking drugs that are metabolized 
Wording made consistent with IB


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Original text with changes shown
New wording
Reason/Justification for change
metabolized by CYP1A2 (examples listed in Appendix F) 
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.
by CYP1A2 (examples listed in Appendix F) 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.
Section 7.2. Disallowed Concomitant Medications During Study (Other sections affected by this change: Section 8.2.3 Termination/ Early Discontinuation)
Interferons IFN-β 1a or 1b
...
Moderate/strong inhibitors of CYP3A4, for example, 
ketoconazole and erythromycin (as listed in Appendix E) are 
disallowed for 2 weeks prior to the baseline visit through to 
30 days after the final dose of laquinimod. Laquinimod is 
extensively metabolized predominantly by CYP3A4, and 
ketoconazole and fluconazole, strong and moderate inhibitors 
of CYP3A4, were found to inhibit the metabolism, leading to 
2.5- and 3.1-fold increases in laquinimod exposure, 
respectively.
IFN-β 1a or 1b
...
Moderate/strong inhibitors of CYP3A4, for example, 
ketoconazole and erythromycin (as listed in Appendix E) are 
disallowed for 2 weeks prior to the baseline visit through to 
30 days after the final dose of laquinimod. Laquinimod is 
extensively metabolized predominantly by CYP3A4, and 
ketoconazole and fluconazole, strong and moderate inhibitors of 
CYP3A4, were found to inhibit the metabolism, leading to 2.5-
and 3.1-fold increases in laquinimod exposure, respectively.
Clarification
Section 8.2.3. Termination/ Early Discontinuation (Other sections affected by this change: Section 8.3. Early Treatment Discontinuation)
(new text)
Subjects who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures until 
completion of the study (with the exception of procedures 
associated with drug dispensing and accountability, pregnancy 
testing, and GFR estimation [including body weight 
measurement]).
Additional follow-up added for 
safety reasons
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.


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
Section 8.3. Early Treatment Discontinuation
An early termination visit should be completed for all 
subjects who prematurely discontinue from the study and do 
not agree to or cannot continue all scheduled visits and 
procedures. It includes subjects who took at least one dose in 
the MS-LAQ-301E study.
An early termination visit should be completed for all subjects 
who prematurely discontinue from the study and do not agree to 
or cannot continue all scheduled visits and procedures. It 
includes subjects who took at least one dose in the MS-LAQ-
301E study.
Clarification
Section 8.3.1.1. Post Early Discontinuation Follow-Up Visit
(new text)
Note: This section specifically pertains to subjects that 
discontinue treatment early but do not agree to continue follow 
up.
Clarification
In case of early termination of the study due to an AE for 
which the relationship with the study drug is characterized as 
‘Reasonable Possibility’,Moderate and strong CYP3A4 
inhibitors are disallowed during the 30 days after the last 
dose has been administered.
Moderate and strong CYP3A4 inhibitors are disallowed during 
the 30 days after the last dose has been administered.
Text removed as this restriction is 
more general
Section 8.3.2.2. Pregnancy (Other sections affected by this change: 10.2.3. Safety Laboratory Evaluations; APPENDIX G. GUIDANCE ON SAFETY 
MONITORING)
Teva considers the prevention of exposure to laquinimod 
during pregnancy to be of great importance, and following 
consultation with the CHMP and Data Safety Committee 
(DMC) has decided to introduce additional language and 
measures for pregnancy prevention in this amendment and in 
a revised informed consent form.
(text deleted)
Text removed as was specific to a 
previous amendment
Additionally, monthly pregnancy tests (urine dipstick and/or
serum pregnancy β-hCG test, as applicable per the relevant 
time point) will be performed (except for where subjects 
have discontinued study drug but are continuing to attend 
study visits for follow-up).
Additionally, monthly pregnancy tests (urine dipstick and/or
serum pregnancy β-hCG test, as applicable per the relevant time 
point) will be performed (except for where subjects have 
discontinued study drug but are continuing to attend study visits 
for follow-up).
Clarification
Section 8.3.2.3. Invasive Cancer (Other sections affected by this change: APPENDIX G. 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 drug.
Subjects who are diagnosed with a malignant solid or liquid 
tumor while participating in the study should stop study drug.
Correction of terminology
Section 8.3.2.4. 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 
New stopping rule to avoid higher 
exposures to laquinimod


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
in the study should stop study medication.
Section 8.3.2.5. Renal Impairment
(new section)
To avoid exposures to higher levels of laquinimod (see 
Section 3.3.1), a stopping rule related to renal impairment has 
been introduced. Subjects who develop renal disease associated 
with moderate or severe functional impairment, defined as 
glomerular filtration rate (GFR) ≤60 mL/min/1.73 m2, while 
participating in the study should stop study medication 
temporarily and the GFR assessment should be repeated. If the 
renal impairment is confirmed (GFR ≤60 mL/min/1.73 m2), the 
subject should stop study medication permanently.
New stopping rule to avoid higher 
exposures to laquinimod
Section 8.3.5. Unscheduled Visit
(new text)
Serum or urine β-hCG test may be performed
Added to make consistent with 
study flow chart
Section 8.3.5.1. Unscheduled Samples
(new section)
According to the judgment of the investigator or medical 
monitor, the following unscheduled samples may be collected to 
assist with further investigations of cardiovascular events or 
other clinical event of interest:
urgent safety laboratory test panel (see Section 10.2.3.1)
pharmacokinetic blood sample
sample for potential biomarker analysis
Additional samples can be 
collected
Section 8.3.5.1.1. Unscheduled Pharmacokinetic Samples
(new section)
Unscheduled pharmacokinetic blood samples may be collected at 
the discretion of the investigator or medical monitor at any time 
to assist with further investigations of cardiovascular events or 
other clinical event of interest. The samples should be collected 
as soon as possible in association with the event.
Details of sample collection and processing are provided in the 
Laboratory Manual.
Additional samples can be 
collected
Section 8.3.5.1.2. 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 
Additional samples can be 
collected


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
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.
Section 10.2.1.1. Protocol Defined Adverse Events for Expedited Reporting
(new section)
Ischemic cardiac events (such as myocardial infarction, unstable 
angina, acute coronary syndrome etc), and cerebrovascular 
events (such as cerebral arterial occlusion, cerebral ischemia, etc) 
should be reported to the sponsor within 48 hours, including 
completion of the corresponding dedicated CRF.
Due to cardiovascular findings at 
higher dose levels, adverse events 
for expedited reporting have been 
identified.
Section 10.2.2. Abdominal Computed Tomography Scan
(new section)
In case of pancreatitis or suspected pancreatitis, an abdominal 
computed tomography (CT) scan should be performed as soon as 
possible in order to clarify the diagnosis and enable assessment 
of severity of this condition. An MRI may be performed as an 
alternative to the CT scan.
Added for consistency with other 
laquinimod protocols
Section 10.2.3. Safety Laboratory Evaluations (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E (Visits 1E) 
and Onwards]; Section 8.2.3. Termination/ Early Discontinuation)
hs-CRP
hs-CRP
It is specifically hs-CRP that 
should be measured
In case of abnormal CPK result: troponin or and CPK-MB 
will be tested
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 hemoglobin decrease of > 1g/dL from the subject’s 
hemoglobin level at Baseline, subjects will be re-tested to 
ascertain true decrease. If true decrease, a thorough anemia 
work-up will be done including:
directed medical history and physical examination
blood smear, serum iron, ferritin, total iron binding capacity, 
folic acid, B12, haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, and 
hepcidin
additional investigations and follow-up per Investigator’s 
discretion or Sponsor’s request
(text deleted)
Anemia panel will no longer be 
performed (this assessment was 
included to help understand the 
mode of action of laquinimod, 
with any changes expected to 
occur in the first few months of 
treatment, and was not pertinent to 
subject’s direct safety)
Urinalysis
pH
(text deleted)
Urinalysis will no longer be 
performed for consistency with 


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
Glucose
Ketones
Erythrocytes, Leukocytes
Protein
other laquinimod studies and 
because the clinical information 
gained from such a test would be 
minimal in this study.
Section 10.2.3.1. Urgent Safety Laboratory Panel
(new section)
Unscheduled urgent safety laboratory samples may be collected 
at the discretion of the investigator or medical monitor at any 
time to assist with further investigations of cardiovascular events 
or other clinical event of interest. The samples should be 
collected as soon as possible in association with the event.
The following tests (and others, if required) will be performed on 
these samples:
serum chemistry panel, including fibrinogen and hs-CRP
hematology panel
CPK-MB
troponin I
Unscheduled samples can be 
collected for further investigation 
of clinical events of interest
Section 10.2.4. Vital Signs and Weight (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E (Visits 1E) and 
Onwards])
Body weight will be measured at Month 0E [Baseline 
(Termination visit of the MS LAQ 301 study)] and every 12 
months thereafter,all visits until Termination/early 
discontinuation, and as long as the subject continues study 
drug treatment.
Body weight will be measured at all visits until 
Termination/early discontinuation, and as long as the subject 
continues study drug treatment.
Weight will now be measured at 
all visits
Section 10.2.7. Glomerular Filtration Rate Estimation (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits [Months 1E (Visits
1E) and Onwards]; Section 10.2.3. Safety Laboratory Evaluations)
(new section)
Significant changes in laquinimod exposure, in particular in 
terms of unbound drug fraction, are predicted in patients with 
moderate and severe renal impairment (see Section 3.3.1). 
Consequently, GFR will be estimated at all visits to monitor 
renal function in the study in order to identify subjects with 
potentially impaired laquinimod clearance. Subjects with a 
confirmed GFR ≤60 mL/min/1.73 m2 should stop study 
medication temporarily and the GFR assessment should be 
repeated. If the renal impairment is confirmed (GFR 
≤60 mL/min/1.73 m2), the subject should stop study medication 
permanently (see Section 8.3.2.5).
Following recent findings connecting Gd based contrast agents 
and nephrogenic systemic sclerosis, GFR value should be 
evaluated prior to performing an MRI scan, where administration 
GFR estimation added to monitor 
renal function


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
of Gd-based contrast agent is planned. The central laboratory 
will provide the GFR value prior to the scheduled MRI tests. In 
case GFR estimation is not provided by the central laboratory, 
calculation should be done at the site, prior to any MRI scan via 
the following web calculator:
http://www kidney.org/professionals/kdoqi/gfr calculator.cfm
In case GFR is ≤60 mL/min, the MRI scan should be performed 
without contrast (Gd) and further evaluation of renal impairment 
is required (refer to Section 8.3.2.5)
Section 10.2.8. Cardiovascular Risk Assessment and Management (Other sections affected by this change: Section 8.2.2. Scheduled Treatment Visits 
[Months 1E (Visits 1E) and Onwards])
(new section)
Evaluation and management of major modifiable cardiac risk 
factors (eg, diabetes, high blood pressure, hyperlipidemia, 
tobacco smoking) will be performed at the time points indicated 
in Table 5. In addition, an evaluation should take place as soon 
as possible for subjects already in the study, following approval 
of Amendment #3.
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 11. SAFETY AND PHARMACOVIGILANCE (Other sections affected by this change: Section 13.3. Subject Confidentiality; Section 14.4.1.1. Data 
Collection; APPENDIX D. MRI PROTOCOLS (INCLUDING MT AND MRS))
The following information should be provided to accurately 
and completely record the event:
1.
Investigator Name and Center Number
2.
Subject Number
3.
Subject initials
4.
Subject Demographics
The following information should be provided to accurately and 
completely record the event:
1.
Investigator Name and Center Number
2.
Subject Number
Subject initials and demographics 
should no longer be recorded
Section 13.2. Informed Consent (Other sections affected by this change: 8.2.2. Scheduled Treatment Visits [Months 1E (Visits 1E) and Onwards]
(new text)
Subjects continuing on laquinimod 0.6 mg will be re-consented 
with information about the cardiovascular risk seen in higher 
doses (see Section 3.4.1.1.7).
Subjects continuing on the study 
with this amendment will be 
re-consented.
Section 17. 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:
Section added for consistency with 
sponsor’s current protocol 
template


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
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.
Section 17.1. 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
Section added for consistency with 
sponsor’s current protocol 
template


Protocol No: MS-LAQ-301E
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Original text with changes shown
New wording
Reason/Justification for change
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 17.2. Handling of Study Drug at the Investigational Center
(new section)
The investigator is responsible for retaining the product in 
question in a location separate from the investigator’s clinical 
study supplies. The sponsor may request that the investigator 
return the product for further evaluation and/or analysis. If this is 
necessary, the clinical study monitor or designee will provide the 
information needed for returning the study drug.
If it is determined that the investigational center must return all 
study drug, the sponsor will provide the information needed to 
handle the return.
The integrity of the randomization code and corresponding 
blinded clinical supplies will be maintained whenever possible. 
A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a 
reason to unblind the clinical supplies for an affected subject.
Section added for consistency with 
sponsor’s current protocol 
template
Section 17.3. Adverse Events or Serious Adverse Events Associated with a Product Complaint
(new section)
If there is an adverse event or serious adverse event due to 
product complaint, the protocol should be followed for recording 
and reporting (Section 11).
Section added for consistency with 
sponsor’s current protocol 
template
Section 17.4. 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 D. MRI PROTOCOLS (INCLUDING MT AND MRS)
Check that the subject can successfully undergo MRI 
examination, including GFR estimation.
Following recent findings connecting Gd based contrast 
agents and nephrogenic systemic sclerosis, GFR value should 
be evaluated prior to performing an MRI scan, where 
Check that the subject can successfully undergo MRI 
examination, including GFR estimation.
Following recent findings connecting Gd based contrast agents 
and nephrogenic systemic sclerosis, GFR value should be 
evaluated prior to performing an MRI scan, where administration 
Added requirement for GFR 
estimation


Protocol No: MS-LAQ-301E
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109
Original text with changes shown
New wording
Reason/Justification for change
administration of Gd-based contrast agent is planned. The 
central laboratory will provide the GFR value prior to the 
scheduled MRI tests. In case GFR estimation is not provided 
by the central laboratory, calculation should be done at the 
site, prior to any MRI scan via the following web calculator:
http://www kidney.org/professionals/kdoqi/gfr calculator.cf
m
In case GFR is ≤60 mL/min, the MRI scan should be 
performed without contrast (Gd) and further evaluation of 
renal impairment is required (refer to Section 8.3.2.5)
of Gd-based contrast agent is planned. The central laboratory 
will provide the GFR value prior to the scheduled MRI tests. In 
case GFR estimation is not provided by the central laboratory, 
calculation should be done at the site, prior to any MRI scan via 
the following web calculator:
http://www kidney.org/professionals/kdoqi/gfr_calculator.cfm
In case GFR is ≤60 mL/min, the MRI scan should be performed 
without contrast (Gd) and further evaluation of renal impairment 
is required (refer to Section 8.3.2.5) 
APPENDIX E. MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 INDUCERS:
(section, including tables, updated to make consistent with 
current IB)
(see Appendix E for new wording)
Updated for consistency with 
current IB
APPENDIX F. LIST OF MEDICATIONS THAT SHOULD BE USED WITH CAUTION
(section, including tables, updated to make consistent with 
current IB)
(see Appendix F for new wording)
Updated for consistency with 
current IB
APPENDIX G. GUIDANCE ON SAFETY MONITORING
(new text)
4.
Guidance on Monitoring Subjects with Elevated
Pancreatic Amylase Levels
Pancreatic amylase will be measured at each study visit. Lipase 
will be tested in case of abnormal pancreatic amylase results and 
on all follow up visits until normalization of pancreatic amylase 
levels. 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.
Guidance updated for consistency 
with body of the protocol


Protocol No: MS-LAQ-301E
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110
22.2.
Global Amendment #2
At the time of issuance of this amendment there were 639 ongoing subjects in the 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 and all substantive changes are listed in the summary 
table below.


Protocol No: MS-LAQ-301E
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111
Previous approved wording
Amended or new wording
Reason/Justification for 
change
Section 8.2: Detailed Study Plan
None.

For all subjects who are female of child-
bearing potential:

The use of effective contraception will 
be ascertained at each study visit (should 
be recorded in the source documents).

Subjects will be instructed during each 
visit about the teratogenicity and 
potential delayed risks for a child 
exposed in uterus to laquinimod

Subjects will be reminded about (should 
be recorded in the source documents) the 
importance of stopping the study drug 
and informing the site in any case of 
suspected pregnancy (positive home 
urine test result, delay of menstruation or 
any other reason suggesting pregnancy)
Teva considers the prevention of 
exposure to laquinimod during 
pregnancy to be of great 
importance, and following 
consultation with the CHMP 
and Data Safety Committee 
(DMC) has decided to introduce 
additional language and 
measures for pregnancy 
prevention in this amendment 
and in a revised informed 
consent form.
To strengthen the preventative 
measures, the 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 enrollment, furthermore 
a serum beta HCG test prior to 
randomization
Section 8.2.1: Baseline Visit (Month 0E) (Visit 0E) (Termination visit of the MS-LAQ-301 study) Procedures
Serum pregnancy test (β-hCG) for women of child-bearing 
potential
Serum pregnancy test (β-hCG) for women of child-bearing 
potential. In case of positive result, the subject will not be 
eligible to participate in the extension and will be 
considered a screening failure for the extension phase.
Section 8.2.3: Termination/ Early discontinuation Visit
Female subjects of child-bearing potential will be reminded to 
continue using an acceptable method of contraception up to 30 
days from the date of the last dose of the IMP
The use of effective contraception will be ascertained 
(should be recorded in the source documents) and they will 
be reminded to use two acceptable methods of 
contraception up to 30 days from the date of the last dose 
of the IMP


Protocol No: MS-LAQ-301E
Amended Protocol 03
ALLEGRO Extension Study
112
Previous approved wording
Amended or new wording
Reason/Justification for 
change
Clinical study protocol synopsis (study design), Section 8.2.1: Baseline Visit Month 0E) (Visit 0E) (Termination visit of 
the MS-LAQ-301 study) Procedures, Section 8.2.2: Scheduled treatment visits [Months 1E (Visit 1E) and onwards]
in any case of suspected pregnancy […]
in any case of suspected pregnancy (positive urine β-hCG 
test results, delay of menstruation or any other reasons 
suggesting pregnancy) […]
Section 8.3.2.2: Pregnancy (NEW SECTION)
None.
See Section 8.3.2.2
Appendix G – Guidance on safety monitoring
The section has been greatly 
revised to bring in line with 
current experience. Please see 
section for full details.
See Appendix G.
Clinical study protocol synopsis AND Section 6.2: Exclusion criteria (note regarding returning subjects)
None.
Female subjects of childbearing potential who may want to 
get pregnant in the future, and are interested in re-starting 
laquinimod treatment following delivery and cessation of 
breastfeeding may be able to re-enroll in the study after 
meeting inclusion/exclusion criteria in Appendix G. 
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 […]
The Sponsor realized that there 
might be female subjects of 
childbearing potential who are 
participating in this long-term 
study that might want to get 
pregnant in the future, and 
might be interested in 
continuing taking Laquinimod 
after giving birth. The Sponsor 
would like to assure that these 
women do not conceive during 
treatment with laquinimod and 
are given the opportunity to 
return to the study, if they wish, 
following childbirth and 
lactation. Therefore, the 
protocol has been amended to 
say that these subjects may be 
re-enrolled after meeting 
inclusion/exclusion criteria.


Protocol No: MS-LAQ-301E
Amended Protocol 03
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113
Previous approved wording
Amended or new wording
Reason/Justification for 
change
Section 7.1: Allowed concomitant medications/therapies
The use of CYP1A2 substrates (e.g. theophylline, warfarin) 
during the treatment period is permitted. However, due to the 
fact that laquinimod is an inducer of CYP1A2 in vitro, subjects 
who are treated with these medications should be monitored for 
a possible reduction in their effect or blood level and their 
(CYP1A2 substrates) dose should be adjusted accordingly.
Clinical studies have shown laquinimod 0.6 mg to be a 
potent inducer of CYP1A2. Subjects taking drugs that are 
metabolized by CYP1A2 (examples listed in Appendix F) 
should be advised that plasma levels of these drugs could 
decrease when combined with laquinimod. Physicians 
should consider increasing the dose of such medications 
upon initiation of laquinimod treatment; in this case, dose 
reduction of the CYP1A2 inhibitor should be considered if 
laquinimod is stopped.
Drug-Drug interaction studies have been performed with 
laquinimod doses of 0.6 mg and 1.2 mg. These studies 
show that laquinimod at both doses is a weak inhibitor of 
CYP3A4. Subjects taking drugs that are metabolized by 
CYP3A4 (specifically those with a Narrow Therapeutic 
Index listed in Appendix F) should be advised that plasma 
levels of these drugs could increase when combined with 
laquinimod.
Laquinimod is a potent inducer 
of CYP1A2. A recently 
completed drug-drug interaction 
study confirmed that laquinimod 
at the dose of 1.2 mg is also a 
weak CYP3A4 inhibitor. 
Therefore, these paragraphs 
were included to emphasize the 
risk related to the concomitant 
use of laquinimod and drugs 
that are metabolized by 
CYP1A2 or CYP3A4.
In addition, a new appendix 
(Appendix F) has been added to 
present partial lists of CYP3A4 
substrates with a narrow 
therapeutic index and of drugs 
known to be metabolized by 
CYP1A2.
Appendix F – List of allowed medication during the study that should be used with caution (NEW APPENDIX)
None.
Appendix F
Clinical study protocol synopsis
The allowed treatment for a relapse will be intravenous 
methylprednisolone 1 g/day for up to 5 consecutive days.
The allowed treatment for a relapse will be intravenous 
methylprednisolone 1 g/day or oral steroids for up to 5 
consecutive days.
In order to align the protocol 
with more recent clinical study 
protocols with laquinimod, 
allowed treatment for relapses 
includes a short course of 
glucocorticosteroids (e.g., IV 
methylprednisolone 1g/day for 
up to 5 consecutive days or oral 
steroids). Extended courses of 
steroids beyond 5 days 
constitute a protocol violation. 
No tapering off is allowed.
Section 7.1: Allowed concomitant medications/therapies
Short-term treatment with corticosteroids will be allowed 
during acute relapses; Allowed treatment for relapses is a fixed 
dose of IV methylprednisolone 1 g/day for a maximum of five 
consecutive days. No tapering off is allowed.
Short-term treatment with corticosteroids will be allowed 
during acute relapses; Allowed treatment for relapses is a 
fixed dose of IV methylprednisolone 1 g/day or oral 
steroids for a maximum of five consecutive days. No 
tapering off is allowed.
Section 7.2: Disallowed concomitant medications during study

-Oral steroids

-Parenteral steroids (except if given as defined by 
protocol for treatment of an acute relapse as specified in 

Oral steroids and parenteral steroids (except 
if given as defined by protocol for treatment of an acute 
relapse as specified in Section 7.1)


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Reason/Justification for 
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Section 7.1)
Section 7.2: Disallowed concomitant medications during study

Inhibitors of CYP3A; for example ketocanozole 
and erythromycin (as listed in Appendix E)

Moderate/strong inhibitor of CYP3A; for 
example ketocanozole and erythromycin (as listed in 
Appendix E)

Inducers of CYP3A4 such as rifampin or 
carbamazepine (more examples are provided in Appendix 
E). Use of CYP3A4 inducers may results in reduced 
laquinimod plasma concentrations and reduced 
effectiveness
Laquinimod is mainly 
metabolized by the CYP3A4 
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 
lead to an approximately 80% 
reduction in the plasma levels of 
laquinimod, as measured by the 
area under the plasma 
concentration-time curve 
(AUC). Use of CYP3A4 
inducers (Carbamazepine, 
Phenytoin, Phenobarbital, St. 
John's Wort) may result in 
reduction of laquinimod plasma 
concentrations and may reduce 
its effectiveness. Therefore, 
CYP3A4 inducers have been 
added as disallowed 
medications in all clinical 
studies with Laquinimod. The 
Laquinimod Investigator's 
Brochure Edition 7 has been 
updated with the above 
information in Section 6.7.1.
In addition, the list of 
moderate/strong CYP3A4 
inhibitor not allowed in the 
study was updated.
Section 8.3.1.1: Post early discontinuation follow-up visit
In case of early termination of the study due to an AE for which 
the relationship with the study drug is characterized as 
‘Reasonable Possibility’, CYP3A4 inhibitors are disallowed 
during the 30 days after the last dose has been administered.
In case of early termination of the study due to an AE for 
which the relationship with the study drug is characterized 
as ‘Reasonable Possibility’, moderate and strong CYP3A4 
inhibitors are disallowed during the 30 days after the last 
dose has been administered.
Appendix E – List* of systematically-administered** CYP3A4 inhibitors which are disallowed prior and during the 
study and CYP3A4 inducers
Cardiac drugs/antiarrhythmic agents
amiodarone
diltiazem
nifedipine
verapamil
mibefradil
Antimicrobial agents
Erythromycin
Clarithromycin
Troleandomycin
Telithromycin
Antifungals/Imidazoles
Fluconazole
Itraconazole
Ketoconazole
Miconazole
Voriconazole
A partial list of moderate/strong CYP3A4 inhibitors:
Medication 
class
Drug name
Protease 
inhibitors
indinavir, saquinavir, lopinavir, 
nelfinavir, amprenavir,atazanavir, 
darunavir, ritonavir
Antivirals
boceprevir, telaprevir
Antifungals
Ketoconazole, Itraconazole, 
voriconazole, posaconazole, 
fluconazole
Antibiotics
troleandomycin, clarithromycin, 
telithromycin, ciprofloxacin, 
erythromycin


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HIV drugs:
Protease Inhibitors, such as indinavir, ritonavir and others
Delavirdine
Antidepressants
fluoxetine
fluvoxamine
nefazodone
Others/antituberculosis and antimalarial
isoniazid
quinine
cimetidine
zileuton
aprepitant
[…]
***In case of early termination of the study due to AE which is 
considered as 'Reasonable Possibility' related to the study drug, 
CYP3A4 inhibitors are disallowed during 30 days after the last 
dose of the study drug was taken.
Antidepressant
nefazodone
Calcium 
channel blocker
Diltazem, verapamil, mibefradil
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 7.2: Disallowed concomitant medications during study

Interferons

Glatiramer Acetate (Copaxone®)

Natalizumab (Tysabri®)

Inhibitors of CYP3A4; for example, ketoconazole and 
erythromyicin (as listed in Appendix 5)

Mitoxantrone (Novantrone®)

Natalizumab (Tysabri®)

Fingolimod (Gilenya)

Interferons

Dimethyl fumarate (Tecfidera)

Glatiramer Acetate (Copaxone®)
The protocol has been updated 
to include several new drugs 
recently approved for use in 
RRMS.
In addition, the medication 
4-amino pyridine (Ampyra, 


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
Oral steroids

Parenteral steroids (except if given as defined by protocol 
for treatment of an acute relapse as specified in Section 
7.1).

Chemotherapeutic agents

4-amino pyridine or 3,4 diaminopyridine 

IV Immunoglobulin (Ig) and any other experimental agents 

Other Immunosuppressive or immunomodulating agents

Teriflunomide (Aubagio)

Alemtuzumab (Lemtrada)

Cladribine

Rituximab

Ocrelizumab

Atacicept

Belimumab

Ofatumumab

Inducers of CYP3A4 such as rifampin or 
carbamazepine (more examples are provided in
Appendix E). Use of CYP3A4 inducers may results 
in reduced laquinimod plasma concentrations and 
reduced effectiveness

Moderate/strong inhibitors of CYP3A4, for 
example, ketoconazole and erythromycin (as listed 
in Appendix E)

Mitoxantrone (Novantrone®)

Oral steroids

Parenteral steroids (except if given as defined by 
protocol for treatment of an acute relapse as 
specified in Section7.1)

Adrenocorticotrophic hormone (ACTH)

Chemotherapeutic agents

Cytotoxic agents

Cyclophosphamide

IV Immunoglobulin (Ig)

Plasmapheresis

Any other experimental agents

Other Immunosuppressive or immunomodulating 
agents
Fampyra) has been removed 
from the list of disallowed 
concomitant medications. 
Indeed, this drug is now allowed 
during the study as it is no 
longer an experimental drug (it 
has received FDA approval and 
indicated to improve walking in 
adult subjects with multiple 
sclerosis MS who have walking 
disability).
Clinical study protocol synopsis AND Section 10.2.2: Safety laboratory evaluations
CPK

In case of abnormal CPK result: troponin or CPK-
The Sponsor has decided to 


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
Alkaline Phosphatase

Pancreatic Amylase
[…]

Hemoglobin.
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 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, 
haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, 
and hepcidin

additional investigations and follow-up 
per the Investigator’s discretion or 
Sponsor’s request.
remove the stopping rules of 
monitoring of inflammatory 
conditions, monitoring the 
potential of developing 
thrombosis and monitoring of 
serum pancreatic amylase based 
on updated safety analyses and 
to align the protocol with more 
recent clinical study protocol 
with laquinimod. Complete 
blood count, amylase, CRP and 
fibrinogen are routinely 
monitored during scheduled 
visits. The subjects with these 
laboratory abnormalities should 
be managed and treated 
according to the best medical 
practice.
In case of abnormal CPK 
results, testing of troponin or 
CPK MB (which was formally 
only specified as reflex testing 
in the laboratory manual) are 
currently specified in the 
protocol. A requirement for 
testing urine myoglobin in case 
of CPK >2000 U/L, was added.
In addition, in case of abnormal 
pancreatic amylase results, 
lipase will be tested.
In case of low hemoglobin 
levels, a thorough anemia 
work-up will be done.
Following discussion with the 
Section 8.3.2: Safety stopping rules
Inflammatory Events:
The subject's participation in the study will be discontinued 
immediately upon meeting either one of the following criteria:
A combination of elevated CRP (≥3xULN) or WBC (≥2xULN) 
or fibrinogen (≥ 3x ULN) with significant signs/symptoms 
suggestive of inflammation of non infectious origin (e.g. 
arthralgia, chest pain, chest discomfort or edema).
An established diagnosis of either of the following: pericarditis, 
New subsections added; see Section 8.3.2.2 and Section 
8.3.2.3 for full text.


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pleuritis, pleural effusion, newly diagnosed non infectious 
arthritis or primary peritonitis.
Thromboembolic events:
In any suspicion for thrombotic events, all measures should be 
taken in order to establish or to exclude the diagnosis. The 
decision as per the continuation of the study drug will be made 
on a case by case basis.
Pancreatitis:
Any subject with an established diagnosis 
(radiographically/sonographically based) of acute pancreatitis 
will be immediately withdrawn from the study.
European Medicines Agency, 
two new conditions were 
included among the stopping 
rules (women who become 
pregnant during the study and 
subjects diagnosed with 
invasive cancer).
Clinical study protocol synopsis – Study duration
Study duration: Treatment phase: starting from completion of 
the MS-LAQ-301 study (Termination visit), until laquinimod 
0.6 mg is commercially available for the treatment of multiple 
sclerosis (MS) patients or until the development of laquinimod 
0.6 mg for MS is stopped by the Sponsor.
Study design: In this open-label study, the subjects will be 
treated with laquinimod 0.6 mg (regardless of their initial 
treatment assignment during the MS-LAQ-301 study) until 
laquinimod 0.6 mg is commercially available for the treatment 
of MS patients or until its development for MS is stopped.
Study duration: Treatment phase: starting from 
completion of the MS-LAQ-301 study (Termination visit), 
as long as the Sponsor continues the development of 
laquinimod 0.6 mg for Relapsing Remitting Multiple 
Sclerosis (RMMS).
Study design: In this open-label study, the subjects will be 
treated with laquinimod 0.6 mg (regardless of their initial 
treatment assignment during the MS-LAQ-301 study) as 
long as the Sponsor continues the development of 
laquinimod 0.6 mg for RMMS.
The Sponsor reasoned that the 
long term follow-up for safety 
and efficacy is of utmost 
importance and would like to 
maintain the subjects under this 
clinical protocol. The Sponsor 
would like to prolong the study 
as long as the Sponsor continues 
the development of laquinimod 
0.6 mg for RMMS patients. 
Therefore, the duration of the 
study will no longer be 
dependent on commercial 
availability of laquinimod 
0.6mg.
Section 4: Study objectives
To make treatment with oral laquinimod 0.6 mg available to all 
subjects who participated in the double-blind, 
placebo-controlled MS-LAQ-301 study and who completed the 
Termination visit of this study according to the MS-LAQ-301 
protocol until laquinimod 0.6 mg is commercially available for 
the treatment of MS patients or until its development for MS is 
stopped.
To make treatment with oral laquinimod 0.6 mg available 
to all subjects who participated in the double-blind, 
placebo-controlled MS-LAQ-301 study and who 
completed the Termination visit of this study according to 
the MS-LAQ-301 protocol as long as the Sponsor 
continues the development of laquinimod 0.6 mg for 
RMMS.


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Section 5.1: Overview and plan
Scheduled in-clinic visits will be conducted at Baseline (month 
0E; the Termination visit of MS-LAQ-301 will serve as the 
baseline visit of MS-LAQ-301E) and at months 1E, 2E, 3E, 6E 
and every 6 months thereafter, until laquinimod 0.6 mg is 
commercially available for the treatment of MS patients or its 
development for MS is stopped.
Scheduled in-clinic visits will be conducted at Baseline 
(month 0E; the Termination visit of MS-LAQ-301 will 
serve as the baseline visit of MS-LAQ-301E) and at 
months 1E, 2E, 3E, 6E and every 6 months thereafter, as 
long as the Sponsor continues the development of 
laquinimod 0.6 mg for RMMS.
Section 5.2: Rational for study design, dose and population
Provide laquinimod 0.6 mg once daily to all subjects who 
successfully complete the double-blind, placebo-controlled MS-
LAQ-301 study until it is commercially available (in each of 
the relevant countries).
Provide laquinimod 0.6 mg once daily to all subjects who 
successfully complete the double-blind, placebo-controlled 
MS-LAQ-301 study as long as the Sponsor continues the 
development of laquinimod 0.6 mg for RRMS.
Section 8.1: Study period
The study, in which all eligible subjects will be treated with 
daily laquinimod 0.6 mg, will last until laquinimod 0.6 mg is 
commercially available for the treatment of MS patients or until 
its development for MS is stopped.
The study, in which all eligible subjects will be treated 
with daily laquinimod 0.6 mg, will last as long as the 
Sponsor continues the development of laquinimod 0.6 mg 
for RMMS.
Section 8.2.3: Termination early discontinuation
Upon commercial availability of laquinimod 0.6 mg for the 
treatment of MS patients (or a decision of the Sponsor to stop 
the development of laquinimod 0.6 mg for MS patients), the 
local clinical trial management will notify the site teams when 
to invite the subjects to the site, in order to perform the 
Termination visit.
Subjects who have performed all Termination visit activities 
(either in case of commercial availability of laquinimod 0.6 mg 
for MS patients or in case the Sponsor decides to stop the 
development of laquinimod 0.6 mg for MS patients) will be 
regarded as completers.
Upon a decision of the Sponsor to stop the development of 
laquinimod 0.6 mg for RMMS patients, the local clinical 
trial management will notify the site teams when to invite 
the subjects to the site, in order to perform the Termination 
visit.
Subjects who have performed all Termination visit 
activities (in case the Sponsor decides to stop the 
development of laquinimod 0.6 mg for RMMS patients) 
will be regarded as completers.


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Clinical study protocol synopsis – MRI scan at Termination/early discontinuation visit
Following the results of the MS LAQ 301 study, the Sponsor 
may decide to perform a Magnetic Resonance imaging (MRI) 
scan at Termination/early discontinuation visit for all subjects 
(not only those who participate in the MRI ancillary study).
Magnetic Resonance Imaging (MRI) scan at 
Termination/early discontinuation visit will be performed 
on subjects who participated in the MRI ancillary study 
only.
The Sponsor has decided not to 
perform Termination/Early 
discontinuation visit MRI 
assessments for all subjects in 
the study. No changes apply to 
the MRI assessments for the 
MRI ancillary study.
Section 8.1: Study period (Task flow chart)
In the table: MRI (T1, T2) all subjects (Termination/early 
discontinuation)
In the footnote of the table: i
Optional. Following the 
results of the MS LAQ 301 study, the Sponsor may decide to 
perform an MRI scan at Termination/early discontinuation visit 
for all subjects (not applicable for those who participate in the 
MRI ancillary study). In case of completion according to the 
protocol, this scan may be performed within 14 days prior to 
the Termination or as late as 14 days after Termination visit, 
(provided the subject was not treated with another 
immunomodulating/ immunosuppressive treatment for MS). In 
case of early termination, this scan may be performed as late as 
14 days after early termination visit, (provided the subject was 
not treated with another immunomodulating/ 
immunosuppressive treatment for MS).
None.
Section 8.2.3: Termination/Early discontinuation
Following the results of the MS LAQ 301 study, the Sponsor 
may decide to perform an MRI scan at Termination/early 
discontinuation visit for all subjects (not aaplicable for those 
who participate in the MRI ancillary study). In case of 
completion according to the protocol this scan may be 
performed within 14 days prior to the Termination or as late as 
14 days after Termination visit, (provided the subject was not 
treated with another immunomodulating/ immunosuppressive 
treatment for MS). In case of early termination, this scan may 
be performed as late as 14 days after early termination visit, 
(provided the subject was not treated with another 
None.


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immunomodulating/ immunosuppressive treatment for MS). 
This scan will include:
T1weighted, after administration of Gdgadopentetic 
acid (GdDPTA)
T2weighted
3D T1weighted
Section 10.1.7: Optional assessment –Termination MRI scan
Following the results of the MSLAQ301 study, the Sponsor 
may decide to perform an MRI scan at Termination/early 
discontinuation visit for all subjects (not applicable for those 
who participate in the MRI ancillary study). In case of 
completion according to the protocol, this scan may be 
performed within 14 days prior to the Termination oras late as 
14 days after Termination visit, (provided the subject was not 
treated with another immunomodulating/ immunosuppressive 
treatment for MS). In case of early termination, this scan may 
be performed as late as 14 days after early termination visit, 
(provided the subject was not treated with another 
immunomodulating/ immunosuppressive treatment for MS). 
This scan will include:
T1weighted, after administration of Gdgadopentetic 
acid (GdDPTA)
T2weighted
3D T1weighted
The following parameters will be assessed in this optional scan:
Number of T1 Gdenhancing lesions
Number of new T2 lesions
Volume of T2 lesions
Number of new hypointense T1 lesions on enhanced T1 scans 
("black holes")
Volume of new hypointense T1 lesions on enhanced T1 scans
Brain volume
Steroid treatment for relapse (see Section 7.1) will not affect the 
schedule of this optional MRI scan. Where possible, the scan 
should be performed prior to steroid treatment.
None (the section has been removed).


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All MRI data will be interpreted by the MRIAC.
Appendix D –MRI Protocols (including MT and MRS)
OPTIONAL MRI SCAN
Following the results of the MSLAQ301 study, the Sponsor 
may decide to perform an MRI scan at Termination/early 
discontinuation visit for all subjects (not applicable for those 
who participate in the MRI ancillary study). In case of 
completion according to the protocol, this scan may be 
performed within 14 days prior to the Termination or as late as 
14 days after Termination visit, (provided the subject was not 
treated with another immunomodulating/ immunosuppressive 
treatment for MS). In case of early termination, this scan may 
be performed as late as 14 days after early termination visit, 
(provided the subject was not treated with another 
immunomodulating/ immunosuppressive treatment for MS). 
This scan will include:
T1weighted, after administration of Gdgadopentetic 
acid (GdDPTA)
T2weighted
3D T1weighted
The following parameters will be assessed in this optional scan:
Number of T1 Gdenhancing lesions
Number of new T2 lesions
Volume of T2 lesions
Number of new hypointense T1 lesions on enhanced T1 scans 
("black holes")
Volume of hypointense T1 lesions on enhanced T1 scans 
("black holes")
Brain volume: Percentage of brain volume change from 
Termination scan of MSLAQ301 core study.
None.


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Reason/Justification for 
change
Clinical study protocol synopsis
The Sponsor will inform the sites when to change from Period 1 
to Period 2.
All neurological/medical assessments may be performed 
by a single Study Physician/Neurologist since all the sites 
are now in Period 2 of the study.
There is no longer need to 
distinguish between study 
period 1 and 2 since all the 
subjects are now in the study 
period 2.
Similarly, there is no need for 
distinction between the Treating 
and the Examining Physicians/ 
Neurologists.


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Section 5.1.1: Study periods
The medical/neurological assessments of the subjects at each 
clinical site will be performed differently in each of the 
following study periods.
Period 1 :
In this period, either two separate Neurologists or two 
Physicians will continue to assess the subjects in the MS-LAQ-
301E study (as in the MS-LAQ-301 study). An Examining 
Neurologist/Physician will assess the subject’s neurological 
status, unaware of subject’s well-being and a Treating 
Neurologist/Physician will decide whether a subject 
experienced a relapse and will treat the subject as needed.
In order to maintain reliable evaluation and reduce the potential 
for bias the following actions will be undertaken:
The Examining Neurologist/Physician will be the only one to 
evaluate the subject neurologically.
The Examining Neurologist/ Physician will have no access to 
the subject's file, including previous neurostatus forms, RDC 
system and adverse events.
A decision as per treatment of a relapse will be under the sole 
responsibility of the Treating Neurologist/ Physician.
Period 2:
In this period, there will be no need for 2 separate physicians to 
assess the subjects in the MS-LAQ-301E study. From that 
moment, subjects participating in the MS-LAQ-301E study will 
be assessed by a single physician/Neurologist ("Study 
Physician/ Neurologist").
The study will begin with medical/neurological assessments 
which will be performed as described in Period 1 (identical to 
the assessment methods in the MS LAQ 301 study)
The sponsor will inform the sites when to change the method of 
medical/neurological assessments from Period 1 to Period 2.
The medical/neurological assessments of the subjects at 
each clinical site will no longer be performed differently 
since all the sites are now in study period 2.
Period 1 :
In this period, either two separate Neurologists or two 
Physicians will continue to assess the subjects in the MS-
LAQ-301E study (as in the MS-LAQ-301 study). An 
Examining Neurologist/Physician will assess the subject’s 
neurological status, unaware of subject’s well-being and a 
Treating Neurologist/Physician will decide whether a 
subject experienced a relapse and will treat the subject as 
needed.
In order to maintain reliable evaluation and reduce the 
potential for bias the following actions will be undertaken:
The Examining Neurologist/Physician will be the only one 
to evaluate the subject neurologically.
The Examining Neurologist/ Physician will have no access 
to the subject's file, including previous neurostatus forms, 
remote data capture (RDC) system and adverse events 
(AEs).
A decision as per treatment of a relapse will be under the 
sole responsibility of the Treating Neurologist/ Physician.
Period 2:
In this period, there will be no need for 2 separate 
physicians to assess the subjects in the MS-LAQ-301E 
study. Subjects participating in the MS-LAQ-301E study 
will be assessed by a single physician/Neurologist ("Study 
Physician/ Neurologist").


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Section 7.1: Allowed concomitant medications/therapies
Topical and inhaled steroids are allowed at the discretion of the 
Treating Physician (or theStudy Physician, were applicable, 
see Section 5.1.1)for indications other than MS.
Topical and inhaled steroids are allowed at the discretion 
of the Study Physician/Neurologist for indications other 
than MS.
Section 8.2.2: Scheduled treatment visit [Months 1E (Visit 1E) and onwards]
In order to verify whether the test has been performed 
and to record the result of the test (see AppendixF), a 
mandatory phone call will be performed by theTreating
Neurologist/ Physician (or Study Physician, where applicable)
or by the site’s nurse/ study coordinator within 72 hours after 
the test was scheduled to be performed.

In order to verify whether the test has been 
performed and to record the result of the test (see 
Appendix G), a mandatory phone call will be performed by 
the Study Neurologist/ Physician or by the site’s nurse/ 
study coordinator within 72 hours after the test was 
scheduled to be performed.
Section 8.3.5: Unscheduled visit
Should the visit be related to a relapse, this will be clearly 
indicated on the eCRF and the Examining
Neurologist/Physician (or Study Physician, where applicable)
will carry out a complete neurological evaluation 
(FS/AI/EDSS/Timed 25 Foot walk).
Should the visit be related to a relapse, this will be clearly 
indicated on the eCRF and the Study
Neurologist/Physician will carry out a complete 
neurological evaluation (FS/AI/EDSS/Timed 25 Foot 
walk).
Section 8.3.6: Visits during relapses (scheduled and unscheduled)
The Examining Neurologist/Physician (or Study Physician/ 
Neurologist, where applicable, see Section 5.1.1)will evaluate 
the subject within 7 days of symptoms onset, conditional upon a 
symptomatic period of ≥ 48 hours.
The relapse assessment will be documented in the source 
documents and in the eCRF accordingly. A complete 
neurological assessment, including FS, AI EDSS and Timed 25 
Foot walk, will be performed by the Examining
Neurologist/Physician (or Study Physician, where applicable, 
see Section 5.1.1).
The decision as to whether the neurological change is 
considered a relapse will be made by the Treating 
Neurologist/Physician [or by the Study Physician, where 
applicable (see Section 5.1.1), based on the criteria listed in 
Appendix B].
Corticosteroids therapy (as described in Section 7.1) may be 
given for a confirmed relapse at the discretion of the Treating
Neurologist/Physician (or by the Study Physician, where 
The Study Physician/ Neurologist, will evaluate the subject 
within 7 days of symptoms onset, conditional upon a 
symptomatic period of ≥ 48 hours.
The relapse assessment will be documented in the source 
documents and in the eCRF accordingly. A complete 
neurological assessment, including FS, AI EDSS and 
Timed 25 Foot walk, will be performed by the Study
Neurologist/Physician.
The decision as to whether the neurological change is 
considered a relapse will be made by the Study
Neurologist/Physician, based on the criteria listed in 
Appendix B].
Corticosteroids therapy (as described in Section 1.7) may 
be given for a confirmed relapse at the discretion of the 
Study Neurologist/Physician and must be recorded in the 
source documents and eCRF.


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applicable, see Section 5.1.1)and must be recorded in the 
source documents and eCRF.
Section 10.1.1: On study relapse evaluation & determination
Subjects will be instructed to telephone their study site within 
48 hours should any symptoms suggestive of a relapse appear.
The Treating Neurologist/Physician (or theStudy 
Physician/Neurologist, where applicable) (see Section 5.1.1and 
Section 18.1.2)will evaluate the subject once any symptom 
suggestive of a relapse occurs.
In case of a suggestive relapse during a scheduled or 
unscheduled visit in
Period 1(see Section 5.1.1):
The Treating Neurologist/Physician will refer the 
subject to the Examining Neurologist/Physician for 
performance of neurological evaluations and obtain EDSS score 
(see Section 18.1.3).
An Examining Neurologist/Physician will assess the 
subject’s neurological status, unaware of subject’s well being 
and a Treating Neurologist/ Physician will decide whether a 
subject experienced a relapse and will treat the subject as 
needed.
In case of a suggestive relapse during a scheduled or 
unscheduled visit in Period 2(see Section 5.1.1):
The evaluation of symptoms as well as the 
neurological evaluations/ EDSS will be made by the Study 
Physician(see Section 18.1.4).
Based on the assessment of symptoms and the 
EDSS/FS evaluation, the Study Physician will decide whether a 
subject experienced a relapse and will treat the subject as 
needed.
In any case, the neurological evaluation of the subject (by The 
Examining Neurologist in Period 1 or by the Study 
Physician/Neurologist in Period 2)will be performed within 7 
days of symptoms onset, conditional upon a symptomatic 
period of ≥ 48 hours.
Subjects will be instructed to telephone their study site 
within 48 hours should any symptoms suggestive of a 
relapse appear.
The Study Physician/Neurologist will evaluate the subject 
once any symptom suggestive of a relapse occurs.
In case of a suggestive relapse during a scheduled or 
unscheduled visit:

The evaluation of symptoms as well as the 
neurological evaluations/ EDSS will be made by the Study 
Physician/Neurologist.

Based on the assessment of symptoms and 
the EDSS/FS evaluation, the Study Physician/Neurologist
will decide whether a subject experienced a relapse and 
will treat the subject as needed.
In any case, the neurological evaluation of the subject by 
the Study Physician/Neurologist will be performed within 
7 days of symptoms onset, conditional upon a symptomatic 
period of ≥ 48 hours.


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Sections 18.1.2: The treating Neurologist/Physician (applicable in Period 1)
The Treating Neurologist/Physician will be responsible for 
subject eligibility evaluation, the supervision of the study drug 
administration, the recording and treating of adverse events, the 
monitoring of safety assessments, including routine laboratory 
parameters, and coordinating MRI performance. He/she will 
determine if a subject experiences a relapse and whether to treat 
the relapse or not and he/she will decide whether to treat the 
subject as needed.
None.
Section 18.1.3: The examining Neurologist/Physician (applicable in Period 1)
The Examining Neurologist1 will be responsible for all 
neurological examinations. Throughout the study, the 
Examining Neurologist/Physician will remain unaware of the 
safety profile. For each subject, the same Examining Physician 
should be used for all neurological exams performed 
throughout the study.
It is particularly important that:
The Treating Neurologist/Physician and the 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.
Footnote:
1The Examining Neurologist can be a physician neurologist or 
other appropriately qualified and documented healthcare 
professional as deemed by the Principal Investigator and agreed
upon by the Sponsor.
None.


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Old Section 18.1.4/New Section 18.1.2: The Study Physician/Neurologist
The Study Physician/Neurologist (applicable in Period 2)
In case where there is no need for distinction between the 
Treating and the Examining Physicians/ Neurologists (Period 2) 
(to be communicated to the clinical sites by the Sponsor, or 
Sponsor's designee), the Study Physician/ Neurologist will be 
responsible for the general medical evaluations as well as the 
neurological assessments. The Study Physician will make the 
decision as to whether the neurological change is considered a 
relapse, based on EDSS/FS scores obtained by him/her.
The Study Physician/Neurologist
The Study Physician/Neurologist will be responsible for 
the general medical evaluations as well as the neurological 
assessments. The Study Physician/Neurologist will make 
the decision as to whether the neurological change is 
considered a relapse, based on EDSS/FS scores obtained 
by him/her.
Section 19.2: Data monitoring committee (DMC)
During Period 1, the DMC Chairperson will interact with the 
Sponsor’s statistician. Within this work frame, the study un
blinded statistician, will produce and distribute reports to the 
DMC members. The statistician of the DMC will address any 
statistical question raised by the DMC during data review, and 
will perform data analyses according to the DMC’s request. 
During Period 2, this interaction may be done via the Global 
Clinical Leader.
None.
Appendix B - Definitions
In Period 1 (see Section 5.1.1), the subjects’ general medical 
evaluations will be assessed separately from their neurological 
assessment evaluations by two different Neurologists/ 
Physicians. An Examining Neurologist/Physician will assess 
the subject’s neurological examination, unaware of subject’s 
well being and a Treating Neurologist/ Physician will decide 
whether a subject experienced a relapse and will prescribe 
steroids or other concomitant medications as needed.
The Treating Neurologist/Physician will make the decision as 
to whether the neurological change is considered a relapse, 
based on EDSS/FS scores as assessed by the Examining 
Neurologist/ Physician (see Relapse Definition, above).
Follow up visits to monitor the course of the relapse until 
stabilization will be made at the Treating Neurologist/Physician 
discretion, in addition to the assessment at the next scheduled 
visit.
In Period 2 (see Section 5.1.1), there will be no distinction 
between the Treating Neurologist/ Physician and the 
Examining Neurologist/ Physician. In such cases, a single 
Study Physician/Neurologist will be responsible for the 
general medical evaluations as well as the neurological 
assessments. The Study Physician/Neurologist will make 
the decision as to whether the neurological change is 
considered a relapse, based on EDSS/FS scores obtained 
by him/her. The Study Neurologist/ Physician will follow-
up on the subject during the course of a relapse, until 
stabilization.
Relapse Evaluation Procedures
Subjects will be instructed to telephone their study site 
within 48 hours should any symptoms suggestive of a 
relapse appear.
The Study Neurologist/ Physician will evaluate the subject 


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In Period 2 (see Section 5.1.1), there will be no distinction 
between the Treating Neurologist/ Physician and the Examining 
Neurologist/ Physician. In such cases, a single Study Physician 
will be responsible for the general medical evaluations as well 
as the neurological assessments. The Study Physician will make 
the decision as to whether the neurological change is considered 
a relapse, based on EDSS/FS scores obtained by him/her. The 
Study Neurologist/ Physician will follow-up on the subject 
during the course of a relapse, until stabilization.
Relapse Evaluation Procedures
Subjects will be instructed to telephone their study site within 
48 hours should any symptoms suggestive of a relapse appear.
In Period 1, the Examining Neurologist/ Physician will evaluate 
the subject within 7 days of symptoms onset, conditional upon a 
symptomatic period of ≥ 48 hours:
The Treating Neurologist/Physician will evaluate the subject 
once any symptom suggestive of a relapse occurs.
In case of a suggestive relapse during a scheduled or 
unscheduled visit, the Treating Neurologist/Physician will refer 
the subject to the Examining Neurologist/Physician.
In Period 2, all of the above mentioned relapse evaluation 
activities will be performed by the Study Neurologist/ 
Physician.
within 7 days of symptoms onset, conditional upon a 
symptomatic period of ≥ 48 hours:
The Study Neurologist/Physician will evaluate and treat 
the subject once any symptom suggestive of a relapse 
occurs.


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Appendix I: MSFC administration instruction
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.
For subjects with significant gait impairment, the Study 
Neurologist/Physician should have the subject use a rolling 
walker even if this is not the subject's customary device.
Section 11: Safety and pharmacovigilance
SAE reporting
In order to satisfy regulatory requirements, any Serious Adverse 
Event, whether deemed IMP-related or not, must be reported to 
the Local Clinical Management as soon as possible after the 
investigator or coordinator has become aware of its occurrence.
The SAE form completion and reporting must not be delayed 
even if all of the information is not available at the time of the 
initial contact.
The SAE should be submitted within 24 hours of becoming 
aware of the event to the Local Clinical Management. The local 
Clinical Management will forward the report to the Local 
Safety Officer who will forward the SAE report to the Global
Pharmacovigilance Unit:
SAE originated in Europe and rest of the world should be sent 
to:
Global Drug Safety and Pharmacovigilance Unit (Israel)
SAE originated in USA will be sent to:
SAE originated in Canada will be sent to:
SAE reporting
In order to satisfy regulatory requirements, any SAE, 
whether deemed IMP-related or not, must be reported to 
the CRO as soon as possible after the investigator or 
coordinator has become aware of its occurrence. The SAE 
form completion and reporting must not be delayed even if 
all of the information is not available at the time of the 
initial contact.
The SAE should be submitted within 24 hours of becoming 
aware of the event to the CRO. The CRO will forward the 
report to the appropriate Pharmacovigilance unit at Teva or 
the LSO who will forward the SAE report to the 
appropriate Pharmacovigilance unit at Teva:
SAE originated in Europe and rest of the world should be 
sent to:
Global Drug Safety and Pharmacovigilance Unit (Israel)
SAE originated in USA will be sent to:
Teva USA clinical safety mailbox
SAE originated in Canada will be sent to:
Teva Canada clinical safety mailbox


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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 Local 
Clinical Management.
For both initial and follow-up SAE reports the Local Clinical 
Management forwards this information to the 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 Local Clinical Management/ Local Safety Officer 
for local submission to the regulatory authorities (CA) and 
EC/IRBs and investigators according to regulations.
In Period 1, blinding will be maintained for the people who are 
involved directly in the study, therefore in case of a SUSAR 
case only the Local Safety Officer will receive the un blinded 
report for regulatory submission, while the others will receive a 
blinded report (Teva S.O.P 50.11.16). This precaution is not 
relevant for Period 2.
[…]
Pregnancy reports: Pregnancy reports should be forwarded to 
the Pharmacovigilance for data entry to the global safety 
database. This includes also normal pregnancies without AE. 
The pregnancies reporting procedure should be the same as the 
SAE reporting procedure.
The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of birth, 
and presence or absence of any birth defect, congenital 
abnormalities or maternal and newborn complications. 
Pregnancy follow up should be recorded on a specific eCRF 
provided by Local Clinical Trial Management.
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.
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 the LSO 
who forwards it to the appropriate Pharmacovigilance unit 
at Teva within 48 hours. The Pharmacovigilance units at 
Teva will submit a summary of the clinical course of the 
SAEs back to the CRO/ LSO for local submission to the 
regulatory authorities (competent authorities [CA]) and 
EC/Institutional Review Boards (IRBs) and investigators 
according to regulations.
[…]
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.


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Section 8.3.1: Criteria for early treatment discontinuation
None.
[…]
8)
Planned pregnancy
9)
Lack of efficacy (according to the Investigator’s 
decision)
[…]
Two additional criteria for early 
treatment discontinuation have 
been included: pregnancy (due 
to fact that laquinimod is 
contraindicated in pregnancy) 
and lack of efficacy.
Section 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 6.1 Inclusion Criteria
2.
Women of child-bearing potential must practice an
acceptable method of birth control [acceptable methods of birth 
control in this open label extension phase include: surgical 
sterilization, intrauterine devices, oral contraceptive, 
contraceptive patch (or hormone releasing vaginal ring), long
acting injectable contraceptive, partner’s vasectomy or double
barrier method (condom or diaphragm with spermicide)] during 
the study and up to 30 days after the last dose of the study 
drug..
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 18.2.6 Global Clinical Safety Director
The Global Clinical Safety Director will be 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 and will 
act as liaison with the external DMC (see details below).
Section deleted
Text deleted to bring up to date 
with current process.
Section 18.2.7.
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 Officer is 
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.


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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.
Entire document
-
Numbering of Appendices has been changed throughout 
the text.
Updated cross-references to 
appendices (due to addition of a 
new Appendix F).
In addition, literature references 
have been changed to reflect the 
changes in the protocol


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23.
CHANGES TO PATIENT ENTRY CRITERIA
Not applicable.


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APPENDIX A. DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS: 
2005 REVISIONS TO THE “MCDONALD CRITERIA”
Every attempt will be made to obtain documentation of relapses that occurred within one and 
two years prior to study entry. If written documentation is not available, the Investigator will 
contact the subject’s physician by phone in order to obtain all information of the subject’s 
relapses. This should be documented as a phone-call report.
MS Diagnosis
Confirmation of RRMS diagnosis according to the revised McDonald criteria will be performed 
during screening.
In April 2001, an international panel in association with the NMSS of America recommended 
diagnostic criteria for multiple sclerosis. These criteria have become known as the McDonald 
criteria after their lead author. They make use of advances in MRI techniques and are intended to 
replace the Poser Criteria and the older Schumacher Criteria. In March 2005 in Amsterdam, 
nearly 5 years after the publication of the McDonald criteria (a), the International Panel reached 
consensus on the 2005 Revisions to the "McDonald Criteria Diagnostic Criteria for Multiple 
Sclerosis"(a).
                                                
a
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the 
International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127


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Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the “McDonald Criteria”
Clinical Presentation
Additional Data Needed
Two or more attacksa; objective clinical
evidence of two or more lesions
Noneb
Two or more attacksa; objective clinical 
evidence of one lesion
Dissemination in space, demonstrated by:
MRIc or
Two or more MRI-detected lesions consistent with MS plus 
positive CSFd or
Await further clinical attacka implicating a different site
One attacka; objective clinical evidence of two 
or more lesions
Dissemination in time, demonstrated by:
MRIe or
Second clinical attacka
One attacka; objective clinical evidence of one 
lesion (monosymptomatic presentation;
clinically isolated syndrome)
Dissemination in space, demonstrated by:
MRIc or
Two or more MRI-detected lesions consistent with MS plus 
positive CSFd and
Dissemination in time, demonstrated by:
MRIe or
Second clinical attacka
a An attack is defined as an episode of neurological disturbance for which causative lesions are likely to be inflammatory and demyelinating in 
nature. There should be subjective report (backed up by objective findings) or objective observation that the event lasts for at least 24 hours
b No additional tests are required; however, if tests (MRI, CSF) are undertaken and are negative, extreme caution needs to be taken before 
making a diagnosis of MS. Alternative diagnoses must be considered. There must be no better explanation for the clinical picture and some 
objective evidence to support a diagnosis of MS.
c Space dissemination demonstrated by MRI should have three of the following conditions: At least one gadolinium-enhancing lesion or nine T2
hyperintense lesions if there is no gadolinium enhancing lesion; At least one infratentorial lesion; At least one juxtacortical lesion; At least 
three periventricular lesions. A spinal cord lesion can be considered equivalent to a brain infratentorial lesion: an enhancing spinal cord lesion 
is considered to be equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute together with individual brain 
lesions to reach the required number of T2 lesions.
d Positive CSF determined by oligoclonal bands detected by established methods (isoelectric focusing) different from any such bands in serum, 
or by an increased IgG index .
e Time dissemination demonstrated by MRI should have one of the following conditions: Detection of gadolinium enhancement at least 3 
months after the onset of the initial clinical event, if not at the site corresponding to the initial event; Detection of a new T2 lesion if it appears 
at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event
CSF = cerebrospinal fluid, MRI = magnetic resonance imaging, MS = multiple sclerosis


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APPENDIX B. DEFINITIONS
Relapse (attack)
A relapse will be defined as the appearance of one or more new neurological abnormalities or the 
reappearance of one or more previously observed neurological abnormalities.
This change in clinical state must last at least 48 hours and be immediately preceded by an 
improving neurological state of at least thirty (30) days from onset of previous relapse.
This criterion is different from the clinical definition of relapse: "at least 24 hours duration of 
symptomsa". Since "in study" relapse definition must be supported by an objective neurological 
evaluation (see next paragraph), a neurological deficit must sustain long enough to eliminate 
pseudo-relapses.
An event will be counted as a relapse only when the subject's symptoms are accompanied by 
observed objective neurological changes, consistent with at least one of the following:

an increase of at least 0.5 in the EDSS score as compared to previous evaluation.

an increase of one grade in the score of 2 or more of the 7 FS as compared to previous 
evaluation.

an increase of 2 grades in the score of one FS as compared to the previous evaluation.
The EDSS/FS/AI (in the first visit indicative for a relapse, as well as in follow up visits) will be a 
part of a complete neurological assessment performed by the Examining Neurologist/ Physician 
(or the Study's Neurologist/ Physician, in case all subjects in the MS-LAQ-301 double-blind 
placebo-controlled study have completed (or early terminated) their treatment period).
The subject must not be undergoing any acute metabolic changes such as fever or other medical 
abnormality. A change in bowel/bladder function or in cognitive function must not be entirely 
responsible for the changes in EDSS or FS scores.
                                                
a Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis (McDonald, Ann. 
Neurol. 2001;50:121-127)


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In Period 2 (see Section 5.1.1), there will be no distinction between the Treating Neurologist/ 
Physician and the Examining Neurologist/ Physician. In such cases, a single Study 
Physician/Neurologist will be responsible for the general medical evaluations as well as the 
neurological assessments. The Study Physician/Neurologist will make the decision as to whether 
the neurological change is considered a relapse, based on EDSS/FS scores obtained by him/her. 
The Study Neurologist/ Physician will follow-up on the subject during the course of a relapse, 
until stabilization.
Relapse Evaluation Procedures
Subjects will be instructed to telephone their study site within 48 hours should any symptoms 
suggestive of a relapse appear.
The Study Neurologist/ Physician will evaluate the subject within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥48 hours.
The Study Neurologist/Physician will evaluate and treat the subject once any symptom 
suggestive of a relapse occurs.
Relapsing-Remitting (R-R) Multiple Sclerosis (MS)
RRMS is characterized by clearly defined acute attacks with full recovery or with sequelae and 
residual deficit upon recovery, periods between disease relapses characterized by a lack of 
disease progression (Lublin 1996)a.
                                                
a Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis. Neurol 1996;46:907-911.


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


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APPENDIX D. MRI PROTOCOLS (INCLUDING MT AND MRS)
INTRODUCTION
All of the MRI scans will be evaluated in accordance with local clinical practice. Any 
pathological finding(s) not related to MS will be reported by the responsible radiologist to the 
Treating Investigator consistent with existing local procedures.
The electronic data derived from each MRI scan will be sent to the MRI-AC for approval and 
processing.
All subjects who participated in the Frequent MRI ancillary study (in the MS-LAQ-301 Study) 
and continue to the MS-LAQ-301E study will be offered to participate in an MRI ancillary study 
in the open-label extension. A separate informed consent form will need to be signed for this 
purpose. The MRI scans will be performed at months 0E [Baseline; this is the Termination scan 
of the MS-LAQ-301 study)] and every 12 months thereafter, until termination/early 
discontinuation visit.
The Baseline scan (month 0E) of the MS-LAQ-301E study will be the same scan as the 
Termination scan of the MS-LAQ-301 study (According to the MS-LAQ-301 protocol, the 
Termination MRI scan of the MS-LAQ-301 study will be performed within 4 days prior to the 
Termination visit). This scan is a part of the MS-LAQ-301 protocol.
In case the Termination visit of the study is scheduled to less than 14 days after the performance 
of a scheduled MRI scan – the scan should not be repeated.
The following parameters will be assessed at each scheduled scan:

Number of T1 Gd-enhancing lesions

Number of new T2 lesions

Volume of T2 lesions

Number of new hypointense T1 lesions on enhanced T1 scans ("black holes")

Volume of hypointense T1 lesions on enhanced T1 scans ("black holes")

Brain volume: Percentage of brain volume change from:

Baseline scan of the MS-LAQ-301E (month 0E) (Termination visit of the MS-
LAQ-301 study) to all of the scans obtained in MS-LAQ-301E study (i.e. month 
12E, month 24E, etc).


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SCANNER DEVICE
Devices supplied by various manufacturers can be used. The following requirements apply:
Scanners should have at least 1.5 Tesla magnetic field strength.
The same scanner must be used for each subject for the entire duration of the study.
Software and hardware upgrades may be permissible but must be reported to MRI-AC and may 
require a re-approval process (including Dummy Run, see below) for the site.
Scanner must be able to create a back up copy of all subject scans performed.
The back up copy of baseline scan obtained for the MS-LAQ-301E open-label extension Study
should be used for subject repositioning during all study duration.
Electronic backups of all scans must be archived at each site.
POSITIONING THE SUBJECT
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.
Following recent findings connecting Gd-based contrast agents and nephrogenic systemic 
sclerosis, GFR value should be evaluated prior to performing an MRI scan, where administration 
of Gd-based contrast agent is planned. The central laboratory will provide the GFR value prior to 
the scheduled MRI tests. In case GFR estimation is not provided by the central laboratory, 
calculation should be done at the site, prior to any MRI scan via the following web calculator:
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm
In case GFR is ≤60 mL/min, the MRI scan should be performed without contrast (Gd) and 
further evaluation of renal impairment is required (refer to Section 8.3.2.5)
Enter the subject data into the scanner console, using:

study number (protocol number, site number, subject number)

date of birth/sex

weight

Visit number


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Explain the scanning procedure to the subject and position her/him in the scanner in the most 
comfortable position.
Insert an IV 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.
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.


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MRI ACQUISITION PROTOCOL
The acquisition protocol is accomplished with seven series of scans. The first three scans are for 
localization, the fourth for a quick check of localization, the fifth to provide T2-weighted and 
proton-density-weighted images, the sixth to provide a 3D pre-contrast T1-weighted sequence 
and the seventh to provide post-contrast delineation of enhancing lesions. As noted, the first 
three imaging scans are for the purpose of localization and for them a tri-pilot localizer scan, if 
available, may be substituted. If this option is employed, following the tri-pilot localizer the 
protocol continues with scans referred to as Series 4,5,6 and 7. In this case, there will be five 
scans in each protocol acquisition. The primary objective for the localizing scans is to provide an 
optimal prescription for the scans that will be subjected to quantitative analysis. The MRI-AC 
will perform this analysis on Series 5, 6 and 7. The prescribed scan parameters must be followed 
absolutely in order to make possible quantitative analysis. The only permitted exceptions are 
those noted below.
General Notes:
Do not use SMASH, SENSE, GRAPPA or related techniques. Parallel acquisition is not 
permitted by this protocol.
If using a multi-channel head coil, turn on intensity correction if available. This is done as 
follows:
On PHILIPS scanners: Acquire a coil sensitivity map. In the GEOMETRY tool select: CLEAR: 
YES. Body tuned: NO.
On SIEMENS scanners: in the Resolution task card, select NORMALIZE by activating this filter 
with the drop down option ON.
On GE scanners select SCIC (surface coil intensity correction).
Do not deviate from the specifications for the field of view (FOV). If the cranial size is large, the 
whole brain may not fall within the scanning range. In this case do not change slice number (44) 
and do leave slice group centered at the inferior borders of the genu and splenium of the corpus 
callosum. In this case the portion of the brain that is covered will be analyzed and the study will 
be valid.
Where a range of values are achievable for TE, use the smallest acceptable value.


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The study allows a rectangular FOV for certain scans as noted below, but the protocol always 
requires 100% sampling in the frequency encode direction. With some scanners care must be 
taken to avoid an automated reduction in this parameter that can result in scan rejection.
For Siemens, set “percentage sampling”=100% and “half fourier”=no
For Philips scanner, set “scan percentage”=100% and “half scan”=no
Leave the reconstruction matrix the same as the acquisition matrix and do not select the 
“interpolation” option, available on some scanners, by which reconstruction is done with a larger 
matrix than was acquired. All Siemens users must turn off “Interpolation” which is found under 
“Resolution” o the scanner console. Philips users should make sure that reconstruction matrix is 
256.
The following order for sequences will be kept:
1) T1-weighted axial scout
2) T1-weighted coronal scout
3) T1-weighted sagittal scout
These first three scans are for the purpose of localization and for them a tri-pilot localizer scan, if 
available, may be substituted. If this option is employed, following the tri-pilot localizer continue 
with #4.
4) Rapid T1-weighted SE or T2-weighted FSE/TSE axial (this is for repositioning check)
Sequences from 1 to 4 will be done to obtain reference images for subject’s repositioning (For 
more details see MRI guideline). The MRI-AC center will not verify the acquisition parameters 
of these four sequences. In the MRI manual, acquisition parameters are suggested to help the set 
of these sequences.
The sequences of the main protocol, which will be checked in terms of acquisition 
parameters and quality of the images, are those numbered from 5 to 7.
5) T2-weighted FSE/TSE
6) T1 weighted MP-RAGE (for Siemens), 3D-fast SPGR (for GE), 3D-TFE (for Philips)
7) T1-weighted SE post gadolinium


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SEQUENCE PARAMETERS FOR 1.5 TESLA SCANNER
a) Sequences for positioning and repositioning the subjects (no check by MRI-AC):
Sequence 1: T1-weighted axial scout
TR (ms)
TE
(ms)
# of
slices
Slice
Thickne
ss (mm)
Inter-Slice
Gap
FOV 
(mm)
Matrix
# of
average
Phase
encoding
100
10-20
3
5
5
210-230
256 x 128
1
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)
Sequence 2: T1-weighted coronal scout
TR 
(ms)
TE 
(ms)
# of
slices
Slice
Thickness 
(mm)
Inter-Slice
gap
FOV 
(mm)
Matrix
# of
average
Phase
encoding
100
10-20
1
5
-
210-230
256 x 128
1
L-R
From the coronal scout make a sagittal scout image, aligned with the falx cerebri and other 
midline structures, such as the third ventricle.
Sequence 3: T1-weighted sagittal scout
TR (ms)
TE 
(ms)
# of
slices
Slice
Thickness 
(mm)
Inter-Slice
gap
FOV 
(mm)
Matrix
# of
average
Phase
encoding
500-650
10-20
1
5
-
210-230
256 x 128
1 to 3
A-P
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 genu and splenium of the corpus callosum. 
For a correct positioning of the subject at baseline and a subsequent repositioning during 
the follow up, the use of the inferior borders of the genu and splenium of the corpus 
callosum as reference is a main requirement of the protocol.
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.


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Sequence 4a: Rapid T1-weighted Spin Echo
TR 
(ms)
TE 
(ms)
# of
slices
Slice
Thickness 
(mm)
Inter-Slice
Gap
FOV 
(mm)
Matrix
# of
average
Phase
encoding
600
10-20
22
3
3
250
140 x 128
1
L-R
OR
Sequence 4b: T2-weighted Turbo Spin Echo axial
TR 
(ms)
TE 
(ms)
# of
slices
Slice
Thickness 
(mm)
Inter-Slice
Gap
FOV 
(mm)
Matrix
# of
average
Phase
encoding
2200-
3000
30-50/
60-100
22
3
3
250
256 x 128
1
L-R
Please note that the back-up, (saved also on disc), of this first series of T1 or T2 axial images 
should be done 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).
b) Sequences of the main protocol (check by MRI-AC):
Sequence 5: T2-weighted Fast/Turbo Spin Echo (axial)
a.
a single series of 2 concatenated and interleaved packages of 22 slices each (44 images)
TR 
(ms)
TE 
(ms)
# of
slices
Slice
Thickness 
(mm)
Inter-
Slice
Gap
FOV 
(mm)
Matrix
# of
average
Percentage 
of 
sampling
Phase
encoding
ETL
2500-
3500
14-50/
90-120
22
3
0
250
256 x 
256
1
100%
L-R
4-6
OR
b.
two series of 22 images
TR 
(ms)
TE 
(ms)
# of
slice
s
Slice
Thickness 
(mm)
Inter
-Slice
Gap
FOV 
(mm)
Matrix
# of
average
Percentage 
of sampling
Phase
encoding
ETL
2500-
3500
14-50/
90-120
22
3
3
250
256 x 
256
1
100%
L-R
4-6
Position an axial presaturation slab (50-80 mm) inferior to the slice group to suppress flow-
related artifacts.


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The 44 interleaved slices are acquired in a single series or, alternatively, in two series of 22 
slices. Scans with additional slices will not be accepted.
Some scanners allow 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, it is preferable to use this option. The number of acquisition is 
automatically calculated by the system according to the specified TR. Please, check that the 
number of acquisition is set to 2 (Siemens scanner refers to this parameter as “concatenation”, 
GE scanners as “acquisitions”, and Philips scanner as “Packages” on the “Info” page). If the 
number of acquisitions is greater than 2, adjust upward TR by small steps to obtain 2 
acquisitions.
If two series of 22 slices may be acquired, the first series must have slice positions as fast series 
whereas the second one must have slice positions shifted 3 mm caudally compared with the first 
one, such that when both series are combined, the desired region is covered. The intent is to have 
contiguous coverage of the prescribed region with 44 interleaved slices (no slice gap).
Please, note that for the main protocol only 44 slices are required. Scans with additional 
slices will not be accepted.
Sequence 6:T1 weighted MP-RAGE (for Siemens), 3D-fast SPGR (for GE), 3D-TFE (for 
Philips)
TR 
(ms)
TE 
(ms)
# of 
slices
Slice 
thickness 
(mm)
FOV 
(mm)
Matrix
# of
average
Orientation
Flip 
Angle
TI
(sec)
Phase
encoding
8-15
3-5
160
1.2
256x256
256 x 
256
1
Sagittal
10-15
1.1
A-P
L-R
For Siemens scanners, set TR (which is intended as the time between inversion pulses) in the 
range of 2000-2300 ms.
For Philips scanners, set shot mode = multi shot and the TFE factor = 256; then set the shot 
interval in the range 2000-2300 ms.
Position the box in order to have the top just above the scalp. Rotate the box by the same amount 
that was used for sagittal scout.
Perform a bolus injection of Gd-DPTA using the IV 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). Before Gd 
administration 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.


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Sequence 7: T1-weighted conventional Spin Echo (axial)
a.
a single series of 2 concatenated packages of 22 slices each (44 images)
TR 
(ms)
TE 
(ms)
# of 
slices
Slice 
thickness 
(mm)
Inter-
Slice
gap
FOV 
(mm)
Matrix
# of
average
Percentage 
of 
sampling
Phase
encoding
Presaturat
ion 
slab/flow 
compensat
ion
600-
650
10-
20
22
3
0
250
256 x 
256
2
100%
L-R
yes
OR
b.
two series of 22 images
TR 
(ms)
TE 
(ms)
# of 
slices
Slice 
thickness 
(mm)
Inter-
Slice 
gap
FOV 
(mm)
Matrix
# of
average
Percentage 
of 
sampling
Phase
encoding
Presaturat
ion 
slab/flow 
compensat
ion
600-
650
10-
20
22
3
3
250
256 x 
256
2
100%
L-R
yes
Position an axial presaturation slab (50-80 mm) inferior to the slice group to suppress flow-
related artifacts.
In case of two series acquisition, 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.
In case of 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 Gadolinium-
Gadopentetic Acid (Gd-DTPA) injection.
For dual-echo and post-contrast T1-weighted scans, if possible, to speed up the examination, use 
a rectangular 3/4 FOV (i.e., reduce the phase-encoding matrix by 25%). 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).


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MRI PARAMETERS FOR 3.0 TESLA SCANNER
Please, read the general rules listed in the MRI acquisition protocol section, before proceeding 
with sequences set up.
The scanning procedure is the same as of the 1.5 Tesla, using the following parameters for the 
main protocol:
T2 weighted FSE/TSE
a.
a single series of 2 concatenated packages of 22 slices each (44 images)
TR
(ms)
TE1/ 
TE2
(ms)
ETL
# of 
slices
Slice 
thickness 
(mm)
Inter-
Slice 
gap
FOV 
(mm)
Matrix
# of 
average
Percentage 
of sampling
Phase
encoding
2200-
3300
15-
40/90-
120
2-7
22
3
0
240
256 x 
256
1
100%
L-R
OR
b.
two series of 22 images
TR
(ms)
TE1/ 
TE2
(ms)
ETL
# of 
slices
Slice 
thickness
(mm)
Inter-
Slice 
gap
FOV 
(mm)
Matrix
# of 
average
Percentage 
of 
sampling
Phase
encoding
2200-
3300
15-
40/
90-
120
2-7
22
3
3
240
256 x 
256
1
100%
L-R
Position an axial presaturation slab (50-80 mm) inferior to the slice group to suppress flow-
related artifacts.
The 44 interleaved slices are acquired in a single series or, alternatively, in two series of 22 
slices. Scans with additional slices will not be accepted.
Some scanners allow 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, it is preferable to use this option. The number of acquisition is 
automatically calculated by the system according to the specified TR. Please, check that the 
number of acquisition is set to 2 (Siemens scanner refers to this parameter as “concatenation”, 
GE scanners as “acquisitions”, and Philips scanner as “Packages” on the “Info” page). If the 
number of acquisition is greater than 2, adjust upward TR by small steps to obtain 2 acquisitions.
If two series of 22 slices may be acquired, the first series must have slice positions as fast series 
whereas the second one must have slice positions shifted 3 mm caudally compared with the first 


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one, such that when both series are combined, the desired region is covered. The intent is to have 
contiguous coverage of the prescribed region with 44 interleaved slices (no slice gap).
Please, note that for the main protocol only 44 slices are required. Scans with additional 
slices will not be accepted.
Sequence 2: T1 weighted MP-RAGE (for Siemens), 3D-fast SPGR (for GE), 3D-TFE (for 
Philips)
TR 
(ms)
TE 
(ms)
# of 
slices
Slice 
thickness
FOV 
(mm)
Matrix
# of
average
Orientation
Flip 
Angle
TI (sec)
Phase
encoding
8-15
3-5
160
1.2
256x256
256 x 
256
1
Sagittal
8-12
1.1
A-P
L-R
For Siemens scanners, set TR (which is intended as the time between inversion pulses) 
=3000 ms.
For Philips scanners, set shot mode = multi shot and the TFE factor = 256; then set the shot 
interval = 3000 ms.
Position the box in order to have the top just above the scalp. Rotate the box by the same amount 
that was used for sagittal scout.
Perform a bolus injection of Gd-DPTA using the IV 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). Before Gd 
administration 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 3D images.
Sequence 3. T1 weighted 3-D FLASH (for Siemens) SPGR (for GE) FFE (for Philips) post 
contrast images
TR (ms)
TE (ms)
# of slices
Slice 
thickness
(mm)
Slab 
thickness
(mm)
Matrix
NEX
5-9
2-5
In phase
44
3
132
256 x 
192
1
FOV (A-P) 
(mm)
FOV (L-R) 
(mm)
FOV (C-C) 
(mm)
Flip Angle
BW
240
180
132
15°
62.5 kHz or 
250Hz/pixel


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Data Transmission
Retain a digital copy of all imaging results (including scout images) at the participating site.
For each subject, forward a copy of all the images (axial-coronal and sagittal localizers, PD-T2-
weighted FSE/TSE, pre- and post-contrast T1-weighted images) in digital form to the MRI-AC 
within 3 working days from the scan date (see MRI guideline). Do not send hard copies or films.
As a general guideline, the acceptable media, ordered by preference is listed below:

Network transfer ftp

CD-ROM

Electronic tapes: 4mm DAT or 8mm tape digital linear tape (DLT)
Preferentially, the data will be exported in DICOM format. Compression of the data is allowed if 
it does not cause any loss of information.
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. The e-mail 
addresses for network transfer will be provided separately to MRI sites.
In addition, the required MRI forms, completely filled in and signed, should be faxed to the 
MRI-AC in Italy to 
 
.
In case fax machine is not available, please scan the signed forms and send them by email.
MRI-AC will provide a password to sites that will choose network transfer option.
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.


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MRI SCAN QUALITY CONTROL
Each MRI scan received by the MRI-AC will be reviewed within 3 working days, starting from 
the time of the MRI approval and analysis forms have been produced (please, refer to the scan 
arrival date reported on the approval form).
The MRI-AC will notify the site radiologist, the LCM, and the Corporate Coordination Center 
via transmission of the Scan Acceptance Form. If a repeat of one or more scans is required, this 
should be accomplished as soon as possible and in all cases within two weeks of the rejected 
scan.
In case of unsatisfactory image quality, the scans will be rejected and it must be repeated within 
2 weeks from the date of the first assessment.
MRI DUMMY RUN PROCEDURE
The dummy run procedure will be required in case of change/upgrade of the MRI 
scanner/machine or as requested by the MRI-AC.
The results of this procedure allow the MRI-AC to verify 1) that the data from a given site is of 
sufficient quality to support the quantitative analysis required by this study; 2) that the methods 
used by the site to acquire the data are consistent and adequate to obtain reproducible data; 3) 
that the acquisition parameters required by the protocol are stored in the image header.
The “dummy run” procedure should take in account the following points:
1. A scan must be performed on a clinically definite relapsing MS subject, to show that 
lesions can be visualized with adequate contrast for quantitative analysis.
2. The Dummy Run protocol consists of two executions of the standard MRI Acquisition 
protocol with the exceptions that IV access is not obtained and gadolinium contrast is not 
injected.
3. the subject should be properly positioned in the scanner
4. technician should use the same acquisition parameters defined by the protocol (see 
paragraphs “MRI parameters for 1.5 tesla scanner” and “MRI parameters for 3.0 tesla 
scanner”)
5. the sequences to be acquired are:
a.
a dual echo scan
a.
3D T1-weighted scan
b. post contrast T1-weighted scan without administration to the subject of any contrast 
agent


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Dummy run electronic data together with a complete MRI parameters form (see MRI guideline) 
must be sent to the MRI-AC within 3 working days.
The approval of the dummy run is crucial for the site eligibility. Only sites with approved 
dummy run scan will be allowed to perform MRI scans in subjects participating in the study.
The MRI AC will evaluate the consistency and adequacy of the study scanning procedures.
Any deviation from the MRI protocol requirement has to be motivated and discussed with the 
MRI-AC.
Only three attempts of dummy run scan are allowed.
(For the detailed procedure of MRI dummy run please refer to MRI guideline)
Magnetic Resonance Spectroscopy
Month 0E (Baseline) – this is the Termination visit scan of the MS-LAQ-301 study and therefore 
should not be repeated.
This scan will be performed again at Month 24E and every 24 months thereafter, until 
Termination visit. The Termination scan should be performed within 4 days prior to the 
Termination visit's date.
In case clinical Termination visit is scheduled to less than 1 month after the performance of a 
scheduled MRS scan – the scan should not be repeated.
Each site should use the same scanner for each subject for the entire duration of the study.
The electronic data should be sent to the MRI-AC in 
 Italy that will conduct the data 
analysis for the MRS sub-study.
MRS Protocol
Proton MRS data must be obtained from a volume of interest (VOI) located in the central white 
matter (50mm left-right x 70mm anterior-posterior x 15mm cranio-caudal) using a 90˚-180˚-180˚ 
(PRESS) volume selective sequence. The VOI must be centered on the body of the corpus 
callosum using a long echo time (TR 2000, TE 272). The MRS voxel should be positioned 
cranio-caudally on the FSE/TSE so that the superior portion of the lateral ventricles are visible 
only in the most inferior 1 or 2 MRI slices that intersect the MRS voxel. The VOI should be 
centred left-right so that the brain mid-line is located in the centre of the VOI and should be 
positioned anterior-posterior so that the anterior corners and posterior corners are equidistant 
from the skull.
The analysis of each examination will be based on within subject differences of the value for the 
NAA/creatinine ratio.


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MR Images showing the MRS voxel placement superimposed on the intersecting MRI slices 
should be sent to the MRS-AC along with an image of the spectrum. These images may be 
provided as electronic picture files or as hardcopy. They will be used to verify correct 
positioning of the MRS voxel and to assess the quality of the spectrum (based on magnetic field 
homogeneity, signal to noise ratio, water suppression and freedom from other artifacts).
Dummy Run
In certain circumstances, this procedure may be requested by the MRI-AC in the MS-LAQ-301E 
study.
The same procedure as for the main protocol will be applied for centre certification.
Scanner change/upgrade
If the MR scanner is changed or upgraded in a way that will change the quantification of the 
MRS parameters over the course of the study, the MRI-AC and MRS-AC must be informed
Healthy Volunteers
To control for differences within and across sites, 3 healthy volunteers will be scanned at each 
site at each scheduled scan.
In case of scanner change/upgrade, the healthy volunteers must be rescanned before and after the 
scanner change/upgrade. This is to ensure that the upgrade did not result in a material change in 
the MRS sequences, or to allow correction for the change that occurred during the upgrade.
Electronic Data
The same procedures used for the main protocol should be used for the back-up and forwarding 
of MRS data. The raw, time-domain MRS data files should be exported in the appropriate 
scanner-specific data format and forwarded to the MRS-AC for central analysis
Analysis
The following analysis will be performed:
Change in NAA/creatinine resonance intensity ratio of the examined central brain region.


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MAGNETIZATION TRANSFER (MT) PROTOCOL
Proton density weighted gradient-echo MR imaging will be performed with and without an MT 
saturation pulse at the following visits:
Month 0E (Baseline). This is the Termination scan of the MS-LAQ-301 study and will be a part 
of the MS-LAQ-301E MT ancillary study protocol
Month 12E: +/- 4 days of month 12 visit and then every 12 months thereafter, until Termination 
visit. Each scan will need to be performed +/- 4 days from the relevant visit schedule. 
Termination scan will need to be performed 4 days prior to the scheduled date of the Termination 
visit.
In case the clinical Termination visit is scheduled to less than 1 month after the performance of a 
scheduled MT scan – the scan should not be repeated.
Each center should use the same scanner for each subject for the entire duration of the study.
The electronic data should be sent to the MRI Analysis Center (MRI-AC) in 
 Italy that will 
conduct the data analysis for the MT sub-study.
For this study the following MT parameters will be assessed:

Magnetization Transfer Ratio (MTR) of new MS lesions at study termination;

MTR changes of selected NAWM areas;

Average lesion MTR at entry, and at each scan thereafter

MTR histogram analysis at entry, and at each scan thereafter.
SCANNING REQUIREMENTS
Scanning requirements are the same as for the MRI protocol. However, only centers using 1.5 
Tesla scanners may participate in the MT protocol.


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MT DUMMY RUN PROCEDURE
In certain circumstances, this procedure may be requested by the MRI-AC.
The same procedure of the MRI protocol will be applied for center certification, taking in 
account of the following:
1. The MT dummy run has to be performed on an healthy subject
2. The MT dummy run sequences to be acquired are two:
a. Sequence 1: gradient-echo WITHOUT the MT pulse
b. Sequence 2: gradient-echo WITH the MT pulse.
ACQUISITION PARAMETERS:
The MT scans will be performed after the T2-weighted FSE/TSE scan, but before the 3D T1-
weighted scan and the injection of gadolinium contrast agent.
The slice positioning parameters (shift and rotation angle) of the MT series shall be the same as 
for the previous T2-weighted FSE/TSE scan (see MRI main protocol). Use the "history" or 
"repeat" function if your scanner has this facility to reproduce the same slice positions.
The MT scans will comprise a total of two image series. The first series shall be performed 
without the MT pulse, and the second series with the MT pulse.
MT Sequence: spoiled 2-dimensional gradient-echo
a.
Philps scanner
TR 
(ms)
TE 
(ms)
Excitation 
pulse flip 
angle
# of
slices
Slice 
thickness 
(mm)
Orientation
FOV 
(mm)
Matrix
Inter-
Slice
gap
# 
average
Phase 
encodin
g
1850-
2000
12-15 40 degrees
44, 
interleaved
3
axial
250 mm
256 x 
256
0
1
L>R
Do not use any presaturation slabs.
Do Not use Rectangular Field of View.
b.
Siemens, GE scanner
TR 
(ms)
TE 
(ms)
Excitation 
pulse flip 
angle
# of
slices
Slice 
thickness 
(mm)
Orientatio
n
FOV 
(mm)
Matrix
Inter-
Slice
gap
# 
average
Phase 
encodin
g
1400-
1500
12-15 40 
degrees
44, 
interleaved
3
axial
250 mm
256 x 
256
0
1
L>R


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Do not use any presaturation slabs.
Do Not use Rectangular Field of View.
For the second series, where an off-resonance MT pulse shall be applied, the MT pulse shall 
have the following characteristics:
MT pulse is applied once just before every excitation pulse. This is the standard way to apply 
MT for most scanners.
The characteristics of the MT saturation pulse shall be chosen according to the type of MRI 
scanner used
The characteristics of the MT saturation pulse shall be in concordance with the following 
guidelines (for any scanner type not listed below, please contact the MRI-AC for further 
guidance).
a.
Siemens Scanners (including Magnetom Vision, Symphony and Sonata):
Only one type of MT pulse is available. This is turned on and off using the check-box 
in the Protocol window. On the Symphony and Sonata, the check-box is in the 
"Contrast" tab.
c.
Philips scanners:
Choose the off-resonance MT saturation pulse option. This pulse has a Sinc-Gauss 
shape, an offset frequency of 1.1 kHz, a duration of 14.9 ms, and an effective flip 
angle of 620 degrees.
d. GE scanners:
Use an MT pulse flip angle of 500 degrees (variable mtflip=500), and offset 
frequency of 1200 Hz (MT freq=1200), and an MT pulse shape of "8ms Fermi pulse" 
(opuser12=1). Please consult with your local GE application specialist for further 
information about how to set up the MT protocol if necessary.
e.
Other scanner types:
Please consult with your local scanner manufacturer's representative and the MRI-AC 
in order to implement the MT protocol. The protocol you should aim for is:
Duration of MT pulse
Flip angle
Frequency offset
Close to 7.68 milliseconds
500 degrees
1500 Hz
It must be ensured that the scanner makes no adjustments to the transmitter power and receiver 
gain settings between the non-MT and with MT series.


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On Siemens Vision, Symphony and Avanto scanners, this requires no action on the part of the 
user.
On Philips machines, ensure that both series are performed as a "dynamic scan". On the 
"Contrast" page, choose the off-resonance MT saturation pulse option. On the "Dynamics" page, 
select 2 dynamics, and then select MT=on for the second dynamic only.
On General Electric machines (Signa and LX) perform an auto prescan for the first series as 
normal, then perform a manual prescan for subsequent series, accepting the settings without 
adjustment. Ask your local manufacturer representative for help with the procedure for MT 
scanning if these instructions are unclear.
In case machine constraints do not allow such image acquisition, the MRI-AC should be 
contacted and the image acquisition negotiated with it on a center-by-center basis.
HEALTHY VOLUNTEERS
To control for differences within and across sites, 3 healthy volunteers will be scanned at each 
site at each scheduled MT scan.
In healthy subjects, in addition to the MT sequences, a dual-echo sequence with the same 
parameters of the MRI protocol has to be acquired.
Any pathological findings will be reported by local radiologist to Treating Investigator 
according to local clinical practice.
ELECTRONIC DATA
The same procedures used for the MRI protocol should be used for the back-up and forwarding 
of MT data to the MRI-AC.
SCANNER CHANGE/UPGRADE
If the MR scanner is changed or upgraded in a way that will change the quantification of the 
MTR parameters over the course of the study, the MRI-AC must be informed and the healthy 
volunteers must be rescanned before and after the scanner change/upgrade, before subject 
scanning is resumed. This is to ensure that the upgrade did not result in a material change in the 
MT pulse sequence, or to allow correction for the change that occurred during the upgrade.


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


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


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


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


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


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2. In case Baseline value was above ULN and ALT or AST is ≥2 times the Baseline value.
Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the eCRF.
Additional Tests/Evaluations

Serology for Hepatitis A, B, and C viruses (central laboratory).

Serology for autoimmune hepatitis: anti-nuclear antibodies, ASMA, anti-LKM 
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.

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.


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


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2. Use of Moderate/Strong CYP3A4 Inhibitors
Laquinimod PK is affected by moderate and strong CYP3A4 inhibitors; therefore, 
moderate/strong CYP3A4 inhibitors are disallowed during study and 30 days after the last dose 
has been administered. A partial list of commonly used CYP3A4 inhibitors is presented in 
Appendix E.
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 levels. 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 child-bearing potential will be instructed about the teratogenicity and 
potential delayed risks for a child exposed in uterus to laquinimod. These subjects will also be 
counseled about the importance of using two acceptable methods of birth control throughout the 
entire treatment duration and until 30 days after the last dose of treatment was administered and 
about the need to stop treatment immediately if pregnancy is suspected.


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


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c.
A mandatory phone call will be performed by the Study Neurologist/ Physician or by 
the site’s nurse/ study coordinator every month in order to verify whether the test has 
been performed and to record the result of the test in the subject’s file. In case of a 
suspected pregnancy, the subject will be instructed to stop taking the study drug and 
arrive to the site as soon as possible for an unscheduled visit, with the remaining 
study medications. In the site, a quantitative urine β-hCG pregnancy test should be 
performed and the rest of the activities will be as in 2.
In case of an established diagnosis of pregnancy, the Study Physician/Neurologist should discuss 
with the subject the potential teratogenicity and delayed risks for a child exposed in utero to 
laquinimod. The possibility of termination of the pregnancy should be discussed. In case the 
subject decides to continue the pregnancy, she will be followed to determine outcome, including
spontaneous or elective termination, details of birth, and presence or absence of any birth defect, 
congenital abnormalities or maternal and newborn complications.
Female subjects of child-bearing potential who might want to get pregnant in the future, and 
might be interested in continuing taking laquinimod after giving birth and have stopped 
breastfeeding may be able to re-enroll in the study after meeting inclusion/exclusion criteria 
below. Re-enrollment will be permitted on a case-by-case basis. Notwithstanding, Teva is under 
no obligation to re-enroll such subjects and reserves the right to re-enroll or reject enrolment of 
such returning subjects for no reason and on its sole discretion. A new informed consent form 
should be signed before re-enrollment.
Inclusion criteria for returning subjects
Subjects must meet all inclusion criteria in order to be eligible for the study:
1. Subjects must have completed the Termination visit of MS-LAQ-301E (completion of all 
Termination visit activities) according to the MS-LAQ-301E 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 [IV, intramuscular (IM) and/or per os (PO)] or 
adrenocorticotrophic hormone (ACTH), 60 days prior to re-enrollment.
4. Women of child-bearing potential (for example women who are not postmenopausal or 
surgically sterilized) must practice an acceptable method of birth control for 30 days 
before taking the study drug and two acceptable methods of birth control for the duration 
of the study and until 30 days after the last dose of study medication. Acceptable methods 
of birth control include: intrauterine devices, barrier 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.


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6. Subjects must be able to comprehend, sign and date a written informed consent prior to
re-enrolling into the MS-LAQ-301E study.
Exclusion criteria for returning subjects
Any of the following conditions will exclude the subject from re-enrolling into the study:
1. Premature discontinuation from the MS-LAQ-301 study, for any other reason than 
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®), Interferon-β (either 1a or 1b),
fingolimod (Gilenya®), dimethyl fumarate (Tecfidera) or IV Ig (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.


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16. Pregnancy [according to serum β-hCG performed within 7 days prior to re-initiation of 
treatment] or breastfeeding.
17. Serum levels ≥3xULN of either ALT or AST at re-enrollment visit.
18. Serum direct bilirubin which is ≥2xULN at re-enrollment visit.
19. Subjects with clinically significant or unstable medical or surgical condition detected or 
worsened during the MS-LAQ-301 or MS-LAQ-301E study, which preclude safe 
participation and completion of the MS-LAQ-301E study.
20. Any malignancies, excluding basal cell carcinoma, in the 5 years prior to re-enrollment.
21. Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous 
Insufficiency (CCSVI) within 3 months prior to re-enrollment.


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Table 10:
Study Task Flow Chart for Returning Subjects after Planned Pregnancy
Visit
V0E1
V1E1
V2E1
V3E1
V41
Every 6 
months
Every 12 
months
Every 24 
months
Termination/
Early 
Discontinuation
Un-
scheduled 
Visita, b
Month
0E1
1E1
2E1
3E1
6E1
Informed Consent for returning females
X
Eligibility Criteria for returning females
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Cardiovascular risk factor assessment and management
c
X
X
Physical Examination
X
X
X
X
X
X
Vital Signs
Xd
X
X
X
X
X
Xe
Xe
Xe
X
ECG
X
X
X
X
X
X
X
Safety Laboratory Evaluation (CBC, Chemistry, 
markers of inflammation, GFR estimation)
X
X
X
X
X
X
X
X
X
X
Serum β-hCGf
X
X
X
X
X
X
X
X
X
X
Urine β-hCGf (on site)
X
X
X
X
X
X
X
X
X
X
Ascertaining use of effective contraception
X
X
X
X
X
X
X
X
X
X
Discuss the importance of Contraceptionf
X
X
X
X
X
X
X
X
X
X
Urine β-hCGf (self check, at home)
EVERY 1 MONTH BETWEEN 
SCHEDULED VISITS
AE
X
X
X
X
X
X
X
X
X
X
Neurological examination (EDSS/FS/AI/ 25 foot walk)
X
X
X
X
X
X
X
Evaluation of Relapseg
X
X
X
X
X
X
X
X
X
X
MSFCh
X
X
X
X
X
X
Binocular Low-Contrast Visual Acuity
X
X
X
X
X
X
MFIS
X
X
X
X
X
X
Mandatory phone calls (pregnancy tests)i
EVERY 1 MONTH BETWEEN
SCHEDULED VISITS
Mandatory phone calls (general well-being, all 
subjects)j
EVERY 3 MONTHS 
BETWEEN SCHEDULED VISITS
Drug Compliance & Dispensing
X
X
X
X
X
X
X
X
Xk
X


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Visit
V0E1
V1E1
V2E1
V3E1
V41
Every 6 
months
Every 12 
months
Every 24 
months
Termination/
Early 
Discontinuation
Un-
scheduled 
Visita, b
Month
0E1
1E1
2E1
3E1
6E1
Termination Documentation and Notification of Early 
Termination
X
Unscheduled Samples
Xl
a Vital signs and AEs are mandatory activities in an unscheduled visit. All other activities are optional and may be performed as deemed necessary by the 
investigator. Chest X-ray may also be performed in this visit.
AE = Adverse Event, AI = Ambulation Index, β-hCG = beta-human Chorionic Gonadotropin, CBC = Complete Blood Count, ECG = Electrocardiogram, EDSS 
= Kurtzkle’s Expanded Disability Status Scale, FS = Functional System, GFR = glomerular filtration rate, MFIS = Modified Fatigue Impact Scale, MSFC = 
Multiple Sclerosis Functional Composite
b Post treatment follow up visit in cases of early discontinuation (In which vital signs, review of AEs and concomitant medications, as well as pregnancy test are 
mandatory. All other marked activities are optional).
c In addition, an evaluation should take place as soon as possible for subjects already in the study, following approval of Amendment #3
d Post-dose vital signs will be measured at Baseline and after 30 and 60 minutes, whereas the pre-dose vital signs will be taken from the last measurement in the 
MS-LAQ-301 study.
e Weight will be measured at every visit until Termination/Early discontinuation.
f For women of childbearing potential. Serum pregnancy test (β-hCG) for women of child-bearing potential within the 7 days prior to re-initiation of treatment
g Relapse evaluation will be performed in scheduled as well as unscheduled visits as deemed necessary by the Investigator/Coordinator
h The PASAT and 9-HPT will be performed at Months 0E [Baseline (Termination visit of the MS-LAQ-301 study)], 6E and every 6 months (every scheduled 
visit) thereafter, until Termination/early discontinuation visit. The Timed 25 Foot walk test will be performed each time neurological evaluation is performed.
i For women of child-bearing potential; to be performed within 72 hours of the scheduled home pregnancy test
j The call will be documented in the source documents. For women of child-bearing potential, there is no need to perform a separate call, as this question will be 
a part of the monthly pregnancy urine test call.
k Only drug retrieval
l Unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or samples for potential biomarker analyses may be collected at the 
discretion of the investigator or medical monitor at any time to assist with further investigations of cardiovascular events or other clinical event of interest. The 
samples should be collected as soon as possible in association with the event.
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]).


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APPENDIX H. MODIFIED FATIGUE IMPACT SCALE (MFIS)
INSTRUCTIONS
Following is a list of statements that describe how fatigue may affect a person. Fatigue is a 
feeling of physical tiredness and lack of energy that many people experience from time to time. 
In medical conditions like MS, feelings of fatigue can occur more often and have a greater 
impact than usual. Please read each statement carefully, and then circle the one number (0, 1, 
2,…) that best indicates how often fatigue has affected you in this way during the past 4 weeks. 
Please answer every question. If you are not sure which answer to select, please choose the one 
answer that comes closest to describing you.
Because of my fatigue
during the past 4 weeks…
Almost
Never   Rarely   Sometimes Often    Always
1.
I have been less alert.
0
   1
         2
   3
       4
2.
I have had difficulty 
paying attention for 
long periods of time.
0
   1
         2
   3
       4
3.
I have been unable to 
think clearly 
0
   1
         2
   3
       4
4.
I have been clumsy 
and uncoordinated 
0
   1
         2
   3
       4
5.
I have been forgetful 
0
   1
         2
   3
       4
6.
I have had to pace myself 
in my physical activities 
0
   1
         2
   3
       4
Because of my fatigue
during the past 4 weeks…
Almost
Never Rarely   Sometimes 
Often    Always
7.
I have been less motivated
to do anything that requires
physical effort
0
   1
         2
   3
       4
8.
I have been less motivated
to participate in social 
activities.
0
   1
         2
   3
       4


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9.
I have been limited in my 
ability to do things away
from home. 
0
   1
         2
   3
       4
10.
I have had trouble 
maintaining physical effort
for long periods. 
0
   1
         2
   3
       4
11.
I have had difficulty 
making decisions
0
   1
         2
   3
       4
12.
I have been less motivated
to do anything that requires
physical effort
0
   1
         2
   3
       4
13.
my muscles have felt weak
0
   1
         2
   3
       4
14.
I have been physically 
uncomfortable 
0
   1
         2
   3
       4
15.
I have had trouble finishing
tasks that require thinking
0
   1
         2
   3
       4
Because of my fatigue
during the past 4 weeks…
Almost
Never Rarely   Sometimes 
Often    Always
16.
I have had difficulty 
organizing my thoughts
when doing things at home
or at work
0
   1
         2
   3
       4
17.
I have been less able to 
complete tasks that require
physical effort. 
0
   1
         2
   3
       4
18.
My thinking has been 
slowed down
0
   1
         2
   3
       4
19.
I have had trouble
concentrating
0
   1
         2
   3
       4
20.
I have limited my
physical activities.
0
   1
         2
   3
       4
21.
I have needed to rest more
often or for longer periods.
0
   1
         2
   3
       4


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APPENDIX I.
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 > (greater than or equal to) 
.05, round down if hundredth's place is <.05 (e.g., 32.45" would round to 32.5" but 32.44" would 
round to 32.4"). Once the time is recorded, be sure to reset the stopwatch.
Trial 2
After completing the first timed walk, position the subject just behind the line where s/he is not 
standing, repeat the same instructions, and have the subject complete the walk again.
Assistive Devices
The goal is to have the subject use the same assistive device at each study visit. The treating 
neurologist will select an assistive device at the beginning of the study for each subject that 
needs one, keeping in mind that the subject may deteriorate modestly during the trial.
In general, subjects should use their customary assistive device(s), NOT the least assistance 
possible to complete the test. For subjects with significant gait impairment, the Study
Neurologist/Physician should have the subject use a rolling walker even if this is not the subject's 
customary device. In general, non-wheeled walkers should not be used. If a subject does use an 
assistive device, this should be noted on the Record Form.
Completing the Record Form
Record any circumstances that you believe may have affected the subject's performance. These 
are factors that may have affected the trial but were not severe enough to necessitate repetition of 
the trial. Examples include, but are not limited to, the following:
The subject had a cold or reports not feeling well.
The subject tripped but did not fall.


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


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


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


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


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Once it is clear that the subject possesses sufficient understanding of the task, begin Part 1. 
Before starting Part 1, remind him/her: "Remember if you get lost, just jump back in because I 
can't stop the test once it has begun." Discourage talking and oral calculations during the test, 
only the subject's answers should be spoken out loud. The subject may need prompting to 
continue the test if she/he gets lost. After five consecutive 'no responses,' redirect the subject 
quickly by saying, "Jump back in," but do not stop the tape.
Completing the PASAT Record Form
Circle all correct answers. Write in any incorrect responses in the space provided. Place a dash 
when no response was given. If the subject corrects him/herself after giving a response, count the 
amended answer as the response. The amended response is the one that will be used in 
determining total correct, regardless of whether it was the correct or incorrect response. Slash 
through the old response and write in "SC" with a circle around it to indicate that the subject 
self-corrected.
Each section of the PASAT has a maximum of 60 correct answers (i.e., 61 digits are presented 
for each part). Count the total number correct (number of circled answers) for PASAT-3 and 
record on both the PASAT Record Form and the Summary Score Sheet.
Finally record any circumstances that you believe may have affected the subject's performance. 
These are factors that may have affected the trial, but were not severe enough to necessitate 
repetition of the trial. Examples include, but are not limited to, the following:
Subtle noises outside of the testing room
Subject reports frustration or mild distress
Subject talked during test (other than to give answers)
If a trial must be repeated, indicate this and specify the reason why it had to be repeated. 
Examples of reasons to repeat a trial include, but are not limited to, the following:
Test interrupted (e.g. someone walked into the room or other major disturbance)
Examiner error, such as starting the tape in the wrong place or using the wrong form.
Record only totals for the successfully completed PASAT-3.
If the subject is unable to perform the PASAT (i.e., cannot get at least two correct on any 3" 
practice and at least one correct on the test portion), the examiner should indicate "Unable to 
complete due to cognitive limitations" and record any specific observations. If the subject did not 
complete a trial for any other reason, record the reasons for this as well (e.g., subject refused to 
complete test, etc.).
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 J.
LOW-CONTRAST SLOAN LETTER CHART TESTING 
FOR PATIENTS WITH MULTIPLE SCLEROSIS
Low-Contrast Sloan Letter Chart Testing
For Patients with Multiple Sclerosis:
Testing Protocol Manual
(BINOCULAR TESTING)
Laura J. Balcer, M.D., M.S.C.E.
University of Pennsylvania
The following are instructions for testing patients using the front illuminated Low-Contrast 
Sloan Letter Charts (LCSLC - Precision Vision, LaSalle, IL). The inter-rater reliability of this 
testing protocol has been shown to be extremely high in patients with multiple sclerosis and in 
visually-asymptomatic volunteers. A standardized script with instructions to be read to the 
patient by the examiner is included below. The examiner should read through the following 
instructions and practice testing prior to examining study patients.
Preparation and Set-Up:
1. Set room lighting level to 80-100 cd/m2 (equivalent is about 80-100 foot-candles). This 
level illumination may be achieved in a bright exam room/hallway with fluorescent 
lighting. Having exact lighting is less important than using the same room/area for each 
patient/testing session.
2. Place the charts at 2 meters distance from the patient’s eyes. An artist’s easel or similar 
device may be used, as may a ledge, stand, or chair to prop the charts perpendicular to the 
floor. Use a pre-measured string or tape to measure the distance from the patient’s eyes 
(bridge of nose) to the testing charts at the beginning of each testing session (each 
patient).
3. The 100%, 2.5%, and 1.25% charts will be used for testing.
4. Patients should wear their usual distance correction for testing (glasses or contact lenses 
that are used for driving, etc.). The same glasses or contact lenses (same prescription) 
should be used for each testing session throughout the study.
5. Patients should be asked to read the charts with both eyes open.
Vision Testing:
1. Instruct patient to read slowly, letters only, left to right, starting at the top of the chart.
2. Instruct the patient that they are not allowed to re-read any line.


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3. The patient is allowed to correct a “mis-speak” of a single letter only if he/she does so 
before reading the next letter---instruct the patient of this.
4. During the chart reading, PUSH (encourage) the patient until he/she cannot read any 
letters after being told to guess.
5. The patient must guess at each letter, even if he/she cannot easily read it, until he/she 
cannot or does not correctly identify any of the 5 letters on a particular line.
6. Stopping Rule: Once the patient cannot or does not correctly identify any of the 5 letters 
on a line after attempting it, STOP. Go on to the next chart.
7. Test all 3 charts in the same order (100%, 2.5%, 1.25%) for each patient.
8. During testing, circle all letters read correctly on the data forms for each chart (with both 
eyes). Put an “X” through each incorrectly identified letter; leave unattempted letters 
unmarked.
9. Fill in the number of letters correct at the end of each line of 5 letters. Record the total 
number of letters correct for each chart at the bottom of the column. The Snellen visual 
acuity equivalent (i.e., 20/20 or 6/6) for the patient corresponds to the lowest line on the 
100% chart (black on white) for which the patient identifies 3 or more letters correctly.
10. If a patient is unable to identify any of the letters correctly on the first line of any of the 3 
charts, please indicate this at the top of the data collection form.
Script for Testing to be Read to Patient:
These instructions should be read to the patient once he/she is comfortably seated in front of the 
charts at 2 meters distance (see above for instructions on Preparation and Set-Up):
1. I am going to show you 3 different eye charts with letters on them. The letters will 
become increasingly lighter for each chart.
2. For each chart, please begin at the very top of the chart and read each letter slowly, from 
left to right on each line.
3. If you miss-speak on a letter or feel you have identified it incorrectly, you may correct 
your response only before you read the next letter.
4. You are not allowed to re-read an entire line.
5. Please try not to lean forward in the chair while reading the letters.
After the first chart (100% chart) has been uncovered, say:


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1. You may begin reading the letters.
2. Please start at the top of the chart.
For each chart, allow the patient to continue reading letters until he/she either:
1. Does not identify any of the 5 letters on any given line correctly say:
You may stop. We will go on to the next chart now.
OR
2. States that they are unable to read any more letters point to the line which is next for 
the patient to attempt (use the yellow-tipped pointer only) and say:
Can you read any of the letters on this line?
a) If patient responds no say: Please guess if you can.
If patient responds that they cannot say:
You may stop. We will go on to the next chart now.
b) If patient responds yes or begins reading, then continue to record responses until 
the patient cannot or does not correctly identify any of the 5 letters on a given line.
Stopping Rule: For each chart, once the patient cannot or does not identify any of the 5 letters 
correctly on a given line, say: You may stop. We will go on to the next chart now.
Please use the yellow-tipped pointer only to point to the charts (pens and fingers may leave 
marks). The examiner may point to the chart when requested by the patient to indicate the line 
that they are attempting/should attempt next.
Repeat the above procedure for each of the 3 charts (100%, 2.5%, and 1.25% in that order) with 
both eyes open.


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


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