A Multinational, Multicenter, Randomized, Double Blind, Parallel Group, Placebo Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients With Primary Progressive Multiple Sclerosis (PPMS)
Phase: PHASE2
Conditions: Primary Progressive Multiple Sclerosis
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Clinical Study Protocol with Global Amendment 02
A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of
Once Daily Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients
with Primary Progressive Multiple Sclerosis (PPMS)
Study TV5600-CNS-20006
(ARPEGGIO - A Randomized Placebo-controlled trial
Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes)
NCT02284568 
Protocol Amendment 02 Approval Date: 01 February 2016

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
1
 
Clinical Study Protocol with Global Amendment 02
A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily 
Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients with Primary Progressive 
Multiple Sclerosis (PPMS)
Phase 2
Study TV5600-CNS-20006 (ARPEGGIO - A Randomized Placebo-controlled trial 
Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes)
IND number: 71,287
EudraCT number: 2014-001579-30
Protocol Amendment 02 Approval Date: 01 February 2016
Sponsor 
Monitor
Teva Pharmaceutical Industries Ltd.
PPD Development, LP
5 Basel
Petach Tikva, Israel
929 North Front Street
Wilmington, North Carolina 28401, US
Authorized Representative (Signatory)
Sponsor Teva Pharmaceutical Industries Ltd.
Sponsor’s Medical Expert
Sponsor’s Safety Officer
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceutical Industries, Ltd.
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Conference on Harmonization (ICH); United States (US) Code of 
Federal Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the 
study); local country regulations; and the sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Pharmaceutical 
Industries Ltd., and/or its affiliate. The recipient agrees that no information contained herein may be 
published or disclosed without written approval from the Sponsor.
© 2016 Teva Pharmaceutical Industries, Ltd. All rights reserved.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
2
AMENDMENT HISTORY
The protocol for study TV5600-CNS-20006 (ARPEGGIO) (original protocol dated 
21 July 2014) has been amended and reissued as follows:
Global Amendment 02
01 February 2016
301 patients enrolled to date
Global Amendment 01
01 July 2015
49 patients enrolled to date
Details about the changes and rationale for each change are provided in Section 17.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
3
INVESTIGATOR AGREEMENT

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
4
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Clinical Research Organization (CRO)
PPD Development, LP
929 North Front Street
Wilmington, North Carolina 28401
United States
Central Magnetic Resonance Imaging (MRI)
 
VU University Medical Center Amsterdam
De Boelelaan 1118
1081 HV Amsterdam
The Netherlands
Central Optical Coherence Tomography (OCT)
Heinrich Heine University
Moorenstr. 5 40225, Duesseldorf
Germany 
Other Vendors
This study employs the services of multiple third-party vendors (central clinical laboratory, 
bioanalytical laboratory, pharmacogenomics laboratory, electronic data capture, etc). The names 
and addresses of the vendors are provided in the Study Laboratory Manual and/or manuals from 
the various vendors. These manuals will be in the Trial Master File.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
5
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the study Medical Monitor listed below: 
North America
EMEA/APAC
For operational issues, contact the operational lead listed below: 
Teva Pharmaceuticals Industries, Ltd
12 Hatrufa St., Sapir Industrial Zone
Netanya 42504, Israel
For serious adverse events:
Send by e-mail/facsimile to local safety officer/contract research organization (LSO/CRO). 
E-mail address and fax number will be provided in the serious adverse event case report form 
(CRF). In the event of difficulty transmitting the form, contact the sponsor’s study personnel 
identified above for further instruction.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
6
CLINICAL STUDY PROTOCOL SYNOPSIS
Sponsor: Teva Pharmaceutical Industries Ltd
Title of Study: A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled 
Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily Oral Administration of Laquinimod (0.6 or 
1.5 mg) in Patients with Primary Progressive Multiple Sclerosis (PPMS)
Study Number: TV5600-CNS-20006 (ARPEGGIO - A Randomized Placebo-controlled trial Evaluating 
laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes)
EudraCT/IND Number(s): EudraCT Number 2014-001579-30; IND 71,287
Name of Active Ingredient: sodium 5-chloro-3-(ethyl(phenyl)carbamoyl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-
olate
Name of Investigational Product: Laquinimod
Phase of Clinical Development: 2
Number of Investigational Centers Planned: Approximately 120
Countries Planned: Approximately 10
Number of Patients Planned: Approximately 375
Study Population: Patients with Primary Progressive Multiple Sclerosis (PPMS)
Planned Study Period: Q4 2014 to Q3 2017
Objectives: The objectives of this study are to assess the efficacy, safety, and tolerability of a once daily oral dose 
of laquinimod (0.6 or 1.5 mg) compared to placebo in PPMS patients.
Diagnosis and Criteria for Inclusion: Patients may be included in the study only if they meet all of the following 
criteria: 
1.
Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised 
McDonald criteria.a
2.
Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain 
and spinal cord.
3.
Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both 
screening and baseline visits.b
4.
Documented evidence of clinical disability progression in the 2 years prior to screening.
5.
Functional System Score (FSS) of 2 for the pyramidal system or gait impairment due to lower extremity 
dysfunction.
6.
Patients must be between 25 to 55 years of age, inclusive.
7.
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 
2 acceptable methods of birth control during all study duration and until 30 days after the last dose of 
treatment is administered. Acceptable methods of birth control in this study include: intrauterine devices, 
barrier methods (condom or diaphragm with spermicide), and hormonal methods of birth control (eg, oral 
contraceptive, contraceptive patch, long-acting injectable contraceptive). 
8.
Patients must sign and date a written informed consent prior to entering the study.
9.
Patients must be willing and able to comply with the protocol requirements for the duration of the study.
                                                
a Polman CH, Reingold SC, Banwell B., et al. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the 
“McDonald Criteria” Ann Neurol 2011; 69:292-302.
b A capped randomization procedure will be employed to ensure that the number of EDSS 6.0 and 6.5 patients will 
be no more than 20% of all enrolled patients.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
7
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet any of the following 
criteria:
1.
Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of 
optic neuritis.
2.
Progressive neurological disorder other than PPMS.
3.
Any MRI record showing presence of cervical cord compression.
4.
Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the 
clinical signs and symptoms.
5.
Relevant history of vitamin B12 deficiency.
6.
Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
7.
Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a 
currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, 
provided no other exclusion criteria are met.
8.
Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine 
within 48 weeks prior to baseline.
9.
Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen 
Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous 
immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with 
either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
11. Prior use of monoclonal antibodies ever, except for:
a.
natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the 
patient is John Cunningham (JC) virus antibody test negative (as per medical history)
b.
rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 
80 cells/µL
12. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone 
>5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the 
total lifetime maximal dose.
13. Previous use of laquinimod.
14. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) 
systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
16. Previous total body irradiation or total lymphoid irradiation.
17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
18. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) 
within 12 weeks prior to baseline.
19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
20. Use of inducers of CYP3A4 within 2 weeks prior to baseline. 
21. Pregnancy or breastfeeding.
22. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) at screening.
23. Serum direct bilirubin which is ≥2×ULN at screening.
24. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the 
Investigator) would preclude safe and complete study participation, as determined by medical history, 
physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray. Such conditions may 
include:
a.
A major cardiovascular event (eg, myocardial infarction, acute coronary syndrome, decompensated 
congestive heart failure, pulmonary embolism, coronary revascularization) that occurred during the 
past 24 weeks prior to baseline.
b.
Any acute pulmonary disorder.
c.
A central nervous system (CNS) disorder other than MS that may jeopardize the patient’s participation 
in the study, including such disorders that are demonstrated on the baseline MRI.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
8
d.
A gastrointestinal disorder that may affect the absorption of study medication.
e.
Renal disease.
f.
Any form of acute or chronic liver disease.
g.
Known human immunodeficiency virus positive status.
h.
A history of drug and/or alcohol abuse.
i.
Unstable psychiatric disorder.
j.
Any malignancies, excluding basal cell carcinoma, in the 5 years prior to baseline.
25. A known history of hypersensitivity to gadolinium (Gd).
26. Glomerular filtration rate (GFR) 60 mL/min/1.73 m2 at screening visit.
27. Inability to successfully undergo MRI scanning, including claustrophobia.
28. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to 
mannitol, meglumine or sodium stearyl fumarate.
Special cases may need a central review by an eligibility evaluation committee prior to baseline.
Study Drug Dose, Mode of Administration, and Administration Rate:

0.6 mg arm: 1 capsule containing 0.6 mg laquinimod and the other 2 containing placebo, to be 
administered orally once daily.

1.5 mg arm: 3 capsules containing 0.5 mg laquinimod to be administered orally once daily (Note: this 
arm was discontinued as of 01 January 2016).

Placebo arm: 3 capsules containing placebo to be administered orally once daily.
Duration of Participation: The study will include screening up to 6 weeks and 2 parts: Part A (core study) and 
Part B (data analysis).
Part A will last at least 48 weeks, and individual patients will experience variable treatment durations, depending on 
the order of enrollment. 
Once the last ongoing patient completes the week 48 visit, the sponsor will declare end of Part A and begin 
performing study analyses.
In Part B, patients will continue their randomly-assigned blinded treatments with visits every 12 weeks until the 
completion visit. After up to approximately 24 weeks of Part B, or once data analysis has been completed and the 
design of a potential extension study has been finalized (including blinded or open-label treatment allocation), 
patients will be invited to the clinic for the completion visit and will be offered the opportunity to continue into an 
extension study.
General Design and Methodology: This is a multinational, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study, to evaluate the efficacy, safety, and tolerability of daily oral administration of laquinimod 
(0.6 or 1.5 mg) in PPMS patients.
Prior to 01 January 2016, eligible patients were randomized in a 1:1:1 ratio into one of the following treatment arms:

Laquinimod 0.6 mg daily

Laquinimod 1.5 mg daily

Daily placebo
As of 01 January 2016, following a decision to discontinue the laquinimod 1.5 mg dose arm, additional eligible 
patients who are enrolled will be randomized in a 1:1 ratio into one of the following treatment arms:

Laquinimod 0.6 mg daily

Daily placebo
A capped randomization procedure will be employed to ensure that the number of EDSS 6.0 and 6.5 patients will be 
no more than 20% of all enrolled patients.
Patients will have the following study visits: screening visit (-6 weeks), baseline visit (week 0), weeks 4, 8, 12, 24, 
36, 48, and every 12 weeks until study completion or early termination (ET).
The following assessments will be performed at the specified time points:

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
9

Vital signs (temperature, pulse, blood pressure) and weight at all visits.

Physical examination at all visits until study completion/ET, if applicable.

ECG at screening, week 0 (3 recordings, 10 minutes apart), weeks 4, 8, 12, 24, and every 24 weeks 
thereafter until completion/ET, if applicable.

Chest X-ray at screening (can be omitted if the report of a chest X-ray performed within 24 weeks of 
screening is obtained, or if a screening chest X-ray is considered unacceptable per local regulations).

Review concomitant medications at all visits.

Record adverse events at all visits.

Cardiovascular risk assessment and management at screening, week 96, week 144, and as soon as 
possible for patients already in the study, following approval of Global Amendment 2.

Safety laboratory tests:

Serum chemistry (including electrolytes, fibrinogen, glucose, urea, creatinine, ALT, AST, 
gamma-glutamyl transpeptidase [GGT], alkaline phosphatase, creatine phosphokinase [CPK], 
C-reactive protein [CRP], pancreatic amylase, total protein, albumin, direct and total bilirubin) at 
all visits.

Estimation of GFR at all visits

Fasting lipid profile at weeks 0 and 48 and every 48 weeks until completion/ET, if applicable.

Serum thyroid stimulating hormone (TSH), triiodothyronine (T3), and free thyroxine (T4) at 
weeks 0 and 24 and every 24 weeks until completion/ET, if applicable.
-
Coagulation profile (prothrombin time [PT], activated partial thromboplastin time [aPTT] and 
international normalized ratio [INR]), to be tested only if required according to Guidance on 
Safety Monitoring).

HTLV-I/II at screening.

Complete blood count (CBC) with differential at all visits.

B12 at screening

Anemia panel (blood smear, serum iron, ferritin, total iron binding capacity, folic acid, 
haptoglobin, interleukin [IL]-1, IL-6, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and 
hepcidin) at baseline.

In case of hemoglobin decrease of >1 g/dL from the patient’s hemoglobin level at baseline:
-
patient will be re-tested to confirm decrease
-
if decrease confirmed, a thorough anemia work-up will be done including:

directed medical history and physical examination

anemia panel (blood smear, serum iron, ferritin, total iron binding capacity, 
folic acid, haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, and hepcidin) and B12

additional investigations and follow-up per the investigator’s discretion or 
sponsor’s request

Urinalysis at screening.

Serum pregnancy test (beta human chorionic gonadotropin [β-hCG]) for women of child-bearing 
potential within 7 days prior to randomization and at all visits.

Urine pregnancy test (β-hCG) for women of child-bearing potential at all visits. In case of positive 
result, study drug should not be dispensed, until results of serum β-hCG test are available. The rest
of the visit activities should be performed.

Starting from week 12 visit, between study visits, women of child-bearing potential will be 
provided with home pregnancy urine β-hCG test kits and will be instructed how to perform the 
test. The site staff will schedule the home test to be performed every 28 ±2 days. To verify 
whether the test has been performed and to record the result of the test, a mandatory phone call 
will be performed by the Treating Neurologist or by the site’s nurse/study coordinator within 
72 hours after the test was scheduled to be performed and the patient will be asked specific 
questions regarding the test. In case of a suspected pregnancy (positive urine β-hCG test result, 
delay of menstruation or any other reason suggesting pregnancy), the caller will ensure that the 
study drug has been stopped and the patient will be instructed to arrive to the study site as soon as 
possible (within 10 days) for further evaluations with the remaining study medications.

Blood samples for evaluation of potential biomarkers will be collected at weeks 0, 24, and 48.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
10

Pharmacokinetic study: blood samples for analysis of laquinimod plasma concentrations will be 
collected at weeks 4, 8, 12, 24 and 48.

A pharmacogenomic sample will be collected at baseline (week 0) as permitted by local regulations; if 
the sample is not obtained at baseline for any reason, it should be collected at the next possible visit.

All patients will undergo brain and cervical spinal cord MRI scans at week 0 (without and with Gd), 
week 24 (without Gd), and week 48 (without Gd). ET visit will include MRI for patients who 
prematurely terminate treatment subsequent to the week 36 visit and prior to week 48.

EDSS and FSS will be performed at screening, week 0, and every 12 weeks until completion/ET, if 
applicable.

Timed 25-foot walk (T25FW), 9-Hole Peg test (9HPT), and symbol digit modalities test (SDMT) will 
be performed at week 0, and every 12 weeks until completion/ET, if applicable. At weeks 0, 48, and 
every 48 weeks thereafter, SDMT will be performed as part of the Brief International Cognitive 
Assessment for Multiple Sclerosis (BICAMS) assessment.

BICAMS, including SDMT, will be evaluated at weeks 0, 48, and every 48 weeks thereafter.

Low contrast visual acuity (LCVA) will be assessed at weeks 0 and 24 and every 24 weeks until 
completion/ET, if applicable.

Walking ability will be assessed by the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) at 
weeks 0 and 12 and every 12 weeks until completion/ET.

Ancillary studies:

Cerebrospinal fluid (CSF) (to be performed in selected sites) will be collected from all patients 
who signed an appropriate, Ethic Committee (EC) approved informed consent form, at week 48.

Optical coherence tomography (OCT) evaluation (to be performed in selected sites) will be 
performed in all patients who signed an appropriate, EC approved informed consent form, at 
weeks 0, 48, and 96 to assess retinal thickness.
Primary Efficacy Endpoint: 
Brain atrophy (BA), as defined by Percentage in Brain Volume Change (PBVC) from baseline to week 48.
Secondary Efficacy Endpoints:

Time to confirmed disability progression (CDP), defined as increase in EDSS of 1 point from 
baseline EDSS if EDSS at entry is ≤5.0, or increase of 0.5 points if EDSS at entry is 5.5. This 
increase should be confirmed after at least 12 weeks. Progression cannot be confirmed during a 
relapse, although relapses are rare in PPMS. 

Time to CDP as measured by 2 types of events for each individual (progression cannot be confirmed 
during a relapse):

An increase from baseline in EDSS score (≥1 point from baseline EDSS if EDSS at entry is ≤5.0, 
or increase of ≥0.5 point if EDSS at entry is ≥5.5), confirmed after at least 12 weeks, or

An increase of at least 20% from baseline in T25FW score, confirmed after at least 12 weeks.

Change from baseline to week 48 in the T25FW score.

The number of new T2 brain lesions at week 48.
Exploratory Endpoints:

Change from baseline to week 48 in the BICAMS score (California Verbal Learning Test–II 
[CVLT-II], Brief Visuospatial Memory Test – Revised [BVMT-R], and SDMT).

Time to CDP as measured by at least 1 of 4 types of events for each individual (progression cannot be 
confirmed during a relapse):

An increase from baseline in EDSS score (≥1 point from baseline EDSS if EDSS at entry is ≤5.0, 
or increase of ≥0.5 point if EDSS at entry is ≥5.5), confirmed after at least 12 weeks or

An increase of at least 20% from baseline in T25FW score, confirmed after at least 12 weeks or

An increase of at least 30% from baseline in the 9HPT score, confirmed after at least 12 weeks or

A decrease of at least 20% from baseline in the SDMT score, confirmed after at least 12 weeks.

Time to CDP confirmed after at least 24 weeks.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
11

New T1-hypointense lesions, changes in T1-hypointense lesion volume, and changes in T2 lesion 
volume.

Other MRI parameters, including thalamic, cortical, white matter, and cervical cord atrophy, number of 
cervical cord T2 lesions, and normal-appearing brain tissue average magnetization transfer ratio 
(MTR).

Modified Rankin scale (mRS) (at week 72, visit 8).

T25FW.

9HPT.

LCVA.

MSWS-12.
Other Endpoints:

relapses

pharmacokinetic measures (determination of plasma concentration of laquinimod)

pharmacogenomic measures

potential biomarker measures

ancillary studies measures
Safety Endpoints:

Safety:

adverse events

vital signs

ECG findings

clinical laboratory parameters

concomitant medication usage

Tolerability:

proportion of patients (%) who prematurely discontinue treatment, reasons for discontinuation,
and time to ET

proportion of patients (%) who prematurely discontinue treatment due to adverse events and time 
to ET due to adverse events
Statistical Considerations:
Sample size calculations were based on the following assumptions:

2-sided alpha level of 5%

treatment difference (delta) of 0.3 in PBVC

standard deviation of 0.8
Under the above assumptions 252 patients enrolled for 0.6 mg and placebo (126 per arm) will provide 84% power to 
detect a statistically significant result for the 0.6 mg laquinimod arm comparison to placebo. To adjust for the 
anticipated 10% dropouts, the sample size was increased to 280 patients. Adding 95 patients on 1.5 mg yields a total 
of 375 patients.
Due to the decision from 01 January 2016 to discontinue the laquinimod 1.5 mg dose arm, and a low study exposure 
at this time, the laquinimod 1.5 mg dose arm will be presented descriptively only, and will not be included in any 
inferential analyses.
In addition, all efficacy analyses will be performed based on the measurements recorded during the study treatment 
period, ie, data captured following an early termination visit will be excluded from the analyses. The data captured 
after an early termination visit will be used for the sensitivity analyses of the primary and secondary endpoints.
Based on that, the following analyses will be performed using data collected during Part A (Core Study):
1.
Primary Endpoint Analysis:

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
12
The primary efficacy endpoint for this study is BA as measured by the PBVC from baseline to week 48. This 
endpoint will be analyzed using the modified intent-to-treat 1 (mITT1) population with at least 1 post-baseline 
PBVC value, and will include assessments taken up to/including early termination/study completion visit (data 
recorded following an early termination visit will be excluded from this analysis). BA will be analyzed using 
baseline-adjusted repeated measures analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast 
will be constructed in order to compare between laquinimod 0.6 mg and placebo. The model will be comprised from 
the treatment group as a class variable (2 levels). In addition to the treatment group, week (categorical), week by 
treatment group, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and 
Country/Geographical Region (CGR) will be used as covariates. Additionally, week (categorical) will be specified 
as a repeated effect and unstructured (UN) correlation matrix will be used to model intra-subject correlation. In case 
a convergence issue will arise using the UN correlation matrix, (1) AR1 or (2) Compound Symmetry (CS) will be 
used to enable model convergence (in this order).
2.
Secondary Endpoints Analysis:
a.
Time to CDP as measured by EDSS confirmed after at least 12 weeks will be analyzed using the
intent-to-treat (ITT) population and data from all the study assessments up to/including early 
termination/study completion visit (data recorded following an early termination visit will be excluded 
from this analysis). This analysis will be performed using baseline adjusted Cox’s proportional hazards 
regression model (SAS® PROC PHREG) in which 1 contrast for comparing laquinimod 0.6 mg to 
placebo will be constructed. In addition to treatment group, categorical EDSS at baseline (≤4.5 or 
>4.5), age at baseline, natural logarithm of T2 lesion volume at baseline, and CGR will be used as 
covariates. 
b.
Time to CDP, confirmed after at least 12 weeks as measured by EDSS or T25FW will be analyzed 
using the ITT population and data from all the study assessments up to/including early 
termination/study completion visit (data recorded following an early termination visit will be excluded 
from this analysis). This analysis will be performed using baseline adjusted Cox’s proportional hazards 
regression model (SAS® PROC PHREG) in which 1 contrast for comparing laquinimod 0.6 mg to 
placebo will be constructed. In addition to treatment group, categorical EDSS at baseline (≤4.5 or 
>4.5), age at baseline, T25FW at baseline, natural logarithm of T2 lesion volume at baseline, and CGR 
will be used as covariates.
c.
Change from baseline in the T25FW score at week 48 will be analyzed on the mITT2 population and 
will include assessments taken up to/including early termination/study completion visit (data recorded 
following an early termination visit will be excluded from this analysis). Since this variable might not 
follow normal distribution, the ranked values of this measurement will be defined and analyzed using 
baseline-adjusted repeated measures ANCOVA (SAS® PROC MIXED) in which 1 contrast will be 
constructed in order to compare between laquinimod 0.6 mg and placebo. In addition to treatment 
group, T25FW score at baseline and CGR will be used as covariates. Due to the fact that the 
ANCOVA model will use ranked values and not the actual changes in the T25FW, Hodges-Lehmann 
estimates will be used in order to present the magnitude of the treatment effect and the corresponding 
two-sided 95% confidence limit.
d.
The number of new brain T2 lesions at week 48 will be analyzed using the mITT1 population with at 
least 1 post-baseline T2 scan available if it was performed at least 36 weeks under treatment and will 
include assessments taken up to/including early termination/study completion visit (data recorded 
following an early termination visit will be excluded from this analysis). This analysis will be 
performed using baseline adjusted negative binomial regression model (SAS® PROC GENMOD) in 
which 1 contrast for comparing laquinimod 0.6 mg to placebo will be constructed. In addition to the 
treatment group, the natural logarithm of T2 lesion volume at baseline, age at baseline, and CGR will 
be used as covariates.
All the secondary analyses mentioned in this section will be repeated while including observations that were 
recorded following an early termination visit.
Detailed statistical modeling of exploratory endpoints, as well as combined part A and B data, will be described in 
the Statistical Analysis Plan (SAP). Similarly, descriptive statistics for safety and tolerability measures will also be 
described in the SAP.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
13
All statistical tests will be performed at 5% nominal significance level to further define the effects estimates of 
laquinimod but not for strict statistical inferences.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
14
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............4
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................5
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................22
1.
BACKGROUND INFORMATION...........................................................................26
1.1.
Introduction.................................................................................................................26
1.1.1.
Study Rationale...........................................................................................................27
1.1.1.1.
Rationale for Laquinimod 0.6 mg Dose .....................................................................28
1.1.1.2.
Rationale for Laquinimod 1.5 mg Dose .....................................................................29
1.1.1.3.
Rationale for Primary Endpoint..................................................................................30
1.2.
Name and Description of Investigational Product......................................................30
1.3.
Findings from Nonclinical and Clinical Studies.........................................................31
1.3.1.
Nonclinical Studies.....................................................................................................31
1.3.1.1.
Pharmacology .............................................................................................................31
1.3.1.2.
Metabolism and Pharmacokinetics.............................................................................31
1.3.1.3.
Toxicology..................................................................................................................31
1.3.2.
Clinical Studies...........................................................................................................33
1.3.2.1.
Clinical Pharmacology Studies...................................................................................33
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................34
1.4.
Known and Potential Risks and Benefits to Human Patients.....................................36
1.4.1.
Known and Potential Risks and Benefits for Laquinimod .........................................36
1.4.1.1.
Details of Important Adverse Drug Reactions............................................................38
1.4.1.2.
Potential Safety Issues with Laquinimod ...................................................................40
1.4.2.
Overall Risk Benefit Statement ..................................................................................41
1.5.
Selection of Drugs and Dosages.................................................................................42
1.6.
Compliance Statement................................................................................................42
1.7.
Population To Be Studied...........................................................................................43
1.8.
Relevant Literature and Data......................................................................................43

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
15
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................44
2.1.
Purpose of the Study...................................................................................................44
2.2.
Study Objectives.........................................................................................................44
3.
STUDY DESIGN .......................................................................................................45
3.1.
General Design and Study Schema.............................................................................45
3.2.
Primary and Secondary Measures and Endpoints ......................................................47
3.2.1.
Primary Efficacy Measures and Endpoints.................................................................47
3.2.2.
Secondary Efficacy Measures and Endpoints.............................................................47
3.2.3.
Exploratory Efficacy Measures and Endpoints ..........................................................47
3.2.4.
Other Measures and Endpoints...................................................................................48
3.2.5.
Safety Measures and Endpoints..................................................................................48
3.2.6.
Tolerability Measures and Endpoints.........................................................................48
3.2.7.
Pharmacokinetic Measures and Endpoints.................................................................48
3.3.
Randomization and Blinding......................................................................................49
3.3.1.
Emergency Code Breaking.........................................................................................49
3.3.2.
Reducing Assessment Bias.........................................................................................50
3.4.
Study Drugs and Dosage ............................................................................................50
3.4.1.
Investigational Product and Dosage ...........................................................................50
3.4.2.
Other Study Drugs and Dosage ..................................................................................51
3.4.3.
Manufacturing and Packaging....................................................................................51
3.4.4.
Packaging and Labeling..............................................................................................51
3.4.5.
Distribution, Storage, Dispensing and Return............................................................51
3.5.
Duration of Patient Participation ................................................................................51
3.6.
Safety Guidelines and Stopping Rules .......................................................................51
3.6.1.
Pregnancy ...................................................................................................................51
3.6.2.
Liver Enzymes............................................................................................................52
3.6.3.
Cancer.........................................................................................................................52
3.6.4.
Liver Impairment........................................................................................................52
3.6.5.
Renal Impairment .......................................................................................................53
3.6.6.
Temporary Discontinuation of Study Drug Treatment...............................................53
3.6.7.
Early Termination (ET) ..............................................................................................53
3.7.
Study Drug Supply and Accountability......................................................................53
3.7.1.
Study Drug Storage and Security ...............................................................................53

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
16
3.7.2.
Study Drug Accountability.........................................................................................54
3.8.
Maintenance of Randomization and Blinding............................................................54
3.9.
Source Data Recorded on the Case Report Form.......................................................54
3.10.
Time Schedule ............................................................................................................55
3.11.
Study Procedures ........................................................................................................55
3.11.1.
Screening Procedures..................................................................................................63
3.11.1.1.
Re-Screening...............................................................................................................64
3.11.2.
Baseline Visit Procedures (Week 0)...........................................................................65
3.11.2.1.
Between 6 weeks (42 days) and 14 days Prior to Baseline ........................................65
3.11.2.2.
Up to 42 days Prior to Baseline..................................................................................65
3.11.2.3.
Up to 7 days Prior to Baseline....................................................................................65
3.11.2.4.
Pre-randomization.......................................................................................................65
3.11.2.5.
Post Randomization....................................................................................................66
3.11.3.
Scheduled Treatment Visits (Visits 1 to 6, Weeks 4 to 48, and Every 
12 weeks Thereafter) ..................................................................................................66
3.11.4.
Early Termination (ET) Visit......................................................................................69
3.11.5.
Completion Visit.........................................................................................................70
3.11.6.
Unscheduled Visit.......................................................................................................71
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................73
4.1.
Patient Inclusion Criteria ............................................................................................73
4.2.
Patient Exclusion Criteria...........................................................................................73
4.3.
Withdrawal Criteria and Procedures...........................................................................75
4.3.1.
Patient Withdrawal Criteria........................................................................................76
5.
TREATMENT OF PATIENTS..................................................................................77
5.1.
Study Drugs Administered .........................................................................................77
5.2.
Prior and Concomitant Therapy or Medication..........................................................77
5.2.1.
Disallowed Previous Medications/Therapies .............................................................77
5.2.2.
Concomitant Medications/Therapies During Study ...................................................78
5.2.2.1.
Allowed Medications/Therapies During Study ..........................................................78
5.2.2.2.
Disallowed Concomitant Medications/Therapies During Study................................79
5.3.
Procedures for Monitoring Patient Compliance .........................................................80
5.4.
Total Blood Volume ...................................................................................................80
6.
ASSESSMENT OF EFFICACY ................................................................................81

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
17
6.1.
Primary Efficacy Variables.........................................................................................81
6.2.
Secondary Efficacy Variables.....................................................................................81
6.3.
Exploratory/Other Efficacy Variables ........................................................................81
6.4.
Methods and Timing of Assessing, Recording, and Analyzing Efficacy Data ..........82
6.4.1.
MRI Evaluations.........................................................................................................82
6.4.2.
Neurological Evaluations (EDSS and FSS)................................................................83
6.4.3.
Timed 25-Foot Walk (T25FW) ..................................................................................83
6.4.4.
9-Hole Peg Test (9HPT) .............................................................................................83
6.4.5.
Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) 
Score ...........................................................................................................................83
6.4.6.
Symbol Digit Modalities Test (SDMT)......................................................................84
6.4.7.
Modified Rankin Scale ...............................................................................................84
6.4.8.
Low Contrast Visual Acuity (LCVA).........................................................................84
6.4.9.
12-Item Multiple Sclerosis Walking Scale (MSWS-12) ............................................85
6.4.10.
Relapse Evaluation .....................................................................................................85
6.4.10.1.
On-Study Relapse Evaluation.....................................................................................85
6.4.10.2.
The Treating Neurologist............................................................................................85
6.4.10.3.
The Examining Neurologist........................................................................................85
6.4.10.4.
Relapse Determination................................................................................................85
7.
ASSESSMENT OF SAFETY.....................................................................................87
7.1.
Adverse Events ...........................................................................................................87
7.1.1.
Definition of an Adverse Event ..................................................................................87
7.1.2.
Recording and Reporting Adverse Events..................................................................88
7.1.3.
Severity of an Adverse Event .....................................................................................89
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................89
7.1.5.
Serious Adverse Events..............................................................................................90
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................90
7.1.5.2.
Expectedness...............................................................................................................90
7.1.5.3.
Reporting a Serious Adverse Event............................................................................90
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................92
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................92
7.1.8.
Medical Emergencies..................................................................................................93
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................93

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
18
7.2.
Pregnancy ...................................................................................................................93
7.3.
Clinical Laboratory Tests ...........................................................................................94
7.3.1.
Serum Chemistry ........................................................................................................94
7.3.2.
Complete Blood Count ...............................................................................................95
7.3.3.
Anemia Panel..............................................................................................................96
7.3.4.
Urgent Safety Laboratory Panel .................................................................................96
7.3.5.
Serology......................................................................................................................96
7.3.6.
Urinalysis....................................................................................................................97
7.3.7.
Other Clinical Laboratory Tests .................................................................................97
7.4.
Vital Signs and Weight...............................................................................................97
7.5.
Electrocardiography....................................................................................................97
7.6.
Physical Examinations................................................................................................98
7.7.
Glomerular Filtration Rate Estimation .......................................................................98
7.8.
Cardiovascular Risk Assessment and Management ...................................................98
7.9.
Other Safety Measures and Variables: Concomitant Therapy or Medication............98
8.
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACOGENOMICS/OTHER ANCILLARY STUDIES.................................99
8.1.
Pharmacokinetic Variables.........................................................................................99
8.2.
Potential Biomarker Measures....................................................................................99
8.3.
Pharmacogenomic Variables ......................................................................................99
8.4.
Other Ancillary Studies ............................................................................................100
8.4.1.
Cerebrospinal Fluid (CSF) Assessment....................................................................100
8.4.2.
Optical Coherence Tomography (OCT) Evaluation.................................................100
9.
STATISTICS ............................................................................................................101
9.1.
Study Design and Randomization ............................................................................101
9.2.
Sample Size and Power Considerations ...................................................................101
9.3.
Populations ...............................................................................................................101
9.3.1.
Intent-to-Treat (ITT) Population...............................................................................101
9.3.2.
Modified ITT 1 (mITT1) Population........................................................................101
9.3.3.
Modified ITT 2 (mITT2) Population........................................................................101
9.3.4.
Safety (ST) Population .............................................................................................101
9.3.5.
Per-Protocol (PP) Population....................................................................................102
9.4.
Data Handling Conventions......................................................................................102

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
19
9.5.
Study Population.......................................................................................................102
9.5.1.
Patient Disposition....................................................................................................102
9.5.2.
Demographic and Baseline Characteristics ..............................................................102
9.6.
Efficacy Analysis......................................................................................................102
9.6.1.
Primary Variable.......................................................................................................102
9.6.2.
Secondary Variables .................................................................................................103
9.6.3.
Exploratory/Other Variables.....................................................................................104
9.6.4.
Planned Method of Analysis.....................................................................................104
9.6.4.1.
Primary Efficacy Analysis........................................................................................105
9.6.4.2.
Sensitivity Analyses..................................................................................................105
9.6.4.3.
Secondary Efficacy Analysis....................................................................................106
9.6.4.4.
Exploratory Efficacy Analysis..................................................................................107
9.7.
Multiple Comparisons and Multiplicity....................................................................107
9.8.
Safety Variables and Analysis..................................................................................107
9.8.1.
Safety Variables........................................................................................................107
9.8.2.
Safety Analysis .........................................................................................................107
9.9.
Pharmacokinetic Analysis ........................................................................................108
9.10.
Planned Interim Analysis..........................................................................................108
9.11.
Reporting Deviations from the Statistical Plan ........................................................108
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................109
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................110
11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................110
11.1.1.
Protocol Amendments ..............................................................................................110
11.1.2.
Protocol Deviations ..................................................................................................110
11.2.
Information to Study Personnel................................................................................110
11.3.
Study Monitoring......................................................................................................111
11.4.
Clinical Product Complaints.....................................................................................111
11.4.1.
Product Complaint Information Needed from the Investigational Center................112
11.4.2.
Handling the Study Drug at the Investigational Center............................................112
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................113
11.4.4.
Documenting a Product Complaint ..........................................................................113
11.5.
Audit and Inspection.................................................................................................113

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
20
12.
ETHICS ....................................................................................................................114
12.1.
Informed Consent .....................................................................................................114
12.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.......................................................................................................................114
12.3.
Confidentiality Regarding Study Patients ................................................................114
12.4.
Declaration of the End of the Clinical Study............................................................114
12.5.
Registration of the Clinical Study.............................................................................115
13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND RECORD 
KEEPING .................................................................................................................116
13.1.
Data Collection.........................................................................................................116
13.2.
Data Quality Assurance ............................................................................................116
13.3.
Archiving of Case Report Forms and Source Documents........................................117
13.3.1.
Investigator Responsibilities.....................................................................................117
13.3.2.
Sponsor Responsibilities...........................................................................................117
14.
FINANCING AND INSURANCE...........................................................................118
15.
REPORTING AND PUBLICATION OF RESULTS..............................................119
16.
REFERENCES .........................................................................................................120
17.
SUMMARY OF CHANGES TO PROTOCOL .......................................................123
17.1.
Amendment 02 Dated 01 February 2016..................................................................123
17.2.
Amendment 01 Dated 01 July 2015 .........................................................................139
APPENDIX A.
RELAPSE DEFINITION ................................................................................151
APPENDIX B.
GUIDANCE ON SAFETY MONITORING...................................................153
APPENDIX C.
MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 
INDUCERS ..............................................................................................................158
APPENDIX D.
DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS: 2010 
REVISIONS TO “MCDONALD CRITERIA”........................................................160
APPENDIX E.
CYP3A4 AND CYP1A2 SUBSTRATES........................................................161
APPENDIX F.
MRI PROCEDURES .......................................................................................163
APPENDIX G.
NEUROSTATUS ............................................................................................164
APPENDIX H.
INSTRUCTIONS FOR THE TIMED 25-FOOT WALK ...............................175
APPENDIX I.
INSTRUCTIONS FOR THE 9-HOLE PEG TEST ..........................................177
APPENDIX J.
MODIFIED RANKIN SCALE.........................................................................179
APPENDIX K.
12-ITEM MULTIPLE SCLEROSIS WALKING SCALE (MSWS-12).........180
APPENDIX L.
OCT ANCILLARY STUDY DESIGN AND METHODOLOGY..................181

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
21
LIST OF TABLES
Table 1:
ALLEGRO: Summary of Efficacy Results ................................................................35
Table 2:
BRAVO: Summary of Efficacy Results.....................................................................35
Table 3:
Tabulated List of Adverse Reactions..........................................................................37
Table 4:
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for Alanine Aminotransferase, Aspartate Aminotransferase, and 
Gamma-Glutamyl Transpeptidase Tests.....................................................................38
Table 5:
Study Procedures and Assessments  (up to Week 48)................................................56
Table 6:
Study Procedures and Assessments  (from Week 60) ................................................60
Table 7:
Changes to the Protocol (Global Amendment 02)....................................................124
Table 8:
Changes to the Protocol (Global Amendment 01)....................................................140
Table 9:
A Partial List of Cytochrome P450 3A4 Substrates with a Narrow 
Therapeutic Index .....................................................................................................161
Table 10:
A Partial List of Drugs that are Mainly Metabolized by 
Cytochrome P450 1A2 .............................................................................................162
Table 11:
Modified Rankin Scale Scores..................................................................................179
Table 12:
Retinopathies and Other Ocular Diseases Leading to OCT Ancillary Study 
Exclusion of Affected Eyes ......................................................................................182
LIST OF FIGURES
Figure 1:
Overall Study Schema (prior to 01 January 2016) .....................................................46
Figure 2:
Overall Study Schema (from 01 January 2016) .........................................................46

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
22
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
HCG
beta human chorionic gonadotropin
9HPT
9-Hole Peg test
AhR
aryl hydrocarbon receptor
ALT
alanine aminotransferase (SGPT)
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
ARR
annualized relapse rate
ASMA
anti smooth muscle antibodies
AST
aspartate aminotransferase (SGOT)
AUC
area under the concentration by time curve
BA
brain atrophy
BBB
blood brain barrier
BICAMS
Brief International Cognitive Assessment for Multiple Sclerosis
BP
blood pressure
BVMT-R
Brief Visuospatial Memory Test – Revised
CBC
complete blood count
CCSVI
chronic cerebrospinal venous insufficiency
CDMS
clinical data management system 
CDP
confirmed disability progression 
CFR
Code of Federal Regulations
CGR
Country/Geographical Region
CIOMS
Council for International Organizations of Medical Sciences 
CK-MB
creatine kinase MB isoenzyme
Cmax
maximum plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase
CRF
case report form (refers to any media used to collect study data [ie, paper or electronic])
CRO
contract research organization
CRP
C-reactive protein
CSC
Clinical Supply Chain 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
23
Abbreviation
Term
CSF
cerebrospinal fluid
CVLT-II
California Verbal Learning Test–II
CYP
cytochrome P450
DLC
dioxin-like compound
DMC
Data Monitoring Committee 
EAE
experimental autoimmune encephalomyelitis
EC
Ethics Committee
ECG
electrocardiogram
EDSS
Expanded Disability Status Scale
ET
early termination
EU
European Union
FSS
Functional System Score
GCP
Good Clinical Practice
Gd
gadolinium
GdE
Gadolinium enhancing
GFR
glomerular filtration rate
GGT
gamma-glutamyl transpeptidase
HDL
high density lipoprotein
HTLV-I/II
human T lymphotropic virus Type I and II
I3C
indole-3-carbinol
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
IL
interleukin
IMP
investigational medicinal product
INN
international non-proprietary name
INR
International Normalized Ratio 
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat 
IUPAC
International Union of Pure Applied Chemistry

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
24
Abbreviation
Term
IVIG
intravenous immunoglobulin
IVRS
interactive voice response system
IWRS
interactive web response system
JC
John Cunningham
LCVA
low contrast visual acuity
LDL
low density lipoprotein
LKM
liver kidney microsomal
LSO
local safety officer 
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities 
mITT
modified intent-to-treat
MoA
mechanism of action
MRI
magnetic resonance imaging
mRS
modified Rankin scale
MS
multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
MSWS-12
12-Item Multiple Sclerosis Walking Scale
MTD
maximum tolerated dose
MTR
magnetization transfer ratio
NF
nuclear factor
OCT
optical coherence tomography
OTC
over-the-counter
PBVC
Percentage in Brain Volume Change
PGx
pharmacogenomic(s)
PP
per-protocol
PPK
population pharmacokinetic
PPMS
primary progressive multiple sclerosis
PT
prothrombin time
QC
quality control
RBC
red blood cell
RNFL
retinal nerve fiber layer 
RRMS
relapsing remitting multiple sclerosis

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
25
Abbreviation
Term
SAP
statistical analysis plan
SDMT
symbol digit modalities test
SDV
source document verification
SOC
system organ class
SOP
standard operating procedure
SPMS
secondary progressive multiple sclerosis
ST
Safety (population)
SUSAR
suspected unexpected serious adverse reaction
T25FW
timed 25-foot walk
T3
triiodothyronine
T4
thyroxine
TCDD
2,3,7,8-tetrachloro-p-dibenzodioxin
tmax
time to maximum observed drug concentration
TNF
tumor necrosis factor
TSH
thyroid stimulating hormone
ULN
upper limit of the normal range
US
United States (of America)

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
26
1.
BACKGROUND INFORMATION
1.1.
Introduction 
Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disorder of the central 
nervous system (CNS), characterized by inflammation and demyelination, as well as 
oligodendrocyte and neuron dysfunction. The prevalence varies considerably, from regions with 
low prevalence (<5 cases per 100000) across much of central Asia, to areas with high prevalence 
(greater than 30 cases per 100000) across the United States (US), Canada, Australia and large 
parts of Europe and northern Asia ranging from 50 to 100 per 100000.
Approximately 15% of MS patients develop a sustained deterioration of neurological function 
without distinct exacerbations from the onset; this MS phenotype is known as primary 
progressive multiple sclerosis (PPMS) (Lassmann and van Horssen 2012, Lublin et al 2014). At 
diagnosis, approximately 85% of patients have relapsing remitting multiple sclerosis (RRMS), 
characterized by recurrent acute exacerbations of neurological dysfunction (relapses), followed 
by recovery. Over time, the majority of patients with RRMS will develop secondary progressive 
multiple sclerosis (SPMS), in which a less acute inflammatory and more neurodegenerative 
course of the disease takes over. SPMS develops with progression in disability independent of
relapses which usually have subsided. The diagnosis of the transition into this SPMS phase of the 
disease is usually made retrospectively.
Progressive MS subtypes, such as PPMS and SPMS, typically feature gait dysfunction due to 
steadily worsening spastic paraparesis, progressive urinary symptoms, and gradual cognitive 
decline (Koch 2013). The disease mechanisms driving progressive MS remain unresolved, and 
there is currently no animal model available that accurately reproduces this phenomenon. 
Therapeutic options for progressive MS are currently limited to symptomatic treatments and 
physiotherapy (Koch 2013); in this context, a therapy which is effective in limiting the 
neurodegenerative process and associated disability accumulation would address a major unmet 
medical need in the treatment of MS. Recently, positive results have been reported in a PPMS 
trial with the monoclonal antibody ocrelizumab.
The investigational medicinal product (IMP), laquinimod (international non-proprietary name 
[INN]), also known by the laboratory code TV-5600 or ABR-215062 sodium salt, is a 
quinoline-3-carboxamide derivative. It is a novel chemical compound with the International 
Union of Pure and Applied Chemistry (IUPAC) name sodium 
5-chloro-3-(ethyl(phenyl)carbamoyl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-olate.
Laquinimod, an innovative oral immunomodulator, is currently undergoing a third Phase 3 study 
of its development for RRMS (see Section 1.3.2). Its emerging clinical and magnetic resonance 
imaging (MRI) efficacy profile, supported by extensive pre-clinical evidence, suggests a direct 
protective effect in the CNS, largely independent of its peripheral anti-inflammatory effects, 
supporting the evaluation of laquinimod’s efficacy in progressive MS.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
27
1.1.1.
Study Rationale 
Several disease modifying treatments have been registered to treat RRMS, mostly targeting 
relapse activity and MRI parameters of inflammation, however their effects on brain tissue 
damage and progressive disability are limited. 
Some of the neurodegenerative process in the MS brain are due to inflammation transmigrating 
from the peripheral blood and lymphatic system and some are independent (Lassmann and van 
Horssen 2011, Luessi 2012). Importantly, degeneration starts at the earliest stages of the disease
and may be responsible for the slow accrual of disability observed in progressive MS subtypes
(Trapp 1998).
While none of the tested drugs which work in RRMS have been efficacious in progressive MS, 
some key learnings have emerged. Given what is known about the pathophysiology of 
progressive MS, it is reasonable to assume that beneficial drugs would ideally enter the CNS, 
target microglial and astrocytic activation (Prineas et al 2001), mitigate axonal degeneration 
(Fitzner and Simons 2010), or block glutamate excitotoxicity (Gonsette 2008), as well as 
promote remyelination (Irvine and Blakemore 2008). Laquinimod is a small molecule that 
passively crosses the blood brain barrier (BBB) and is detectable in CNS tissues. It has been 
shown to modulate several significant pathways common to key neurodegenerative diseases. 
More specifically, laquinimod modulates the immune cell lineages in the periphery and in the 
CNS. In the periphery, laquinimod down-regulates monocytic activation and pro-inflammatory 
cytokine secretion. In the CNS, laquinimod reduces tissue damage by down regulating microglial 
and astrocytic activation, which is a major cause for tissue destruction, myelin, axonal and 
neuronal loss.
In the toxic cuprizone rodent model, a well-known model of demyelination and secondary 
neurodegenerative BBB damage, laquinimod penetrated the intact BBB (Brück and Wegner 
2011) and prevented demyelination, microglia activation, axonal transections, reactive gliosis 
and oligodendroglial apoptosis (Brück et al 2012, Matsushima and Morell 2001).
In addition, 2 recent separate experimental autoimmune encephalomyelitis (EAE) studies 
revealed that laquinimod can regulate synaptic transmission by increasing inhibitory GABAergic 
post-synaptic currents and reducing glutamatergic excitatory post-synaptic currents (Ruffini et al
2013), and improve axonal remyelination and integrity (Moore et al 2013), thus supporting its
functional neuroprotective and neurorestorative effects.
Importantly, the clinical efficacy profile of laquinimod derived from the 2 completed pivotal 
RRMS studies, ALLEGRO and BRAVO, is distinctive and different from other disease 
modifying treatments in MS because the reduction in disease progression is consistently larger 
than expected based on the relapse based outcomes. 
In the pooled analysis, laquinimod demonstrated a 34% reduction in disability progression 
confirmed after 3 months and a 45% to 47% reduction in disability confirmed at 6, 9, and 
12 months. By using the Sormani meta-analysis, it was found that the predicted reduction in 
3-month confirmed disability progression (CDP) with laquinimod, given the observed effect on 
relapses, should be only 5%, whereas the observed reduction in 3-month CDP using the relative 
risk was 29% (p=0.007), suggesting a pronounced dissociation between the effect on relapses 
and the effect on disability. 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
28
The central action is further supported by laquinimod’s consistent effect on reduction of brain 
atrophy (BA) (30%) as well as other MRI markers of neurodegeneration including thalamic 
atrophy, preservation of magnetization transfer ratio (MTR) in whole brain and in 
normal-appearing white matter, and reduction in the evolution of permanent T1 hypointense 
lesions (Filippi 2013). While the effects on brain volume change occur early following treatment 
initiation, this effect is evidence for central CNS target organ engagement and will be utilized as 
the primary endpoint in this study.
Further assessment of the large RRMS clinical study dataset was performed in order to assess
patient subgroups which may be more informative with respect to a progressive MS population. 
Post-hoc analyses were performed on subgroups defined by baseline Expanded Disability Status 
Scale (EDSS) and presence of relapses during study. These subgroup analyses showed that in 
those with baseline EDSS >3, laquinimod treatment led to a 40% reduction in 3-month CDP, and 
a 53% reduction in 6-month CDP compared to placebo. Patients in the EDSS >3 group who 
received placebo declined by 2.79 seconds more on the timed 25-foot walk (T25FW) after 
24 months compared to patients who were treated with laquinimod (p=0.0035; relative 
difference=59%). Also, although the number of events was low, laquinimod treatment reduced 
3-month CDP by 38.9% in patients who were relapse-free throughout the studies.
Taken together, pre-clinical and clinical data support testing of the hypothesis that laquinimod 
exerts its effect by a direct protective effect in the CNS largely independent of its peripheral 
anti-inflammatory effects. This preclinical and clinical profile meets the requirements for clinical 
testing of laquinimod as a candidate drug in progressive MS.
The rationale for including exclusively PPMS patients in this study is to allow testing of 
laquinimod in a relatively homogenous patient population. 
1.1.1.1.
Rationale for Laquinimod 0.6 mg Dose
The selection of the 0.6 mg as the therapeutic dose for pivotal RRMS studies was based on 
results from two Phase 2 clinical studies (01506203 and LAQ/5062) and an ascending-dose 
study (99506202).
In the Phase 2 Study 01506203, which evaluated daily doses of laquinimod 0.1 and 0.3 mg, only 
the 0.3 mg dose reduced the cumulative number of active lesions at week 24. In the Phase 2b 
Study LAQ/5062, which evaluated daily doses of laquinimod 0.3 and 0.6 mg, only the 0.6 mg 
dose achieved a statistically significant (p=0.0048) 40% reduction in the mean cumulative 
number of gadolinium enhancing (GdE) T1 lesions at weeks 24, 28, 32, and 36 (the primary 
endpoint of the study). However, unlike in Study 01506203, statistical significance was not 
achieved on this primary endpoint for laquinimod 0.3 mg versus placebo. The lack of effect for 
the 0.3 mg dose is attributed to the fact that study LAQ/5062 used a standard gadolinium (Gd) 
dose for detection of enhancing MS lesions, whereas Study 01506203 used a triple Gd dose. 
The data from the two Phase 3 studies were obtained with the 0.6 mg dose, here the clinical 
hypothesis was generated, including data from subgroups with aspects of progressive disease or 
more advanced RRMS. This extensive safety and efficacy database derived from RRMS makes 
the use of 0.6 mg as a reference dose useful, as it will allow comparison to these data. The 
current study includes laquinimod 0.6 mg as the minimal effective dose noted in previous RRMS 
studies with laquinimod.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
29
1.1.1.2.
Rationale for Laquinimod 1.5 mg Dose
The Phase 2 studies (01506203 and LAQ/5062) suggest a dose response up to 0.6 mg based on 
MRI parameters. In addition, in the rodent cuprizone model laquinimod reduces callosal 
demyelination in a dose-dependent manner supportive of a linear dose response.
In light of the dose-dependent effects, evaluation of a higher dose of laquinimod in the current 
Phase 2 study is appropriate and to test whether a further dose response on the pronounced effect 
on brain volume preservation is noted and whether this 1.5 mg dose is associated with greater 
efficacy on other endpoints, while preserving an adequate safety and tolerability profile. Notably, 
an ongoing Phase 3 study in RRMS included a laquinimod dose of 1.2 mg (CONCERTO).
Two studies to evaluate the maximum tolerated dose (MTD) of laquinimod in healthy volunteers 
and MS patients have been performed. A multiple ascending dose study in MS patients 
(Study MS-LAQ-101), in which a safety committee recommended dose escalation following data 
availability for each dosing cohort, did not reveal dose-dependent adverse events, laboratory or 
electrocardiogram (ECG) findings up to and including the dose of 2.7 mg/day. The results of 
Study MS-LAQ-101 did not reproduce the results from an earlier multiple ascending-dose study 
in healthy volunteers and MS patients (Study 99506202), which had established a dose of 
1.2 mg/day as the MTD in MS patients, based solely on laboratory findings that were predefined 
in the protocol as dose limiting toxicity (increased levels of C-reactive protein [CRP]) and 
fibrinogen). The sample size, treatment duration (4 weeks) and overall exposure were greater in 
Study MS-LAQ-101 compared to Study 99506202, and assessment of tolerability of dose was 
based on a combination of clinical evaluation and laboratory parameters. Hence, study 
MS-LAQ-101 is considered to more accurately represent the safety profile of higher doses of 
laquinimod, justifying the use of the 1.5 mg dose. The last cohort of patients received 2.7 mg 
laquinimod with no dose limiting adverse events or laboratory findings. An MTD has not been 
established as the dose escalation beyond 2.7 mg which had no dose limiting effects was not 
performed. Therefore, laquinimod 1.5 mg was selected as the maximal dose to be tested for the 
current study. 
While laquinimod at the 0.6 mg dose has been extensively studied in RRMS, this is the first 
study assessing laquinimod in PPMS patients, bridging the 0.6 mg dose experience and assessing 
a higher dose of 1.5 mg versus placebo. 
Note: On 30 December 2015 the Data Monitoring Committee (DMC) for the CONCERTO and 
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): in CONCERTO there were 6 such cases in the 1.2 mg 
arm but none in the 0.6 mg or placebo arms, along with a myocardial infarction in the 
ARPEGGIO 1.5 mg dose group and a cerebral infarction in a 31-year old patient in the 1.2 mg 
arm of CONCERTO. Due to these events and the DMC recommendation to stop all laquinimod 
treatment arms above 0.6 mg in the MS trials, the 1.5 mg treatment arm in the ARPEGGIO 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 
arm will be continued while the sponsor closely monitors cardiovascular events in all laquinimod 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
30
studies. Additional measures implemented in this protocol amendment include an emphasis on 
disallowed medications and stopping rules for organ impairment (ie, factors which may increase 
laquinimod exposure), as well as regular evaluation and management of major modifiable 
cardiovascular risk factors.
1.1.1.3.
Rationale for Primary Endpoint
MRI-measured BA is a quantitative measure of the irreversible tissue loss observed in MS
(Miller et al 2002). Accordingly, significant associations were found between cerebral atrophy 
and worsening of disability (Barkhof et al 2001, Fisher et al 2000, Kalkers et al 2001, Losseff et
al 1996, Pagani et al 2005), as well as with decline in cognitive functions (Christodoulou et al
2003). In the first large study in untreated patients with MS with different disease subtypes it was 
shown that BA proceeds relentlessly throughout the course of MS, with a rate that seems largely 
independent of the MS subtype, when adjusting for baseline brain volume (De Stefano 2010).
Reduced brain volume loss (measured by Percentage in Brain Volume Change [PBVC] from 
baseline to month 24) was consistently demonstrated in laquinimod studies: ALLEGRO 32.8% 
reduction compared to placebo (p<0.0001); BRAVO 28% reduction compared to placebo 
(p=0.0001).
Several longitudinal studies have reported that BA predicts disability progression and cognitive
impairment over the longer term. Even if correlation between BA and disability has been 
difficult to establish within the time frame of clinical studies, a recent meta-analysis of 
randomized controlled studies demonstrated a correlation between the effect of treatments on BA 
and the effect of treatments on disability progression (Sormani et al 2013a). The time course of 
the PBVC effect of laquinimod has not been clearly defined, however, preliminary data (Teva on 
file) suggest that there is a potential for the effect to occur early following treatment initiation. 
Therefore, PBVC measures at 24 and 48 weeks may serve as a biomarker for laquinimod’s CNS 
target organ engagement and allow for the assessment of a potential dose response.
1.2.
Name and Description of Investigational Product 
The IMP, laquinimod (INN), also known by the laboratory code TV-5600 or ABR-215062 
sodium salt, is a quinoline-3-carboxamide derivative. It is a novel chemical compound with the 
IUPAC name sodium 5-chloro-3-(ethyl(phenyl)carbamoyl)-1-methyl-2-oxo-1,2-dihydroquinolin-
4-olate.
Laquinimod is supplied as white opaque cap and body hard gelatin capsules filled with white to 
off-white granulate. The capsules contain laquinimod sodium and are available in doses 
equivalent to 0.5 or 0.6 mg laquinimod. Placebo capsules are also supplied.
The capsules are packed in aluminium blister cards and should be stored at room temperature 
(+15°C to +25°C). A more detailed description of the product is given in Section 3.4.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
31
1.3.
Findings from Nonclinical and Clinical Studies 
1.3.1.
Nonclinical Studies 
1.3.1.1.
Pharmacology
In models of MS (EAE and cuprizone), the mechanism of action (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 
nuclear factor (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.
1.3.1.2.
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 decrease of CYP3A4 activity and is 
a strong inducer of CYP1A enzymes. CYP1A induction is a biomarker of activation of the aryl 
hydrocarbon receptor (AhR) transcription factor: activation of this pathway by laquinimod has 
been demonstrated. 
For a complete overview of the ADME-PK program of laquinimod, please refer to the 
laquinimod Investigator’s Brochure (IB).
1.3.1.3.
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 32- to 257-fold above the 
originally intended clinical dose of 1.5 mg/day based on maximal plasma concentrations.
Overall, the non clinical safety program identified several safety issues. Specifically, the 
toxicities identified are pro-inflammatory effects (including thyroiditis), mild liver toxicity, and 
mild reductions of red blood cell (RBC) indices. In general, the severity of these effects was 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
32
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 (>32) above the originally intended clinical dose of 
1.5 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) 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.
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 offspring exposed in utero to laquinimod at doses slightly 
higher than the originally intended clinical dose of 1.5 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 unknown. 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 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
33
could be evaluated, but there were no treatment-related malformations at doses up to 9-fold the 
expected plasma exposure at the originally intended clinical dose of 1.5 mg/day. Based on the 
above, humans should not be exposed to laquinimod during pregnancy.
Based on calculations from a study to determine laquinimod levels in monkey semen, in which 
the semen:plasma ratio of laquinimod was 0.32, the estimated exposure to a female partner of 
laquinimod-treated male patient via semen is approximately 600-fold lower than the exposure 
after oral administration of laquinimod at a dose of 1.5 mg, indicating that the risk of male-
mediated embryo-fetal toxicity through laquinimod treatment is negligible.
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 patients, 
frequent and proactive monitoring of patients and appropriate stopping rules. Furthermore, an 
independent DMC will be assigned to assess the data (see Section 7).
1.3.2.
Clinical Studies 
Fifteen Phase 1 studies in healthy volunteers and MS patients were completed. A 
placebo-controlled pharmacokinetic bridging study in Japanese and Caucasian patients was 
completed.
Two Phase 2 studies (1 placebo-controlled [01506203] and 1 open-label [03506207]) in MS 
patients were completed. Two Phase 2b studies, LAQ/5062 (a randomized, double-blind, 
parallel-group, placebo-controlled study) and its double-blind active extension study 
(LAQ/5063) with 2 laquinimod doses (0.3 and 0.6 mg/day) were also completed. Based on the 
efficacy and safety results of LAQ/5062, an amendment to the protocol of LAQ/5063 study was 
submitted to change it into an open-label study (LAQ/5063OL) with the 0.6 mg/day dose as a 
single active arm; this study is still ongoing.
Two Phase 3 studies, MS-LAQ-301 (ALLEGRO) and MS-LAQ-302 (BRAVO) were completed. 
Open-label extension studies MS-LAQ-301E and MS-LAQ-302E are currently ongoing.
A Phase 3 study, LAQ–MS-305 (CONCERTO), is ongoing with laquinimod doses of 
0.6 mg/day. As of 01 January 2016, and based on DMC recommendations, the 1.2 mg/day arm 
was discontinued .
For further details refer to the laquinimod IB.
1.3.2.1.
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 maximum plasma drug concentration (tmax) to 
approximately 5 hours and reduction of the maximum plasma concentration (Cmax) by 30%. Food 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
34
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; therefore, laquinimod may affect the systemic exposure of other drugs metabolized by 
CYP3A4 and CYP1A2. For additional information on concomitant use of laquinimod with 
CYP1A2 and CYP3A4 substrates, 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 a 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.
1.3.2.2.
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 endpoints (EDSS, cumulative 
GdE T1 lesions and cumulative new T2 lesions) were met (Table 1). 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
35
Table 1:
ALLEGRO: Summary of Efficacy Results
Endpoints
% 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 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
Endpoints
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 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
36
relationship between relapse rate and disability observed for other disease modifying therapies 
(Sormani et al 2010). This effect was consistent between the 2 studies (EDSS; ALLEGRO: 
35.9% [p=0.0122], BRAVO: 33.5% [p=0.04a]. In addition, treatment with laquinimod 
demonstrated reduction in BA: ALLEGRO: 32.8% [p<0.0001], BRAVOa : 27.4% [p<0.0001]).
The safety profile of laquinimod is detailed in Section 1.4.
1.4.
Known and Potential Risks and Benefits to Human Patients 
1.4.1.
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 count
increased, platelets decreased) and elevation of blood CRP or fibrinogen levels; these laboratory 
changes are generally mild and asymptomatic.
The safety profile of laquinimod is provided in detail below:
Table 3 presents the list of possible adverse drug reactions.
The following definitions apply to the frequency terminology used hereafter:
Very common (≥ 1/10)
Common (≥1/100 to < 1/10)
Uncommon (≥1/1000 to < 1/100)
Rare (≥1/10000 to < 1/1000)
Very rare (< 1/10000)
Not known (cannot be estimated from the available data)
Note: the table has been updated in line with the updated Reference Safety Information; 
myocardial infarction and cerebrovascular accident are now included.
                                                
a 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

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
37
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
Very Common:
Decreased platelets, increased white blood cells
Common:
Anemiaa
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, blood 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.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
38
1.4.1.1.
Details of Important Adverse Drug Reactions
1.4.1.1.1. 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 2 weeks in the absence of a clear 
alternative explanation; if the elevation exceeded 8 times the ULN, laquinimod was discontinued 
without further delay.
Table 4:
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for Alanine Aminotransferase, Aspartate Aminotransferase, and 
Gamma-Glutamyl Transpeptidase Tests
Test
Range of Increase
Placebo
Laquinimod 0.6 mg
AST (IU/L)
Patients with Normal Test 
at Baseline:
N = 977
Patients with Normal Test 
at Baseline:
N = 950
> 1 and ≤3 x ULN
83 (8.5%)
159 (16.7%)
> 3 and ≤5 x ULN
6 (0.6%)
9 (0.9%)
> 5 and ≤8 x ULN
4 (0.4%)
1 (0.1%)
> 8 x ULN
2 (0.2%)
0 (0.0%)
ALT (IU/L)
Patients with Normal Test 
at Baseline:
N = 930
Patients with Normal Test 
at Baseline:
N = 888
> 1 and ≤3 x ULN
165 (17.7%)
262 (29.5%)
> 3 and ≤5 x ULN
5 (0.5%)
30 (3.4%)
> 5 and ≤8 x ULN
6 (0.6%)
5 (0.6%)
> 8 x ULN
7 (0.8%)
5 (0.6%)
GGT (IU/L)
Patients with Normal Test 
at Baseline:
N = 930
Patients with Normal Test 
at Baseline:
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%)
The percentages listed in the table refer to all patients with normal values at baseline.
ULN = Upper limit of normal range; AST = aspartate aminotransferase; ALT = alanine aminotransferase; 
GGT = gamma-glutamyl transpeptidase; IU/L = international units/L

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
39
1.4.1.1.2. 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.
1.4.1.1.3. Elevated Blood C-Reactive Protein Level
An increase in blood CRP level has not been found in clinical studies in patients 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 CRP was slightly higher in the laquinimod group compared to 
placebo. In the MS-LAQ-101 dose-escalation study, a higher proportion of patients with 
elevations in CRP was seen in the laquinimod groups compared to placebo.
1.4.1.1.4. Back and Neck Pain
Treatment with laquinimod has been associated with an increased incidence of back and neck 
pain. Back and neck pains usually occurred during the first 3 months of treatment, were 
generally of mild severity, but occasionally occurred at a later time point, were of longer 
duration, or required symptomatic treatment.
1.4.1.1.5. 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.
1.4.1.1.6. 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 white blood cells:
Treatment with laquinimod has been associated with a generally mild increase of the total white 
blood cell count that was consistent across white blood cell subtypes, without clinical 
manifestations.
1.4.1.1.7. Cardiovascular Events (on Doses Above Laquinimod 0.6 mg)
On 30 December 2015, a DMC review of 8 unblinded cases from the ARPEGGIO and 
CONCERTO studies found an imbalance in serious cardiovascular events in the high dose 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
40
treatment arms in the study: 6 cases of myocardial infarction 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 infarction in a 31-year old man on the 1.2 mg treatment arm. In the ARPEGGIO study, 
1 myocardial infarction 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 these events, the DMC recommended stopping all laquinimod treatment arms above 
0.6 mg in the laquinimod MS trials. 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 was 
necessary. 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.
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.
1.4.1.2.
Potential Safety Issues with Laquinimod
1.4.1.2.1. 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 slightly 
higher than the originally intended clinical dose of 1.5 mg/day in humans (Section 1.3.1.3). The 
relevance to humans of these findings is not known, but cannot be excluded. 
Exposure to laquinimod during pregnancy should be avoided. 
To prevent such exposure, women who are of child-bearing potential (for example women who 
are not postmenopausal or surgically sterilized) must practice an acceptable method of birth 
control (Section 4.1) for 30 days before initiation of treatment, and 2 acceptable methods of birth 
control throughout treatment duration and for 30 days after cessation of treatment. Acceptable 
methods of birth control in this study include: intrauterine devices, barrier methods (condom or 
diaphragm with spermicide), and hormonal methods of birth control (eg, oral contraceptive, 
contraceptive patch, 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. Women of child-bearing 
potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment. 
During treatment, if pregnancy is suspected despite all recommended precautions (based on a 
positive pregnancy test, delay in menstruation or any other reason to suspect pregnancy), 
treatment should be discontinued immediately. The patient should be reminded of the potential 
risk to the fetus, and all options, including termination of pregnancy, should be discussed.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
41
All patients 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.
1.4.1.2.2. Cancer
The 2-year carcinogenicity studies in rats demonstrated an increase in uterine and oral cancers
(Section 1.3.1.3). 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 0.6 mg/day with an increased risk of cancer.
1.4.1.2.3. 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 10,000 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.
1.4.2.
Overall Risk Benefit Statement
This is the first study to evaluate laquinimod treatment in patients with PPMS.
The effects of laquinimod in the 2 pivotal studies in RRMS describe a robust and consistent 
effect on 3, 6, and 12 months CDP. This effect is larger than expected based on the outcomes 
projected from the relapse and suggests an effect on disability progression independent from 
inflammation (Sormani et al 2013b). This effect has also been demonstrated in subgroups 
indicative of transition to progressive stages. 
The effect of laquinimod on PBVC in RRMS patients is also consistent between studies and 
substantiated by an effect on other MRI markers of neurodegeneration. 
The clinical and preclinical aspects of the known MoA support testing of the hypothesis whether 
treatment with laquinimod changes MRI and potentially clinical outcomes in patients with PPMS
in a dose responsive manner. The extensively assessed clinically observed safety profile of 
laquinimod 0.6 mg is favorable.
The 4-week MTD study with doses up to 2.7 mg QD (Study MS-LAQ-101) did not show an 
increase in total adverse events with increased dose. Higher incidence of post baseline shifts to 
abnormally high levels of laboratory parameters compared to the pooled placebo included liver 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
42
enzymes, P-amylase, CRP, and fibrinogen, but most shifts were not to potentially clinically 
significant levels, and no dose response was observed.
Due to cardiovascular events and a DMC recommendation to stop all laquinimod treatment arms 
above 0.6 mg in the MS trials, the 1.5 mg treatment arm 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 was necessary. As of 29 September 2015, 
2347 patients had been exposed to laquinimod 0.6 mg for 10,417 patient-years. It is estimated 
that the rate for myocardial infarction and cardiovascular death for patients treated with 
laquinimod 0.6 mg is about 0.16 per 100 person-years which is within range of the expected 
cardiovascular event incidence in the underlying population. Therefore, while no increased risk 
was seen with laquinimod 0.6 mg, because of the findings with higher doses, there is a potential 
risk that some individuals may be at increased risk of cardiovascular events while taking 
laquinimod 0.6 mg. Appropriate risk mitigation procedures have been implemented via a
protocol amendment to restrict excess drug exposure due to disallowed medications or organ 
impairment, as well as to assure evaluation and management of cardiovascular risk factors.
Given the unmet need for treatments of progressive MS, the data supportive of a potential effect 
of laquinimod in this population, and the identified safety profile of laquinimod, it is judged that 
the administration of laquinimod to patients with PPMS has the potential to yield clinical 
benefits which may outweigh the potential risks, supporting investigation of its role in this 
patient population for which there is equipoise.
1.5.
Selection of Drugs and Dosages 
The rationale for the selection of doses is presented in Sections 1.1.1.1 and 1.1.1.2.
A more detailed description of study drug administration is presented in Section 5.1.
1.6.
Compliance Statement 
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any 
applicable national and local laws and regulations (eg, Title 21 Code of Federal Regulations 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Directive 20/EC and 28/EC). 
Any episode of noncompliance will be documented.
The investigators are responsible for performing the study in accordance with this protocol and 
the applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of each investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national authorities.
Each investigator is responsible for ensuring the privacy, health, and welfare of the patients
during and after the study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. Each investigator and the applicable study staff must be 
familiar with the background to, and requirements of, the study and with the properties of the 
study drug(s) as described in the IB or prescribing information. 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
43
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities.
1.7.
Population To Be Studied 
The current study is a Phase 2 dose ranging study in PPMS patients.
1.8.
Relevant Literature and Data
Relevant literature is cited above. Further literature and data may be found in the current IB.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
44
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study 
This is a Phase 2 study and is intended to serve as a proof of concept for potential treatment with 
laquinimod in patients with PPMS. The study is also aimed at evaluating 2 doses of laquinimod 
in this population.
2.2.
Study Objectives
The objectives of this study are to assess the efficacy, safety, and tolerability of a once daily oral 
dose of laquinimod (0.6 or 1.5 mg) compared to placebo in PPMS patients.
Study endpoints are detailed in Section 3.2.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
45
3.
STUDY DESIGN
3.1.
General Design and Study Schema 
This is a multinational, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study, to evaluate the efficacy, safety and tolerability of daily oral 
administration of laquinimod (0.6 or 1.5 mg) in patients with PPMS.
Prior to 01 January 2016, eligible patients were randomized in a 1:1:1 ratio into 1 of the 
following treatment arms (a total of 286 patients were randomized 1:1:1 prior to 
01 January 2016):

Laquinimod 0.6 mg daily

Laquinimod 1.5 mg daily

Daily placebo
As of 01 January 2016, following a decision to discontinue the laquinimod 1.5 mg dose arm, 
additional eligible patients who are enrolled will be randomized in a 1:1 ratio into one of the 
following treatment arms:

Laquinimod 0.6 mg daily

Daily placebo
A capped randomization procedure will be employed to ensure that the proportion of EDSS 6.0 
and 6.5 patients will not exceed more than 20% of all enrolled patients.
The study will include screening up to 6 weeks and 2 parts: Part A (core study) and Part B (data 
analysis).
Part A will last at least 48 weeks, and individual patients will experience variable treatment 
durations, depending on the order of enrollment.
Once the last ongoing patient completes the week 48 visit, the sponsor will declare end of Part A 
and begin performing study analyses.
In Part B, patients will continue their randomly-assigned blinded treatments with visits every 
12 weeks until the completion visit. After up to approximately 24 weeks of Part B, or once data 
analysis has been completed and the design of a potential extension study has been finalized
(including blinded or open-label treatment allocation), patients will be invited to the clinic for the 
completion visit and will be offered the opportunity to continue into an extension study, if 
applicable.
Patients will have the following study visits: screening visit (-6 weeks), baseline visit (week 0), 
weeks 4, 8, 12, 24, 36, 48, and every 12 weeks until study completion or early termination (ET).
The study schema is presented in Figure 1 (prior to 01 January 2016) and Figure 2 (from 
01 January 2016).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
46
Figure 1:
Overall Study Schema (prior to 01 January 2016)
Screening should occur up to 6 weeks prior to the baseline (week 0) visit
a Part B commences once the last ongoing patient completes week 48; consequently, individual patients will 
experience variable treatment durations, depending on the order of enrollment. As of 01 January 2016, treatment 
was discontinued for patients enrolled to the 1.5 mg arm.
b Patients will be invited for a completion visit once data analysis is complete and the design of a potential extension 
study has been finalized
Figure 2:
Overall Study Schema (from 01 January 2016)
Screening should occur up to 6 weeks prior to the baseline (week 0) visit
a Part B commences once the last ongoing patient completes week 48; consequently, individual patients will 
experience variable treatment durations, depending on the order of enrollment
b Patients will be invited for a completion visit once data analysis is complete and the design of a potential extension 
study has been finalized
Study assessments are detailed (by time point) in Sections 3.11.1 to 3.11.6.
In the event of neurological symptoms suggestive of a relapse, the definitions and procedures in
0 apply. Confirmed relapses must be recorded in the case report form (CRF). Patients with a 
relapse may continue in the study. The suggested treatment for a relapse will be intravenous 
methylprednisolone 500 to 1000 mg/day for 3 to 5 consecutive days.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
47
Pharmacogenomic (PGx) assessments will be performed in all patients, however this can be 
omitted if considered unacceptable per local regulations.
Ancillary studies include assessments of cerebrospinal fluid (CSF) and optical coherence 
tomography (OCT) to assess retinal thickness.
3.2.
Primary and Secondary Measures and Endpoints
3.2.1.
Primary Efficacy Measures and Endpoints
The primary endpoint for this study will be BA as defined by the PBVC from baseline to 
week 48.
3.2.2.
Secondary Efficacy Measures and Endpoints

Time to CDP, defined as increase in EDSS of 1 point from baseline EDSS if EDSS 
at entry is ≤5.0, or increase of 0.5 point if EDSS at entry is 5.5. This increase 
should be confirmed after at least 12 weeks. Progression cannot be confirmed during 
a relapse, although relapses are rare in PPMS. 

Time to CDP as measured by 2 types of events for each individual (progression 
cannot be confirmed during a relapse): 

An increase from baseline in EDSS score (≥1 point from baseline EDSS if EDSS 
at entry is ≤5.0, or increase of ≥0.5 point if EDSS at entry is ≤5.5), confirmed 
after at least 12 weeks, or

An increase of at least 20% from baseline in the T25FW score, confirmed after at 
least 12 weeks.

Change from baseline to week 48 in the T25FW score.

The number of new T2 brain lesions at week 48.
3.2.3.
Exploratory Efficacy Measures and Endpoints

Change from baseline to week 48 in the Brief International Cognitive Assessment for 
Multiple Sclerosis (BICAMS) score (California Verbal Learning Test–II [CVLT-II], 
Brief Visuospatial Memory Test – Revised [BVMT-R], and symbol digit modalities 
test [SDMT]).

Time to CDP as measured by at least 1 of 4 types of events for each individual 
(progression cannot be confirmed during a relapse):

An increase from baseline in EDSS score (≥1 point from baseline EDSS if EDSS 
at entry is ≤5.0, or increase of ≥0.5 point if EDSS at entry is ≥5.5), confirmed 
after at least 12 weeks or

An increase of at least 20% from baseline in T25FW score, confirmed after at 
least 12 weeks or

An increase of at least 30% from baseline in the 9-Hole Peg test (9HPT) score, 
confirmed after at least 12 weeks or

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
48

A decrease of at least 20% from baseline in the SDMT score, confirmed after at 
least 12 weeks.

Time to CDP confirmed after at least 24 weeks. 

New T1-hypointense lesions, changes in T1-hypointense lesion volume, and changes 
in T2 lesion volume.

Other MRI parameters, including thalamic, cortical, white matter, and cervical cord 
atrophy, number of cervical cord T2 lesions, and normal-appearing brain tissue 
average MTR.

Modified Rankin scale (mRS) (at week 72, visit 8).

T25FW.

9HPT.

Low contrast visual acuity (LCVA).

12-Item Multiple Sclerosis Walking Scale (MSWS-12).
3.2.4.
Other Measures and Endpoints

relapses

pharmacokinetic measures (determination of plasma concentration of laquinimod)

PGx measures

potential biomarker measures

ancillary studies measures
3.2.5.
Safety Measures and Endpoints 
The safety of laquinimod will be assessed throughout the study by evaluating adverse events, 
vital signs, ECG findings, clinical laboratory parameters, and concomitant medication usage. 
3.2.6.
Tolerability Measures and Endpoints 

Proportion of patients (%) who prematurely discontinue treatment, reasons for
discontinuation, and time to ET.

Proportion of patients (%) who prematurely discontinue treatment due to adverse 
events, and time to ET due to adverse events.
3.2.7.
Pharmacokinetic Measures and Endpoints 
Blood samples for determination of plasma concentration of laquinimod will be collected at 
weeks 4, 8, 12, 24 and 48. The patient should be instructed to take the daily oral dose at the same 
time each day. The date and time of the blood sample, as well as the date and time of the last 
study drug dose prior to the sample will be recorded in the source document and on the CRF.
Pharmacokinetics of laquinimod will be evaluated in this study using a population 
pharmacokinetics (PPK) approach. The PPK model may also include any unscheduled 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
49
pharmacokinetic samples collected to assist with further investigations of cardiovascular events 
or other clinical event of interest (see Section 8.1). Details of sample collection and processing 
are provided in the Laboratory Manual.
3.3.
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Patients will be randomly assigned 
to receive treatment with laquinimod at a dosage of 0.6 or 1.5 mg/day, or placebo in a 1:1:1 ratio
(prior to 01 January 2016) or randomly assigned to receive treatment with laquinimod at a 
dosage of 0.6 mg/day, or placebo in a 1:1 ratio (from 01 January 2016). Patients, investigators, 
and study site personnel will remain blinded to treatment assignment during the study.
Laquinimod and placebo will be packaged and administered in a blinded manner. All patients 
that discontinued the 1.5 mg dose have been unblinded.
The randomization number will be generated by the sponsor or a vendor following specifications 
from the sponsor’s biostatistics department. A statistician not assigned to the study will be 
responsible for reviewing the randomization number.
The sponsor’s clinical personnel involved in the study will be blinded to the study drug identity 
until the database is locked for analysis (end of Part A) and the treatment assignment revealed.
Patients will be randomly assigned to treatment through a qualified randomization service 
provider (eg, interactive response technology [IRT]). 
This system is used to ensure a balance across treatment groups. A capped randomization 
procedure will be employed to ensure that the number of EDSS 6.0 and 6.5 patients will be no 
more than 20% of all enrolled patients.
The patient number assigned during the screening visit through the interactive voice response 
system (IVRS)/interactive web response system (IWRS) will be used to identify patients during 
the whole course of the study regardless of the randomization number assigned during the 
randomization visit. The randomization number assigned is solely for treatment group allocation. 
In addition to the randomization number, the IVRS/IWRS will assign a pack number. The patient
will be supplied and treated throughout the study with IMP labeled with the pack number/s 
assigned by IVRS/IWRS at each visit.
3.3.1.
Emergency Code Breaking
In case of a serious adverse event, pregnancy, or in cases when knowledge of the study drug 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
drug assignment as deemed necessary, mainly in emergency situations. Individual treatment
codes, indicating the treatment randomization for each randomized patient, will be available to
the investigator(s) at the study center via the IRT, via the internet.
If possible, the sponsor should be notified of the event prior to breaking of the code. If this is not 
possible, the sponsor should be notified immediately afterwards, and the patient’s drug code 
assignment should not be revealed. Breaking of the treatment code can always be performed by 
the site without prior approval by the sponsor.
In case of pregnancy, if deemed necessary by the investigator, the patient’s drug assignment may 
be unblinded; however, the sponsor should not be notified of the treatment assignment.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
50
The circumstances leading to the breaking of the code should be fully documented, in the 
investigator’s study files and in the patient’s source documentation. Treatment assignment 
should not be recorded in any study documents or source document.
For adverse events that are defined as: Suspected, Unexpected, Serious, Adverse Reaction 
(SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance may independently request that the treatment code be revealed (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct, analysis, and reporting of the data.
3.3.2.
Reducing Assessment Bias
To maintain reliable evaluation and reduce the potential for bias, the following actions will be 
undertaken:

Site clinicians may serve as either Examining Neurologist or Treating Neurologist.

Both Examining Neurologist and Treating Neurologist will remain blinded to study 
drug assignment.

Only an Examining Neurologist will administer the EDSS and Functional System 
Scores (FSS).

The Examining Neurologist will not have access to the patient’s medical records or 
source documents, including previous EDSS/FSS forms or adverse events.

Safety evaluations and other clinical considerations will be the sole responsibility of 
the Treating Neurologist. The Treating Neurologist will be responsible for patient 
eligibility evaluation, the supervision of the study drug administration, clinical 
assessment and treatment, the recording and treating of adverse events, the 
monitoring of safety assessments, including routine laboratory parameters, and 
coordinating MRI performance.

The Treating Neurologist and the Examining Neurologist will be instructed not to 
discuss the patients with each other. In particular, the Treating Neurologist and 
Examining Neurologist will not discuss the performance or scoring of the EDSS/FSS.

Patients will be instructed not to discuss their general health condition and adverse 
events with the Examining Neurologist.

Only a trained, blinded rater will administer the T25FW, 9HPT, BICAMS, and 
SDMT. The blinded rater need not be a physician or nurse. The blinded rater will not 
have access to the patient’s medical records or source documents, including previous 
T25FW, 9HPT, BICAMS, or SDMT forms.
3.4.
Study Drugs and Dosage
3.4.1.
Investigational Product and Dosage

0.6 mg arm: 1 capsule containing 0.6 mg laquinimod and the other 2 containing 
placebo, to be administered orally once daily.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
51

1.5 mg arm: 3 capsules containing 0.5 mg laquinimod to be administered orally once 
daily (Note: this arm was discontinued as of 01 January 2016).
3.4.2.
Other Study Drugs and Dosage

Placebo arm: 3 capsules containing placebo to be administered orally once daily.
3.4.3.
Manufacturing and Packaging
Laquinimod capsules and placebo capsules are manufactured and packaged in compliance with 
current good manufacturing practice (GMP) standards and guidelines applicable to study drugs 
by Teva Pharmaceutical Industries, Ltd.
3.4.4.
Packaging and Labeling
The secondary packaging and labeling for patients is under the responsibility of the Clinical 
Supply Chain (CSC) of Teva Pharmaceutical Industries Ltd and is according to EU regulations 
and ICH guidelines as adopted by the FDA – GCP (E6). Patients will receive weekly packs each 
containing 3 distinct labeled blisters in accordance with the associated treatment arm. The 
blisters will be used to accomplish the dosing of 1 of the 3 treatment arms. One capsule from 
each blister should be taken daily. Both blisters and outer pack will be labeled with a unique 
pack number.
3.4.5.
Distribution, Storage, Dispensing and Return
Distribution of study drugs will be performed under sponsor's responsibility. If the study drug 
supplies appear to be damaged/missing upon arrival at the investigational site, the sponsor should 
be contacted immediately. Study drug supplies will be kept in a secure, limited-access, 
temperature-controlled storage area. Only authorized personnel will have access to the study 
drug. The study site personnel at each site will be responsible for correct storage and handling of 
the study drug. All study drug packs must be stored at room temperature 15°C to 25°C/59°F to 
77°F. Study drug packs will be dispensed to the patient at the study site at each dispensing visit 
through the IRT. Patients will be instructed to return all used blisters and unused study drug at 
each visit. The Site Investigator/site coordinator is responsible for performing study drug 
accountability at the site. The Monitor is responsible for the accountability of the returned study 
drugs.
3.5.
Duration of Patient Participation 
For each patient, the study will consist of a screening phase of up to 6 weeks, Part A (core study) 
of at least 48 weeks, and Part B (data analysis) of up to approximately 24 weeks or until data 
analysis is completed and the design of a potential extension study has been finalized. Following 
the completion visit, patients will be offered the opportunity to continue into an extension study.
3.6.
Safety Guidelines and Stopping Rules
3.6.1.
Pregnancy
Exposure to laquinimod during pregnancy must be avoided. Therefore, women of childbearing 
potential (for example women who are not postmenopausal or surgically sterilized) must practice 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
52
an acceptable method of birth control for 30 days before taking the study treatment and have a 
negative serum pregnancy test within 7 days prior to initiation of treatment.
To further emphasize the importance of use of acceptable contraception and avoidance of 
pregnancy under laquinimod exposure, and to reduce as much as possible the exposure to 
laquinimod if a pregnancy occur despite all recommended measures, all patients who are women 
of child-bearing potential (for example women who are not postmenopausal or surgically
sterilized) will be instructed about the teratogenicity and potential delayed risks for a child 
exposed in utero to laquinimod. These patients will also be counseled about the importance of 
using 2 methods of acceptable contraception throughout treatment duration, and until 30 days 
after the last dose of treatment is administered, and about the need to stop treatment immediately 
if pregnancy is suspected.
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).
In case of suspected pregnancy (positive urine beta human chorionic gonadotropin [β-hCG] test 
result, delay of menstruation or any other reason suggesting pregnancy), the study drug will be 
suspended, and follow-up will be done as detailed in Appendix B.
3.6.2.
Liver Enzymes
For any increase of ALT or AST to ≥2×ULN, the “Guidance on Safety Monitoring” in
Appendix B should be thoroughly followed.
In the following circumstances, the patient’s participation in the study will be discontinued
immediately and liver enzymes will be monitored until normalization or stabilization, according
to the guidance in Appendix B:

Any increase in ALT or AST to ≥3×ULN, combined with international normalized 
ratio (INR) >1.5 or total bilirubin >2×ULN.

Any increase in ALT or AST to ≥3×ULN, which is accompanied by nausea,
vomiting, fever, rash, or eosinophilia.

Any increase in ALT or AST to levels ≥5× but <8×ULN, which is persistent for
≥2 weeks of repeated measurements.

Any increase in ALT or AST to levels ≥8×ULN.

In any case where monitoring of liver enzymes cannot be performed according to the
protocol guidance (see Appendix B).
3.6.3.
Cancer
Patients who are diagnosed with a malignant solid or liquid tumor while participating in the 
study should stop study medication.
3.6.4.
Liver Impairment
To avoid exposures to higher levels of laquinimod (see Section 1.3.2.1), a stopping role related 
to liver impairment has been introduced. Patients who develop any chronic liver disease 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
53
associated with hepatic function impairment while participating in the study should stop study 
medication.
3.6.5.
Renal Impairment
To avoid exposures to higher levels of laquinimod (see Section 1.3.2.1), a stopping role related 
to renal impairment has been introduced. Patients 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 patient should stop study medication permanently.
3.6.6.
Temporary Discontinuation of Study Drug Treatment
Temporary discontinuation is defined as missing of more than 3 consecutive doses of the study
drug. Skipping 14 or more consecutive doses of study drug will be considered a major protocol
violation.
In the event of temporary study drug discontinuation, the local clinical management should be 
notified. The patient will report any temporary discontinuation to the investigator and will be 
instructed by the investigator regarding continuation of treatment based on the reason and 
duration of discontinuation.
3.6.7.
Early Termination (ET)
An ET visit should be completed for all patients who prematurely terminate treatment or who 
become pregnant (see Section 3.11.4 for details of procedures).
In all cases of ET due to ongoing adverse event, manifestation of a severe degree of intolerance 
to study drug and/or ongoing MS relapse, the patient should remain under medical observation 
and followed until the medical condition returns to baseline or is considered stable or chronic.
Early termination refers to the study drug termination and not termination of the patient from the 
study. Patients will be encouraged to continue all scheduled visits and procedures after study 
drug discontinuation (with the exception of drug dispensing and accountability, pregnancy 
testing, and pharmacokinetic sampling).
Women of child bearing potential should continue using 2 acceptable contraception methods up 
to 30 days after the last dose of treatment was administered.
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.
3.7.
Study Drug Supply and Accountability 
3.7.1.
Study Drug Storage and Security
Study drug (laquinimod and placebo) must be stored at room temperature (15°C to 25°C), in a 
dry, temperature-controlled, securely locked, substantially-constructed cabinet or enclosure. The 
study site personnel at each site will be responsible for correct storage and handling of the study 
drug.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
54
3.7.2.
Study Drug Accountability 
Each study drug shipment will include a packing slip, listing the contents of the shipment. The
return instructions and the applicable forms will be provided to the site. The investigator is 
responsible for ensuring that deliveries of study drug and other study materials from the sponsor 
are correctly received and recorded, handled and stored safely and properly in accordance with 
the local regulations, and used in accordance with this protocol. 
A record of study drug accountability (ie, study drug and other materials received, used, retained, 
returned) must be prepared and signed by the principal investigator or designee, with an account 
given for any discrepancies. Reconciled study drug will be returned to the sponsor or its 
designee.
During the study, all unused study drugs and the corresponding accountability forms must be
returned by the monitor to the sponsor or sponsor’s designee on an on-going basis for
reconciliation and destruction. A photocopy of these records must be kept at the study sites.
The accountability of the returned study drugs should be performed and recorded by the
sponsor’s assigned monitor. The Patient Number, the date, batch code/batch number, pack
number and quantity of study drugs returned by the patient will be checked for correctness and
recorded on the appropriate accountability forms, to be provided by the CSC via IWRS and/or 
IVRS. The monitor will use the IRT to record the returns.
3.8.
Maintenance of Randomization and Blinding 
The relevant SOPs regarding the maintenance of randomization and blinding will be followed by 
sponsor’s/vendor’s personnel.
Staff responsible for bioanalysis and pharmacokinetic data analysis will not have access to any 
clinical data and will provide concentration data to other staff members in a manner that will not 
identify individual patients (ie, a dummy patient identifier will be linked to an individual 
patient’s concentration data).
For a SUSAR, the sponsor’s Global Patient Safety and Pharmacovigilance Department may 
independently request that the treatment code be revealed if needed (on a case-by-case basis). If 
this occurs, the investigator will remain blinded to treatment.
All patients that discontinued the 1.5 mg dose have been unblinded.
3.9.
Source Data Recorded on the Case Report Form 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the investigational center obtains written 
documentation from the sponsor, before the beginning of the study, indicating which data are 
permitted to be recorded directly onto the CRF. 
Source data, including test results and/or assessments (eg, clinical laboratory test results, ECG 
data, safety and efficacy measurements) collected by institutions outside of the study center are 
sent to the study center, where they are retained but not entered into the CRF. These results may 
be sent directly to the sponsor for entry into the clinical database (see Section 13.1).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
55
The CRFs are filed in the sponsor’s central file. 
3.10.
Time Schedule
The study is expected to start in Q4 2014 and be completed in Q3 2017. Approximately 
375 patients from approximately 120 investigational centers in approximately 10 countries are 
planned to be enrolled in the study.
3.11.
Study Procedures 
Study procedures and assessments with their timing are summarized in Table 5 (up to week 48) 
and Table 6 (from week 60).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
56
Table 5:
Study Procedures and Assessments (up to Week 48)
Visit
Screening
Baseline
1
2
3
4
5
6
ET
Unscheduled Visita
Study weekb
up to -6
0
4
8
12
24
36
48
Informed consent
X
Eligibility criteria
X
X
Medical and MS history
X
Cardiovascular risk factor 
assessment and 
managementc
X
Prior and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
Randomization
X
First dose at site
X
Adverse event
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signsd
X
Xd
X
X
X
X
X
X
X
X
ECG
X
Xe
X
X
X
X
X
X
Chest X-rayf
X
Anemia panelg
X
Anemia panel is performed if there is a confirmed hemoglobin decrease of >1 g/dL from baseline
B12
X
B12 is analyzed if there is a confirmed hemoglobin decrease of >1 g/dL from baseline
Safety laboratory testsh
X
X
X
X
X
X
X
X
X
Xi
Fasting lipid profilej
X
X
X
Thyroid function tests
X
X
X
X
GFRk
X
X
X
X
X
X
X
X
X
Xi
HTLV- I/II
X
Urinalysis
X
β-hCGl
X
X
X
X
X
X
X
X
X
Home urine β-hCG testm
Every 28±2 days between visits; telephone confirmation within 72 hours of 
the scheduled home pregnancy test
Ascertain use of acceptable
contraception
X
X
X
X
X
X
X
X
X
X
Call IVRS/IWRS
X
X
X
X
X
X
X
X
X

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
57
Visit
Screening
Baseline
1
2
3
4
5
6
ET
Unscheduled Visita
Study weekb
up to -6
0
4
8
12
24
36
48
Study drug dispensing
X
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
X
MRIn
X
X
X
Xn
EDSS/FSSo
X
X
X
X
X
X
X
T25FWp
X
X
X
X
X
X
9HPTp
X
X
X
X
X
X
SDMTp,q,
Xq
X
X
X
Xq
X
BICAMSp,q
X
X
Xr
LCVA
X
X
X
X
MSWS-12
X
X
X
X
X
X
Pharmacokinetic samples
X
X
X
X
X
Xi
Potential biomarker samples
X
X
X
Xi
Pharmacogenomic samples
X
Ancillary studies
CSF assessmentt
X
OCT evaluation
Xu
X
Xv
Patients who are discontinued from study treatment will be encouraged to continue all scheduled visits and procedures after study drug discontinuation (with the 
exception of procedures associated with drug dispensing and accountability, pregnancy testing, and pharmacokinetic sampling).
a An unscheduled visit may be performed at any time at the patient’s request or per investigator’s discretion. Only mandatory procedures are specified; additional 
assessments per clinical discretion. In addition, 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.
b For the purpose of scheduling study visits, a week is defined as 7±2 days.
c In addition, an evaluation should take place as soon as possible for patients already in the study, following approval of Global Amendment 2.
d Vital signs include temperature, pulse and blood pressure. Height will be measured at screening visit. Weight will be measured at all visits. At baseline (week 
0), pulse and blood pressure will be measured pre dose as well as 30 and 60 minutes after onsite drug administration.
e At baseline (week 0), 3 ECG recordings 10 minutes apart are required before first dose.
f Chest X-ray can be omitted if the report of a chest X-ray performed within 24 weeks of screening is obtained, or if a screening chest X-ray is considered 
unacceptable per local regulations.
g Anemia panel includes blood smear, serum iron, ferritin, total iron binding capacity, folic acid, haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, and hepcidin. Assessed 
at baseline and also at 1 subsequent time point (with B12) if hemoglobin decrease of >1 g/dL from the patient’s hemoglobin level at baseline and the decrease 
is confirmed.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
58
h Serum chemistry (including electrolytes, fibrinogen, glucose, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl 
transpeptidase, alkaline phosphatase, creatine phosphokinase, C-reactive protein, pancreatic amylase [lipase will be tested in case of abnormal pancreatic 
amylase results], total protein, albumin, direct and total bilirubin) and complete blood count (CBC) with differential. Coagulation to be tested only if required 
according to Guidance on Safety Monitoring.
i Unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or samples for potential biomarker analysis 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.
j Fasting lipid profile includes total cholesterol, HDL, LDL (measured), and triglycerides.
k Patients 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 patient should stop study medication permanently.
l For women of child-bearing potential serum β-hCG test will be done at each scheduled study visit. Urine β-hCG tests will be done at each study visit; in case of 
a positive result, study drug should not be dispensed until the serum β-hCG result is available. At baseline, serum β-hCG will be done within 7 days prior to 
randomization, such that the result is available prior to the first dose; urine β-hCG test will also be done on site prior to the first dose.
m Starting from week 12 visit, women of child-bearing potential will be provided with home pregnancy urine β-hCG test kits and will be instructed how to 
perform the test. The site staff will schedule the home test to be performed every 28 ±2 days between study visits.
n MRI scans (without and with gadolinium) will be performed at least 14 days but not more than 6 weeks before baseline. MRI (without gadolinium) will be 
performed within 14 days of the week 24 and week 48 visits. In case of steroid treatment, study MRI should be delayed to allow a minimum of 14 days but not 
more than 28 days from the completion of the steroid course. ET visit will only include MRI for patients who prematurely terminate treatment subsequent to 
the week 36 visit and prior to week 48. Patients who stop treatment before week 36 or after week 48 will not have MRI at ET visit.
o Only an Examining Neurologist will administer the EDSS/FSS. The Examining Neurologist will not have access to the patient’s medical records or source 
documents, including previous EDSS/FSS forms or adverse events.
p Only a trained, blinded rater will administer the T25FW, 9HPT, BICAMS, and SDMT. The blinded rater will not have access to the patient’s medical records 
or source documents, including previous T25FW, 9HPT, BICAMS, or SDMT forms.
q At baseline and at week 48, SDMT will be performed as part of the BICAMS assessment.
r ET visit will only include BICAMS for patients who prematurely terminate treatment subsequent to the week 24 visit and prior to week 48. Patients who stop 
treatment before week 24 or after week 48 will not have BICAMS at ET visit.
s If the pharmacogenomic sample is not obtained at baseline for any reason, it should be collected at the next possible visit. This can be omitted if mandatory 
pharmacogenomic sampling is considered unacceptable per local regulations.
t CSF collection (in selected sites) will be performed for all patients who signed an appropriate, EC approved ICF.
u Week 0 OCT evaluation (in selected sites) will be performed up to 42 days prior to baseline, in all patients who signed an appropriate, EC approved ICF.
v ET visit will only include OCT for patients who prematurely terminate treatment subsequent to the week 24 visit and prior to week 48. Patients who stop 
treatment before week 24 or after week 48 will not have OCT at ET visit.
ET = early termination; MS = multiple sclerosis; ECG = electrocardiogram; GFR = glomerular filtration rate; HTLV-I/II = human T lymphotropic virus Type I 
and II; β-hCG = beta human chorionic gonadotropin; IVRS/IWRS = interactive voice response system/interactive web response system; MRI = magnetic 
resonance imaging; EDSS = Expanded Disability Status Scale; FSS = Functional System Score; T25FW = timed 25 foot walk; 9HPT = 9 Hole Peg test; SDMT = 
symbol digit modalities test; BICAMS = Brief International Cognitive Assessment for Multiple Sclerosis; LCVA = low contrast visual acuity; MSWS-12 = 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
59
12-Item Multiple Sclerosis Walking Scale; CSF = cerebrospinal fluid; OCT = optical coherence tomography; IL = interleukin; IFN = interferon; TNF = tumor 
necrosis factor; HDL = high density lipoprotein; LDL = low density lipoprotein; EC = Ethics Committee; ICF = informed consent form 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
60
Table 6:
Study Procedures and Assessments (from Week 60)
Visit
7
8
9
10
11
12
13
14
15
16
Completiona
ET
Unscheduled Visitb
Study weekc
60
72
84
96
108
120
132d
144d
156d
168d
Cardiovascular risk factor 
assessment and 
managemente
X
X
Prior and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
X
X
Anemia panelg
Anemia panel is performed if there is a confirmed hemoglobin decrease of >1 g/dL from baseline
B12
B12 is analyzed if there is a confirmed hemoglobin decrease of >1 g/dL from baseline
Safety laboratory testsh
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Fasting lipid profilej
X
X
X
X
Thyroid function tests
X
X
X
X
X
X
X
GFRk
X
X
X
X
X
X
X
X
X
X
X
X
Xi
β-hCGl
X
X
X
X
X
X
X
X
X
X
X
X
Home urine β-hCG testm
Every 28±2 days between visits; telephone confirmation within 72 hours of the scheduled home pregnancy test
Ascertain use of
acceptable contraception
X
X
X
X
X
X
X
X
X
X
X
X
X
Call IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
X
Xn
Study drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
EDSS/FSSo
X
X
X
X
X
X
X
X
X
X
X
X
mRS
X
T25FWp
X
X
X
X
X
X
X
X
X
X
X
X
9HPTp
X
X
X
X
X
X
X
X
X
X
X
X
SDMTp,q,
X
X
X
Xq
X
X
X
Xq
X
X
X
X
BICAMSp,q
X
X

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
61
Visit
7
8
9
10
11
12
13
14
15
16
Completiona
ET
Unscheduled Visitb
Study weekc
60
72
84
96
108
120
132d
144d
156d
168d
LCVA
X
X
X
X
X
X
X
MSWS-12
X
X
X
X
X
X
X
X
X
X
X
X
Ancillary study
OCT
Xr
Patients who are discontinued from study treatment will be encouraged to continue all scheduled visits and procedures after study drug discontinuation (with the 
exception of procedures associated with drug dispensing and accountability, pregnancy testing, and pharmacokinetic sampling).
a Once analyses are completed and the design of a potential extension study has been finalized, patients will be invited for a completion visit and offered the 
opportunity to enter into an anticipated extension study.
b An unscheduled visit may be performed at any time at the patient’s request or per investigator’s discretion. Only mandatory procedures are specified; additional 
assessments per clinical discretion. In addition, 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.
c For the purpose of scheduling study visits, a week is defined as 7±2 days.
d It is anticipated that few patients will require visits beyond week 120, however the number of visits required will depend on order and duration of enrollment. 
After week 168, further visits occur every 12 weeks until completion. If necessary, the visit at week 180 would have identical procedures to week 132, the visit 
at week 192 would have identical procedures to week 144. If a visit beyond week 192 is necessary, contact Sponsor for guidance.
e In addition, an evaluation should take place as soon as possible for patients already in the study, following approval of Global Amendment 2.
f Vital signs include temperature, pulse and blood pressure. Weight will be measured at all visits.
g Anemia panel includes blood smear, serum iron, ferritin, total iron binding capacity, folic acid, haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, and hepcidin. Assessed 
at baseline and also at 1 subsequent time point (with B12) if hemoglobin decrease of >1 g/dL from the patient’s hemoglobin level at baseline and the decrease 
is confirmed.
h Serum chemistry (including electrolytes, fibrinogen, glucose, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl 
transpeptidase, alkaline phosphatase, creatine phosphokinase, C-reactive protein, pancreatic amylase [lipase will be tested in case of abnormal pancreatic 
amylase results], total protein, albumin, direct and total bilirubin) and complete blood count (CBC) with differential. Coagulation to be tested only if required 
according to Guidance on Safety Monitoring. 
i Unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or samples for potential biomarker analysis 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.
j Fasting lipid profile includes total cholesterol, HDL, LDL (measured), and triglycerides.
k Patients 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 patient should stop study medication permanently.
l For women of child-bearing potential serum β-hCG test will be done at each scheduled study visit. Urine β-hCG tests will be done at each study visit; in case of 
a positive result, study drug should not be dispensed until the serum β-hCG result is available.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
62
m Starting from week 12 visit, women of child-bearing potential will be provided with home pregnancy urine β-hCG test kits and will be instructed how to 
perform the test. The site staff will schedule the home test to be performed every 28 ±2 days between study visits.
n Study drug will be dispensed at completion visit for those patients continuing to the potential extension study.
o Only an Examining Neurologist will administer the EDSS/FSS. The Examining Neurologist will not have access to the patient’s medical records or source 
documents, including previous EDSS/FSS forms or adverse events.
p Only a trained, blinded rater will administer the T25FW, 9HPT, BICAMS, and SDMT. The blinded rater will not have access to the patient’s medical records 
or source documents, including previous T25FW, 9HPT, BICAMS, or SDMT forms.
q At week 96 and every 48 weeks thereafter, SDMT will be performed as part of the BICAMS assessment
r OCT evaluation (in selected sites) will be performed in all patients who signed an appropriate, EC approved ICF.
ET = early termination; ECG = electrocardiogram; β-hCG = beta human chorionic gonadotropin; IVRS/IWRS = interactive voice response system/interactive 
web response system; EDSS = Expanded Disability Status Scale; FSS = Functional System Score; mRS = modified Rankin scale; T25FW = timed 25 foot walk; 
9HPT = 9 Hole Peg test; SDMT = symbol digit modalities test; BICAMS = Brief International Cognitive Assessment for Multiple Sclerosis; LCVA = low 
contrast visual acuity; MSWS-12 = 12-Item Multiple Sclerosis Walking Scale; OCT = optical coherence tomography; IL = interleukin; IFN = interferon; TNF = 
tumor necrosis factor; HDL = high density lipoprotein; LDL = low density lipoprotein; EC = Ethics Committee; ICF = informed consent form

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
63
3.11.1.
Screening Procedures
Prior to performing any study activities/evaluations, the patient must be thoroughly informed 
about all aspects of the study, including scheduled study visits and activities, and must sign the 
informed consent. A signed copy of the informed consent should be given to the patient. 
Screening should occur up to 6 weeks (42 days) prior to the baseline (week 0) visit. 
The following procedures will be performed:

The patient will be allocated a patient number by the investigator using IVRS and/or 
IWRS. The patient will then be assessed for eligibility criteria.
The activities will include:

Documentation of general, non-MS related medical history (including current and 
past smoking habits).

Complete history of MS including: 

the date of the first symptom 

the date of diagnosis of MS

documentation of clinical disability progression (retrospectively or prospectively 
determined) within the 2 years prior to screening

absence of relapses prior to screening.

All MS medications taken at any time prior to baseline and all concomitant 
medications taken up to 6 weeks prior to baseline will be recorded in the source 
document as well as in the CRF. Source documents from 2 years prior to the baseline
visit should be reviewed for the detection of disallowed medications, according to the 
exclusion criteria and the list in Sections 5.2.1 and 5.2.2.2 and Appendix C.

Vital signs (temperature, pulse, blood pressure [BP]), including height and weight.

Complete physical examination.

EDSS and FSS.

Laboratory tests, including:

complete blood count (CBC) with differential

serum chemistry (including electrolytes, fibrinogen, glucose, urea, creatinine, 
liver enzymes, creatine phosphokinase [CPK], CRP, pancreatic amylase, total 
protein, albumin, direct and total bilirubin).

estimated GFR (see Section 7.7)

human T lymphotropic virus Type I and II (HTLV-I/II)

urinalysis

serum and urine β-hCG in women of child-bearing potential

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
64

B12

ECG.

Chest X-ray (can be omitted if the report of a chest X-ray performed within 24 weeks 
of screening is obtained, or if a screening chest X-ray is considered unacceptable per
local regulations).

Adverse event recording (from the moment the patient signs the informed consent 
form).

Ascertain use of acceptable contraception. Women of child-bearing potential who are 
not yet practicing at least 1 acceptable method of birth control must practice an 
acceptable method for at least 30 days before taking the study drug.

Evaluation and management of major modifiable cardiac risk factors (eg, diabetes, 
high blood pressure, hyperlipidemia, tobacco smoking) and referral to treatment and 
follow-up in suitable clinic if needed.
Following completion of screening procedures by the site, special cases may need a central 
review by an eligibility evaluation committee prior to baseline.
3.11.1.1.
Re-Screening
Re-screening will be permitted on a case by case basis. A new informed consent form should be 
signed in any case of re-screening. A patient may only be re-screened once. Any patient who has 
previously participated in the study and early terminated cannot be re-screened.
A new patient number will be assigned to the patient. 
The required re-screening visit activities should be discussed on a case by case basis with the 
sponsor. 
Mandatory re-screening visit procedures:

vital signs and weight

review of concomitant medications

evaluation of adverse events

pregnancy test

EDSS and FSS 
Optional re-screening procedures:

ECG

physical examination

laboratory tests including estimated GFR

chest X-ray

MRI.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
65
The baseline (week 0) visit should take place within 6 weeks (42 days) from the re-screening 
visit.
3.11.2.
Baseline Visit Procedures (Week 0)
3.11.2.1.
Between 6 weeks (42 days) and 14 days Prior to Baseline

Brain and cervical spinal cord MRI scan without and with Gd.
3.11.2.2.
Up to 42 days Prior to Baseline
For patients participating in the OCT ancillary study, to be conducted only in selected countries 
and sites, after signature of an additional informed consent and ethics committee (EC) approval, 
the following assessment will be done:

OCT evaluation (in selected sites) will be performed in all patients who signed an 
appropriate, EC approved informed consent form, to assess retinal thickness.
3.11.2.3.
Up to 7 days Prior to Baseline

Serum β-hCG in women of child-bearing potential (result must be available prior to 
the first dose at baseline).
3.11.2.4.
Pre-randomization
The following procedures will be performed:

vital signs (temperature, pulse and BP) and weight

physical examination

EDSS and FSS

T25FW and 9HPT

BICAMS, including SDMT

LCVA

MSWS-12

ECG, 3 recordings 10 minutes apart before first dose

review of changes in concomitant medications since screening visit

inclusion/exclusion criteria confirmation, including confirmation of local radiologist 
that no MRI findings other than MS-related findings are present which exclude
patient’s participation in the study

adverse event recording

laboratory tests including:

CBC with differential 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
66

anemia panel (blood smear, serum iron, ferritin, total iron binding capacity, folic 
acid, haptoglobin, interleukin [IL]-1, IL-6, interferon [IFN]-γ, tumor necrosis 
factor [TNF]-α, and hepcidin)

serum chemistry (including electrolytes, fibrinogen, glucose, urea, creatinine, 
liver enzymes, CPK, CRP, pancreatic amylase, total protein, albumin, direct and 
total bilirubin)

estimated GFR

fasting lipid profile (total cholesterol, high density lipoprotein [HDL], low density 
lipoprotein [LDL, measured], triglycerides)

serum thyroid stimulating hormone (TSH), triiodothyronine (T3), and free 
thyroxine (T4)

urine β-hCG test will be performed in women of child-bearing potential

Blood samples for PGx assessment. If the PGx sample is not obtained at baseline for 
any reason, it should be collected at the next possible visit.

blood samples for potential biomarker measures

ascertain use of acceptable contraception
If all inclusion/exclusion criteria have been reviewed and are met, and the patient is eligible for 
treatment, he/she will be randomized (see Section 3.3).
3.11.2.5.
Post Randomization
The following procedures will be performed:

First dose administration of the study drug. 

Vital signs (pulse and BP will be measured predose and 30 and 60 minutes after first 
drug administration).

Adverse event recording will be performed upon any complaint following study drug 
administration (if relevant) or staff observation.

Patients will be given all the necessary supplies and detailed instructions for 
administration of study drug, which will be reviewed with the patient during the visit. 
In addition, patients will be instructed to contact the study center if any questions or 
problems arise.
Patients will be instructed to contact the study site in the event of any change in their medical 
condition, the appearance of any adverse events, or any symptom suggestive of a relapse.
3.11.3.
Scheduled Treatment Visits (Visits 1 to 6, Weeks 4 to 48, and Every 12 weeks 
Thereafter) 
Following the baseline visit, patients will return to the study center at weeks 4, 8, 12, and every 
12 weeks thereafter until completion. A week is defined as 7 ±2 days.
Procedures for study completion are detailed in Section 3.11.5.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
67
The following procedures and evaluations will be performed at these visits:

Call IVRS/IWRS.*

Vital signs (temperature, pulse, BP)

Weight*

Physical examination.

ECG (weeks 4, 8, 12, 24, and every 24 weeks thereafter)

Review concomitant medications.

Record adverse events.

Patient compliance (study drug accountability) and study drug dispensing.*

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 are available. The rest of the visit activities should be performed.*

Starting from week 12 visit, between study visits, women of child-bearing 
potential will be provided with home pregnancy urine β-hCG test kits and will be 
instructed how to perform the test. The site staff will schedule the home test to be 
performed every 28 ±2 days. To verify whether the test has been performed and to 
record the result of the test, a mandatory phone call will be performed by the 
Treating Neurologist or by the site’s nurse/study coordinator within 72 hours after 
the test was scheduled to be performed and the patient will be asked specific 
questions regarding the test. In case of a suspected pregnancy (positive urine 
β-hCG test result, delay of menstruation or any other reason suggesting 
pregnancy), the caller will ensure that the study drug has been stopped and the 
patient will be instructed to arrive to the study site as soon as possible (within 
10 days) for further evaluations with the remaining study medications.*

CBC with differential.

In case of hemoglobin decrease of >1 g/dL from the patient’s hemoglobin level at 
baseline:
-
patient will be re-tested to confirm decrease
-
if decrease confirmed, a thorough anemia work-up will be done 
including: 

directed medical history and physical examination 

anemia panel (blood smear, serum iron, ferritin, total iron 
binding capacity, folic acid, haptoglobin, IL-1, IL-6, IFN-γ, 
TNF-α, and hepcidin) and B12

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
68

additional investigations and follow-up per the investigator’s 
discretion or sponsor’s request

Serum chemistry (including electrolytes, fibrinogen, glucose, urea, creatinine, 
liver enzymes, CPK, CRP, pancreatic amylase, total protein, albumin, direct and 
total bilirubin).

estimated GFR*

Fasting lipid profile at week 48 and every 48 weeks until completion/ET.

Serum TSH, T3, and free T4 at week 24 and every 24 weeks until completion/ET.

Blood samples for potential biomarker measures will be collected at weeks 24 and 48.

Pharmacokinetic study: blood samples for analysis of laquinimod plasma 
concentrations will be collected at weeks 4, 8, 12, 24 and 48.*

Ascertain use of acceptable contraception.*

All patients will undergo brain and cervical spinal cord MRI scans without Gd at 
weeks 24 and 48.

Weeks 24 and 48 MRI will be performed within 14 days of the clinical visit.

In case of steroid treatment, study MRI should be performed before such 
treatment or delayed to allow a minimum of 14 days but not more than 28 days 
from the completion of the steroid course.

EDSS and FSS will be performed every 12 weeks until completion/ET visit (if 
applicable)

T25FW, 9HPT, and SDMT will be performed every 12 weeks until completion/ET 
visit (if applicable). At week 48 and every 48 weeks thereafter, SDMT will be 
performed as part of the BICAMS assessment.

mRS will be evaluated at week 72.

BICAMS, including SDMT, will be evaluated at week 48 every 48 weeks thereafter.

LCVA will be assessed at week 24 and every 24 weeks until completion/ET.

MSWS-12 will be performed at week 12 and every 12 weeks until completion/ET.

Evaluation and management of major modifiable cardiac risk factors (with referral to 
treatment and follow-up in suitable clinic if needed) will be performed at weeks 96
and 144.

Ancillary studies:

CSF (to be performed in selected sites) will be collected from all patients who 
signed an appropriate, EC approved informed consent form, at week 48 (see 
Section 8.4.1 for further details of the assessments).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
69

OCT evaluation (to be performed in selected sites) will be performed in all 
patients who signed an appropriate, EC approved informed consent form, at 
weeks 48 and 96 to assess retinal thickness.
* Patients who are discontinued from study treatment will be encouraged to continue all 
scheduled visits and procedures after study drug discontinuation (with the exception of 
procedures associated with drug dispensing and accountability, pregnancy testing, GFR testing, 
and pharmacokinetic sampling).
3.11.4.
Early Termination (ET) Visit 
The following procedures and evaluations will be performed at this visit:

call IVRS/IWRS

patient compliance (study drug accountability) 

vital signs (temperature, pulse, and BP) and weight 

physical examination 

ECG 

review concomitant medications

record adverse events

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. 

CBC with differential.

serum chemistry

estimated GFR

fasting lipid profile

serum TSH, T3, and free T4 

Ascertain use of acceptable contraception.

EDSS and FSS

T25FW and 9HPT

SDMT 

LCVA 

MSWS-12

MRI scan (without Gd): ET visit will only include MRI for patients who prematurely 
terminate treatment subsequent to the week 36 visit and prior to week 48. Patients 
who stop treatment before week 36 or after week 48 will not have MRI at ET visit. 
MRI will be performed within 14 days of ET visit. In case of steroid treatment, study 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
70
MRI should be performed before such treatment or delayed to allow a minimum of 
14 days but not more than 28 days from the completion of the steroid course.

BICAMS and OCT: ET visit will only include BICAMS and OCT for patients who 
prematurely terminate treatment subsequent to the week 24 visit and prior to week 48. 
Patients who stop treatment before week 24 or after week 48 will not have BICAMS 
and OCT at ET visit.
All reasons for ET will be documented in the source documents and the study drug termination 
CRF form should be recorded with the reason (the most severe) for ET. 
Women of child bearing potential that performed ET should continue using 2 acceptable 
contraception methods up to 30 days after the last dose of oral treatment was administered.
Pregnant women will perform ET visit procedures.
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.
3.11.5.
Completion Visit
The following patients will be considered to have completed the study:

Patients who participated in the study until the sponsor declared the completion of the 
study.
Patients who discontinue study drug but continue to attend scheduled study visits for follow-up 
are not considered to have completed the study.
For patients who performed a visit within the 4 weeks prior to this visit, certain activities that had
already been performed do not need to be repeated. However patient compliance/drug
accountability, review of concomitant medications, vital signs, ECG, and recording of adverse 
events must be performed in any case.
The following procedures and evaluations will be performed at this visit:

Call IVRS/IWRS

Patient compliance/study drug accountability

Vital signs (temperature, pulse and BP) and weight

Physical examination

ECG

Review concomitant medications

Record adverse events

Safety laboratory tests:

serum pregnancy test (β-hCG) for women of child-bearing potential, if applicable 

urine pregnancy test (β-hCG) for women of child-bearing potential, if applicable

CBC with differential

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
71

serum chemistry

estimated GFR

fasting lipid profile

serum TSH, T3, and free T4

Ascertain use of acceptable contraception.

EDSS and FSS

T25FW, 9HPT, and SDMT

LCVA

MSWS-12
Women of child bearing potential should continue using 2 acceptable contraception methods up 
to 30 days after the last dose of oral treatment was administered.
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.
Study drug will be dispensed at completion visit for those patients continuing to the potential
extension study.
3.11.6.
Unscheduled Visit 
An unscheduled visit may be performed at any time during the study at the patient’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:

a new adverse event or an adverse event follow-up

change in concomitant medications

possible relapse

relapse follow-up

laboratory follow-up

study drug dispensing, accountability and/or replacement

patient compliance

repeat MRI scan

other
If the visit is related to a relapse, this will be clearly indicated on the CRF and the Examining 
Neurologist will carry out a complete neurological evaluation (EDSS and FSS).
Mandatory unscheduled visit procedures (except for patients that perform the unscheduled visit 
for repeat MRI scan): 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
72

vital signs

evaluation of adverse events

review of concomitant medications

ascertain use of acceptable contraception.
Additional clinical procedures may be performed by the Treating Neurologist to assure patient 
safety, and must be recorded in the source documentation.
According to the judgment of the investigator or medical monitor, the following unscheduled 
procedures may be performed:

urgent safety laboratory test panel (see Section 7.3.4)

collection of unscheduled pharmacokinetic blood sample

collection of sample for potential biomarker analysis

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
73
4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.1.
Patient Inclusion Criteria 
Patients may be included in the study only if they meet all of the following criteria:
1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 
Revised McDonald criteria (see Appendix D).
2. Baseline MRI showing lesions consistent with PPMS in either or both brain and spinal 
cord.
3. Patients must have an EDSS score of 3 to 6.5, inclusive, at both screening and baseline
visits.a
4. Documented evidence of clinical disability progression in the 2 years prior to screening.
5. FSS of 2 for the pyramidal system or gait impairment due to lower extremity 
dysfunction.
6. Patients must be between 25 to 55 years of age, inclusive.
7. 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 2 acceptable methods of birth control during all study
duration and until 30 days after the last dose of treatment is administered. Acceptable 
methods of birth control in this study include: intrauterine devices, barrier methods 
(condom or diaphragm with spermicide), and hormonal methods of birth control (eg, oral 
contraceptive, contraceptive patch, long-acting injectable contraceptive).
8. Patients must sign and date a written informed consent prior to entering the study.
9. Patients must be willing and able to comply with the protocol requirements for the 
duration of the study. 
4.2.
Patient Exclusion Criteria 
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
1. Patients with history of any MS exacerbations or relapses, including any episodes of optic 
neuritis.
2. Progressive neurological disorder other than PPMS.
3. Any MRI record showing presence of cervical cord compression. 
4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that 
may explain the clinical signs and symptoms.
                                                
a A capped randomization procedure will be employed to ensure that the number of EDSS 6.0 and 6.5 patients will 
be no more than 20% of all enrolled patients.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
74
5. Relevant history of vitamin B12 deficiency.
6. Positive HTLV-I/II serology. 
7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to 
baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to 
baseline would not be exclusionary, provided no other exclusion criteria are met.
8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and 
azathioprine within 48 weeks prior to baseline.
9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate 
(TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β 
(either 1a or 1b), intravenous immunoglobulin (IVIG), or plasmapheresis within 8 weeks
prior to baseline.
10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if 
active washout (with either cholestyramine or activated charcoal) was done 2 months or 
more prior to baseline.
11. Prior use of monoclonal antibodies ever, except for:
a.
natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to 
baseline AND the patient is John Cunningham (JC) virus antibody test negative (as 
per medical history)
b. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical 
history) is higher than 80 cells/µL
12. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. 
Use of mitoxantrone >5 years before screening is allowed in patients with normal 
ejection fraction and who did not exceed the total lifetime maximal dose. 
13. Previous use of laquinimod.
14. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS 
disease modification) systemic (intravenous, intramuscular or oral) corticosteroid 
treatment within 8 weeks prior to baseline.
15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
16. Previous total body irradiation or total lymphoid irradiation.
17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any 
kind. 
18. Patients who underwent endovascular treatment for chronic cerebrospinal venous 
insufficiency (CCSVI) within 12 weeks prior to baseline. 
19. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to baseline.
20. Use of inducers of CYP3A4 within 2 weeks prior to baseline. 
21. Pregnancy or breastfeeding.
22. Serum levels ≥3×ULN of either ALT or AST at screening.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
75
23. Serum direct bilirubin which is ≥2×ULN at screening. 
24. Patients with a clinically significant or unstable medical or surgical condition that (in the 
opinion of the Investigator) would preclude safe and complete study participation, as 
determined by medical history, physical examinations, ECG, laboratory tests or chest 
X-ray. Such conditions may include:
a.
A major cardiovascular event (eg, myocardial infarction, acute coronary syndrome, 
decompensated congestive heart failure, pulmonary embolism, coronary 
revascularization) that occurred during the past 24 weeks prior to baseline.
b. Any acute pulmonary disorder.
c.
A CNS disorder other than MS that may jeopardize the patient’s participation in the 
study, including such disorders that are demonstrated on the baseline MRI.
d. A gastrointestinal disorder that may affect the absorption of study medication.
e.
Renal disease.
f.
Any form of acute or chronic liver disease.
g. Known human immunodeficiency virus positive status.
h. A history of drug and/or alcohol abuse.
i.
Unstable psychiatric disorder.
j.
Any malignancies, excluding basal cell carcinoma, in the 5 years prior to baseline.
25. A known history of hypersensitivity to Gd.
26. GFR 60 mL/min/1.73 m2 at screening visit.
27. Inability to successfully undergo MRI scanning, including claustrophobia.
28. Known drug hypersensitivity that would preclude administration of laquinimod, such as 
hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
Special cases may need a central review of the documentation by an eligibility evaluation 
committee prior to baseline. 
4.3.
Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a patient from the study or stop drug treatment due to any of the 
reasons listed in Section 4.3.1. In addition, a patient may be withdrawn from the study as 
described in Sections 3.6 and 5.3. 
Should a patient decide to withdraw after administration of study drug(s), or should the 
investigator decide to withdraw the patient, all efforts will be made to complete and report all 
observations up to the time of withdrawal. A complete final evaluation at the time of the 
patient’s withdrawal should be made and an explanation given as to why the patient is 
withdrawing or being withdrawn from the study.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
76
The reason for and date of withdrawal from study drug treatment and the reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed onto 
the CRF. If a patient withdraws consent, every attempt will be made to determine the reason. If 
the reason for withdrawal is an adverse event or a clinically significant abnormal laboratory test 
result, monitoring will be continued at the discretion of the investigator (eg, until the event has
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
specific event or test result(s) must be recorded on the source documentation and transcribed 
onto the CRF. 
All evaluations should be performed according to the protocol on the last day the patient takes 
study drug, or as soon as possible thereafter.
4.3.1.
Patient Withdrawal Criteria
A patient may withdraw or be withdrawn from the study for the following reasons:

death

patient withdrew consent

sponsor requested patient to be withdrawn

study terminated by the sponsor

protocol violation

non-compliance with study drug

lost to follow-up/failure to return

adverse event

lack of efficacy (according to the investigators decision)

pregnancy
For patients in the 1.5 mg arm who were withdrawn from study treatment, the reason will be 
recorded as ‘sponsor requested patient to be withdrawn’.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
77
5.
TREATMENT OF PATIENTS
5.1.
Study Drugs Administered
Until 01 January 2016, following the baseline visit patients were randomly assigned in a 1:1:1 
ratio into 1 of the following:

laquinimod capsules 0.6 mg (1 capsule of 0.6 mg laquinimod and 2 capsules of 
placebo)

laquinimod capsules 1.5 mg (3 capsules of 0.5 mg laquinimod)

placebo (3 capsules of placebo) 
From 01 January 2016, following the baseline visit patients will be randomly assigned in a 1:1 
ratio into 1 of the following:

laquinimod capsules 0.6 mg (1 capsule of 0.6 mg laquinimod and 2 capsules of 
placebo)

placebo (3 capsules of placebo) 
Compliance to study drug administration will be monitored.
5.2.
Prior and Concomitant Therapy or Medication 
All MS medications (taken at any time prior to baseline) and all concomitant medications taken 
up to 6 weeks prior to baseline will be recorded in the source document as well as the CRF. 
At each clinic visit after the screening visit, the investigator will ask patients whether they have 
taken any medications (other than study drug), including over-the-counter (OTC) medications, 
vitamins, or herbal or nutritional supplements, since the previous visit. Indication, dosage, and 
start and end dates should be entered on the CRF. 
5.2.1.
Disallowed Previous Medications/Therapies

Use of experimental or investigational drugs in a clinical study within 24 weeks prior 
to baseline.

Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide 
and azathioprine within 48 weeks prior to baseline.

Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate 
(TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), 
interferon-β (either 1a or 1b), IVIG, or plasmapheresis within 8 weeks prior to 
baseline.

Use of with teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, 
except if active washout (with either cholestyramine or activated charcoal) was done 
2 months or more prior to baseline.

Prior use of monoclonal antibodies ever, except for:

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
78

Natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to 
baseline AND the patient is JC virus antibody test negative at screening.

rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19) is higher than 
80 cells/µL.

Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. 
Use of mitoxantrone >5 years before screening is allowed in patients with normal 
ejection fraction and who did not exceed the total lifetime maximal dose. 

Previous use of laquinimod.

Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS 
disease modification) systemic (intravenous, intramuscular or oral) corticosteroid 
treatment within 8 weeks prior to baseline.

Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).

Previous total body irradiation or total lymphoid irradiation.

Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of 
any kind. 

Endovascular treatment for CCSVI within 12 weeks prior to baseline. 

Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to baseline.

Use of inducers of CYP3A4 within 2 weeks prior to baseline. 
Appendix C provides a partial list of CYP3A4 inhibitors and inducers.
5.2.2.
Concomitant Medications/Therapies During Study
5.2.2.1.
Allowed Medications/Therapies During Study
Administration of all medications, including indication, dose, frequency, and route of 
administration will be recorded in the source documentation file and in the CRF.

Symptomatic MS agents, such as anti-cholinergic and spasmolytic drugs, are 
permitted at clinically appropriate doses. Dose changes and initiation of symptomatic 
treatments during the study should be avoided if possible.

Short-term treatment (up to 5 days) with intravenous corticosteroids will be allowed 
during relapses, although these are rare in PPMS. The suggested treatment for a 
relapse will be intravenous methylprednisolone 500 to 1000 mg/day for 3 to 5 
consecutive days.

Other medications, excluding those mentioned in Appendix C may be given 
concomitantly as needed for the patient’s welfare.

Topical and inhaled steroids are allowed at the discretion of the Treating Neurologist
for indications other than MS.

Clinical studies have shown laquinimod to be a strong inducer of CYP1A2. Patients 
taking drugs that are metabolized by CYP1A2 (examples listed in Appendix E)

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
79
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 and 
1.2 mg. These studies showed that laquinimod, at both doses, is a weak inhibitor of 
CYP3A4. Patients taking drugs that are metabolized by CYP3A4 (specifically those 
with a narrow therapeutic index listed in Appendix E) should be advised that plasma 
levels of these drugs could increase when combined with laquinimod.

Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline
is allowed.
5.2.2.2.
Disallowed Concomitant Medications/Therapies During Study

glatiramer acetate 

interferon β-1a

interferon β-1b

natalizumab

fingolimod

teriflunomide

dimethyl fumarate

alemtuzumab

inducers of CYP3A4 such as rifampin (more examples listed in Appendix C)

moderate/strong inhibitors of CYP3A4 such as erythromycin and ketoconazole (more 
examples listed in Appendix C). 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

oral steroids, except as prescribed for non-MS reasons (eg, asthma, chronic 
obstructive pulmonary disease)

parenteral steroids (except if given as defined by protocol for treatment of a relapse as 
specified in Section 5.2.2.1)

chemotherapeutic agents

IVIG

plasmapheresis

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
80

any other experimental agents

other immunosuppressive or immunomodulating agents

other agents with the aim of disease modification
5.3.
Procedures for Monitoring Patient Compliance
Each investigator will be responsible for monitoring patient compliance. A check of study drug 
compliance will be performed during each visit after the initial dispensation of study drug, and 
study drug accountability records will be completed. If the investigator or the sponsor determines 
that the patient is not in compliance with the study protocol, the investigator and the sponsor 
should determine whether the patient should be withdrawn. The IEC/IRB should be notified, 
according to local regulations.
5.4.
Total Blood Volume
The total amount of blood to be drawn during the study for serum chemistry, CBC, 
pharmacokinetic, biomarker and PGx measurements is approximately 550 mL/patient.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
81
6.
ASSESSMENT OF EFFICACY 
6.1.
Primary Efficacy Variables 
BA, as defined by the PBVC from baseline to week 48. See Section 6.4.1 for MRI methodology 
and Section 9.6.4.1 for statistical analysis of BA.
6.2.
Secondary Efficacy Variables

Time to CDP, defined as increase in EDSS of ≥1 point from baseline EDSS, if EDSS 
at entry is ≤5.0 or increase of ≥0.5 point, if EDSS at entry is ≥5.5. This increase 
should be confirmed after at least 12 weeks. Progression cannot be confirmed during 
a relapse. See Section 6.4.2 for EDSS methodology and Section 9.6.4.3 for statistical 
analysis of CDP.

Time to CDP as measured by 2 types of events for each individual (progression 
cannot be confirmed during a relapse): 

An increase from baseline in EDSS score (≥1 point from baseline EDSS if EDSS 
at entry is ≤5.0, or increase of ≥0.5 point if EDSS at entry is ≥5.5), confirmed 
after at least 12 weeks, or

An increase of at least 20% from baseline in the T25FW score, confirmed after at 
least 12 weeks.
See Sections 6.4.2 and 6.4.3 for EDSS and T25FW methodologies, respectively, and 
Section 9.6.4.3 for statistical analysis of CDP.

Change from baseline to week 48 in the T25FW score. See Section 6.4.3 for 
methodology and Section 9.6.4.3 for statistical analysis.

The number of new T2 lesions at week 48. See Section 6.4.1 for MRI methodology, 
and Section 9.6.4.3 for statistical analysis of T2 lesion numbers.
6.3.
Exploratory/Other Efficacy Variables 
For a full list of exploratory/other variables see Section 9.6.3. Exploratory/other endpoints 
include BICAMS (see Section 6.4.5), time to CDP as measured by at least 1 of 4 types of events,
24-week CDP (see Section 6.4.2), T1 hypointense lesions, changes in T1-hypointense lesion 
volume, changes in T2 lesion volume, and MRI (see Section 6.4.1), T25FW (see Section 6.4.3), 
9HPT (see Section 6.4.4), SDMT (see Section 6.4.6), mRS (see Section 6.4.7), LCVA (see 
Section 6.4.8), MSWS-12 (see Section 6.4.9), relapses (see Section 6.4.10), and potential 
biomarker measures (see Section 8.2). Statistical analysis for exploratory endpoints will be 
detailed in the statistical analysis plan (SAP).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
82
6.4.
Methods and Timing of Assessing, Recording, and Analyzing 
Efficacy Data
Methods and timing of assessing efficacy data are discussed in Section 3.11. Procedures for 
recording efficacy data are discussed in Section 13.1, and methods of analyses are discussed in 
Section 9.6.4.
6.4.1.
MRI Evaluations
The patients will undergo up to 3 MRI scans:

baseline (at least 14 days but not more than 6 weeks prior to baseline)

week 24

week 48 (or ET visit if performed after the week 36 visit and prior to week 48).
Gd will be administered at baseline MRI only. In case of steroid treatment, study MRI should be 
performed before or be delayed to allow a minimum of 14 days, but not more than 28 days, from 
the completion of the steroid course.
The following parameters will be assessed:

normalized brain volume - at baseline

PBVC – at week 24 as well as week 48 or ET

T2-lesions volume – at baseline, as well as week 48 or ET

T1 hypointense lesions volume - at baseline, as well as week 48 or ET

number of GdE-T1 lesions – at baseline

number of new T2 lesions - at week 48 or ET

number of new T1 hypointense lesions - at week 48 or ET

thalamic volume, cortical volume, and white matter volume - at baseline

percent volume change (thalamus, cortex, white matter) - at week 48 or ET

normalized cervical cord area based on 3D T1-w acquisition of the cervical cord - at 
baseline

cervical cord area percentage volume change - at week 48 or ET

number of T2 cervical cord lesions based on a sagittal T2 acquisition of the cervical 
cord - at baseline

number of new T2 cervical cord lesions based on a sagittal T2 acquisition of the 
cervical cord - at week 48 or ET

normal-appearing brain tissue average MTR, at baseline, as well as week 48 or ET
If MTR is not performed due to MRI site technical limitations, this would not be considered a 
protocol violation.
Additional details of MRI procedures are presented in Appendix F and in the MRI manual.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
83
6.4.2.
Neurological Evaluations (EDSS and FSS)
Neurological evaluations (EDSS and FSS) will be performed in a treatment blinded manner by 
the Examining Neurologist. The patient will be instructed not to discuss his/her well-being and 
adverse events with the Examining Neurologist. Every effort should be made to ensure that the 
same Examining Neurologist will perform the neurological assessment at all visits for a 
particular patient.
EDSS and FSS will be assessed based on the Neurostatus scoring guidelines (Appendix G), a 
slightly modified neurological examination than the one described by Kurtzke (Kurtzke 1983).
The results will be recorded in standardized and validated examination forms (see Appendix G) 
as well as in the CRF. Fatigue will not contribute to the cerebral FSS and EDSS step.
6.4.3.
Timed 25-Foot Walk (T25FW)
The T25FW is a quantitative measure of lower extremity function. The patient 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 patient walk back the same 
distance. Patients may use assistive devices when doing this task.
The T25FW is administered in person by a blinded, trained rater. The rater need not be a 
physician or nurse.
Full instructions for the T25FW are provided in Appendix H.
6.4.4.
9-Hole Peg Test (9HPT)
The 9HPT is a brief, standardized, quantitative test of upper extremity function. It is a
component of the Multiple Sclerosis Functional Composite (MSFC). Both the dominant and non-
dominant hands are tested twice. The patient is seated at a table with a small, shallow container 
holding 9 pegs and a wood or plastic block containing 9 empty holes. A stopwatch is started and 
the patient picks up the 9 pegs, 1 at a time as quickly as possible, puts them in the 9 holes, and, 
once they are in the holes, removes them again as quickly as possible, 1 at a time, replacing them 
into the shallow container. The total time to complete the task is recorded. Two consecutive trials 
with the dominant hand are immediately followed by 2 consecutive trials with the non-dominant 
hand.
The 9HPT is administered in person by a blinded, trained rater. The rater need not be a physician 
or nurse.
Full instructions for the 9HPT are provided in Appendix I.
6.4.5.
Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) 
Score
The BICAMS battery of tests takes 15 minutes to complete, requires no specialist equipment and 
no specialist expertise in cognitive assessment (Langdon 2012). BICAMS comprises:

SDMT (see Section 6.4.6). While part of BICAMS, it will be administered as a 
standalone test, thus performing this as part of BICAMS is not required.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
84

California Verbal Learning Test–II (CVLT-II) (first 5 recall trials): this comprises a 
16-item word list, with 4 items belonging to each of 4 categories, arranged randomly. 
The list is read aloud 5 times in the same order to the patient, at a slightly slower rate 
than 1 item per second. Patients are required to recall as many items as possible, in 
any order, after each reading of the list. The test can be completed in 5 to 10 minutes, 
including instructions, testing and responses.

Brief Visuospatial Memory Test – Revised (BVMT-R) (first 3 recall trials): this 
requires the patient to inspect a 2 × 3 stimulus array of abstract geometric figures
(Form 1 from the Recall Stimulus Booklet). There are 3 learning trials of 10 seconds. 
The array is removed and the patient is required to draw the array from memory, with 
the correct shapes in the correct position. Scoring of the BVMT-R drawings will be 
performed by a central expert vendor.
The BICAMS is administered in person by a treatment blinded, trained rater. The rater does not 
need to be a physician or nurse.
Full instructions for the BICAMS administration and scoring are provided in the BICAMS
administration manual.
6.4.6.
Symbol Digit Modalities Test (SDMT)
SDMT is a traditional, person-administered cognitive test that measures visual processing speed 
in 5 minutes. It can detect cognitional changes over time and be done orally or in writing. 
Despite its brevity, the SDMT is probably the most robust correlate with abnormal brain MRI 
findings, including brain lesion volume, BA, diffusion tensor indices of normal-appearing brain 
tissue, and retinal thickness. In addition, other findings suggest that compared to other 
well-established measures of cognitive function, it more accurately reflects the qualitative nature 
of self-reported cognitive impairment.
Only verbal administration of the SDMT will be permitted in this study.
Full instructions for SDMT administration and scoring are provided in the BICAMS 
administration manual. Although SDMT is part of BICAMS, it will be administered as a 
standalone test during this study.
6.4.7.
Modified Rankin Scale
The mRS is a commonly used scale for measuring the degree of disability or dependence in the 
daily activities of people who have suffered a stroke or other causes of neurological disability
(Rankin 1957; Farrell et al 1991). The scale runs from 0 (no symptoms) to 5 (severe disability), 
with a score of 6 used in the event of a death (Appendix J).
6.4.8.
Low Contrast Visual Acuity (LCVA)
It has been demonstrated that LCVA, as measured using the Sloan Charts, has a substantial 
capacity to capture visual dysfunction in patients with MS. 
LCVA will be assessed for each eye separately and then binocularly, at week 0 (baseline), 
week 24, and every 24 weeks until completion/ET. At each visit, the letter acuity will be 
captured using 100%, 2.5%, and 1.25% contrast charts, from a distance of 2 meters, with the 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
85
patient’s usual distance correction. In case the patient is not familiar with the English/Roman 
alphabet, the Tumbling E charts will be used.
Detailed instructions for LCVA administration are provided in the operations manual.
6.4.9.
12-Item Multiple Sclerosis Walking Scale (MSWS-12)
The MSWS-12 was designed as a disease-specific, patient-based instrument, ie a patient reported 
outcome, for use in clinical studies and clinical practice, to capture the complex impact of MS on 
walking ability (Hobart et al 2003). It contains 12 questions with ordered responses, and has a 
recall period of 2 weeks (Appendix K). Individual items are scored on a Likert scale. The test 
takes less than 5 minutes to complete.
6.4.10.
Relapse Evaluation
6.4.10.1.
On-Study Relapse Evaluation
Relapses are rare events in PPMS. In the event of neurological symptoms suggestive of a relapse,
patients will be instructed to telephone their study site within 48 hours. The Treating Neurologist 
will evaluate the patient once any symptom suggestive of a relapse occurs. During a scheduled or 
unscheduled visit, in case of a suggested relapse, the Treating Neurologist will refer the patient
to the Examining Neurologist for performance of EDSS and FSS assessments. The Examining 
Neurologist will evaluate the patient within 7 days of symptom onset, conditional upon a 
symptomatic period of ≥48 hours.
6.4.10.2.
The Treating Neurologist
The Treating Neurologist will determine if a patient experiences a relapse (see relapse definition,
0) and whether to treat the relapse or not. The Treating Neurologist will remain blinded to study 
drug assignment.
6.4.10.3.
The Examining Neurologist
The Examining Neurologist will be responsible for all EDSS and FSS assessments. Throughout 
the study, the Examining Neurologist will remain unaware of the safety profile and will be kept 
blinded to all treatment assignments. For each patient, the same Examining Neurologist should 
be used for all neurological exams performed throughout the study.
Note: It is particularly important that the Treating Neurologist and the Examining Neurologist do 
not discuss safety issues or performance or scoring of the EDSS/FSS with each other. The
Examining Neurologist will not ask the patient any questions regarding his/her well being.
The Treating Neurologist will inform the patient of the importance of not discussing safety issues 
with the Examining Neurologist.
6.4.10.4.
Relapse Determination
An Examining Neurologist will administer the EDSS and FSS, unaware of patient’s well-being.
The Treating Neurologist will make the decision as to whether the neurological change is 
considered a relapse (see relapse definition, 0). Clinical relapses must be recorded in the CRF. 
Patients with a relapse may continue in the study.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
86
The Treating Neurologist will prescribe steroids or other concomitant medications as needed. 
The suggested treatment for a relapse will be intravenous methylprednisolone 500 to 
1000 mg/day for 3 to 5 consecutive days.
Follow-up visits to monitor the course of the relapse until stabilization will be made at Treating 
Neurologist discretion, in addition to the assessment at the next scheduled visit.
In the case of an ongoing relapse at the study completion/ET visit, patients will be followed up 
until relapse stabilization, wherever possible.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
87
7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study staff by evaluating the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, 
physical examination findings and concomitant medication usage.
During the conduct of the study, an independent DMC will review accumulating safety data on a 
regular basis to ensure the continuing safety of the study patients and study conduct issues.
The DMC will be composed of independent physicians with expertise in the relevant therapeutic 
field and other relevant experts, such as a statistician. The DMC will receive safety data 
periodically. They will have the right to recommend discontinuation of the study for safety 
reasons. 
DMC sessions can be open or closed. During open sessions, representatives of the sponsor may 
be present and information is provided and discussed in a blinded fashion. During closed 
sessions, the only participants are members of the DMC and the designated unblinded 
statistician. 
The DMC chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the study. The sponsor will work closely with the committee to 
provide the necessary data for review.
7.1.
Adverse Events 
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment. 
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of the study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during the study will not be considered adverse 
events. 
Worsening of the disease under study should be recorded as an adverse event only if the 
presentation and/or outcome is more severe than would normally be expected from the normal 
course of the disease in a particular patient.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
88

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions. (Note: A condition recorded as pre-existing 
that is intermittently symptomatic [eg, headache] and which occurs during the study 
should be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures or during any washout phase of the 
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, or require medical treatment or further diagnostic work-up, or are considered 
by the investigator to be clinically significant. Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events, but will be evaluated to monitor data
from patients who do not meet screening criteria 

all events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
AST or ALT ≥3×ULN, plus either bilirubin ≥2×ULN or INR >1.5) or Hy’s Law 
events require immediate study treatment cessation and reporting as a serious adverse 
event
7.1.2.
Recording and Reporting Adverse Events 
For adverse event recording, the study period is defined for each patient as that time period from 
signature of the informed consent form through the end of the follow-up period. For this study, 
the follow-up period is defined as 30 days after the last dose of study drug. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the Serious Adverse Event Form must 
also be completed and the serious adverse event must be reported immediately (see 
Section 7.1.5.3.1).
At each contact with the patient, the investigator or designee must query the patient for adverse 
events by asking an open-ended question such as, “Have you had any unusual symptoms or 
medical problems since the last visit? If yes, please describe.” All reported or observed signs and 
symptoms will be recorded individually, except when considered manifestations of a medical 
condition or disease state. A precise diagnosis will be recorded whenever possible. When such a 
diagnosis is made, all related signs, symptoms, and any test findings will be recorded collectively 
as a single diagnosis on the CRF and, if it is a serious adverse event, on the Serious Adverse 
Event Form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
89
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF. 
The relationship of each adverse event to study drug treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded 
as described below.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the choices on the following scale:
Mild: 
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe: 
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows:
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events which, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events, which, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

it does not follow a reasonable temporal sequence 
from the administration of the test drug.

it could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

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
(related)
This category applies to 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 nor felt with 
a high degree of certainty to be 
related to the study drug.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

it follows a reasonable temporal sequence from 
administration of the drug.

it cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

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.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
90
7.1.5.
Serious Adverse Events 
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

death

a life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death

inpatient hospitalization or prolongation of existing hospitalization means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled for an elective procedure or for treatment of a pre-existing 
condition that has not worsened during participation in the study will not be 
considered serious adverse events. 

persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions)

a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness 
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the laquinimod IB.
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events.
7.1.5.3.
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1) 
that occur during the study period (including the protocol-defined follow-up period), regardless 
of judged relationship to treatment with the study drug, must be reported to the sponsor by the 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
91
investigator within 24 hours of when the investigator learns about it. Completing the serious 
adverse event form and reporting the event must not be delayed, even if not all the information is 
available. The investigator does not need to actively monitor patients for adverse events once the 
study has ended. Serious adverse events occurring to a patient after the treatment of that patient
has ended should be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the Teva local safety officer (LSO) or other 
designated personnel (a contract research organization [CRO] in a country without a Teva LSO) 
Contact information is in the Clinical Study Personnel Contact Information section; the LSO will 
forward the report to the sponsor’s Global Patient Safety and Pharmacovigilance Department.
The following information should be provided to record the event accurately and completely:

study number TV5600-CNS-20006 (ARPEGGIO)

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility)
Additional information may include the following:

age and gender of patient

date of first dose of study drug

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant therapy (including doses, routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data 

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death: 

cause of death (whether or not the death was related to study drug)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the study drug, study 
procedures, and to underlying disease.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
92
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigational center within 24 hours of when it becomes 
known to the same address as the initial report. 
For all countries, the sponsor’s Global Patient Safety and Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences (CIOMS) form/XML 
file to the LSO/CRO for local submission to the regulatory authorities and IEC/IRBs and 
investigators, according to regulations. The investigator is responsible for ensuring that the 
IEC/IRB is also informed of the event, in accordance with local regulations.
The blinding will be maintained for the people who are involved directly in the study. Therefore, 
in case of a SUSAR, only the LSO (or CRO personnel involved with safety regulatory 
submissions) will receive the unblinded report for regulatory submission; the others will receive 
a blinded report. 
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 7.2).
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of laquinimod and the appropriate regulatory authorities/EC.
In addition to notifying the investigators and regulatory authorities/EC, other measures may be 
required, including the following: 

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to laquinimod
7.1.6.
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.
7.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from the study at any time at 
the discretion of the investigator. If a patient is withdrawn wholly or in part because of an 
adverse event, both the adverse event page and termination page of the CRF will be completed at 
that time. 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
93
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the sponsor as soon as possible of all patients who are being considered 
for withdrawal due to adverse events. Additional reports must be provided when requested.
If a patient is withdrawn from the study for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event that in the opinion of 
the investigator is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be need to take a prohibited medication, not the adverse event.
7.1.8.
Medical Emergencies
Medical emergencies must be reported to the individual identified in the clinical study personnel 
contact information section of this protocol.
Equipment, supplies, and properly skilled medical personnel must be accessible for an adverse 
event requiring immediate treatment. Any dose of study drug (whether the investigational 
product, reference therapy, or a placebo), whether taken intentionally or unintentionally, in 
excess of that prescribed must be immediately reported to the sponsor. When the identification of 
the study drug must be known, the investigator must follow the procedures outlined in 
Section 3.8. 
7.1.9.
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study. Any 
departures from the protocol because of adverse events must be noted on the CRF and in source 
documents, along with the reason for such departures. 
7.2.
Pregnancy 
Patients who are 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 use 2 acceptable methods of contraception throughout 
treatment duration and until 30 days after the last dose of treatment.
Acceptable methods of birth control include intrauterine devices, barrier methods (condom or 
diaphragm with spermicide), and hormonal methods of birth control (eg, oral contraceptive, 
contraceptive patch, long-acting injectable contraceptive).
The patients’ 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.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
94
Additionally, pregnancy tests (urine dipstick and/or serum pregnancy β-hCG test, as applicable 
per the relevant time point) will be performed.
All pregnancies of women participating in study that occur during the study, or within 30 days 
after the last dose of treatment was administered, are to be reported immediately to the individual 
identified in the clinical study personnel contact information section of this protocol, and the 
investigator must provide the LSO/CRO with the pregnancy form. The process for reporting a 
pregnancy is the same as that for reporting a serious adverse event (see Section 7.1.5.3).
Any woman who becomes pregnant during the study will discontinue treatment. Patients 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 adverse 
event or serious adverse event, as appropriate.
If the pregnancy does not continue to term, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.3.
Clinical Laboratory Tests
Clinical laboratory tests will be measured as detailed in the sections below.
7.3.1.
Serum Chemistry
The following serum chemistry tests will be performed at all study visits (except where stated):

electrolytes

fibrinogen

glucose

urea

creatinine (Note: GFR will be estimated at all visits)

ALT

AST

GGT

alkaline phosphatase

CPK

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
95

in case of CPK results >ULN, creatine kinase MB isoenzyme (CK-MB) and 
troponin will be tested by the central laboratory.

in case of CPK >10×ULN, an unscheduled visit to assess urine myoglobin will be 
required. The following blood tests will be repeated at the unscheduled visit: 
CPK, blood urea nitrogen, creatinine, electrolytes including potassium, calcium, 
phosphate.

CRP

pancreatic amylase

lipase will be tested in case of abnormal pancreatic amylase results

total protein

albumin

direct and total bilirubin

fasting lipid profile at weeks 0 and 48 and every 48 weeks until completion/ET.

TSH, T3, and T4 at weeks 0 and 24 and every 24 weeks until completion/ET.

Coagulation profile (prothrombin time [PT], activated partial thromboplastin time 
[aPTT] and INR),to be tested only if required according to Guidance on Safety 
Monitoring (see Appendix B).
7.3.2.
Complete Blood Count
CBC (with differential) will be performed at all study visits (except where stated) and will 
comprise the following tests:

Absolute neutrophil count

hemoglobin

hematocrit

platelet count

RBC count

mean corpuscular hemoglobin (MCH)

mean corpuscular hemoglobin concentration (MCHC)

mean corpuscular volume (MCV)

white blood cell (WBC) count and differential count

polymorphonuclear leukocytes (neutrophils)

lymphocytes

eosinophils

monocytes

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
96

basophils
7.3.3.
Anemia Panel
The anemia panel is assessed at baseline and also at 1 subsequent time point (with B12) if 
hemoglobin decrease of >1 g/dL from the patient’s hemoglobin level at baseline and the decrease 
is confirmed.

At baseline: blood smear, serum iron, ferritin, total iron binding capacity, folic acid, 
haptoglobin, IL-1, IL-6, interferon IFN-γ, TNF-α, and hepcidin. 

In case of hemoglobin decrease of >1 g/dL from the patient’s hemoglobin level at 
baseline:

patient will be re-tested to confirm decrease

if decrease confirmed, a thorough anemia work-up will be done including: 
directed medical history and physical examination 
anemia panel (blood smear, serum iron, ferritin, total iron binding 
capacity, folic acid, haptoglobin, IL-1, IL-6, IFN-γ, TNF-α, and hepcidin) 
and B12
additional investigations and follow-up per the investigator’s discretion or 
sponsor’s request
7.3.4.
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 will be performed on these samples:

serum chemistry panel (see Section 7.3.1)

CBC panel (see Section 7.3.2)

CK-MB

troponin
7.3.5.
Serology

Serology for hepatitis A, B and C viruses (to be performed in a central laboratory, 
only if required according to Guidance on Safety Monitoring, see Appendix B)

Serology for autoimmune hepatitis: anti-nuclear antibodies, anti smooth muscle 
antibodies (ASMA), anti-liver kidney microsomal (LKM) antibodies (to be performed 
in a central laboratory, only if required according to the Guidance on Safety 
Monitoring, see Appendix B)

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
97
7.3.6.
Urinalysis
Urinalysis, performed at the screening visit, will include the following:

protein

glucose

ketones

erythrocytes

leukocytes

pH
7.3.7.
Other Clinical Laboratory Tests

Serum pregnancy test (β-hCG) for women of child-bearing potential at all visits; at 
baseline, this will be done within 7 days prior to the initiation of treatment, such that 
the result is available prior to the first dose.

Urine pregnancy test (β-hCG) for women of child-bearing potential at all visits. In 
case of positive result, study drug should not be dispensed, until results of serum 
β-hCG test are available. The rest of the visit activities should be performed.

Starting from week 12 visit, between study visits, women of child-bearing potential 
will be provided with home pregnancy urine β-hCG test kits and will be instructed 
how to perform the test. The site staff will schedule the home test to be performed 
every 28 ±2 days. To verify whether the test has been performed and to record the 
result of the test, a mandatory phone call will be performed by the Treating 
Neurologist or by the site’s nurse/study coordinator within 72 hours after the test was 
scheduled to be performed. In case of a suspected pregnancy (positive urine β-hCG 
test result, delay of menstruation or any other reason suggesting pregnancy), the caller 
will ensure that the study drug has been stopped and the patient will be instructed to 
arrive to the study site as soon as possible (within 10 days) for further evaluations 
with the remaining study medications.
7.4.
Vital Signs and Weight
Vital signs will be measured as detailed in Section 3.11. Weight will be measured at all visits.
7.5.
Electrocardiography 
Central ECG reading is used in this study and ECGs should be performed according to central 
ECG reading instructions.
The patient should rest for at least 10 minutes before measurement is taken. Twelve-lead ECGs 
should be performed following the patient being in a supine position for 5 minutes. Three 
recordings will be performed before first dose during the baseline visit.
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 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
98
interpretation. All communications and diagnoses should be filed in the source documentation 
file.
Objective alerts are pre-defined as described in the central ECG reading manual. In these cases 
the site and the sponsor will be informed immediately.
The final decision whether the ECG findings are of clinical significance is under 
investigator/local cardiologist responsibility.
All unscheduled ECGs must be performed through central ECG reading.
7.6.
Physical Examinations 
Any abnormal findings assessed by the investigator as clinically significant should be recorded 
in the relevant CRF modules (eg, adverse event, medical history).
7.7.
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 1.3.2.1). 
Consequently, GFR will be estimated at all visits to monitor renal function in the study in order 
to identify patients with potentially impaired laquinimod clearance. Patients 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 patient 
should stop study medication permanently (see Section 3.6.5).
Following recent findings connecting Gd-based contrast agents and nephrogenic systemic 
sclerosis, the GFR result should be available prior to the baseline MRI scan. GFR estimation will 
be done in accordance with the central laboratory creatinine value measurement performed at the
screening visit. The central laboratory will report estimated GFR; however, if the result is not 
available prior to the baseline MRI scan, the CKD-EPI Creatinine Equation (2009) from the 
following online GFR calculator should be used by the investigator:
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm
7.8.
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 and Table 6. In addition, an evaluation should take place as soon as possible for patients 
already in the study, following approval of Global Amendment 2.
Cardiovascular risk management should be conducted according to evidence-based, local 
standard-of-care procedures. Patients will undergo referral to a suitable clinic if needed.
7.9.
Other Safety Measures and Variables: Concomitant Therapy or 
Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.2.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
99
8.
ASSESSMENT OF PHARMACOKINETICS/
PHARMACOGENOMICS/OTHER ANCILLARY STUDIES
8.1.
Pharmacokinetic Variables
Samples will be analyzed for laquinimod using an appropriate validated method. Incurred sample 
reanalysis may be performed. 
Blood samples (approximately 4 mL) will be collected from all patients at weeks 4, 8, 12, 24, 
and 48 for plasma concentration measurements of laquinimod.
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.
The dates and times of study drug administration and the date and time of each pharmacokinetic 
sample will be recorded on the source documentation and transcribed onto the CRF. 
Pharmacokinetics of laquinimod will be evaluated in this study using a PPK approach. Details of 
blood sampling collection and processing are provided in the Laboratory Manual.
8.2.
Potential Biomarker Measures
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) gene and RNA expression; 3) proteomic profile; and/or 4) other relevant 
biomarkers.
Details of sample collection and processing are provided in the Laboratory Manual.
Analysis will be performed if and when required. Since new biomarker techniques continue to be 
developed, the method and laboratory that will be recommended cannot be anticipated.
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.
8.3.
Pharmacogenomic Variables
PGx studies investigate the association between genetic sequence polymorphisms and/or gene 
expression signatures and clinical response to a certain therapeutic intervention. It may help 
explaining inter-individual variability and subsequently identify population subgroups that 
respond differently to the drug. Furthermore, regulatory guidance and white papers indicate that 
PGx analyses employing DNA collected from all study participants may support investigation of 
unexpected adverse events.
In order to allow any subsequent analyses, appropriate samples will be requested from all 
patients in the study; however this can be omitted if considered unacceptable per local 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
100
regulations. PGx assessment might include DNA variations potentially associated with clinical 
treatment responses to laquinimod (eg, clinical effect, pharmacokinetics, tolerability, and safety 
features or disease susceptibility and severity features). The final list of genes that might be 
investigated will be selected at a later stage before the analysis so as to allow updating with new 
scientific information. Genomic analysis could also include a sequencing of the whole genome if 
required.
The PGx sample should be collected at baseline; if the sample is not obtained at baseline for any 
reason, it should be collected at the next possible visit.
8.4.
Other Ancillary Studies
8.4.1.
Cerebrospinal Fluid (CSF) Assessment
Putative neuroprotective effects of laquinimod will be explored in a subset of patients (only 
selected sites will participate) by analyzing CSF levels of axonal, neuronal, and/or inflammatory 
markers. CSF will be collected via lumbar puncture according to standard or local practice, using 
atraumatic needles. Additional detail can be found in the CSF Ancillary Study Manual.
CSF (to be performed in selected sites) will be collected from all patients who signed an 
appropriate, EC approved informed consent form, at week 48.
8.4.2.
Optical Coherence Tomography (OCT) Evaluation 
OCT is a fast, non-invasive, interferometric technique that allows imaging of the retina, 
including the retinal nerve fiber layer (RNFL), which is principally composed of the axons of the 
ganglion cells that form the optic nerves. Since these axons are nonmyelinated until they 
penetrate the lamina cribrosa, the RNFL is an ideal structure for visualizing subtle processes of 
axonal degeneration.
Retinal degeneration in MS not only reflects a morphological correlate of the functional visual 
deficits in MS patients, but also mirrors the overall disability assessed by the EDSS and the BA 
measured by MRI. Therefore, OCT is an ideal tool for visualizing the processes of 
neurodegeneration, neuroprotection, and neurorepair in MS.
Additional detail can be found in Appendix L and the OCT Ancillary Study manual.
OCT (to be performed in selected sites) will be performed in all patients who signed an 
appropriate, EC approved informed consent form, at week 0 (can be performed up to 42 days 
prior to baseline), week 48 (or ET visit if performed after the week 24 visit and prior to 
week 48), and week 96 to assess retinal thickness.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
101
9.
STATISTICS 
9.1.
Study Design and Randomization
This study is a multinational, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study, to evaluate the efficacy, safety and tolerability of daily oral 
administration of laquinimod (0.6 or [until 01 January 2016] 1.5 mg) in patients with PPMS.
Randomization will be as described in Section 3.3. The analyses described in Sections 9.6 and 
9.8 will be performed using data collected during Part A (Core Study). Data collected during 
Part B may be used for additional exploratory analyses as will be described in a SAP, to be
approved and signed prior to unblinding the Part A data.
9.2.
Sample Size and Power Considerations
Sample size calculations were based on the following assumptions:

2-sided alpha level of 5%

treatment difference (delta) of 0.3 in PBVC

standard deviation of 0.8
Under the above assumptions 252 patients enrolled for 0.6 mg and placebo (126 per arm) will 
provide 84% power to detect a statistically significant result for 0.6 mg laquinimod arm 
comparison to placebo. To adjust for the anticipated 10% dropouts, the sample size was 
increased to 280 patients. Adding 95 patients on 1.5 mg yields a total of 375 patients.
9.3.
Populations 
9.3.1.
Intent-to-Treat (ITT) Population
The intent-to-treat (ITT) population will include all randomized patients. In this population, 
treatment will be assigned based on the treatment to which patients were randomized, regardless 
of which treatment they actually received.
9.3.2.
Modified ITT 1 (mITT1) Population 
The modified ITT 1 (mITT1) population is a subset of the ITT set. It will include all patients in 
the ITT population with at least 1 post baseline PBVC assessment.
9.3.3.
Modified ITT 2 (mITT2) Population 
The modified ITT 2 (mITT2) population is a subset of the ITT set. It will include all patients in 
the ITT population with at least 1 post baseline efficacy assessment.
9.3.4.
Safety (ST) Population
The safety (ST) population will include all randomized patients who receive at least 1 dose of 
study drug. In this population, treatment will be assigned based upon the treatment patients 
actually receive, regardless of the treatment to which they were randomized. 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
102
9.3.5.
Per-Protocol (PP) Population
The Per Protocol (PP) population is a subset of the mITT1 population and will consist of all 
patients with no major protocol violations.
9.4.
Data Handling Conventions
Only the observed data from the patients will be used in the statistical analyses. There is no plan 
to estimate missing data.
The censoring rules for time to event analysis will be as described in Section 9.6.2.
9.5.
Study Population
The ITT population (see Section 9.3) will be used for all study population summaries unless 
otherwise noted. Summaries will be presented by treatment group and for all patients.
9.5.1.
Patient Disposition
Data from patients screened, patients screened but not randomized (and reason not randomized), 
patients who are randomized (ITT), patients randomized but not treated (and reason not treated), 
patients in the safety, mITT1, mITT2, and PP populations, patients who complete the study, and 
patients who perform ET will be summarized using descriptive statistics. Data from patients who 
perform ET will also be summarized by reason for discontinuation using descriptive statistics.
9.5.2.
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including MS history, medical history, prior 
medications, ECG findings, and baseline MRI will be examined to assess the comparability of 
the treatment groups and will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, standard deviation, standard error, median, 
minimum, and maximum) will be provided. For categorical variables, patient counts and 
percentages will be provided. Categories for missing data will be presented if necessary.
Treatment groups will be compared for all baseline variables, using an appropriate methodology. 
Further details will be specified in the SAP.
9.6.
Efficacy Analysis 
Due to the decision from 01 January 2016 to discontinue the laquinimod 1.5 mg dose arm, and a 
low study exposure at this time, the laquinimod 1.5 mg dose arm will be presented descriptively 
only, and will not be included in any inferential analyses.
In addition, all efficacy analyses will be performed based on the measurements recorded during 
the study treatment period, ie, data captured following an early termination visit as described in 
Section 3.6.7 will be excluded from the analyses. The data captured after an early termination 
visit will be used for the sensitivity analyses of the primary and secondary endpoints.
9.6.1.
Primary Variable
The primary variable for this study will be BA as defined by the PBVC from baseline to 
week 48.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
103
9.6.2.
Secondary Variables
1. Time to CDP.
Time to CDP will be defined as increase in EDSS of 1 point from baseline EDSS, if EDSS at 
entry is ≤5.0 or increase of 0.5 point, if EDSS at entry is 5.5. This increase should be 
confirmed after at least 12 weeks. Progression cannot be confirmed during a relapse.
To calculate the time of CDP, the following algorithm will be used:
Let Et be an EDSS measurement of the patient under consideration observed at time (measured 
by weeks from the patient’s baseline date). 
Let E0 be the baseline EDSS measurement for that patient. 
Let s = t +12.
The time to CDP for the patient under consideration is defined as t if all the following conditions 
hold:
1.
If 
5
0
0 
E
then let
1


. Otherwise, let
5.0


.
2.



0
E
Et
.
3. For any t < q1< s, if the patient’s EDSS was evaluated at time q1, then Eq1 ≥ E0 + ∆
4. Eq2 ≥ E0 + ∆ for some q2 ≥s, and at time q2, the patient was not experiencing a relapse.
5.
t is the earliest time point during the study in which conditions 2-4 hold.
If no such t exists, then the time to confirmed progression will be right censored by the patient’s 
last EDSS evaluation date from Part A of the study. In case time t exists without fulfilling 
conditions 3 and 4 because time q2 is after the patient completed Part A of the study (or 
performed ET), and therefore cannot be seen, then the right censored will be on time t and not in 
the last EDSS evaluation.
If a patient died due to MS disease progression, then this patient will be analyzed as having CDP 
and the time to CDP will be calculated using the onset date of progression.
If a patient died due to MS before having progression, then the time to disability progression will 
be censored using the date of death.
2. Time to CDP event defined by reaching at least 1 of the following 2 types of event for 
each individual:

An increase from baseline in EDSS score (≥1 point from baseline EDSS, if EDSS at 
entry is ≤5.0 or increase of ≥0.5 point, if EDSS at entry is ≥5.5), confirmed after at 
least 12 weeks, or

An increase of at least 20% from baseline in the T25FW score, confirmed after at 
least 12 weeks
Similar algorithm to that described for CDP as measured by EDSS confirmed after at least
12 weeks will be used for definition and censoring rules of this variable.
3. Change from baseline to week 48 in the T25FW score.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
104
4. The number of new T2 lesions at week 48.
9.6.3.
Exploratory/Other Variables

Change from baseline to week 48 in the BICAMS score (CVLT-II, BVMT-R, and 
SDMT)

Time to CDP as measured by at least 1 of 4 types of events for each individual 
(progression cannot be confirmed during a relapse):

An increase from baseline in EDSS score (≥1 point from baseline EDSS if EDSS 
at entry is ≤5.0, or increase of ≥0.5 point if EDSS at entry is ≥5.5), confirmed 
after at least 12 weeks or

An increase of at least 20% from baseline in T25FW score, confirmed after at 
least 12 weeks or

An increase of at least 30% from baseline in the 9HPT score, confirmed after at 
least 12 weeks or

A decrease of at least 20% from baseline in the SDMT score, confirmed after at 
least 12 weeks

Time to CDP confirmed after at least 24 weeks. 

New T1-hypointense lesions, changes in T1-hypointense lesion volume, and changes 
in T2 lesion volume.

MRI, including thalamic, cortical, white matter, and cervical cord atrophy, number of 
cervical cord T2 lesions, and normal-appearing brain tissue average MTR.

mRS (at week 72, visit 8).

T25FW.

9HPT.

LCVA.

MSWS-12

Relapses.

Pharmacokinetic measures (determination of plasma concentration of laquinimod)

PGx measures.

Potential biomarker measures.

Ancillary studies measures.
9.6.4.
Planned Method of Analysis
The mITT1 and mITT2 populations (see Section 9.3) will be used for all efficacy analyses, 
unless otherwise noted. Summaries will be presented by treatment group. 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
105
9.6.4.1.
Primary Efficacy Analysis
The primary efficacy variable for this study is BA as measured by the PBVC from baseline to 
week 48. This endpoint will be analyzed using the mITT1 population with at least 
1 post-baseline PBVC value and will include assessments taken up to/including early 
termination/study completion visit (data recorded following an early termination visit will be 
excluded from this analysis). BA will be analyzed using baseline-adjusted repeated measures 
analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast will be 
constructed in order to compare between laquinimod 0.6 mg and placebo. 
The model will be comprised from the treatment group as a class variable (2 levels). In addition 
to the treatment group, week (categorical), treatment by week interaction, normalized brain 
volume at baseline, natural logarithm of T2 lesion volume at baseline, and Country/Geographical 
Region (CGR) will be used as covariates. Additionally, week (categorical) will be specified as a 
repeated effect and unstructured (UN) correlation matrix will be used to model intra-subject 
correlation. In case a convergence issue will arise using the UN correlation matrix, (1) AR1 or 
(2) Compound Symmetry (CS) will be used to enable model convergence (in this order).
Mean values of the PBVC from baseline to weeks 24 and 48 will be summarized using 
descriptive statistics.
The assumption of a no treatment-by-covariate interaction will be evaluated by a separate 
repeated measures ANCOVA model (SAS® PROC MIXED) with the items treatment, week 
(categorical), week by treatment interaction, CGR, baseline, and treatment-by-baseline covariate 
interaction included in the model. If there is evidence of treatment-by-covariate interaction 
(p≤0.10), further exploration of this interaction will be done graphically/descriptively and the 
treatment p-values will still be reported from the main effects model (repeated measures 
ANCOVA from above). 
The consistency of treatment effects among different CGR will be evaluated by a separate 
repeated measures ANCOVA model (SAS® PROC MIXED) with treatment, week (categorical), 
week by treatment interaction, CGR, and treatment-by-CGR interaction in the model. If there is 
evidence of a treatment-by-CGR interaction (p≤0.10), a descriptive summary of treatment 
differences for each CGR will be used to identify the Country (or Countries) for which the 
treatment effects are consistent with the remaining countries. This will be an exploratory analysis 
and the treatment p-values will still be reported from the main effects model (repeated measures 
ANCOVA from above).
9.6.4.2.
Sensitivity Analyses
The robustness of the primary analysis results will be explored by applying it, as described in the 
previous section, to the PP population as well. In addition the, following sensitivity analysis will 
be performed:

Repeat the primary analysis without introduction of covariates except for the 
treatment group, week, and treatment by week interaction.

Repeat the primary analysis when introducing additional baseline covariates variables 
that differ appreciably between the treatment groups, if any. The list of baseline 
measurements will be provided in the SAP.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
106

Repeat the primary analysis while including observations that were recorded 
following an early termination visit.
9.6.4.3.
Secondary Efficacy Analysis
a.
Time to CDP as measured by EDSS confirmed after at least 12 weeks will be 
analyzed using the ITT population and data from all the study assessments up 
to/including early termination/study completion visit (data recorded following an 
early termination visit will be excluded from this analysis). This analysis will be 
performed using a baseline adjusted Cox’s proportional hazards regression model 
(SAS® PROC PHREG) in which 1 contrast for comparing laquinimod 0.6 mg to 
placebo will be constructed. In addition to treatment group, categorical EDSS at 
baseline (≤4.5 or >4.5), age at baseline, natural logarithm of T2 lesion volume at 
baseline, and CGR will be used as covariates.
The adequacy of the proportional hazards assumption will be confirmed by including 
1 time-dependent covariate of dose (as dummy variable) by log (time) interactions in 
the analysis model and testing each of them at the 5% level. In case the proportional 
hazards assumption will be rejected, the log rank test (SAS® PROC LIFTEST) will be 
used for statistical inference.
b. Time to CDP, confirmed after at least 12 weeks as measured by EDSS or T25FW will 
be analyzed using the ITT population and data from all the study assessments up 
to/including early termination/study completion visit (data recorded following an 
early termination visit will be excluded from this analysis). This analysis will be 
performed using baseline adjusted Cox’s proportional hazards regression model 
(SAS® PROC PHREG) in which 1 contrast for comparing laquinimod 0.6 mg to 
placebo will be constructed. In addition to treatment group, categorical EDSS at 
baseline (≤4.5 or >4.5), age at baseline, T25FW at baseline, natural logarithm of T2 
lesion volume at baseline, and CGR will be used as covariates. 
The adequacy of the proportional hazards assumption will be confirmed by including 
1 time-dependent covariate of dose (as dummy variables) by log (time) interactions in 
the analysis model and testing each of them at the 5% level. If the proportional 
hazards assumption will be rejected, the log rank test (SAS® PROC LIFTEST) will be 
used for statistical inference.
c.
Change from baseline in the T25FW score at week 48 will be analyzed on the mITT2 
population and will include assessments taken up to/including early termination/study 
completion visit (data recorded following an early termination visit will be excluded 
from this analysis). Since this variable might not follow normal distribution, the 
ranked values of this measurement will be defined and analyzed using baseline 
adjusted repeated measures ANCOVA (SAS® PROC MIXED) in which 1 contrast 
will be constructed in order to compare between laquinimod 0.6 mg and placebo. In 
addition to treatment group, T25FW score at baseline and CGR will be used as 
covariates. Due to the fact that the ANCOVA model will use ranked values and not 
the actual changes in the T25FW, Hodges-Lehmann estimates will be used in order to 
present the magnitude of the treatment effect and the corresponding two-sided 95% 
confidence.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
107
d. The number of new brain T2 lesions at week 48 will be analyzed using the mITT1
population with at least 1 post-baseline T2 scan available if it was performed at least 
36 weeks under treatment and will include assessments taken up to/including early 
termination/study completion visit (data recorded following an early termination visit 
will be excluded from this analysis).. This analysis will be performed using baseline 
adjusted negative binomial regression model (SAS® PROC GENMOD) in which 1 
contrast for comparing laquinimod 0.6 mg to placebo will be constructed. In addition 
to the treatment group, the natural logarithm of T2 lesion volume at baseline, age at 
baseline, and CGR will be used as covariates.
All the secondary analyses mentioned in this section will be repeated while including 
observations that were recorded following an early termination visit.
9.6.4.4.
Exploratory Efficacy Analysis
Detailed methodology for analyses of exploratory efficacy and other variables will be specified 
in the SAP signed and approved before treatment unblinding.
9.7.
Multiple Comparisons and Multiplicity
All statistical tests will be performed at 5% nominal significance level to further define the 
effects estimates of laquinimod but not for strict statistical inferences. Therefore, no adjustments 
will be made for the preplanned multiple comparisons.
9.8.
Safety Variables and Analysis
9.8.1.
Safety Variables
All safety analysis will be performed for ST population. Summaries will be presented by 
treatment group and for all patients unless otherwise noted. 
The overall safety and tolerability of laquinimod treatment will be assessed throughout the study 
by evaluating adverse events and the following additional safety variables:

clinical laboratory tests

vital signs

12-lead ECG

concomitant medications use throughout the study
9.8.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) category for the analyses of safety. Summaries will be presented for all adverse events 
(overall and by severity), adverse events determined by the investigator to be related to study 
treatment (ie, reasonable possibility; see Section 7.1.4) (defined as related or with missing 
relationship) (overall and by severity), serious adverse events, and adverse events causing ET. 
Patient listings of serious adverse events and adverse events leading to discontinuation will be 
presented.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
108
Changes in laboratory and vital signs measurement data will be summarized descriptively. All 
values will be compared with prespecified boundaries to identify potentially clinically significant 
changes or values, and such values will be listed. Additionally, descriptive summaries of 
potentially clinically significant abnormal values (clinical laboratory or vital signs) will be 
provided.
The use of concomitant medications will be summarized by preferred term and therapeutic class 
using descriptive statistics. Concomitant medications will include all medications taken while 
patient participated in the study.
For continuous variables, descriptive statistics (n, mean, standard deviation, standard error, 
median, minimum, and maximum) will be provided for actual values and changes from baseline 
to each time point. For categorical variables, patient counts and percentages will be provided. 
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report. 
9.9.
Pharmacokinetic Analysis
A single blood sample will be collected from all patients at weeks 4, 8, 12, 24 and 48. 
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.
Pharmacokinetics of laquinimod will be evaluated using a PPK approach. The PPK model may 
also include any unscheduled pharmacokinetic samples collected to assist with further 
investigations of cardiovascular events or other clinical event of interest (see Section 8.1).The 
effect of covariates on the pharmacokinetics of laquinimod will be evaluated. Possible covariates 
will include demographic variables (eg, age, gender, body weight and ethnicity), clinical 
variables, concomitant medications, blood and urine chemistry variables and markers of renal 
function (creatinine clearance and serum creatinine).
The date and time of the blood sample, as well as the date and time of the last study drug dose 
prior to the sample will be recorded on the CRF.
9.10.
Planned Interim Analysis
No interim analysis is planned for this study. 
9.11.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the complete statistical plan, the clinical study report, or any 
combination of these, as appropriate.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
109
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that patient
confidentiality is maintained in accordance with local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, study drug label records, protocol required worksheets, and CRFs that are used as the 
source (see Section 3.9).
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
110
11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB, except when necessary to 
address immediate safety concerns to the patients or when the change involves only logistics or 
administration. The principal investigator and the sponsor will sign the protocol amendment. 
11.1.2.
Protocol Deviations
Any significant deviation from the protocol will be considered a protocol violation. Protocol 
violations include nonadherence on the part of the patient, the investigator, or the sponsor to 
protocol-specific inclusion/exclusion criteria, primary objective variable criteria, or GCP 
guidelines; noncompliance to study drug administration; use of prohibited medications; or any 
other deviations that may have an impact on the processes put in place for the care and safety of 
the patients. Protocol violations will be identified and recorded by investigational center
personnel on the CRF. All protocol violations will be reported to the responsible IEC/IRB, as 
required.
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documentation from the 
medical representative. The decision will be based on ensuring the safety of the patient and 
preserving the integrity of the study. 
Deviations from the inclusion/exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
eligibility criteria was entered into a study, they must immediately inform the sponsor of the 
protocol violation. If such patient has already completed the study or has withdrawn early, no 
action will be taken but the violation will be recorded.
11.2.
Information to Study Personnel
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff become involved). The investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 
investigational center authorization form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring they comply with the protocol. Additional information will be 
made available during the study when new staff become involved in the study and as otherwise 
agreed upon with either the investigator or the study monitor.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
111
11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and each investigator. The 
main responsibilities of the study monitors are to visit each investigator before, during, and after 
the study to ensure adherence to the protocol, that all data are correctly and completely recorded 
and reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitors will contact each investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, to include specific electronic 
source documentation [see Section 3.9]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification (SDV) flags to the CRF and will ensure that 
all required electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. Each investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication.
11.4.
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 and/or clinical device supplies used in a 
clinical research study sponsored by Teva. Examples of a product complaint include but are not 
limited to the following: 

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc.)

defective components

missing or extra units (eg, primary container is received at the site 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

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
112
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 patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible. 
11.4.1.
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

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient 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 complaint must not be delayed because not all the required information can be 
immediately obtained. Known information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding information.
11.4.2.
Handling the 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 of the 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 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
113
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event, the protocol should be followed.
11.4.4.
Documenting a Product Complaint
The investigator will record a description of the product complaint in the source documentation 
as well as any actions taken to resolve the complaint and to preserve the safety of the patient. 
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.
11.5.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor Global Clinical 
Quality Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) an investigational center audit.
Each investigator must accept that regulatory authorities and sponsor representatives may 
conduct inspections to verify compliance with GCP guidelines.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
114
12.
ETHICS 
12.1.
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. Written informed consent will be obtained from each patient before any study specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, according to the IEC/IRB requirements. 
Overall, this study includes: (I) an informed consent for the clinical study (main study),(II) 
informed consent forms for the ancillary studies (CSF and OCT), and (III) informed consent 
forms for dummy run scans (MRI and OCT) required prior to initiation of the study and ancillary 
study respectively.
The patient’s willingness to participate in the study will be documented in writing in a consent 
form, which will be signed and personally dated by the patient. The investigator will keep the 
original consent forms, and copies will be given to the patients. It will also be explained to the 
patients that they are free to refuse entry into the study and free to withdraw from the study at 
any time without prejudice to future treatment.
Written and/or oral information about the study in a language understood by the patient will be 
given to all patients.
12.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards 
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center 
before the IEC/IRB and health authority (where applicable) for the center give written approval 
or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients 
The investigator must assure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification code (eg, initials and identification number).
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential.
12.4.
Declaration of the End of the Clinical Study 
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
115
12.5.
Registration of the Clinical Study 
This clinical study will be registered on clinical trials registry websites according to Teva 
standard procedures.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
116
13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND 
RECORD KEEPING 
13.1.
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21 CFR part 11. Before being used to capture data from this 
study, the CDMS will be fully validated to ensure that it meets the scientific, regulatory, and 
logistical requirements of the study. Before using the CDMS, all users will receive training on 
the system and any study-specific training. After they are trained, users will be provided with 
individual system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient screened according to the data source. 
Patient identity should not be discernible from the data provided on the CRF. Data will be 
verified using the data source by the study monitor, and reviewed for consistency by Data 
Management using both automated logical checks and manual review. All data collected will be 
approved by the investigator at the investigational center. This approval acknowledges the 
investigator’s review and acceptance of the data as being complete and accurate. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center), the results will be sent to the investigational center, where they will be retained 
but not entered into the CRF. These results may also be sent electronically to the sponsor (or 
organization performing data management) for direct entry into the clinical database (see 
Section 3.9). Laboratory test results will not be entered into the CRF unless otherwise noted in 
the protocol.
For patients who enter a study but do not meet screening criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2.
Data Quality Assurance 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality assurance, will 
comply with international regulatory guidelines (eg, ICH GCP). Data management and control 
processes specific to this study, along with all steps and actions taken regarding data 
management and data quality assurance, will be described in a data management plan.
CRFs received will be processed and reviewed for completeness, consistency, and the presence 
of mandatory values. Applicable terms will be coded according to the coding conventions for 
this study. Logical checks will be implemented to ensure data quality and accuracy. Any 
necessary changes will be made in the clinical database, and data review and validation 
procedures will be repeated as needed. Data from external sources will be compared with the 
information available in the CDMS. Discrepancies found will be queried.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
117
Data corrections in the CDMS will be made using the CDMS update function. For each instance 
of data modifications, the system requires a reason for the change and keeps a complete audit 
trail of the data values, dates and times of modifications, and authorized electronic approvals of 
the changes.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate.
13.3.
Archiving of Case Report Forms and Source Documents 
13.3.1.
Investigator Responsibilities 
All records related to the study (ie, source data, source documents, CRFs [see Section 3.9], data 
results from other sources [see Section 13.1], copies of protocols and protocol amendments, drug 
accountability forms, correspondence, patient identification lists, signed informed consent forms, 
and other essential documents) must be retained until the sponsor notifies the institution, in 
writing, that records may be destroyed. 
If the sponsor has not provided written notification of records destruction after 10 years from 
study completion (or earlier in the event of an institution closing), and the institution determines 
the study record retention is unduly burdensome, the institution may submit a written request to 
the sponsor at least 60 days before the planned disposition of the study records. No study 
document or image (eg, scan, radiograph, ECG tracing) should be destroyed without prior 
written agreement between the sponsor and each investigator. Should an investigator wish to 
assign the study records to another party or move them to another location, advance written 
notice will be given to the sponsor.
13.3.2.
Sponsor Responsibilities 
The sponsor will be responsible for the processing and quality control (QC) of the data. Data 
management and filing will be carried out as described in the sponsor’s SOPs for clinical studies.
If data management and filing of documents for this study are delegated to a contract 
organization, these functions will be carried out as described in the SOPs for clinical studies at 
that organization. These SOPs will be reviewed by the sponsor before the start of data 
management and filing activities. The original CRFs will be archived by the sponsor. 
Center-specific CRFs will be provided to the respective investigational centers for archiving.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
118
14.
FINANCING AND INSURANCE
A separate financial agreement will be made between the principal investigator and the sponsor 
before the study drug is delivered.
This clinical study is insured in accordance with the corresponding local legal provisions. 
The policy coverage is subject to the full policy terms, conditions, extensions, and exclusions.
Excluded from the insurance cover are, inter alia, damages to health and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Form FDA 3454. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed. 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
119
15.
REPORTING AND PUBLICATION OF RESULTS 
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results. 
The sponsor is responsible for preparing a clinical study report, in cooperation with the 
coordinating investigator. The final report is signed by the sponsor and, if applicable, by the 
coordinating investigator.
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the coordinating investigator for comments and 
suggestions. An endorsement of the final report will be sought from the coordinating
investigator.
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Uniform Requirements for Manuscripts Submitted to Biomedical Journals” as established by 
the International Committee of Medical Journal Editors (www.ICMJE.org). Authorship will be 
restricted to parties who have editorial or conceptual input to protocol design, collection of data 
and/or analysis, interpretation of data, and manuscript preparation. The publications committee 
established by the sponsor will oversee this process. Additional publications may follow. Policies 
regarding the publication of the study results are defined in the financial agreement. 
No patent application(s) based on the results of the study may be made by the investigator nor 
may assistance be given to any third party to make such an application without the written 
authorization of the sponsor.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
120
16.
REFERENCES
Barkhof F, van Waesberghe JH, Flippi M, Yousry T, Miller DH, Hahn D, et al. T1 hypointense 
lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment. Brain 
2001;124:1396–402.
Brück W, Pförtner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V, Hanisch UK, Regen T, van 
Rossum D, Brakelmann L, Hagemeier K, Kuhlmann T, Stadelmann C, John GR, Kramann N, 
Wegner C. Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced 
demyelination. Acta Neuropathol. 2012 Sep;124(3):411-24
Brück W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011 Jul 
15;306(1-2):
Christodoulou C, Krupp LB, Liang Z, Huang W, Melville P, Roque C, et al. Cognitive 
Performance and MR markers of cerebral injury in cognitively impaired MS patients. Neurology 
2003;60:1793–798.
Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ. Measuring the impact of MS on 
walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology. 2003 Jan 14;60(1):31-
6.
De Stefano N, Giorgio A, Battaglini M, Rovaris M, Sormani MP, Barkhof F, et al. Assessing 
brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 
2010 Jun 8;74(23):1868-76.
Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack 
(UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991 Dec;54(12):1044-54.
Filippi M, Rocca MA, Pagani E, De Stefano N, Jeffery D, Kappos L, Montalban X, Boyko AN, 
Comi G; on behalf of the ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod in 
multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg 
Psychiatry. 2013 Sep 12. doi: 10.1136/jnnp-2013-306132. [Epub ahead of print]
Fisher E, Rudick RA, Cutter G, Baier M, Miller D, Weinstock-Guttman B, et al. Relationship 
between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. 
Mult Scler 2000;6:373–77.
Fitzner D, Simons M. Chronic progressive multiple sclerosis - pathogenesis of 
neurodegeneration and therapeutic strategies. Curr Neuropharmacol. 2010 Sep;8(3):305-15.
Gonsette RE. Neurodegeneration in multiple sclerosis: the role of oxidative stress and 
excitotoxicity. J Neurol Sci. 2008 Nov 15;274(1-2):48-53.
Irvine KA, Blakemore WF. Remyelination protects axons from demyelination-associated axon 
degeneration. Brain. 2008 Jun;131(Pt 6):1464-77.
Kalkers NF, Bergers E, Castelijns JA, van Walderveen MA, Bot JC, Ader HJ, et al. Optimizing 
the association between disability and biological markers in MS. Neurology 2001;57:1253–58.
Koch MW, Cutter G, Stys PK, Wee Young V, Metz LMl. Nat. Rev. Neurol 2013;9:496–503.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
121
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology 1983;33(11):1444-52.
Langdon DW, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson S, Hämäläinen P, Hartung 
HP, Krupp L, Penner IK, Reder AT, Benedict RH. Recommendations for a Brief International 
Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler. 2012 Jun;18(6):891-8.
Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and 
pathogenesis. Nat. Rev. Neurol 2012;8;647–56.
Lassmann H. and van Horssen J. The molecular basis of neurodegeneration in multiple sclerosis. 
FEBS Lett. 2011 Dec 1;585(23):3715-23.
Losseff NA, Wang L, Lai HM, Yoo DS, Gawne-Cain ML, McDonald WI, et al. Progressive 
Cerebral atrophy in multiple sclerosis. A serial MRI study. Brain 1996; 119:2009–19.
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, 
Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, 
Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, 
Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, 
Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: The 2013 revisions.
Neurology. 2014 May 28. pii: 10.1212/WNL.0000000000000560. [Epub ahead of print].
Luessi F, Siffrin V, Zipp F. Neurodegeneration in multiple sclerosis: novel treatment strategies. 
Expert Rev Neurother 2012 Sep;12(9):1061-76.
Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and 
remyelination in the central nervous system. Brain Pathol. 2001 Jan;11(1):107-16.
McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, 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.
Miller, DH, Barkhof, F, Frank, JA, Parker, GJ, Thompson, AJ. Measurement of atrophy in 
multiple sclerosis: pathological basis methodological aspects and clinical relevance. Brain 2002; 
125: 1676–1695.
Moore S, Khalaj AJ, Yoon J, Patel R, Hannsun G, Yoo T, Sasidhar M, Martinez-Torres L, 
Hayardeny L, Tiwari-Woodruff SK. Therapeutic laquinimod treatment decreases inflammation, 
initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.
Brain Behav. 2013 Nov;3(6):664-82.
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.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
122
Pagani, E, Rocca, MA, Gallo, A, Rovaris, M, Martinelli, V, Comi, G, et al. Regional brain 
atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype. 
AJNR Am J Neuroradiol 2005; 26: 341–6.
Polman CH, Reingold SC, Banwell B., et al. Diagnostic Criteria for Multiple Sclerosis: 2010 
Revisions to the “McDonald Criteria” Ann Neurol 2011; 69:292-302.
Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP.
Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol. 2001 
Nov;50(5):646-57.
Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 
1957 May;2(5):200-15.
Ruffini F, Rossi S, Bergamaschi A, Brambilla E, Finardi A, Motta C, Studer V, Barbieri F, De 
Chiara V, Hayardeny L, Comi G, Centonze D, Martino G. Laquinimod prevents inflammation-
induced synaptic alterations occurring in experimental autoimmune encephalomyelitis. Mult 
Scler. 2013 Jul;19(8):1084-94.
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.
Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with 
treatment effect on disability in multiple sclerosis. Ann Neurol. 2013a Sep 5. doi: 
10.1002/ana.24018. [Epub ahead of print].
Sormani MP, Cutter G, Comi G, Vollmer T, Sorensen PS, Ladkani D, Sasson N, Knappertz V. 
Evaluating the relationship between laquinimod's effects on relapse and disability progression. 
Mult Scler 2013b;19:(S1) 503.
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the 
lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278-85.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
123
17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 02 Dated 01 February 2016
The primary reason for this global amendment was to discontinue treatment for patients 
receiving 1.5 mg laquinimod, and to implement additional safety measures to help ensure the 
safety of subjects (both ongoing subjects and those still to be enrolled) receiving 0.6 mg 
laquinimod. To avoid increased exposure to laquinimod at the 0.6 mg dose, stopping rules have 
been introduced for renal impairment and hepatic impairment, with additional assessments of 
GFR introduced for increased monitoring of renal function.
Table 5 and Table 6 (Study Procedures and Assessments) have been revised to reflect changes 
described below. An additional study schema (Figure 2) has been included to reflect the 
amended study design.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate). A determination of which changes are considered to be substantial will be 
dependent on the region, and will be indicated in the covering letter or application form that 
accompanies the amendment in that region.
Where appropriate, the informed consent form will be amended to reflect the changes introduced 
into the protocol.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
124
Table 7:
Changes to the Protocol (Global Amendment 02)
Original text with changes shown
New wording
Reason/Justification for 
change
TITLE PAGE
Sponsor’s Safety Officer
Teva Pharmaceutical Industries, Ltd.
Sponsor’s Safety Officer
Teva Pharmaceutical Industries, Ltd.
Change of personnel
1.1. Introduction
Therapeutic options for progressive MS are currently limited to 
symptomatic treatments and physiotherapy (Koch 2013); in this 
context, a therapy which is effective in limiting the 
neurodegenerative process and associated disability accumulation 
would address a major unmet medical need in the treatment of MS. 
Recently, positive results have been reported in a PPMS trial with 
the monoclonal antibody ocrelizumab.
Therapeutic options for progressive MS are currently limited to 
symptomatic treatments and physiotherapy (Koch 2013); in this 
context, a therapy which is effective in limiting the 
neurodegenerative process and associated disability accumulation 
would address a major unmet medical need in the treatment of 
MS. Recently, positive results have been reported in a PPMS trial 
with the monoclonal antibody ocrelizumab.
New information 
available.
1.1.1.2. Rationale for Laquinimod 1.5 mg Dose
(new text)
Note: On 30 December 2015 the Data Monitoring Committee 
(DMC) for the CONCERTO and 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): in CONCERTO there were 6 such cases in the 1.2 
mg arm but none in the 0.6 mg or placebo arms, along with a 
myocardial infarction in the ARPEGGIO 1.5 mg dose group and a 
cerebral infarction in a 31 year old patient in the 1.2 mg arm of 
CONCERTO. Due to these events and the DMC recommendation 
to stop all laquinimod treatment arms above 0.6 mg in the MS 
trials, the 1.5 mg treatment arm in the ARPEGGIO 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 arm will be continued while the sponsor closely 
Text added to reflect 
cardiovascular findings at 
doses higher than 0.6 mg 
laquinimod

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
125
Original text with changes shown
New wording
Reason/Justification for 
change
monitors cardiovascular events in all laquinimod studies. 
Additional measures implemented in this protocol amendment 
include an emphasis on disallowed medications and stopping rules 
for organ impairment (ie, factors which may increase laquinimod 
exposure), as well as regular evaluation and management of major 
modifiable cardiovascular risk factors.
1.3.1.3. Toxicology
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 32- to 257-fold above the 
originally intended clinical dose of 1.5 mg/day based on maximal 
plasma concentrations.
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 
32- to 257-fold above the originally intended clinical dose of 1.5 
mg/day based on maximal plasma concentrations.
Reflecting that 1.5 mg is 
no longer an intended 
clinical dose (changed 
several other times in this 
section)
It is the sponsor's position that tThis 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, a smallan
increase in the incidence of oral cavity squamous cell 
carcinomastumors was noted in mid and high dose female rats (2/60 
in each group). The oral effects may relate to the AhR activation 
properties of laquinimod since similar lesions were seen following 
lifelong exposure of rats to other AhR activators. However, the 
incidence of oral cavity tumors in rats treated with laquinimod was 
lower than that seen with industrial chemicals such as 2,3,7,8-
tetrachloro-p-dibenzodioxin (TCDD) (NTP TR-521) and dioxin-like 
compounds (DLCs), and was more similar to the incidence seen 
with the dietary ingredient indole-3-carbinol (I3C) found in 
cruciferous vegetables. Of note, the oral tumors seen with I3C were 
considered by the US National Toxicology Program as irrelevant 
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) 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 
Text updated to reflect 
current version of IB

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
126
Original text with changes shown
New wording
Reason/Justification for 
change
for I3C risk assessment (NTP TR-584). No increased incidence of 
oral tumors was seen in humans exposed to TCDD, indicating a 
species specific response in rats. Therefore, oral cavity tumors 
induced by laquinimod in rats after a lifelong exposure do not imply 
an elevated carcinogenicity risk in humans. Humans, in general, 
also seem to be less sensitive to AhR activation by laquinimod than 
rats, as shown by the differential gene expression profiles discussed 
in the IBwith other AhR activators, including industrial chemicals 
(such as 2,3,7,8 tetrachloro p dibenzodioxin [TCDD] and 
dioxin like compounds [DLCs]) and the dietary ingredient indole 3
carbinol (I3C) found in cruciferous vegetables. However, the 
incidence of oral cavity tumors in rats treated with laquinimod was 
lower than that seen with TCDD and DLCs, and was more similar 
to the incidence seen with I3C. Importantly, the oral cavity tumors 
seen with TCDD in rats did not translate into increased incidence of 
oral tumors in exposed humans, indicating a species difference in 
this response between rats and humans. It should be noted that 
several lines of evidence suggest that the oral lesions seen in rats 
are mediated by direct contact of the rat oral mucosa with high 
concentrations of laquinimod in the dosing solution during the 
gavage procedure. An effect on the oral mucosa in rats is not 
considered relevant to humans, who take laquinimod as a capsule 
that dissolves in the stomach. Based on sponsor’s calculations, in 
the human stomach, the local concentration of laquinimod is 
expected to be low, and the type of epithelium exposed is not 
considered sensitive to the effects of laquinimod, with safety 
margins greater than 13 (dogs), 20 (rats) and 1000 (mice) for 
exposure in the stomach.
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.
1.3.2.
Clinical Studies
A Phase 3 study, LAQ–MS-305 (CONCERTO), is ongoing with 
laquinimod doses of 0.6 mg/day and 1.2 mg/day, is ongoing. As of 
01 January 2016, and based on DMC recommendations, the 1.2 
mg/day arm was discontinued
A Phase 3 study, LAQ–MS-305 (CONCERTO), is ongoing with 
laquinimod doses of 0.6 mg/day. As of 01 January 2016, and 
based on DMC recommendations, the 1.2 mg/day arm was 
discontinued
High dose level has now 
been discontinued in 
CONCERTO.
1.3.2.1. Clinical Pharmacology Studies
Laquinimod is extensively metabolized, predominantly by 
CYP3A4. Laquinimod metabolites levels in plasma are very low 
Laquinimod is extensively metabolized, predominantly by 
CYP3A4. Laquinimod metabolites levels in plasma are very low 
Added text on hepatic and 
renal impairment as 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
127
Original text with changes shown
New wording
Reason/Justification for 
change
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; therefore, laquinimod may affect the systemic exposure 
of other drugs metabolized by CYP3A4 and CYP1A2. For 
additional information on concomitant use of laquinimod with 
CYP1A2 and CYP3A4 substrates, 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 a 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.
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; therefore, 
laquinimod may affect the systemic exposure of other drugs 
metabolized by CYP3A4 and CYP1A2. For additional 
information on concomitant use of laquinimod with CYP1A2 and 
CYP3A4 substrates, 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 a 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.
background for new 
stopping rules
1.4.1. 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.
Note: the table has been updated in line with the updated 
Reference Safety Information; myocardial infarction and 
cerebrovascular accident are now included.
Updated in line with 
changes to the IB

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
128
Original text with changes shown
New wording
Reason/Justification for 
change
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
Table 3: Tabulated List of Adverse Reactions
Cardiac disorders 
Uncommon: Myocardial infarction
Nervous system disorders
Very Common: Headache 
Rare
Cerebrovascular accident
1.4.1.1.7.
Cardiovascular Events (on Doses Above Laquinimod 0.6 mg)
(new section)
On 30 December 2015, a DMC review of 8 unblinded cases from 
the ARPEGGIO and CONCERTO studies found an imbalance in 
serious cardiovascular events in the high dose treatment arms in 
the study: 6 cases of myocardial infarction 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 infarction in a 31 year old 
man on the 1.2 mg treatment arm. In the ARPEGGIO study, 1 
myocardial infarction 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 these events, the DMC recommended stopping all 
laquinimod treatment arms above 0.6 mg in the laquinimod MS 
trials. 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 was necessary. 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.
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 
Text added to reflect 
cardiovascular findings at 
doses higher than 0.6 mg 
laquinimod

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
129
Original text with changes shown
New wording
Reason/Justification for 
change
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.
1.4.1.2.2.
Cancer
These findings are likely related to the administration procedure or 
to species-specific mechanisms, regardless, a relevance of these 
cancers to humans cannot be definitively excluded.
These findings are likely related to species-specific mechanisms, 
regardless, a relevance of these cancers to humans cannot be 
definitively excluded.
Administration procedure 
no longer considered a 
factor
1.4.1.2.3.
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. 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 10,000 patient-years. as well 
as the patients exposed to 0.6 mg in the CONCERTO and 
ARPEGGIO study, analysesThis analysis showed that none of these 
safety issues do not constitute a clear signal of concern 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.
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 
10,000 patient-years. as well as the patients exposed to 0.6 mg in 
the CONCERTO and ARPEGGIO study, 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.
1.4.2.
Overall Risk Benefit Statement
(new text)
Due to cardiovascular events and a DMC recommendation to stop Text added to reflect 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
130
Original text with changes shown
New wording
Reason/Justification for 
change
all laquinimod treatment arms above 0.6 mg in the MS trials, the 
1.5 mg treatment arm 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 was necessary. As of 29 September 2015, 
2347 patients had been exposed to laquinimod 0.6 mg for 10,417 
patient-years. It is estimated that the rate for myocardial infarction 
and cardiovascular death for patients treated with laquinimod 0.6 
mg is about 0.16 per 100 person years which is within range of the 
expected cardiovascular event incidence in the underlying 
population. Therefore, while no increased risk was seen with 
laquinimod 0.6 mg, because of the findings with higher doses, 
there is a potential risk that some individuals may be at increased 
risk of cardiovascular events while taking laquinimod 0.6 mg. 
Appropriate risk mitigation procedures have been implemented 
via a protocol amendment to restrict excess drug exposure due to 
disallowed medications or organ impairment, as well as to assure 
evaluation and management of cardiovascular risk factors.
cardiovascular findings at 
doses higher than 0.6 mg 
laquinimod
3.1. General Design and Study Schema (Other sections affected by change: 3.4.1. Investigational Product and Dosage, 5.1. Study Drugs Administered)
Prior to 01 January 2016, eligible patients will bewere randomized 
in a 1:1:1 ratio into 1 of the following treatment arms (a total of 
286 patients were randomized 1:1:1 prior to 01 January 2016):

Laquinimod 0.6 mg daily

Laquinimod 1.5 mg daily

Daily placebo
As of 01 January 2016, following a decision to discontinue the 
laquinimod 1.5 mg dose arm, additional eligible patients who are 
enrolled will be randomized in a 1:1 ratio into one of the following 
treatment arms:

Laquinimod 0.6 mg daily

Daily placebo
Prior to 01 January 2016, eligible patients were randomized in a 
1:1:1 ratio into 1 of the following treatment arms (a total of 
286 patients were randomized 1:1:1 prior to 01 January 2016):

Laquinimod 0.6 mg daily

Laquinimod 1.5 mg daily

Daily placebo
As of 01 January 2016, following a decision to discontinue the 
laquinimod 1.5 mg dose arm, additional eligible patients who are 
enrolled will be randomized in a 1:1 ratio into one of the 
following treatment arms:

Laquinimod 0.6 mg daily

Daily placebo
1.5 mg arm has been 
discontinued. Additional 
study schema added to 
reflect the revised design.
3.1. General Design and Study Schema (Other sections affected by change: 3.5. Duration of Patient Participation, 3.11.5. Completion Visit)
After up to approximately 24 weeks of Part B, or once data analysis After up to approximately 24 weeks of Part B, or once data 
Clarification

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
131
Original text with changes shown
New wording
Reason/Justification for 
change
has been completed and the design of a potential extension study 
design has been finalized (including blinded or open-label treatment 
allocation), patients will be invited to the clinic for the completion 
visit and will be offered the opportunity to continue into an 
extension study, if applicable.
analysis has been completed and the design of a potential 
extension study design has been finalized (including blinded or 
open-label treatment allocation), patients will be invited to the 
clinic for the completion visit and will be offered the opportunity 
to continue into an extension study, if applicable.
3.2.7.
Pharmacokinetic Measures and Endpoints (Other sections affected by change: 9.9. Pharmacokinetic Analysis)
Pharmacokinetics of laquinimod will be evaluated in this study 
using a population pharmacokinetics (PPK) approach. The PPK 
model may also include any unscheduled pharmacokinetic samples 
collected to assist with further investigations of cardiovascular 
events or other clinical event of interest (see Section 8.1).
Pharmacokinetics of laquinimod will be evaluated in this study 
using a population pharmacokinetics (PPK) approach. The PPK 
model may also include any unscheduled pharmacokinetic 
samples collected to assist with further investigations of 
cardiovascular events or other clinical event of interest (see 
Section 8.1).
PPK analysis can include 
the newly added 
unscheduled PK samples.
3.3. Randomization and Blinding (Other sections affected by change: 3.8. Maintenance of Randomization and Blinding)
This is a randomized, double-blind, placebo-controlled study. 
Patients will be randomly assigned to receive treatment with 
laquinimod at a dosage of 0.6 or 1.5 mg/day, or placebo in a 
1:1:1 ratio (prior to 01 January 2016) or randomly assigned to 
receive treatment with laquinimod at a dosage of 0.6 mg/day, or 
placebo in a 1:1 ratio (from 01 January 2016). Patients, 
investigators, and study site personnel will remain blinded to 
treatment assignment during the study. Laquinimod and placebo 
will be packaged and administered in a blinded manner. All patients 
that discontinued the 1.5 mg dose have been unblinded.
This is a randomized, double blind, placebo controlled study. 
Patients will be randomly assigned to receive treatment with 
laquinimod at a dosage of 0.6 or 1.5 mg/day, or placebo in a 1:1:1 
ratio (prior to 01 January 2016) or randomly assigned to receive 
treatment with laquinimod at a dosage of 0.6 mg/day, or placebo 
in a 1:1 ratio (from 01 January 2016). Patients, investigators, and 
study site personnel will remain blinded to treatment assignment 
during the study. Laquinimod and placebo will be packaged and 
administered in a blinded manner. All patients that discontinued 
the 1.5 mg dose have been unblinded.
1.5 mg arm has been 
discontinued and patients 
on that arm unblinded
3.6.3.
Cancer (Other sections affected by change: APPENDIX B. GUIDANCE ON SAFETY MONITORING)
Patients who are diagnosed with invasive cancer a malignant solid
or liquid tumor while participating in the study should stop study 
medication.
Patients who are diagnosed with a malignant solid or liquid tumor 
while participating in the study should stop study medication.
Correction of terminology
3.6.4.
Liver Impairment (Other sections affected by change: APPENDIX B. GUIDANCE ON SAFETY MONITORING)
(new section)
To avoid exposures to higher levels of laquinimod (see Section 
1.3.2.1), a stopping role related to liver impairment has been 
introduced. Patients who develop any chronic liver disease 
associated with hepatic function impairment while participating in 
the study should stop study medication.
New stopping rule 
implemented to avoid 
increased exposure to 
laquinimod in cases of 
organ impairment
3.6.5.
Renal Impairment (Other sections affected by change: APPENDIX B. GUIDANCE ON SAFETY MONITORING)

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
132
Original text with changes shown
New wording
Reason/Justification for 
change
(new section)
To avoid exposures to higher levels of laquinimod (see Section 
1.3.2.1), a stopping role related to renal impairment has been 
introduced. Patients 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 patient should stop 
study medication permanently.
New stopping rule 
implemented to avoid 
increased exposure to 
laquinimod in cases of 
organ impairment
3.6.7.
Early Termination (ET)
(new text)
Early termination refers to the study drug termination and not 
termination of the patient from the study. Patients will be 
encouraged to continue all scheduled visits and procedures after 
study drug discontinuation (with the exception of drug dispensing 
and accountability, pregnancy testing, and pharmacokinetic 
sampling).
Clarification due to 
discontinuation of 1.5 mg 
arm
3.11.3.
Scheduled Treatment Visits (Visits 1 to 6, Weeks 4 to 48, and Every 12 weeks Thereafter)
(new text)
* Patients who are discontinued from study treatment will be 
encouraged to continue all scheduled visits and procedures after 
study drug discontinuation (with the exception of procedures 
associated with drug dispensing and accountability, pregnancy 
testing, GFR testing, and pharmacokinetic sampling).
Clarification due to 
discontinuation of 1.5 mg 
arm
3.11.5.
Completion Visit
(new text)
Patients who discontinue study drug but continue to attend 
scheduled study visits for follow up are not considered to have 
completed the study.
Clarification due to 
discontinuation of 1.5 mg 
arm
3.11.5.
Completion Visit
However patient compliance/drug accountability, review of 
concomitant medications, vital signs, ECG, and recording of 
adverse events must be performed in any case.
However patient compliance/drug accountability, review of 
concomitant medications, vital signs, ECG, and recording of 
adverse events must be performed in any case.
Added ECG to list of 
activities that must be 
performed at completion 
visit.
3.11.6.
Unscheduled Visit
(new text)
According to the judgment of the investigator or medical monitor,
the following unscheduled procedures may be performed:
Additional assessments for 
monitoring of cardiac risk

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
133
Original text with changes shown
New wording
Reason/Justification for 
change

urgent safety laboratory test panel (see Section 7.3.4)

collection of unscheduled pharmacokinetic blood 
sample

collection of sample for potential biomarker analysis
4.3.1.
Patient Withdrawal Criteria
(new text)
For patients in the 1.5 mg arm who were withdrawn from study 
treatment, the reason will be recorded as ‘sponsor requested 
patient to be withdrawn’.
Clarification due to 
discontinuation of 1.5 mg 
arm
5.2.2.1. Allowed Medications/Therapies During Study

Short-term treatment (up to 5 days) with intravenous 
corticosteroids will be allowed during acute relapses, 
although these are rare in PPMS. The suggested 
treatment for a relapse will be intravenous 
methylprednisolone 500 to 1000 mg/day for 3 to 5 
consecutive days.

Short-term treatment (up to 5 days) with intravenous 
corticosteroids will be allowed during relapses, 
although these are rare in PPMS. The suggested 
treatment for a relapse will be intravenous 
methylprednisolone 500 to 1000 mg/day for 3 to 5 
consecutive days.
Treatment can be given for 
any relapses (not just acute 
relapses) and short-term 
defined.
5.2.2.2. Disallowed Concomitant Medications/Therapies During Study
(new text)
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.
Rationale for disallowed 
medication added
5.4. Total Blood Volume
The total amount of blood to be drawn during the study for serum 
chemistry, CBC, pharmacokinetic, biomarker and PGx 
measurements is approximately 500 550 mL/patient.
The total amount of blood to be drawn during the study for serum 
chemistry, CBC, pharmacokinetic, biomarker and PGx 
measurements is approximately 550 mL/patient.
Adjustment to allow for 
unscheduled tests
6.4.5.
Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Score

Brief Visuospatial Memory Test – Revised 
(BVMT-R) (first 3 recall trials): this requires the 
patient to inspect a 2 × 3 stimulus array of abstract 
geometric figures (Form 1 from the Recall Stimulus 
Booklet). There are 3 learning trials of 10 seconds. 
The array is removed and the patient is required to 
draw the array from memory, with the correct shapes 

Brief Visuospatial Memory Test – Revised 
(BVMT-R) (first 3 recall trials): this requires the 
patient to inspect a 2 × 3 stimulus array of abstract 
geometric figures (Form 1 from the Recall Stimulus 
Booklet). There are 3 learning trials of 10 seconds. 
The array is removed and the patient is required to 
draw the array from memory, with the correct shapes 
Details of scoring added

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
134
Original text with changes shown
New wording
Reason/Justification for 
change
in the correct position. Scoring of the BVMT-R 
drawings will be performed by a central expert 
vendor.
in the correct position. Scoring of the BVMT-R 
drawings will be performed by a central expert 
vendor.
7.1.6.
Protocol Defined Adverse Events for Expedited Reporting
No protocol defined adverse events for expedited reporting were 
identified for this study.
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.
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.
7.3.1.
Serum Chemistry

in case of CPK results >ULN, creatine kinase MB 
isoenzyme (CK-MB) and troponin will be tested 
by the central laboratory.

in case of CPK results >ULN, creatine kinase 
MB isoenzyme (CK-MB) and troponin will be 
tested by the central laboratory.
Troponin added (in case of 
CPK >ULN) to give 
additional cardiovascular 
assessment.
7.3.4.
Urgent Safety Laboratory Panel (Other sections affected by change: 3.11. Study Procedures)
(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 will be performed on these samples:

serum chemistry panel (see Section 7.3.1)

CBC panel (see Section 7.3.2)

CK-MB

troponin
Unscheduled laboratory 
test samples may be 
collected to allow further 
investigation of events of 
interest.
7.4. Vital Signs and Weight (Other sections affected by change: 3.11. Study Procedures)
(new text)
Weight will be measured at all visits.
Weight will be used in 
association with GFR 
estimation, so needs to be 
measured at each visit.
7.7. Glomerular Filtration Rate Estimation (Other sections affected by change: 7.3.1. Serum Chemistry, 3.11. Study Procedures)
Significant changes in laquinimod exposure, in particular in terms 
Significant changes in laquinimod exposure, in particular in terms Extra GFR monitoring 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
135
Original text with changes shown
New wording
Reason/Justification for 
change
of unbound drug fraction, are predicted in patients with severe renal 
impairment (see Section 1.3.2.1). Consequently, GFR will be 
estimated at all visits to monitor renal function in the study in order 
to identify patients with potentially impaired laquinimod clearance. 
Patients 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 patient should stop study medication 
permanently (see Section 3.6.5).
GFR is a test used to check renal function.
Following recent findings connecting Gd based contrast agents and 
nephrogenic systemic sclerosis, the GFR result should be available 
prior to the baseline MRI scan. GFR calculation estimation will be 
done in accordance with the central laboratory creatinine value 
measurement performed at the screening visit. The central 
laboratory will report calculated estimated GFR; however, if the 
result is not available prior to the baseline MRI scan, the CKD-EPI 
Creatinine Equation (2009) from the following online GFR 
calculator should be used by the investigator:
of unbound drug fraction, are predicted in patients with severe 
renal impairment (see Section 1.3.2.1). Consequently, GFR will 
be estimated at all visits to monitor renal function in the study in 
order to identify patients with potentially impaired laquinimod 
clearance. Patients 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 patient should stop study medication 
permanently (see Section 3.6.5).
Following recent findings connecting Gd based contrast agents 
and nephrogenic systemic sclerosis, the GFR result should be 
available prior to the baseline MRI scan. GFR estimation will be 
done in accordance with the central laboratory creatinine value 
measurement performed at the screening visit. The central 
laboratory will report estimated GFR; however, if the result is not 
available prior to the baseline MRI scan, the CKD-EPI Creatinine 
Equation (2009) from the following online GFR calculator should 
be used by the investigator:
added in case of decrease 
in renal function. Changed 
terminology to be more 
accurate: estimation 
instead of calculation.
7.8. Cardiovascular Risk Assessment and Management (Other sections affected by change: 3.11. Study Procedures)
(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 
and Table 6. In addition, an evaluation should take place as soon 
as possible for patients already in the study, following approval of 
Global Amendment 2.
Cardiovascular risk management should be conducted according 
to evidence-based, local standard-of-care procedures. Patients will 
undergo referral to a suitable clinic if needed.
Additional assessments for 
monitoring of cardiac risk
8.1. Pharmacokinetic Variables (Other sections affected by change: 9.9. Pharmacokinetic Analysis)
(new text)
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.
Unscheduled samples may 
be collected to allow 
further investigation of 
events of interest.
8.2. Potential Biomarker Measures

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
136
Original text with changes shown
New wording
Reason/Justification for 
change
(new text)
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.
Unscheduled samples may 
be collected to allow 
further investigation of 
events of interest.
9.2. Sample Size and Power Considerations
Under the above assumptions 113 patients enrolled per arm (339 
total) will provide 80% power to detect statistically significant 
result for each laquinimod arm comparison to placebo separately. 
To adjust for the anticipated 10% dropouts, the sample size was 
increased to 375 patients in total (125 per arm). Under the above 
assumptions 252 patients enrolled for 0.6 mg and placebo (126 per 
arm) will provide 84% power to detect a statistically significant 
result for 0.6 mg laquinimod arm comparison to placebo. To adjust
for the anticipated 10% dropouts, the sample size was increased to 
280 patients. Adding 95 patients on 1.5 mg yields a total of 375 
patients.
Under the above assumptions 252 patients enrolled for 0.6 mg and 
placebo (126 per arm) will provide 84% power to detect a 
statistically significant result for 0.6 mg laquinimod arm 
comparison to placebo. To adjust for the anticipated 10% 
dropouts, the sample size was increased to 280 patients. Adding 
95 patients on 1.5 mg yields a total of 375 patients.
Adjusted due to 
discontinuation of 1.5 mg 
arm.
9.6. Efficacy Analysis
(new text)
Due to the decision from 01 January 2016 to discontinue the 
laquinimod 1.5 mg dose arm, and a low study exposure at this 
time, the laquinimod 1.5 mg dose arm will be presented 
descriptively only, and will not be included in any inferential 
analyses.
In addition, all efficacy analyses will be performed based on the 
measurements recorded during the study treatment period, ie, data 
captured following an early termination visit as described in 
Section 3.6.7 will be excluded from the analyses. The data 
captured after an early termination visit will be used for the 
sensitivity analyses of the primary and secondary endpoints.
Revisions to statistical 
analyses following 
discontinuation of the 
1.5 mg arm
9.6.4.1. Primary Efficacy Analysis (Other sections affected by change: 9.6.4.3. Secondary Efficacy Analysis)
The primary efficacy variable for this study is BA as measured by 
the PBVC from baseline to week 48. This endpoint will be analyzed 
using the mITT1 population with at least 1 post baseline PBVC 
value and will include assessments taken up to/including early 
termination/study completion visit (data recorded following an early 
termination visit will be excluded from this analysis). BA will be 
The primary efficacy variable for this study is BA as measured by 
the PBVC from baseline to week 48. This endpoint will be 
analyzed using the mITT1 population with at least 1 post baseline 
PBVC value and will include assessments taken up to/including 
early termination/study completion visit (data recorded following 
an early termination visit will be excluded from this analysis). BA 
Revisions to statistical 
analyses following 
discontinuation of the 
1.5 mg arm

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
137
Original text with changes shown
New wording
Reason/Justification for 
change
analyzed using baseline-adjusted repeated measures analysis of 
covariance (ANCOVA- SAS® PROC MIXED) in which 
12 contrasts will be constructed in order to compare between each 
dose of laquinimod (0.6 and 1.5 mg) and placebo. 
The model will be comprised from the treatment group as a class 
variable (3 2 levels).
will be analyzed using baseline-adjusted repeated measures 
analysis of covariance (ANCOVA- SAS® PROC MIXED) in 
which 1 contrast will be constructed in order to compare between 
laquinimod 0.6 mg and placebo. 
The model will be comprised from the treatment group as a class 
variable (2 levels).
9.6.4.2. Sensitivity Analyses
(new text)

Repeat the primary analysis while including 
observations that were recorded following an early 
termination visit.
New analysis added
9.6.4.3. Secondary Efficacy Analysis
a.
Time to CDP as measured by EDSS confirmed after at 
least 12 weeks will be analyzed using the ITT 
population and data from all the study assessments up 
to/including early termination/study completion visit 
(data recorded following an early termination visit 
will be excluded from this analysis). This analysis will 
be performed using a baseline adjusted Cox’s 
proportional hazards regression model (SAS® PROC 
PHREG) in which 2 1 contrasts for comparing each of 
laquinimod doses 0.6 mg to placebo will be 
constructed. In addition to treatment group, 
categorical EDSS at baseline (≤4.5 or >4.5), age at 
baseline, natural logarithm of T2 lesion volume at 
baseline, and CGR will be used as covariates.
The adequacy of the proportional hazards assumption 
will be confirmed by including 12 time-dependent 
covariates of dose (as dummy variables) by log (time) 
interactions in the analysis model and testing each of 
them at the 5% level. In case the proportional hazards 
assumption will be rejected for a certain dose, the log 
rank test (SAS® PROC LIFTEST) will be used for 
statistical inference in this dose.
a.
Time to CDP as measured by EDSS confirmed after 
at least 12 weeks will be analyzed using the ITT 
population and data from all the study assessments
up to/including early termination/study completion 
visit (data recorded following an early termination 
visit will be excluded from this analysis). This 
analysis will be performed using a baseline adjusted 
Cox’s proportional hazards regression model (SAS®
PROC PHREG) in which 1 contrast for comparing 
laquinimod 0.6 mg to placebo will be constructed. In 
addition to treatment group, categorical EDSS at 
baseline (≤4.5 or >4.5), age at baseline, natural 
logarithm of T2 lesion volume at baseline, and CGR 
will be used as covariates.
The adequacy of the proportional hazards 
assumption will be confirmed by including 
1 time-dependent covariate of dose (as dummy 
variable) by log (time) interactions in the analysis 
model and testing each of them at the 5% level. In 
case the proportional hazards assumption will be 
rejected, the log rank test (SAS® PROC LIFTEST) 
will be used for statistical inference.
Revisions to statistical 
analyses following 
discontinuation of the 
1.5 mg arm.
Similar changes made to 
bullets b through d in this 
section.
9.6.4.3. Secondary Efficacy Analysis
(new text)
All the secondary analyses mentioned in this section will be 
repeated while including observations that were recorded 
Additional analyses

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
138
Original text with changes shown
New wording
Reason/Justification for 
change
following an early termination visit.
9.6.4.4. Dose Response (section deleted)
A separate model using the above primary analysis methodology 
with treatment group as a continuous variable will be constructed in 
order to test a linear dose response relationship. Placebo patients 
will be assigned with zero value and laquinimod patients will be 
assigned with a numeric value of either 0.6 or 1.5 reflective of their 
treatment assignments. One contrast for linear slope will be 
constructed.
(section deleted)
Analysis removed as only 
0.6 mg dose following 
discontinuation of 1.5 mg 
laquinimod.
APPENDIX C. MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 INDUCERS
(new text)
Moderate and strong CYP3A4 inhibitors are prohibited because 
concomitant administration is predicted to increase laquinimod 
exposure and may increase the likelihood of adverse events.
Clarification

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
139
17.2.
Amendment 01 Dated 01 July 2015
The primary reasons for this global amendment were to introduce an additional secondary 
efficacy endpoint (change from baseline to week 48 in the T25FW score) and an additional 
exploratory efficacy measure (mRS). The T25FW endpoint was added due to its established role 
in quantifying clinically meaningful benefit in MS, and due to the beneficial effects seen on this 
measure in previous RRMS trials of laquinimod.
Other important changes include:

Omission of the interim analysis (this was intended to provide actionable information 
with respect to an ongoing planned Phase 3 trial; however, the rationale no longer 
applies, since that trial will not be initiated in parallel with ARPEGGIO).

Omission of baseline CSF sampling (omitted in order to maximize participation in the 
week 48 sampling, which is more important scientifically; the decision was taken 
based feedback from an expert who noted that previous trials were not successful in 
consistently collecting 2 CSF samples, whereas the yield was better with a single CSF 
collection).

Creation of 2 separate mITT populations: mITT1 and mITT2 (mITT1 introduced 
specifically for the primary endpoint; mITT2 is what was previously defined as the 
mITT population).
Table 5 and Table 6 (Study Procedures and Assessments) have been revised to reflect changes 
described below.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate). A determination of which changes are considered to be substantial will be 
dependent on the region, and will be indicated in the covering letter or application form that 
accompanies the amendment in that region.
Where appropriate, the informed consent form will be amended to reflect the changes introduced 
into the protocol.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
140
Table 8:
Changes to the Protocol (Global Amendment 01)
Original text with changes shown
New wording
Reason/Justification for change
1.3.1.2. Metabolism and Pharmacokinetics ((Other sections affected by change: 5.2.2.1. Allowed Medications/Therapies during Study)
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 decrease of CYP3A4 
activity and is a strong inducer of CYP1A enzymes
Language updated to make 
consistent with other laquinimod 
protocols and Investigator’s 
Brochure
1.3.1.3. Toxicology
(new text added)
Based on calculations from a study to determine 
laquinimod levels in monkey semen, in which the 
semen:plasma ratio of laquinimod was 0.32, the estimated 
exposure to a female partner of laquinimod-treated male 
patient via semen is approximately 600 fold lower than the 
exposure after oral administration of laquinimod at a dose 
of 1.5 mg, indicating that the risk of male-mediated 
embryo-fetal toxicity through laquinimod treatment is 
negligible.
Rationale added for male patients 
not needing to specifically use 
contraception due to study drug
1.3.2.1. Clinical Pharmacology Studies (Other sections affected by change: 3.6.5. Early Termination (ET); 3.11.4. Early Termination (ET) Visit; 3.11.5. 
Completion Visit)
At doses of 0.6 and 1.2 mg, laquinimod is a weak inhibitor of 
CYP3A4 and a strong inducer of CYP1A2; therefore, laquinimod 
may affect the systemic exposure of other drugs metabolized by 
CYP3A4 and CYP1A2. For additional information on concomitant 
use of laquinimod with CYP1A2 and CYP3A4 substrates, please 
refer to the IB.
At doses of 0.6 and 1.2 mg, laquinimod is a weak inhibitor 
of CYP3A4 and a strong inducer of CYP1A2; therefore, 
laquinimod may affect the systemic exposure of other 
drugs metabolized by CYP3A4 and CYP1A2. For 
additional information on concomitant use of laquinimod 
with CYP1A2 and CYP3A4 substrates, please refer to the 
IB.
Clarification and reference to 
Investigator’s Brochure (which 
discusses these issues more 
comprehensively) added
3.2.2.
Secondary Efficacy Measures and Endpoints (Other sections affected by change: 6.2. Secondary Efficacy Variables; 9.6.2. Secondary Variables; 
9.6.4.3. Secondary Efficacy Analysis)
Change from baseline to week 48 in the T25FW score.
(new text)
Secondary endpoint added
Change from baseline to week 48 in the Brief International 
Cognitive Assessment for Multiple Sclerosis (BICAMS) score.
(text moved from section)
Changed from secondary to 
exploratory endpoint
3.2.3.
Exploratory Efficacy Measures and Endpoints (Other sections affected by change: 3.11.3. Scheduled Treatment Visits (Visits 1 to 6, Weeks 4 to 48, 
and Every 12 weeks Thereafter); 6.3. Exploratory/Other Efficacy Variables; 9.6.3. Exploratory/Other Variables)
Change from baseline to week 48 in the Brief International 
Cognitive Assessment for Multiple Sclerosis (BICAMS) score
(California Verbal Learning Test–II [CVLT-II], Brief Visuospatial 
(text moved to this section and details of specific 
assessment added)
Changed from secondary to 
exploratory endpoint

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
141
Original text with changes shown
New wording
Reason/Justification for change
Memory Test – Revised [BVMT-R], and symbol digit modalities 
test [SDMT])
Modified Rankin scale (mRS) (at week 72, visit 8)
(new text)
Exploratory endpoint added
SDMT
(deleted)
SDMT no longer considered as 
an exploratory endpoint in 
isolation
3.3.1.
Emergency Code Breaking
In case of a serious adverse event, pregnancy, or in cases when 
knowledge of the study drug assignment is needed to make 
treatment decisions, the investigator may unblind the patient’s drug 
assignment through the IRT system, as deemed necessary, mainly in 
emergency situations. Individual treatment codes, indicating the 
treatment randomization for each randomized patient, will be 
available to the investigator(s) at the study center via the IRT, via 
the internet.
If possible, the sponsor should be notified of the event prior to 
breaking of the code, if possible. If this is not possible, the sponsor 
should be notified immediately afterwards, and the patient’s drug 
code assignment should not be revealed. Breaking of the treatment 
code can always be performed by the site without prior approval by 
the sponsor.
…
For adverse events that are defined as: Suspected, Unexpected, 
Serious, Adverse Reaction (SUSAR) (ie, reasonable possibility; see
Section 7.1.4), Global Patient Safety and Pharmacovigilance may 
independently request that the treatment code be revealed (on a 
case-by-case basis) to comply with regulatory requirements. The 
report will be provided in an unblinded manner for regulatory 
submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct, 
analysis, and reporting of the data.break patient’s code to comply 
with regulatory requirements.
In case of a serious adverse event, pregnancy, or in cases 
when knowledge of the study drug assignment is needed to 
make treatment decisions, the investigator may unblind the 
patient’s drug assignment as deemed necessary, mainly in 
emergency situations. Individual treatment codes, 
indicating the treatment randomization for each 
randomized patient, will be available to the investigator(s) 
at the study center via the IRT, via the internet.
If possible, the sponsor should be notified of the event prior 
to breaking of the code. If this is not possible, the sponsor 
should be notified immediately afterwards, and the 
patient’s drug code assignment should not be revealed. 
Breaking of the treatment code can always be performed by 
the site without prior approval by the sponsor.
…
For adverse events that are defined as: Suspected, 
Unexpected, Serious, Adverse Reaction (SUSAR) (ie, 
reasonable possibility; see Section 7.1.4), Global Patient 
Safety and Pharmacovigilance may independently request 
that the treatment code be revealed (on a case-by-case 
basis) to comply with regulatory requirements. The report 
will be provided in an unblinded manner for regulatory 
submission. If this occurs, blinding will be maintained for 
the investigator and for other personnel involved in the 
conduct, analysis, and reporting of the data. 
Text has been updated in line 
with current Teva standards
3.11.2.2.Up to 42 days Prior to Baseline (Other sections affected by change: 8.4.1.
Cerebrospinal Fluid (CSF) Assessment)
CSF collection (in selected sites) will be performed in all patients 
who signed an appropriate, EC approved informed consent form 
(see Section 8.4.1 for further details of the assessments).
(text deleted)
Procedure no longer performed at 
baseline

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
142
Original text with changes shown
New wording
Reason/Justification for change
3.11.4.
Early Termination (ET) Visit
BICAMS and OCT: ET visit will only include BICAMS and OCT 
for patients who prematurely terminate treatment subsequent to the 
week 24 visit and prior to week 48. Patients who stop treatment 
before week 24 or after week 48 will not have BICAMS and OCT 
at ET visit.
(new text)
Additional assessments for 
certain patients at ET visit
4.2. Patient Exclusion Criteria
26. GFR ≤60 mL/min/1.73 m2 at screening visit.
26. GFR ≤60 mL/min/
1.73 m2 at screening visit.
Clarification of units
5.2.2.1. Allowed Medications/Therapies during Study
Symptomatic MS agents, such as anti-cholinergic and spasmolytic 
drugs, are permitted at clinically appropriate doses. Dose changes 
and initiation of symptomatic treatments during the study should be 
avoided if possible.
Symptomatic MS agents, such as anti-cholinergic and 
spasmolytic drugs, are permitted at clinically appropriate 
doses. Dose changes and initiation of symptomatic 
treatments during the study should be avoided if possible.
Clarification
Clinical studies have shown laquinimod to be a potent strong
inducer of CYP1A2. Patients taking drugs that are metabolized by 
CYP1A2 (examples listed in Appendix E) 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.
Clinical studies have shown laquinimod to be a strong 
inducer of CYP1A2. Patients taking drugs that are 
metabolized by CYP1A2 (examples listed in Appendix E) 
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.
Clarification
Drug drug interaction studies have shown been performed with 
laquinimod doses of 0.6 and 1.2 mg. These studies showed that 
laquinimod, at both doses, is a weak inhibitor of CYP3A4
Drug-drug interaction studies have been performed with 
laquinimod doses of 0.6 and 1.2 mg. These studies showed 
that laquinimod, at both doses, is a weak inhibitor of 
CYP3A4
Clarification
5.4. Total Blood Volume
The total amount of blood to be drawn during the study for serum 
chemistry, CBC, pharmacokinetic, biomarker and PGx 
measurements is approximately 500 mL/patient.
The total amount of blood to be drawn during the study for 
serum chemistry, CBC, pharmacokinetic, biomarker and 
PGx measurements is approximately 500 mL/patient.
Clarification
6.4.5.
Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Score
Brief Visuospatial Memory Test – Revised (BVMT-R) (first 
Brief Visuospatial Memory Test – Revised (BVMT-R) 
Additional details added

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
143
Original text with changes shown
New wording
Reason/Justification for change
3 recall trials): this requires the patient to inspect a 2 × 3 stimulus 
array of abstract geometric figures (Form 1 from the Recall 
Stimulus Booklet).
(first 3 recall trials): this requires the patient to inspect a 
2 × 3 stimulus array of abstract geometric figures (Form 1 
from the Recall Stimulus Booklet).
6.4.6.
Symbol Digit Modalities Test (SDMT) (Other sections affected by change: 3.11.2.4. Pre-randomization; 3.11.3. Scheduled Treatment Visits (Visits 
1 to 6, Weeks 4 to 48, and Every 12 weeks Thereafter))
Two forms of the SDMT (Form A and Form B) will be used in this 
study. Alternating SDMT forms will be administered as follows: 
Form A (at baseline, week 24, week 48, and every 24 weeks until 
completion/ET); Form B (at week 12, week 36, and every 24 weeks 
until completion/ET).
(text deleted)
Alternating forms will no longer 
be used
6.4.7.
Modified Rankin Scale
The mRS is a commonly used scale for measuring the degree of 
disability or dependence in the daily activities of people who have 
suffered a stroke or other causes of neurological disability (Rankin 
1957; Farrell et al 1991). The scale runs from 0 (no symptoms) to 5 
(severe disability), with a score of 6 used in the event of a death 
(Appendix J).
(new section)
New efficacy measure added
7.1.5.3.1Invesigator Responsibility
The following information should be provided to record the event 
accurately and completely:
…

patient initials

onset date and detailed description of adverse event
...
Additional information may include the following:
…

explanation of assessment of relatedness
…
On the basis of this assessment, a decision will be made concerning 
the need for further medical intervention. 
…
For all countries, the sponsor’s Global Patient Safety and 
Pharmacovigilance Department will distribute the Council for 
International Organizations of Medical Sciences (CIOMS) 
form/XML file to the LSO/CRO for local submission to the 
regulatory authorities and IEC/IRBs and investigators, according to 
The following information should be provided to record the 
event accurately and completely:
…

onset date and detailed description of adverse 
event
...
Additional information may include the following:
…

explanation of assessment of relatedness
…
For all countries, the sponsor’s Global Patient Safety and 
Pharmacovigilance Department will distribute the Council 
for International Organizations of Medical Sciences 
(CIOMS) form/XML file to the LSO/CRO for local 
submission to the regulatory authorities and IEC/IRBs and 
investigators, according to regulations. The investigator is 
responsible for ensuring that the IEC/IRB is also informed 
of the event, in accordance with local regulations.
Text has been updated in line 
with current Teva standards

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
144
Original text with changes shown
New wording
Reason/Justification for change
regulations. The investigator is responsible for ensuring that the 
IEC/IRB is also informed of the event, in accordance with local 
regulations.
There are countries where the investigator must ensure that the 
IEC/IRB is also informed of the event, in accordance with local 
regulations.
8.4.2.
Optical Coherence Tomography (OCT) Evaluation (Other sections affected by change: 3.11.3. Scheduled Treatment Visits (Visits 1 to 6, Weeks 4 
to 48, and Every 12 weeks Thereafter); APPENDIX L. OCT ANCILLARY STUDY DESIGN AND METHODOLOGY)
OCT (to be performed in selected sites) will be performed in all 
patients who signed an appropriate, EC approved informed consent 
form, at week 0 (can be performed up to 42 days prior to
baseline),and week 48 (or ET visit if performed after the week 24 
visit and prior to week 48), and week 96 to assess retinal thickness. 
OCT (to be performed in selected sites) will be performed 
in all patients who signed an appropriate, EC approved 
informed consent form, at week 0 (can be performed up to 
42 days prior to baseline), week 48 (or ET visit if 
performed after the week 24 visit and prior to week 48), 
and week 96 to assess retinal thickness. 
Additional assessment added at 
week 96
9.3.2.
Modified ITT 1 (mITT1) Population (Other sections affected by change: 9.3.5. Per Protocol (PP) Population; 9.5.1. Patient Disposition; 9.6.4. 
Planned Method of Analysis; 9.6.4.1. Primary Efficacy Analysis)
The modified ITT 1 (mITT1) population is a subset of the ITT set. 
It will include all patients in the ITT population with at least 1 post 
baseline efficacy PBVC assessment.
The modified ITT 1 (mITT1) population is a subset of the 
ITT set. It will include all patients in the ITT population 
with at least 1 post baseline PBVC assessment.
Refinement of statistical analysis 
set definition
9.3.3.
Modified ITT 2 (mITT2) Population (Other sections affected by change: 9.5.1. Patient Disposition; 9.6.4. Planned Method of Analysis)
The modified ITT 2 (mITT2) population is a subset of the ITT set. 
It will include all patients in the ITT population with at least 1 post 
baseline efficacy assessment.
(new text)
Additional statistical analysis set 
included
9.6.2.
Secondary Variables
Let Et be an EDSS measurement of the patient under consideration 
observed at time (measured by months weeks from the patient’s 
baseline date).
...
Let s = t +3 12.
...
5.
3. For any t < q1< s, if the patient’s EDSS was evaluated at 
Let Et be an EDSS measurement of the patient under 
consideration observed at time (measured by weeks from 
the patient’s baseline date). 
...
Let s = t +12.
...
9.
3. For any t < q1< s, if the patient’s EDSS was 
Modification to time of CDP 
algorithm

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
145
Original text with changes shown
New wording
Reason/Justification for change
time q1, then Eq1 ≥ E0 + ∆
6.
4. Eq2 ≥ E0 + ∆ for some q2 ≥ s, and at time q2, the patient 
was not experiencing a relapse.
7.
3. 



0
E
Eq
for some
s
q 
, and at time q, the 
patient was not experiencing a relapse.
8.
4. For any
s
q
t


, if the patient’s EDSS was evaluated 
at time q, then 



0
E
Eq
.
...
In case time t exists without fulfilling conditions 3 and 4 because 
time q2 is after the patient completed Part A of the study (or 
performed ET), and therefore cannot be seen, then the right 
censored will be on time t and not in the last EDSS evaluation.
evaluated at time q1, then Eq1 ≥ E0 + ∆
10. 4. Eq2 ≥ E0 + ∆ for some q2 ≥ s, and at time q2, the 
patient was not experiencing a relapse.
...
11.
In case time t exists without fulfilling conditions 3 
and 4 because time q2 is after the patient completed 
Part A of the study (or performed ET), and therefore 
cannot be seen, then the right censored will be on time 
t and not in the last EDSS evaluation.
9.6.4.2. Sensitivity Analyses
Repeat of the primary analysis without introduction of covariates 
except for the treatment group, week, and treatment by week 
interaction.
Repeat of the primary analysis without introduction of 
covariates except for the treatment group, week, and 
treatment by week interaction.
Modification made to the 
sensitivity testing
9.6.4.3. Secondary Efficacy Analysis
a.
Time to CDP as measured by EDSS confirmed after at least 12 
weeks...In addition to treatment group, categorical EDSS at baseline 
(≤4.5 or >4.5), categorical age at baseline (≤51 or >51 years), 
natural logarithm of T2 lesion volume at baseline, and CGR will be 
used as covariates.
...
b.
Time to CDP, confirmed after at least 12 weeks as measured by 
EDSS or T25FW...In addition to treatment group, categorical EDSS 
at baseline (≤4.5 or >4.5), categorical age at baseline baseline (≤51 
or >51 years), T25FW at baseline, natural logarithm of T2 lesion 
volume at baseline, and CGR will be used as covariates.
...
c.
Change from baseline in the T25FW score at week 48 will be 
a.
Time to CDP as measured by EDSS confirmed after at 
least 12 weeks...In addition to treatment group, categorical 
EDSS at baseline (≤4.5 or >4.5), age at baseline, natural 
logarithm of T2 lesion volume at baseline, and CGR will 
be used as covariates.
...
b.
Time to CDP, confirmed after at least 12 weeks as 
measured by EDSS or T25FW...In addition to treatment 
group, categorical EDSS at baseline (≤4.5 or >4.5), age at 
baseline, T25FW at baseline, natural logarithm of T2 lesion 
volume at baseline, and CGR will be used as covariates.
...
c.
Change from baseline in the T25FW score at week 48 
Continuous age (not categorical) 
will be used as covariate for time 
to CDP. Clarification that it will 
be mITT1 population for new T2 
brain lesion analysis and addition 
of age at baseline as a covariate.
Change from baseline in the 
T25FW score added as a 
secondary analysis.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
146
Original text with changes shown
New wording
Reason/Justification for change
analyzed on the mITT2 population. Since this variable might not 
follow normal distribution, the ranked values of this measurement 
will be defined and analyzed using baseline adjusted repeated 
measures ANCOVA (SAS® PROC MIXED) in which 2 contrasts 
will be constructed in order to compare between each dose of 
laquinimod (0.6 and 1.5 mg) and placebo. In addition to treatment 
group, T25FW score at baseline and CGR will be used as 
covariates. Due to the fact that the ANCOVA model will use ranked 
values and not the actual changes in the T25FW, Hodges Lehmann 
estimates will be used in order to present the magnitude of the 
treatment effect and the corresponding two-sided 95% confidence.
c. d.The number of new brain T2 lesions at week 48 will be 
analyzed using the mITT1 population with at least 1 post baseline 
T2 scan available if it was performed at least 36 weeks under 
treatment. This analysis will be performed using baseline adjusted 
negative binomial regression model (SAS® PROC GENMOD) in 
which 2 contrasts for comparing each of laquinimod doses to 
placebo will be constructed. In addition to the treatment group, the 
natural logarithm of T2 lesion volume at baseline, age at baseline,
and CGR will be used as covariates.
...
d.
Change from baseline to week 48 in the BICAMS score will be 
analyzed using the mITT population with at least 1 post baseline 
BICAMS score, if it was performed at least 36 weeks under 
treatment. This analysis will be performed using baseline adjusted 
analysis of covariance (ANCOVA SAS® PROC GLM) in which 2 
contrasts for comparing each of laquinimod doses to placebo will be 
constructed. In addition to treatment group, BICAMS score at 
baseline and CGR will be used as covariates.
will be analyzed on the mITT2 population. Since this 
variable might not follow normal distribution, the ranked 
values of this measurement will be defined and analyzed 
using baseline adjusted repeated measures ANCOVA 
(SAS® PROC MIXED) in which 2 contrasts will be 
constructed in order to compare between each dose of 
laquinimod (0.6 and 1.5 mg) and placebo. In addition to 
treatment group, T25FW score at baseline and CGR will be 
used as covariates. Due to the fact that the ANCOVA 
model will use ranked values and not the actual changes in 
the T25FW, Hodges Lehmann estimates will be used in 
order to present the magnitude of the treatment effect and 
the corresponding two-sided 95% confidence.
d.
The number of new brain T2 lesions at week 48 will 
be analyzed using the mITT1 population with at least 1 
post baseline T2 scan available if it was performed at least 
36 weeks under treatment. This analysis will be performed 
using baseline adjusted negative binomial regression model 
(SAS® PROC GENMOD) in which 2 contrasts for 
comparing each of laquinimod doses to placebo will be 
constructed. In addition to the treatment group, the natural 
logarithm of T2 lesion volume at baseline, age at baseline, 
and CGR will be used as covariates.
9.10.
Planned Interim Analysis
No interim analysis is planned for this study An interim analysis for 
futility is planned once 50% of patients have completed the week 48 
MRI scan. Based on recruitment estimates this is expected to occur 
72 weeks after study initiation. Interim analysis will be based on the 
PBVC outcome on week 48. If the results of the analysis suggest 
the possibility of futility, a sequence of additional analyses will be 
conducted prior to study termination, including PBVC at week 24 
No interim analysis is planned for this study. 
Interim analysis removed from 
study

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
147
Original text with changes shown
New wording
Reason/Justification for change
for which the majority of data are expected to be available at this 
time. Details of the analytical approach will be specified in the 
Statistical Analysis Plan for Interim Analysis.
11.4.
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 and/or clinical device supplies used in a clinical research 
study sponsored by Teva. Examples of a product complaint include 
but are not limited to the following: 

suspected contamination

questionable stability (eg, color change, flaking, 
crumbling, etc.)

defective components

missing or extra units (eg, primary container is 
received at the site 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 
patient’s drug supply) should be sent back to the sponsor for 
investigative testing whenever possible. 
11.4.1
Product Complaint Information Needed from the 
Investigational Center
In the event that the Product Complaint Form cannot be completed,
(new text)
Text has been added in line with 
current Teva standards

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
148
Original text with changes shown
New wording
Reason/Justification for change
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

patient identifier (patient study number) and 
corresponding visit numbers, if applicable

product name and strength for open-label studies

patient 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 complaint must not be delayed because not all the 
required information can be immediately obtained. Known 
information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding 
information.
11.4.2 Handling the 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 of 
the 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 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
149
Original text with changes shown
New wording
Reason/Justification for change
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 patient.
114.3 Adverse Events or Serious Adverse Events Associated 
with a Product Complaint
If there is an adverse event or serious adverse event, the protocol 
should be followed.
11.4.4 Documenting a Product Complaint
The investigator will record a description of the product complaint 
in the source documentation as well as any actions taken to resolve 
the complaint and to preserve the safety of the patient. 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.
12.1.
Informed Consent
Overall, this study includes: (I) an informed consent for the clinical 
study (main study) and (II) informed consent forms for the ancillary 
studies (CSF and OCT), and (III) informed consent forms for 
dummy run scans (MRI and OCT) required prior to initiation of the 
study and ancillary study respectively.
Overall, this study includes: (I) an informed consent for the 
clinical study (main study),(II) informed consent forms for 
the ancillary studies (CSF and OCT), and (III) informed 
consent forms for dummy run scans (MRI and OCT) 
required prior to initiation of the study and ancillary study 
respectively.
For completeness, dummy run 
informed consent added to this 
section
APPENDIX B.
GUIDANCE ON SAFETY MONITORING
a.
b. If the blood test is negative, the subject patient will 
be contacted and informed about the test result and the study 
drugs will be sent to her by courierdispensed as soon as possible.
b.
b. If the blood test is negative, the patient will 
be contacted and informed about the test result and the 
study drugs will be dispensed as soon as possible.
It has been clarified that it is not 
acceptable to courier study drug 
to the patient in this manner 
12. 5.
Guidance on monitoring patients 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. In case of 
suspected pancreatitis, the patient 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.
(new text)
Subsection added for consistency 
with other laquinimod protocols
and on the advice of the Data 
Monitoring Committee
APPENDIX C.
MODERATE/STRONG CYP3A4 INHIBITORS AND CYP3A4 INDUCERS
(additional CYP3A4 inhibitors added to the medication classes 
(see Appendix C for revised section)
Section updated in accordance 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
150
Original text with changes shown
New wording
Reason/Justification for change
antivirals [danoprevir, ledipasvir, elvitegravir] and antiemetics 
[casopitant, netupitant], and medication class antiarrhythmics
[dronedarone] added.
List of CYP3A4 inducers replaced with table)
with Investigator’s Brochure
APPENDIX E.
CYP3A4 and CYP1A2 substrates
(original protocol text replaced by table)
(see Appendix E for revised section)
Section updated in accordance 
with Investigator’s Brochure
APPENDIX J.
MODIFIED RANKIN SCALE
(new appendix)
(see Appendix J)
Appendix added to document the 
efficacy measure that has been 
added to the study
APPENDIX L. OCT ANCILLARY STUDY DESIGN AND METHODOLOGY
The following criteria lead to exclusion of affected eyes only. 
However, the patient can participate in the OCT ancillary study 
with a single eye, if it is unaffected.
(new text)
Clarification that only affected 
eyes are excluded from the OCT 
assessments, such that patients 
with an unaffected eye can 
participate for that eye only
(in Table 10, the following changes have been made:

title amended to add ‘of affected eyes’

more than 4 diopters (instead of more than 6 diopters) of 
myopia or hyperopia will exclude an eye

correction of error, should be ‘systemic lupus 
erythematosus’, not ‘systemic lupus erythematodes’

footnote added for selected categories, ‘Indicates 
conditions which are likely to affect both eyes and 
therefore lead to exclusion of the patient, even if 1 eye is 
considered unaffected’)
(see Appendix L for revised table)
Corrections and clarifications

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
151
APPENDIX A. RELAPSE DEFINITION
Relapse (attack)
A relapse will be defined as the appearance of 1 or more new neurological abnormalities or 
reappearance or worsening of 1 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 
symptoms.” Since "in study" relapse definition must be supported by an objective neurological 
evaluation (see next paragraph), a neurological deficit must be sustained long enough to 
eliminate pseudo-relapses.
An event is counted as a relapse only when the patient’s symptoms are accompanied by observed 
objective neurological changes. A change in bowel/bladder function or in cognitive function 
must not be entirely responsible for the changes.
The patient must not be undergoing any acute metabolic changes such as fever or other medical 
abnormality.
Relapse Evaluation Procedures
Patients will be instructed to telephone their study site within 48 hours should any symptoms 
suggestive of a relapse appear.
The Treating Neurologist will evaluate the patient once any symptom suggestive of a relapse 
occurs.
In case of a suggestive relapse during a scheduled or unscheduled visit, the Treating Neurologist
will refer the patient to the Examining Neurologist.
The Examining Neurologist will evaluate the patient within 7 days of symptoms onset, 
conditional upon a symptomatic period of ≥48 hours.
Patient Evaluation by the Examining Neurologist
EDSS and FSS will be administered.
Clinical Relapse Determination by the Treating Neurologist
The determination whether objective neurological changes are present consistent with a relapse 
will be made by the Treating Neurologist, without reference to the EDSS and FSS administered 
by the Examining Neurologist.
Follow-up visits to monitor the course of the relapse will be made at the Treating Neurologist’s
discretion.
Protocol-Defined Relapse
In addition to the criteria used by the Treating Neurologist to determine that a clinical relapse has 
occurred, a per-protocol relapse definition will make use of EDSS data to confirm that the 
objective neurological changes include at least 1 of the following:

an increase of at least 0.5 in the EDSS score as compared to previous evaluation

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
152

an increase of 1 grade in the score of 2 or more of the 7 functions from the FSS as 
compared to previous evaluation

an increase of 2 grades in the score of 1 function from the FSS as compared to the 
previous evaluation

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
153
APPENDIX B. GUIDANCE ON SAFETY MONITORING
1. Guidance on Monitoring Patients with Elevated Liver Function Tests
Liver enzymes (ALT, AST, GGT, ALP), as well as direct and total bilirubin will be measured at 
each study visit. 
In any case of elevated ALT or AST to a level exceeding of ≥2×ULN (including patients whose 
baseline ALT or AST levels are ≥2× and ≤3× the ULN, who may be enrolled in the study), a 
thorough medical history and physical examination with a focus on liver disease should be 
undertakena. In addition, the patient should be instructed to refrain from alcoholic beverages. 
In case of symptoms compatible with drug-induced liver injury, the patient 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 Treating 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×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 patient 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 ≥3×ULN
2. In case baseline value was above ULN and ALT or AST is ≥2× 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 CRF.
                                                
a 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

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
154
Additional Tests/Evaluations

Serology for Hepatitis A (antibody, immunoglobulin M and G), B (core antibody 
total, core immunoglobulin M, and surface antigen), and C viruses (central 
laboratory). 

Serology for autoimmune hepatitis: anti-nuclear antibodies (titer), Anti Smooth 
Muscle Antibodies (ASMA), anti-Liver Kidney Microsomal (LKM) antibodies 
(central laboratory). Further testing may be required in case of a positive result for 
Hepatitis B or C.

An ultrasound examination of the liver and biliary tract.

Other diagnostic tests/consultations, as deemed necessary by the investigator, eg,
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 >3×ULN:

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 CRF, 
accompanied by the reference range of the relevant measurements.

Should the abnormality (ALT or AST ≥3× and ≤5×ULN [if baseline value is 
≥2.5×ULN, ALT or AST ≥3.5×ULN and ≤5×ULN]) persist further, the patient 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 ≥5× but less than 8×ULN
In addition to the above procedures required for any elevation to levels >3×ULN:

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.
1.1.3. ALT or AST ≥8×ULN
In addition to the above procedures required for any elevation to levels >3xULN:

The study drug should be discontinued immediately and the ET visit should be 
performed.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
155

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 ≥3×ULN, combined with INR >1.5 or total bilirubin 
>2×ULN

Any increase in ALT or AST to ≥3×ULN, which is accompanied by nausea, 
vomiting, fever, rash, or eosinophilia

Any increase in ALT or AST to levels ≥5× but <8×ULN, which is persistent for 
≥2 weeks of repeated measurements

Any increase in ALT or AST to levels ≥8×ULN

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 patient who meets the above criteria for discontinuation of the study drug should be 
invited to the site to return the study drug. ET 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 ET, the minimal follow-up period will be 30 days and will 
include measurement of liver enzymes at least QW (may be performed in a local 
laboratory, with at least 1 test being sent to the central laboratory).

Every effort should be made to complete the additional tests/ evaluations, as 
described above.
2. Use of Moderate/Strong CYP3A4 Inhibitors
Laquinimod pharmacokinetics are affected by moderate and strong CYP3A4 inhibitors; 
therefore, moderate/strong CYP3A4 inhibitors are disallowed during study and 30 days after the 
last dose has been administered. A partial list of commonly used CYP3A4 inhibitors is presented 
in Appendix C.
3. Management of Patients who are Diagnosed with Cancer 
Patients who are diagnosed with a malignant solid or liquid tumor while participating in the 
study should stop study medication.
4. 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 acceptable contraception and avoidance of 
pregnancy under laquinimod exposure (see Section 1.4), and to reduce as much as possible the 
exposure to laquinimod if a pregnancy occurs despite all recommended measures, all patients 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
156
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 patients will also be 
counseled about the importance of using 2 acceptable methods of birth control throughout the 
entire treatment duration and until 30 days after the last dose of treatment was administered and 
about the need to stop treatment immediately if pregnancy is suspected.
Women of child-bearing potential (for example women who are not postmenopausal or 
surgically sterilized) must practice an acceptable method of birth control for 30 days before 
taking the study drug and 2 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 patients' 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 patient 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 patients 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. At 
baseline, serum β-hCG will be done within 7 days prior to the initiation of treatment, such that 
the result is available prior to the first dose.
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 patient will be contacted immediately and instructed 
to stop taking the study drug. The patient 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 patient 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 patient will be invited to the site for an early 
termination visit
b. If the blood test is negative, the patient will be contacted and informed about the test 
result and the study drugs will be dispensed as soon as possible.
3.
Starting from visit 3 (week 12), the following actions will be taken:
a.
The patient will be provided with home pregnancy urine β-hCG test kits and will be 
guided how to perform the test.
b. The patient 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.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
157
c.
A mandatory phone call will be performed by the Treating Neurologist 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 patient’s file. In case of a 
suspected pregnancy, the patient 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 Treating Neurologist should discuss with 
the patient 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 
patient 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.
5. Guidance on monitoring patients 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. In case of suspected pancreatitis, the patient 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.
6. Liver Impairment
Patients who develop liver disease associated with liver functional impairment while 
participating in the study should stop study medication.
7. Renal Impairment
Patients 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 patient should stop study 
medication permanently.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
158
APPENDIX C. MODERATE/STRONG CYP3A4 INHIBITORS AND 
CYP3A4 INDUCERS
Laquinimod pharmacokinetics are affected by moderate and strong CYP3A4 inhibitors; 
moderate/strong CYP3A4 inhibitors are disallowed within 2 weeks of baseline until 30 days after 
the last dose has been administered.
Moderate and strong CYP3A4 inhibitors are prohibited because concomitant administration is 
predicted to increase laquinimod exposure and may increase the likelihood of adverse events.
A partial list of moderate/strong CYP3A4 inhibitors follows: 
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:

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, such interactions are not expected with 
laquinimod.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
159
CYP3A4 inducers are disallowed within 2 weeks of baseline and during the treatment period.
A partial list of CYP3A4 inducers follows: 
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

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
160
APPENDIX D. DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS: 
2010 REVISIONS TO “MCDONALD CRITERIA”
MS Diagnosis
Confirmation of PPMS diagnosis according to the 2010 revised McDonald criteria (Polman et al,
2011) will be performed during screening and documented in the CRF.
2010 McDonald criteria for diagnosis of MS in disease with progression from onset
PPMS may be diagnosed in patients with:
1. One year of disease progression (retrospectively or prospectively determined)
2. Plus 2 of the 3 following criteriaa: 
A. Evidence for DIS in the brain based on ≥1 T2b lesions in at least 1 area characteristic for MS 
(periventricular, juxtacortical, or infratentorial)
B. Evidence for DIS in the spinal cord based on ≥2 T2b lesions in the cord.
C. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated immunoglobulin G 
index).
a If a patient has a brainstem or spinal cord syndrome, all symptomatic lesions are excluded from the criteria.
b Gadolinium enhancement of lesions is not required
MS = multiple sclerosis; PPMS = primary progressive MS; DIS = lesion dissemination in space; CSF = 
cerebrospinal fluid; IgG = immunoglobulin G
Note: In this study, if criterion C (positive CSF) is applied toward the diagnosis of PPMS, the 
CRF documentation must be accompanied by source documentation of the results issued by the 
clinical laboratory which performed the analysis.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
161
APPENDIX E. CYP3A4 AND CYP1A2 SUBSTRATES
Table 9:
A Partial List of Cytochrome P450 3A4 Substrates with a Narrow 
Therapeutic Index
alfentanil
cyclosporine
diergotamine
ergotamine
fentanyl
pimozide
quinidine
sirolimus
tacrolimus

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
162
Table 10:
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
For additional information on concomitant use of laquinimod with CYP1A2 and CYP3A4 
substrates, please refer to the IB.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
163
APPENDIX F.
MRI PROCEDURES
The patients will undergo up to 3 MRI scans: baseline (at least 14 days but not more than 
42 days prior to baseline), week 24, and week 48 (or ET visit if performed after the week 36 visit 
and prior to week 48). Weeks 24 and 48 (or ET) MRI must be performed within 14 days of study 
visit. Gd will be administered at baseline MRI only. In case of steroid treatment, study MRI 
should be performed before or be delayed to allow a minimum of 14 days, but not more than 
28 days, from the completion of the steroid course.
MRI scans will be obtained according to a standard protocol that will be provided by the MRI 
Reading Center. At baseline only, MRI scans will be obtained before and after Gd 
administration. GFR calculation at the site should be done prior to the baseline MRI scan.
MRI facilities will undergo a qualification procedure, which will include the performance of a 
healthy volunteer dummy run to ensure that the implementation of the standard sequences on 
their system produces appropriate images for measuring the endpoints specified in the protocol. 
The healthy volunteer must sign an EC approved informed consent form. Qualification of sites 
will be formally indicated by a dummy run approval certification. Sites must be qualified prior to 
the first patient inclusion.
Detailed instructions are provided in the MRI Technologist Manual and Operations Manual.
Confidential patient information such as patient full name must be omitted from the scan header, 
the compact-disc labels, and any accompanying documentation. MRI scans will be transferred to 
the MRI Reading Center in electronic format. The procedure for sending electronic data and 
accompanying documentation is specified in the MRI Technologist Manual.
The MRI reading center will perform QC of all images received. If a scan or sequence fails QC, 
it will need to be repeated. If the baseline scan fails QC, rescanning of the patient should be 
performed as soon as possible prior to baseline. In cases of failed QC at all other visits, the 
window for rescanning will be no longer than 2 weeks. Imaging should be reviewed, by the site, 
at the time of acquisition so that any sequences affected by obvious artifacts can be repeated 
immediately.
MRI scans are evaluated locally for any incidental pathology (ie, pathology unrelated to, or 
inconsistent with, the patient’s known MS) according to locally determined procedures. If such 
pathology is found, the Treating Neurologist should be notified. The MRI reading center will 
evaluate the scans for the purposes of performing quantitative measurements and confirming 
Inclusion Criteria #2 (Lesions consistent with PPMS in either or both brain MRI and cervical 
spinal cord MRI). In order not to compromise blinding of the study, the MRI Reading Center 
will not report MRI findings back to the clinical site.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
164
APPENDIX G. NEUROSTATUS

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
165

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
166

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
167

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
168

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
169

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
170

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
171

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
172

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
173

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
174

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
175
APPENDIX H. INSTRUCTIONS FOR THE TIMED 25-FOOT WALK
Description
The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The patient is 
directed to 1 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 patient walk 
back the same distance. Patients 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
If the patient cannot complete Trial 2 of the Timed Walk after a 5-minute rest period.
If the patient 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 patient should be 
directed to 1 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 patient 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 patient as s/he completes the task. Stop timing when the lead foot crosses the 
finish line. The examiner should then record the patient'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 (eg, 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 patient just behind the line where s/he is not 
standing, repeat the same instructions, and have the patient complete the walk again.
Assistive Devices
The goal is to have the patient 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 patient that 
needs 1, keeping in mind that the patient may deteriorate modestly during the trial.
In general, patients should use their customary assistive device(s), NOT the least assistance 
possible to complete the test. For patients with significant gait impairment, the Treating 
Neurologist should have the patient use a rolling walker even if this is not the patient's customary 

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
176
device. In general, non-wheeled walkers should not be used. If a patient 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 patient'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 patient had a cold or reports not feeling well.

The patient tripped but did not fall.
If a situation arises that necessitates the repetition of a trial, indicate the reason a trial had to be 
repeated on the Record Form. Examples of reasons to repeat a trial include, but are not limited 
to, the following:

The patient fell during the walk.

Examiner forgot to start or stop stopwatch.

Examiner forgot to reset stopwatch in between trials.

The patient stopped to talk to someone while walking, or another person/thing 
somehow interfered with walk.
Record only the times for the 2 successfully completed trials of the Timed 25-Foot Walk. If the 
patient could not complete 1 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 patient'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 (ie, patient in a wheelchair now and unable to walk, etc.). If the patient did not complete 
a trial for any other reason, specify this as well (eg, patient fell and was too fatigued to complete 
another trial, patient refused to complete trial).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
177
APPENDIX I.
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
1.
If the subject cannot complete one trial of the 9-HPT in 5 minutes.
4.
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.
5.
If the subject cannot complete a trial with his or her non-dominant hand, end the test.
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.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
178
Record the subject's time under "Dominant hand Trial 1." If the subject stops after having put all 
the pegs into the holes, prompt the subject to remove them as well by saying, "And now remove 
them all." If the subject begins to remove more than one peg at a time, correct him/her by saying, 
"Pick up one peg at a time."
Dominant Hand Trial 2
After the first trial with the dominant hand, say, "Good. Now, I'd like you to do the same thing 
again, once again using your [DOMINANT] hand. See how fast you can put all of the pegs in 
and take them out again. Ready? Begin." Again, start timing as soon as the subject touches the 
first peg, and stop timing when the last peg hits the container. Record the subject's time under 
"Dominant hand Trial 2."
Non-Dominant Hand Trials 1 and 2
After the second trial with the dominant hand, rotate the apparatus 180 degrees such that the side 
with the pegs is now in front of the non-dominant hand and the empty pegboard is in front of the 
dominant hand. Then say, "OK. Now, I'd like you to switch and use your [NON-DOMINANT] 
hand. This time, you can use your [DOMINANT] hand to stabilize the pegboard. Ready? Begin." 
Administer, time and record the two non-dominant hand trials following the procedures 
described above for dominant hand trials.
Completing the Record Form
Record any circumstances that you believe may have affected the subject's performance. These 
are factors that may have affected the trial but were not severe enough to necessitate repetition of 
the trial. Examples include, but are not limited to, the following:

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 (eg, 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 (eg, subject refused).

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
179
APPENDIX J.
MODIFIED RANKIN SCALE
Table 11:
Modified Rankin Scale Scores
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and 
activities
2
Slight disability; unable to carry out all previous activities, but able to look after own 
affairs
without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to attend to 
own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention
6
Dead

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
180
APPENDIX K. 12-ITEM MULTIPLE SCLEROSIS WALKING SCALE 
(MSWS-12)
Version 1, 2000

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
181
APPENDIX L. OCT ANCILLARY STUDY DESIGN AND 
METHODOLOGY
The patients participating in the OCT ancillary study will undergo scheduled OCT testing and 
ophthalmological examination at week 0 (up to 42 days prior to baseline), and follow-up OCT 
testing at weeks 48 and 96. Additional OCT and ophthalmological examinations may be 
performed in case of any AE concerning the patient’s vision. 
The assessments will be performed using the following methodology: 

Ophthalmological examinations at baseline will include slit lamp, impression tonometry, 
refractometry and funduscopy to identify retinal exclusion criteria to this ancillary study.

Spectral domain OCT at week 0 (up to 42 days prior to baseline) and weeks 48 and 96 
will be performed using a Spectralis® device (Heidelberg Engineering) assessing 
peripapillary RNFL, optic nerve head and macula.

Confidentiality of study patients will be maintained and patients will be identified only 
by the study identification numbers.

OCT results as well as ophthalmological parameters will be transferred directly to the 
OCT Reading Center via a designated web site. The OCT reading center will perform 
quality control (QC) of all results received. If a scan fails QC, it will need to be repeated. 

OCT facilities will undergo a qualification procedure, which will include the performance 
of a dummy run to ensure that the implementation of the specific OCT protocol technique 
in the facility’s setting produces appropriate images for comparison with other centers 
and measurement of the endpoints specified in the protocol. For this purpose, after 
signing an EC approved informed consent form, 1 volunteer per site will undergo 
2 consecutive OCT scans measurements on separate days prior to the first patient 
inclusion in the OCT ancillary study. OCT scans should be performed according to the 
manual using the software’s follow-up function to ensure identical positioning on the 
follow up scan. Ophthalmologic examinations or visual testing are not necessary for these 
qualification scans. Qualification of sites will be formally indicated by a dummy run 
approval certification.

Detailed instructions are provided in the OCT operation manuals.
ANCILLARY STUDY ENDPOINTS

Neuronal and axonal atrophy as defined by the change in thickness of the inner retinal 
layers (RNFL, ganglion cell layer, and inner plexiform layer) in macular volume scans 
and 12° peripapillary ring scans from baseline to weeks 48 and 96.

Eyes with an acute optic neuritis during the study interval or with an ocular exclusion 
criterion will be excluded from analysis of the above endpoints.
ANCILLARY STUDY ADDITIONAL EXCLUSION CRITERIA
The following criteria lead to exclusion of affected eyes only. However, the patient can 
participate in the OCT ancillary study with a single eye, if it is unaffected.

Placebo-Controlled Study – Multiple Sclerosis
Clinical Study Protocol with Global Amendment 02
Study TV5600-CNS-20006 (ARPEGGIO)
182
1.
Severe refraction anomaly defined as >4 diopters
2.
Any history of eye surgery
3.
Any history of confounding retinopathy (see Table 12)
4.
Amblyopia
Table 12:
Retinopathies and Other Ocular Diseases Leading to OCT Ancillary Study 
Exclusion of Affected Eyes
Summary 
Diseases
Structural retinal 
pathology
Drusen, cysts, detachment, presence of myelinated axons, naevus, tumor, optic disc oedema, 
central serous chorioretinopathy, more than 4 diopters of myopia or hyperopia.
Vascular 
retinopathy
History of anterior ischemic optic neuropathy (AION) or posterior ischemic optic neuropathy 
(PION), cotton-wool spots, arteriovenous malformation of sinus cavernosus.
Immune 
retinopathya
Neuromyelitis optica, systemic lupus erythematosus, uveitis, birdshot retinochoroiditis.
Infectious 
retinopathya
Viral, bacterial, fungus, HIV, Lyme, secondary syphilis.
Hereditary 
retinopathya
Leber’s, dominant optic atrophy, albinism, cone dystrophy, retinitis pigmentosa.
Iatrogen retinal 
pathology
Retina surgery, photocoagulation, solar retinopathy, Purtscher’s retinopathy, optic nerve sheet 
fenestration, brain surgery affecting the optic pathways.
Metabolic/toxic 
retinopathya
Alcohol-, tobacco- and malnutrition-induced amblyopia, retinopathy induced by amiodarone, 
chloroquine, vigabatrin.
Other exclusion 
criteriaa
Glaucoma, age dependent macular degeneration, acute posterior multifocal placoid pigment 
epitheliopathy, acute macular neuroretinopathy, history of optic neuritis in the last 6 months.
a Indicates conditions which are likely to affect both eyes and therefore lead to exclusion of the patient, even if 1 eye 
is considered unaffected
STATISTICAL METHODOLOGY
All statistical methodology will be specified in a separate SAP.