Clinical trial NCT02215616
Conditions: Huntington's Disease
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2014-10-28; Completion date: 2018-06-19
Enrollment: 352 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to assess the efficacy of laquinimod as treatment in participants with HD after 52 weeks using the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS or TMS).

Detailed description:

Arms: arm 1: Participants will receive 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks. arm 2: Participants will receive 1 capsule of laquinimod 0.5 milligrams (mg) and 2 capsules of matching placebo, orally once daily for 52 weeks. arm 3: Participants will receive 2 capsule of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks. arm 4: Participants will receive 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily.

Note: The treatment of this high dose arm was discontinued as of 10 January 2016.
Interventions: intervention 1: Laquinimod intervention 2: Placebo
Intervention descriptions: intervention 1: Laquinimod capsules will be administered as per the dose and schedule specified in the respective arms. intervention 2: Matching laquinimod placebo will be administered as per the schedule specified in the respective arms.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 04 
A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, Parallel- 
Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 1.0 and 1.5 mg/day) 
as Treatment in Patients with Huntington's Disease 
Study Number TV5600-CNS-20007 
NCT02215616 
Protocol with Amendment 04 Approval Date: 16 February 2016 


 
Placebo-Controlled Study – Huntington's Disease 
Clinical Study Protocol with Am 04  
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1 
 
 
 
Clinical Study Protocol with Amendment 04  
A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 
1.0 and 1.5 mg/day) as Treatment in Patients with Huntington's Disease 
Phase II 
Study TV5600-CNS-20007  
(LEGATO-HD - Laquinimod Efficacy and Safety in a GlobAl Trial Of HD) 
IND 120331 
EudraCT number: 2014-000418-75 
Global Protocol Amendment 04 Approval Date: 16 February 2016 
Sponsor (and Monitor) 
Teva Branded Pharmaceutical Products R&D, Inc. 
41 Moores Rd. 
Frazer, PA 19355 
USA 
 
 
Authorized Representative (Signatory) 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
Sponsor’s Medical Expert 
Sponsor’s Safety Officer 
Teva Branded Pharmaceutical Products R&D, Inc. 
Teva Pharmaceutical Industries, Ltd. 
 
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 Branded 
Pharmaceutical Products R&D, Inc., and its affiliate, Cephalon, Inc. (collectively the “Sponsor”). The 
recipient agrees that no information contained herein may be published or disclosed without written 
approval from the Sponsor. 
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 


 
Placebo-Controlled Study – Huntington's Disease 
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PROTOCOL AMENDMENTS 
A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 
1.0 and 1.5 mg/day) as Treatment in Patients with Huntington's Disease 
Study TV5600-CNS-20007  
(LEGATO-HD - Laquinimod Efficacy and Safety in a GlobAl Trial Of HD) 
 
The original protocol for study TV5600-CNS-20007 (dated 27 May 2014) has been amended and 
reissued as follows: 
Global Protocol Amendment 04 
16 February 2016 
(123 patients randomized to date) 
Administrative Letter 07 
05 November 2015 
Administrative Letter 06 
22 October 2015 
Global Protocol Amendment 03 
24 September 2015 
(75 patients randomized to date) 
Administrative Letter 05 
29 April 2015 
Administrative Letter 04 
21 April 2015 
Administrative Letter 03 
18 February 2015 
Global Protocol Amendment 02 
16 February 2015 
(6 patients enrolled to date) 
Protocol Amendment  
(Local EC UK 02) 
25 January 2015 
Administrative Letter 02 
14 November 2014 
 Protocol Amendment  
(Local EC UK 01) 
30 September 2014 
(0 patients enrolled to date) 
 Global Protocol Amendment 01 
10 September 2014 
(0 patients enrolled to date) 
Administrative Letter 01 
18 July 2014 
Protocol Approval Date 
27 May 2014 
 


 
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INVESTIGATOR AGREEMENT 
 


 
Placebo-Controlled Study – Huntington's Disease 
Clinical Study Protocol with Am 04  
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COORDINATING INVESTIGATOR AGREEMENT 
 


 
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS 
Central Clinical Laboratory 
Quest Diagnostics Clinical Laboratories, Inc.  
27027 Tourney Road 
Suite 2E Valencia, CA 91355  
USA  
 
Quest Diagnostics Limited Unit B1 
Parkway West Industrial Estate Cranford Lane – Heston 
Middlesex TW5 9QA  
UK  
 
Quest Diagnostics Nichols Institute 
33608 Ortega Highway  
San Juan Capistrano, CA 92675-2042  
USA  
 
Central Electrocardiogram Evaluation 
Biomedical Systems Corporation 
77 Projgress Parkway 
St. Louis, MO 63053 
USA 
 
Web and Phone Integrated Interactive Response Technology 
PAREXEL International 
Lady Bay House 
Meadow Grove 
Nottingham 
NG2 3HF 
UK 
 
Computer-Based Rating System 
QuantiMedis GmbH 
Marientalstrasse 43 
48149 Münster 
Germany 
 
Stout Neuropsych Pty Ltd 
44 Stewart Street 
Ormond VIC 3204 
Australia 
 
 
 


 
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Bioanalytical Laboratory  
Teva Pharm. Works Private Ltd. Co (TPW) 
Pallagi St 13 
4042 Debrecen 
Hungary 
 
 
Central MRI Vendor 
IXICO Technologies Limited 
4th Floor, Griffin Court 
15 Long Lane 
London 
EC1A 9PN 
United Kingdom 
 
Scale Management 
Bracket 
575 E. Swedesford Road, Suite 200 
Wayne, PA 19087 
USA 
 
MRS Analysis 
University of British Columbia MRI Research Centre 
Room M10 Purdy Pavilion 
2221 Wesbrook Mall 
Vancouver 
British Columbia 
V6T 2B5 
CANADA 
 
PET Substudy 
Imperial College London 
Hammersmith Hospital, Neurology Imaging Unit 
Du Cane Road 
London 
W12 0NN 
United Kingdom 
 
Collaborator 
Huntington Study Group 
2604 Elmwood Avenue, Suite 335 
Rochester, NY 14618 
USA 
 
European Huntington’s Disease Network 
University of Ulm 
Oberer Eselsberg 45/1 
D-89081 Ulm 
Germany 


 
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the physician listed below:  
Global/EU : 
  
(Located in Germany) 
 
US: 
 
In a study-related medical emergency situation, when assigned Medical Monitors for a study 
cannot be reached, an on-call Physician can be reached 24 hours per day, 7 days per week via an 
ICON Call-Center: 
  
[Toll (not free of charge) telephone number allowing a global reach from both landlines and 
mobile phones] 
On the following internet page (https://icophone.iconplc.com), a list of country-specific toll-free 
telephone numbers is provided. It should be noted that not all countries globally have access to 
toll-free numbers as indicated on the “24/7 Medical Help desk” index. Countries without toll-free 
numbers need to dial the toll (not free of charge) number as indicated above. Toll-free numbers 
are unfortunately not available from mobile phones.  
 
For operational issues, contact the operational lead listed below:  
 
For serious adverse events: 
Send by e-mail/facsimile to local safety officer/contract research organization (LSO/CRO). 
Email address and Fax number will be provided in the serious adverse event (SAE) report form. 
In the event of difficulty transmitting the form, contact the sponsor’s study personnel identified 
above for further instruction. 


 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.  
Title of Study: A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 1.0 and 1.5 mg/day) as 
Treatment in Patients with Huntington's Disease 
Study Number: TV5600-CNS-20007 (LEGATO-HD - Laquinimod Efficacy and Safety in a GlobAl 
Trial Of HD) 
EudraCT/IND Number(s): 2014-000418-75/120331 
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 (TV-5600 or ABR-215062) 
Phase of Clinical Development: II 
Number of Investigational Centers Planned: Approximately ~51 centers  
Countries Planned: North America, Europe and Russia 
Number of Patients Planned: Approximately 300 patients (100 patients within each study arm) plus the 
30 patients that were already randomized to the laquinimod 1.5 mg treatment arm. 
Study Population: The study population will be comprised of patients with adult onset Huntington's 
disease, with a cytosine-adenosine-guanine (CAG) repeat length between 36 and 49, inclusive. The basic 
eligibility criteria will select a population with symptoms of Huntington's disease (HD), as assessed by a 
Unified Huntington's Disease Rating Scale – Total Motor Score (UHDRS-TMS) >5, but with a largely 
retained functional capacity, as assessed with a Unified Huntington's Disease Rating Scale – Total 
Functional Capacity (UHDRS-TFC) score ≥8. 
Planned Study Period: Q4 2014 – Q1 2018  
Primary Study Objective: The primary objective of this study is to assess the efficacy of laquinimod 
(0.5 mg and 1.0 mg qd) in patients with HD after 12 months of treatment using the UHDRS-TMS.  
Secondary Study Objectives:  
• 
To assess the effect of laquinimod on brain atrophy in patients with HD after 12 months of 
treatment using MRI measures of caudate volume. 
• 
To assess the effect of laquinimod on the cognitive capacity in patients with HD after 12 
months of treatment using the cognitive assessment battery (CAB) for patients with HD 
[comprised of: Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail Making 
Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced Tapping at 3 Hz, One Touch 
Stockings of Cambridge (OTS, abbreviated 10 trial version]. 
• 
To assess the effect of laquinimod on the clinical global impression in patients with HD after 
12 months of treatment using the Clinician’s Interview-Based Impression of Change plus 
Caregiver Input (CIBIC-Plus) 
• 
To assess the effect of laquinimod on the functional capacity in patients with HD after 12 
months of treatment using the UHDRS-TFC scale 


 
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Exploratory Study Objectives:  
• 
To assess the effect of laquinimod on brain atrophy in patients with HD after 12 months of 
treatment using MRI measures of whole brain volume, white-matter volume and ventricular 
volume. 
• 
To assess the effect of laquinimod on the functional capacity in patients with HD after 12 
months of treatment using the UHDRS-functional assessment (FA) scale 
• 
To assess the effect of laquinimod on motor function in patients with HD after 12 months of 
treatment using the objective instrument Q-Motor 
• 
To assess the effect of laquinimod on physical performance in patients with HD after 12 
months of treatment using the modified Physical Performance Test (mPPT). 
• 
To assess the effect of laquinimod on the quality of life in patients with HD after 12 months 
of treatment using the Huntington’s Disease Quality of Life (HD-QoL) and EQ-5D-5L 
instruments 
• 
To assess the effect of laquinimod on work productivity in patients with HD after 12 months 
of treatment. 
• 
To assess the effect of laquinimod on functional impairment due to cognitive decline in 
patients with HD after 12 months of treatment using the Clinical Dementia Rating – Sum of 
Boxes (CDR-SB) 
• 
To assess the effect of laquinimod on depression and anxiety in patients with HD after 12 
months of treatment using the Hospital Anxiety and Depression Scale (HADS)  
• 
To assess the effect of laquinimod on behavioral signs and symptoms in patients with HD 
after 12 months of treatment using the Problem Behaviors Assessment-Short form (PBA-s) 
• 
To evaluate the pharmacokinetics of laquinimod and its metabolites in patients with HD 
• 
To investigate the relationship between exposure to laquinimod and its metabolites and 
outcome measures (e.g., clinical effect and toxicity parameters).  
Safety and Tolerability Study Objectives: 
• 
To evaluate safety and tolerability of laquinimod in patients with HD during 12 months of 
treatment by evaluating adverse events (AEs), electrocardiography (ECG), and clinical 
laboratory parameters, vital signs, physical examinations, and premature discontinuations 
from the study.  
Ancillary Study Objectives (substudies): 
• 
To explore potential correlation between genetic polymorphisms in deoxyribonucleic acid 
(DNA) and pharmacokinetics, clinical response to laquinimod, and/or adverse drug reactions, 
if these occur 
• 
To explore potential correlation between ribonucleic acid (RNA) expression profile in blood 
cells and clinical response to laquinimod 
• 
To explore changes in blood cell gene expression profile following treatment with 
laquinimod as potential biomarkers for laquinimod mechanism of action  
• 
To evaluate changes in cytokines and other soluble protein levels following treatment with 
laquinimod as potential biomarkers for laquinimod mechanism of action and/or response 
predictive factors 
• 
To explore gene expression and/or protein profile in monocytes in response to laquinimod 
treatment 
• 
To explore change in microglial activation state in response to treatment with laquinimod 
• 
To explore the potential effect on metabolic changes in the putamen and frontal white matter 
that are associated with the earliest stages of Huntington’s Disease. 


 
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Criteria for Inclusion:  
Patients may be included in the study if they meet all of the following criteria:  
a. [New criterion] Documentation of prior positive genetic testing for HD, or a clinical 
diagnosis of symptomatic HD (Diagnostic Confidence Level 4).  
b.  [Revision 1] Presence of 36-49 CAG repeats, inclusive, in the huntingtin gene based on 
centralized CAG testing during screening.  
c. Male or female between 21-55 years of age, inclusive, with an onset of HD at or after 
18 years of age. 
d. [Revision 1] Women of child-bearing potential (women who are not post-menopausal or who 
have not undergone surgical sterilization) must practice an acceptable method of birth control 
for 30 days before taking the study treatment, and 2 acceptable methods of birth control 
during all study duration and until 30 days after the last dose of treatment was administered. 
Acceptable methods of birth control in this study include: Intrauterine device, barrier method 
(condom or diaphragm with spermicide) and hormonal methods of birth control (e.g., oral 
contraceptive, contraceptive patch, long-acting injectable contraceptive).  
e. A sum of >5 points on the UHDRS-TMS at the screening visit 
f. UHDRS- TFC ≥ 8 at the screening visit. 
g. Able and willing to provide written informed consent prior to any study related procedure 
being performed at the screening visit. Patients with a legal guardian should be consented 
according to local requirements. 
h. Willing to provide a blood sample for genomic CAG analysis at the screening visit. 
i. 
Willing and able to take oral medication and able to comply with the study specific 
procedures.  
j. 
Ambulatory, being able to travel to the study centre, and judged by the investigator as likely 
to be able to continue to travel for the duration of the study  
k. Availability and willingness of a caregiver, informant, or family member to provide input at 
study visits assessing CIBIC-Plus, CDR-SB, PBA-s, and HD-QoL. A caregiver is 
recommended to be someone who attends to the patient at least 2 to 3 times per week for at 
least 3 hours per occasion, and the suitability of the caregiver should be judged by the 
investigator. 
l. 
For patients taking allowed antidepressant medication, the dosing of medication must have 
been kept constant for at least 30 days before baseline and must be kept constant during the 
study.  
Criteria for Exclusion:  
Patients are excluded from participating in this study if 1 or more of the following criteria are met:  
a. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and 
azathioprine within 12 months prior to screening 
b. Previous use of laquinimod 


 
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c. Use of moderate/strong inhibitors of cytochrome P450 (CYP)3A4 within 2 weeks prior to 
randomization. 
d. Use of inducers of CYP3A4 within 2 weeks prior to randomization.  
e. Pregnant or breastfeeding. 
f. [Revision 1] Serum levels ≥2x upper limit of the normal range (ULN) of either alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) at screening. 
g. [Revision 1] Serum direct bilirubin which is ≥1.5xULN at screening.  
h. [Revision 2] Estimated reatinine clearance <60 mL/min at screening, calculated using the 
Cockcroft Gault equation: (140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine 
(mg/dL)  
i. 
[Revision 1] Subjects with a clinically significant or unstable medical or surgical condition 
that may put the patient at risk when participating in the study or may influence the results of 
the study or affect the patient's ability to take part in the study, as determined by medical 
history, physical examinations, ECG, or laboratory tests. Such conditions may include: 
1. A major cardiovascular event (e.g. myocardial infarction, acute coronary syndrome, de-
compensated congestive heart failure, pulmonary embolism, coronary revascularization, 
angina) that occurred prior to randomization. 
2. Significant cardiovascular risk factors (such as, but not limited to, uncontrolled 
hypertension, uncontrolled diabetes), per investigator discretion. 
3. Any acute pulmonary disorder 
4. A central nervous system (CNS) disorder other than HD that may jeopardize the subject's 
participation in the study, including such disorders that are demonstrated on the baseline 
magnetic resonance imaging (MRI) (based on local read). 
5. A gastrointestinal disorder that may affect the absorption of study medication. 
6. Acute or chronic renal disease including acute kidney injury (AKI). 
7. Any form of acute or chronic liver disease. 
8. Known human immunodeficiency virus (HIV) positive status. Patients will undergo an 
HIV test at screening per local requirements, if applicable. 
9. Any malignancies, excluding basal cell carcinoma, in the 5 years prior to randomization. 
j. 
Any clinically significant, abnormal, screening laboratory result which in the opinion of the 
investigator, affects the patients’ suitability for the study or puts the patient at risk if he/she 
enters the study 
k. Unsuitable for MRI (e.g., claustrophobia, metal implants) 
l. 
Alcohol and/or drug abuse within the 12 months prior to screening, as defined by Diagnostic 
and Statistical Manual of Mental Disorders – Fourth Edition Text Revision (DSM-IV TR) 
criteria for substance abuse. For former alcohol and/or drug abusers, the abstinence should be 
confirmed by laboratory tests (drug testing and/or carbohydrate deficient transferrin (CDT) 
level in blood). 


 
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m. Patients with active suicidal ideation during the past month as measured by a most severe 
suicide ideation score of 4 (Active Suicidal Ideation with Some Intent to Act, without 
Specific Plan) or 5 (Active Suicidal Ideation with Specific Plan and Intent) on the baseline 
screening Columbia-Suicide Severity Rating Scale (C-SSRS) or subjects who answer “Yes” 
on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted 
attempt, preparatory acts, or behavior) if the attempt or acts were performed within 1 year of 
screening, or subjects who, in the opinion of the investigator, present a serious risk of suicide. 
n. Patients with known intracranial neoplasms, vascular malformations, or intracranial 
hemorrhage 
o. Known drug hypersensitivity that would preclude administration of laquinimod or placebo, 
such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate. 
p. Swallowing difficulties that would preclude administration of laquinimod or placebo 
capsules. 
q. [Revision 1] Treatment with any investigational product within 30 days of screening or 
patients planning to participate in another clinical study assessing any investigational product 
during the study. Patients in non-interventional and/or observational studies will not be 
excluded from participating in this study. 
r. Treatment with tetrabenazine within 30 days of the study baseline visit 
s. Treatment with antipsychotic medication within 30 days of the study baseline visit 
Study Drug Dose, Mode of Administration, and Administration Rate:  
Investigational Product:  
The dose levels of laquinimod are 0.5, 1.0, and 1.5 mg qd. Every patient will take 3 capsules once daily, 
at the same time of day, during the entire study period.  
• 
Patients randomized to the laquinimod 1.5 mg qd treatment arm will receive 3 capsules of 
0.5 mg laquinimod. (Note: the treatment of this high dose arm was discontinued as of 10 
January 2016) 
• 
Patients randomized to the laquinimod 1.0 mg qd treatment arm will receive 2 capsules of 
0.5 mg laquinimod and 1 capsules of matching placebo. 
• 
Patients randomized to the laquinimod 0.5 mg qd treatment arm will receive 1 capsule of 
0.5 mg laquinimod, and 2 capsules of matching placebo. 
Placebo: Patients randomized to the placebo treatment arm will receive 3 capsules of matching placebo. 
The capsules will be taken orally and must be swallowed whole with a glass of water. The capsule should 
not be opened. Laquinimod can be taken with or without food. 
Method of Blinding and Randomization:  
Prior to 10 January 2016, patients were randomly assigned to receive treatment with laquinimod at a 
dosage of 0.5, 1.0, or 1.5 mg qd or a matching placebo in a 1:1:1:1 ratio.  
As of 10 January 2016, following the decision to discontinue treatment of the laquinimod 1.5 mg dose 
arm, additional eligible patients who are enrolled will be randomized in a 1:1:1 ratio to receive treatment 
with laquinimod at a dosage of 0.5, 1.0 mg qd or a matching placebo. No change was performed to the 
original randomization list except that the patient numbers assigned to laquinimod 1.5 mg/day were 
removed from the list by the interactive response technology (IRT) vendor. 


 
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Patients and investigators will remain blinded to treatment assignment during the study.  
The randomization code will be generated by the Clinical Supply Chain (CSC) department following 
specifications from the Biostatistics Department.  
In addition, the sponsor’s clinical personnel involved in the study will be blinded to the study drug 
identity until the database has been locked for analysis and the treatment assignment revealed.  
Duration of Participation: 
Total study participation will be up to 14 months:  
• 
Screening period of 2 weeks up to 5 weeks  
• 
12 months double-blind, placebo-controlled treatment period  
• 
Safety follow-up period 1 month following the last dose of study medication. 
General Design and Methodology:  
This is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, 
to evaluate the efficacy and safety of daily oral administration of laquinimod (0.5 mg and 1.0 mg) in 
patients with HD. Prior to 10 January 2016, eligible patients were randomly assigned to receive treatment 
with laquinimod at a dosage of 0.5 mg, 1.0 mg, or 1.5 mg/day or a matching placebo in a 1:1:1:1 ratio. 
As of 10 January 2016, treatment with laquinimod was discontinued for all patients in the 1.5 mg dose 
group, and future patients will be randomized in a 1:1:1 ratio to receive laquinimod 0.5 mg/day or 1.0 
mg/day or matching placebo for 52 weeks.  
It is planned to randomize a total of 300 patients (100 patients within each study arm), plus the 30 patients 
that were already randomized to the laquinimod 1.5 mg treatment arm. Patients will be treated with 
investigational product or matching placebo for 12 months, and efficacy and safety will be assessed after 
1, 3, 6, 9 and 12 months of treatment. 
The following assessments will be performed at the specified time points:  
• 
Eligibility criteria will be reviewed and confirmed at screening and baseline. 
• 
Vital signs will be measured at each study visit. 
• 
A physical examination will be performed at each study visit (including weight).  
• 
Cardiovascular risk assessment and management (including smoking history) at screening 
and as soon as possible for patients already in the study, following approval of Global 
Amendment 04. 
• 
The following safety clinical laboratory tests will be performed: 
○ When applicable per local requirements, patients will undergo an HIV test at screening. 
○ Complete blood count (CBC) with differential at each study visit. 
○ 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) and B12 at baseline. 
○ Serum chemistry (including electrolytes, liver enzymes, urea, creatinine, glucose, total 
protein, albumin, total bilirubin, Creatine phosphokinase (CPK), serum conventional C-
reactive protein (CRP), fibrinogen and pancreatic amylase) – at all scheduled visits. 
Estimated creatinine clearance will be calculated at all study visits.  
○ Lipid profile [total cholesterol, high density lipoprotein (HDL), low density lipoprotein 
(LDL), triglycerides] – at baseline and Month 12. 
○ Serum thyroid-stimulating hormone (TSH), T3 and Free T4 at baseline (Month 0), Month 
6 and Month 12  
○ Urinalysis at the screening visit. 


 
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○ Serum beta human chorionic gonadotropin (β-hCG) in women of child-bearing potential 
will be performed at each scheduled study visit. 
○ Urine β-hCG test will be performed in women of child-bearing potential at baseline and 
at each scheduled study visit thereafter.  
○ Starting after visit Month 3 a urine β-hCG test will be performed at home in women of 
child-bearing potential every 28 (±2) days. The patient will be contacted by telephone 
within 72 hours after the scheduled test is to be performed and asked specific questions 
regarding the test. In case of suspected pregnancy (positive urine β-hCG test result), the 
caller will make sure that the study drug has been discontinued and the subject will be 
instructed to arrive to the site as soon as possible (within 10 days) with all remaining 
study drugs capsules.  
• 
When applicable, patients will be screened for drug substances in urine and/or CDT level in 
blood at screening to confirm abstinence in former (more than 12 months from screening) 
alcohol and/or drug abusers.  
• 
Blood for analysis of cytokines and other soluble proteins will be collected at baseline, and at 
Months 6 and 12, concomitant with other blood draw procedures. 
• 
ECG will be performed at screening, baseline, and at Months 1, 3, 6, and 12, and will be 
centrally evaluated.  
• 
Blood sample for genomic analysis and CAG repeat length determination will be drawn at 
screening. 
• 
Adverse Events (AEs) will be monitored throughout the study. 
• 
Suicidality will be monitored throughout the study through administration of the C-SSRS 
• 
Concomitant medications will be monitored throughout the study. 
• 
All subjects will undergo MRI scans at baseline and Month 12. 
• 
Motor function evaluations (UHDRS-TMS and Q-Motor) will be performed at screening, 
baseline and at Months 1, 3, 6 and 12. 
• 
Functional capacity evaluations (UHDRS-TFC and mPPT) will be performed at baseline and 
at Months 6 and 12. The UHDRS-TFC is also performed at screening. 
• 
Clinical global impression will be evaluated by an independent rater using the Clinician's 
Interview-Based Impression of Severity (CIBIS) process at baseline and CIBIC-Plus at 
Months 6 and 12 
• 
Psychiatric and behavioral evaluations (PBA-s and HADS) will be done at baseline and at 
Month 12. 
• 
Cognitive capacity will be evaluated at screening, baseline and at Months 6 and 12, by 
administration of the HD-CAB (SDMT, Emotion Recognition, Trail Making Test, HVLT-R, 
Paced Tapping at 3 Hz, OTS). 
• 
A reduced battery comprised of the SDMT and Trail Making Test will be performed at 
Months 1 and 3. 
• 
Cognitive functional capacity will be assessed at baseline and at Month 12, by clinician rating 
of the CDR-SB scale including information from the patient and the informant, and the sum 
of boxes score will be calculated 
• 
Quality of life will be assessed by the administration of the HD-QoL questionnaire to the 
patient and the informant at baseline and Month 12. The patient will also complete the EQ-
5D-5L and work limitations questionnaire (WLQ) at baseline and Month 12. 
• 
Population Pharmacokinetic (PPK) study: Blood samples for analysis of laquinimod plasma 
concentrations will be collected from all subjects at Months 1, 3, 6 and 12.  


 
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For patients participating in the ancillary studies: 
• 
Blood will be collected for 24-h pharmacokinetic (PK) profiling at selected sites at Month 1 
from approximately 15 patients per each of the three continuing treatment groups, for a total 
of approximately 45 patients. Additionally, PK samples were collected from 2 patients in the 
laquinimod 1.5 mg/day treatment group when the treatment was stopped; no further PK 
samples will be collected from the laquinimod 1.5 mg/day treatment group. 
• 
Blood for monocyte gene expression and protein profile will be collected in a subgroup of 
patients at baseline and Month 12.  
• 
PET scan in a subgroup of patients at baseline and Month 12.  
• 
MRI scans for MRS evaluation will be done in a subgroup of patients at baseline and Month 
12.  
An independent data safety monitoring board (DSMB) will oversee the study. The DSMB will review 
unblinded accumulating safety data on a regular basis to ensure the continuing safety of the study patients 
and study conduct issues. 
Efficacy Variables and Endpoints:  
Primary Efficacy Variable and Endpoint 
The primary efficacy variable and endpoint for this study is change from baseline in the UHDRS-TMS 
(defined as the sum of the scores of all UHDRS-TMS subitems) at Month 12/ ET (evaluated at baseline 
and Months 1, 3, 6 and 12).  
Secondary Efficacy Variables and Endpoints 
The secondary efficacy variables and endpoints for this study are: 
• 
Percent change from baseline in caudate volume at Month 12/ET (evaluated at baseline and 
Month 12) 
• 
Change from baseline in HD-CAB total score (sum of the standardized sub-components) at 
Month 12/ET (evaluated at baseline and Months 6 and 12)  
• 
CIBIC-Plus global score at Month 12/ET (evaluated at Months 6 and 12) as compared to 
baseline (rated by an independent rater) 
• 
Change from baseline in UHDRS- TFC at Month 12/ET (evaluated at baseline, Months 6 and 
12) 
Exploratory Efficacy Variables and Endpoints 
The exploratory efficacy variables and endpoints for this study are: 
• 
Change from baseline in brain atrophy as defined by the percentage change in volume in: 
whole brain volume and white-matter volume at Month 12/ET and absolute change in 
ventricular volume at Month 12/ET (evaluated at baseline and Month 12) 
• 
Change from baseline in UHDRS- FA at Month 12/ET (evaluated at baseline and Months 6 
and 12)  
• 
Change from baseline in Q-Motor assessments at Month 12/ET (evaluated at baseline and 
Months 1, 3, 6 and 12) 
• 
Change from baseline in mPPT at Month 12/ET (evaluated at baseline and Months 6 and 12) 
• 
Change from baseline in HD QoL and EQ-5D-5L at Month 12/ET (evaluated at baseline and 
Month 12) 
• 
Change from baseline in WLQ at Month 12/ET (evaluated at baseline and Month 12) 


 
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• 
Change from baseline in HD-CAB sub-components at Month 12/ET (evaluated at baseline 
and Months 6 and 12):  
Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail Making Test, Hopkins 
Verbal Learning Test, revised (HVLT-R), Paced Tapping at 3 Hz, One Touch Stockings of 
Cambridge (OTS, abbreviated 10 trial version) 
• 
Change from baseline in CDR-SB at Month 12/ET (evaluated at baseline and Month 12)  
• 
Change from baseline in HADS at Month 12/ET (evaluated at baseline and Month 12) 
• 
Change from baseline in PBA-s at Month 12/ET (evaluated at baseline and Month 12) 
Safety Variables and Endpoints:  
Safety variables and endpoints will include the following:  
• 
Adverse events reports throughout the study 
• 
ECG findings throughout the study 
• 
Clinical safety laboratory tests throughout the study 
• 
Vital signs measurements throughout the study 
• 
Physical examination findings throughout the study 
• 
Changes from baseline suicidality (C-SSRS) scores throughout the study 
Tolerability variables and endpoints: 
• 
Proportion of subjects (%) who prematurely discontinued from the study, reason of 
discontinuation and the time to ET 
• 
Proportion of subjects (%) who prematurely discontinued from the study due to AEs and the 
time to ET 
Pharmacogenomic Sub-Study: 
Pharmacogenomic (PGx) assessment will include DNA variations and RNA, gene expression pattern 
potentially associated with clinical treatment responses to laquinimod (e.g. clinical effect, Q-Motor, 
pharmacokinetics, tolerability, and safety features or disease susceptibility and severity features). Samples 
for DNA analysis will be collected at screening (or if not possible, at the next possible visit). Samples for 
RNA analysis will be collected at baseline, Month 6 and 12. 
Other Ancillary Studies: 
• 
Microglial activation state will be investigated in selected patients (N=aiming at 10 per 
treatment arm). Positron emission tomography (PET) scans and imaging analysis of 
microglial activation marker translocator protein (TSPO) will be performed at baseline and 
Month 12.  
• 
Change in putaminal and frontal white matter markers of neuronal integrity (N-acetyl-
aspartate (NAA)) and astrocytosis (myo-inositol) will be investigated at selected sites using 
magnetic resonance spectroscopy (MRS) (N=aiming at 20 per treatment arm) at baseline and 
Month 12. 
• 
Monocyte gene expression and/or protein profile in response to treatment with laquinimod 
will be analyzed at selected sites and patients (N=aiming at 25 per treatment arm). Monocytes 
will be separated from isolated peripheral blood mononuclear cells (PBMC) and be analyzed 
for gene expression and/or protein profile at baseline and Month 12.  
• 
Peripheral cytokine and proteomic analysis in response to treatment with laquinimod will be 
investigated in a subgroup of patients at selected sites at baseline and Months 6 and 12.  


 
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Statistical Considerations:  
Sample Size 
The study aims to detect potential beneficial effects in deteriorating clinical signs and symptoms. Based 
on previous studies in patients with HD, the UHDRS-TMS has been shown to be one of the more 
sensitive clinical measures to detect decline in symptoms of HD. It is estimated that approximately 100 
patients per arm will enable a power of 80% to detect a beneficial effect of 2.5 points or more in the 
change from baseline in UHDRS-TMS of an active laquinimod arm compared to placebo, assuming 
standard deviation (SD) of 6.2 and type I error of 5%. 
As the intention is to investigate laquinimod as a treatment with the potential to slow disease progression 
and prohibit neuronal death in the CNS, the study should also be sized to be able to detect changes in 
brain atrophy rate after treatment with laquinimod. One of the most sensitive measures to detect brain 
atrophy over time in patients with HD is change in the caudate volume. It is estimated that approximately 
100 patients per arm will also enable a power of 80% to detect a beneficial effect of 0.95 (30% of the 
estimated decline in placebo) or more in the percent change from baseline in caudate brain atrophy of an 
active laquinimod arm compared to placebo, assuming SD of 2.36 and type I error of 5%. 
Statistical Analyses  
Due to the decision from 10 January 2016 to discontinue treatment of the laquinimod 1.5 mg dose arm, 
and the low number of enrolled patients compared to the target at this time, data from the laquinimod 
1.5 mg treatment arm will be presented descriptively only, and will not be included in any inferential 
analyses for efficacy or safety. 
Control of Type I Error Rate 
The Hochberg’s Step-Up method for multiple comparisons between treatment arms in combination with 
the hierarchical method between the primary efficacy endpoint and the secondary efficacy endpoints, will 
be used to maintain the experiment wise type I error of 5% level. 
Primary Efficacy Endpoint Analysis 
The change from baseline in UHDRS-TMS will be analyzed using a Repeated Measures model (SAS® 
MIXED procedure with REPEATED sub-command). The model will include the following fixed effects: 
categorical week in trial by treatment interaction, center, and UHDRS-TMS at baseline. The unstructured 
covariance matrix for repeated observations within patients will be used. In case that the model will not 
converge, the Maximum-Likelihood (ML) estimation method will be used instead of the default 
Restricted ML (REML). If the model still does not converge then a simpler covariance structures with 
less parameters will be used, according to the following order: Heterogeneous Autoregressive(1) 
[ARH(1)], Heterogeneous Compound Symmetry (CSH), Autoregressive(1) [AR(1)], and Compound 
Symmetry (CS). The estimated means at the Month 12 visit will be compared between the active 
treatment arms and the placebo arm. 
The Hochberg’s Step-Up method for multiple comparisons between treatment arms will be used to 
control inflation in type I error rate. 
Secondary Efficacy Endpoints Analyses 
According to the hierarchical method to control inflation in type I error rate for multiple endpoints, any 
statistically significant dose that will be observed in the primary analysis will continue to be tested for the 
secondary endpoints at an alpha level of 5%, according to the secondary endpoints order. 
The secondary efficacy endpoints: change from baseline in HD-CAB total score and change from baseline 
in UHDRS- TFC, will be analyzed in the same way as the primary efficacy endpoint except that the 
efficacy endpoint evaluation at baseline will be included in the model instead of baseline UHDRS-TMS.  


 
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The CIBIC-Plus will be analyzed in the same way as the primary efficacy endpoint except that the 
baseline CIBIS (Clinician’s Interview-Based Impression of Severity) will be included in the model as the 
efficacy measure at baseline. 
The percent change from baseline to Month 12/Early Termination in caudate volume will be analyzed 
using an Analysis Of Covariance (ANCOVA) model (SAS® MIXED procedure). The model will include 
the following fixed effects: treatment, center, and caudate volume at baseline. The estimated means at the 
Month 12 visit will be compared between the active treatment arms and the placebo arm. Early terminated 
patient observation will have their Last Observation Carried Forward (LOCF). 
Exploratory Efficacy Endpoints Analyses 
The exploratory efficacy endpoints will be analyzed in the same way as the primary efficacy endpoint 
except that the efficacy endpoint evaluation at baseline will be included in the model instead of baseline 
UHDRS-TMS. 
The change from baseline to Month 12/Early Termination of continuous efficacy endpoints that are 
measured at baseline and at month 12 only, will be analyzed using an ANCOVA model (SAS® MIXED 
procedure). The model will include the following fixed effects: treatment, center, and the efficacy 
measure at baseline. The estimated means at the Month 12 visit will be compared between the active 
treatment arms and the placebo arm. Early terminated patient observation will have their Last Observation 
Carried Forward (LOCF). 
Safety Analyses 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Each patient 
will be counted only once in each preferred term (PT) or system organ class (SOC) category for the 
analyses of safety. Summaries will be presented for all AEs, AEs determined by the investigator to be 
related to study treatment, serious AEs, and AEs causing withdrawal from the study. Summaries will be 
presented by treatment group and for all patients. Patient listings of SAEs and AEs leading to withdrawal 
will be presented. 
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. 
The use of concomitant medications will be summarized by therapeutic class using descriptive statistics. 
Concomitant medications will include all medications taken while the patient is treated with study drug. 
For continuous variables, descriptive statistics (n, mean, SD, 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. Descriptive summaries of SAEs, 
patient withdrawals due to AEs, and potentially clinically significant abnormal values (clinical laboratory 
or vital signs) based on predefined criteria will also be provided. 
 


 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL AMENDMENTS .......................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................4 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............5 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................29 
1. 
BACKGROUND INFORMATION ...........................................................................34 
1.1. 
Introduction .................................................................................................................34 
1.2. 
Name and Description of Investigational Product ......................................................35 
1.3. 
Findings from Nonclinical and Clinical Studies .........................................................36 
1.3.1. 
Nonclinical Studies .....................................................................................................36 
1.3.2. 
Clinical Studies ...........................................................................................................38 
1.3.2.1. 
Clinical Pharmacology Studies ...................................................................................38 
1.3.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................39 
1.4. 
Known and Potential Risks and Benefits to Human Subjects ....................................39 
1.4.1. 
Known and Potential Risks and Benefits for Laquinimod .........................................39 
1.4.1.1. 
Potential Risk Based on Non Clinical Safety Findings ..............................................39 
1.4.1.2. 
Potential Risk Based on Clinical Safety Findings ......................................................40 
1.4.1.3. 
Other Potential Safety Issues with Laquinimod .........................................................44 
1.4.1.4. 
Justification for Using Placebo ...................................................................................45 
1.4.1.5. 
Potential Benefits ........................................................................................................46 
1.4.1.6. 
Overall Benefit-Risk Assessment ...............................................................................46 
1.5. 
Selection of Drugs and Dosages .................................................................................47 
1.6. 
Compliance Statement ................................................................................................49 
1.7. 
Population To Be Studied ...........................................................................................50 
1.8. 
Relevant Literature and Data ......................................................................................50 
2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES .....................................51 
2.1. 
Purpose of the Study ...................................................................................................51 
2.2. 
Study Objectives .........................................................................................................51 


 
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2.2.1. 
Primary Study Objective .............................................................................................51 
2.2.2. 
Secondary Study Objectives: ......................................................................................52 
2.2.3. 
Exploratory Study Objectives: ....................................................................................52 
2.2.4. 
Safety and Tolerability Study Objectives: ..................................................................53 
2.2.5. 
Ancillary Study Objectives: ........................................................................................53 
3. 
STUDY DESIGN .......................................................................................................54 
3.1. 
General Design and Study Schema.............................................................................54 
3.2. 
Primary, Secondary and Exploratory Measures and Endpoints .................................57 
3.2.1. 
Primary Efficacy Measure and Endpoints ..................................................................57 
3.2.2. 
Secondary Efficacy Measures and Endpoints .............................................................57 
3.2.3. 
Exploratory Efficacy Measures and Endpoints ..........................................................57 
3.2.4. 
Safety Measures and Endpoints ..................................................................................58 
3.2.5. 
Tolerability Measures and Endpoints .........................................................................58 
3.2.6. 
Pharmacokinetic Measures and Endpoints .................................................................58 
3.2.6.1. 
Pharmacokinetics (PK) Ancillary Study .....................................................................58 
3.2.6.2. 
Population PK (PPK) Study........................................................................................58 
3.2.7. 
Pharmacodynamic Measures and Endpoints ..............................................................59 
3.2.8. 
Pharmacogenomic Measures and Endpoints ..............................................................59 
3.3. 
Randomization and Blinding ......................................................................................60 
3.4. 
Study Drugs and Dosage ............................................................................................60 
3.4.1. 
Investigational Product and Dosage ...........................................................................60 
3.4.2. 
Other Study Drugs and Dosage - Placebo ..................................................................61 
3.5. 
Duration of Patient Participation ................................................................................61 
3.6. 
Stopping Rules and Discontinuation Criteria .............................................................61 
3.6.1. 
Temporary Discontinuation of Study Drug Treatment ...............................................62 
3.6.2. 
Early Termination (ET) ..............................................................................................62 
3.7. 
Study Drug Supply and Accountability ......................................................................63 
3.7.1. 
Study Drug Storage and Security ...............................................................................63 
3.7.2. 
Study Drug Accountability .........................................................................................63 
3.8. 
Maintenance of Randomization and Blinding ............................................................63 
3.9. 
Source Data Recorded on the Case Report Form .......................................................64 
3.10. 
Time Schedule ............................................................................................................64 
3.11. 
Study Procedures ........................................................................................................65 


 
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3.11.1. 
Procedures for Screening and Enrollment (Visit 1) ....................................................71 
3.11.2. 
Procedures Before Study Drug Treatment and Randomization (Baseline 
[Visit 2]) ......................................................................................................................72 
3.11.3. 
Procedures During Study Drug Treatment .................................................................74 
3.11.3.1. 
Double-Blind Treatment Period (Weeks 4 Through 52 [Visits 3 Through 8]) ..........74 
3.11.4. 
Procedures After Study Drug Treatment ....................................................................78 
3.11.4.1. 
Follow-Up (Week 56, Visit 9) ....................................................................................78 
3.11.5. 
Unscheduled Visits .....................................................................................................79 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................80 
4.1. 
Patient Inclusion Criteria ............................................................................................80 
4.2. 
Patient Exclusion Criteria ...........................................................................................81 
4.3. 
Withdrawal Criteria and Procedures ...........................................................................82 
5. 
TREATMENT OF PATIENTS ..................................................................................84 
5.1. 
Study Drugs Administered .........................................................................................84 
5.2. 
Restrictions .................................................................................................................84 
5.3. 
Prior and Concomitant Therapy or Medication ..........................................................85 
5.3.1. 
Disallowed Previous Medications/Therapies Prior to and During the Study .............85 
5.3.2. 
Other Concomitant Medications/Therapies ................................................................86 
5.3.2.1. 
CYP1A2 ......................................................................................................................86 
5.3.2.2. 
CYP3A4 ......................................................................................................................86 
5.4. 
Procedures for Monitoring Patient Compliance .........................................................86 
5.5. 
Total Blood Volume ...................................................................................................86 
6. 
ASSESSMENT OF EFFICACY ................................................................................88 
6.1. 
Primary Efficacy Variables .........................................................................................88 
6.2. 
Secondary Efficacy Variables .....................................................................................88 
6.2.1. 
Percent Change from Baseline in Caudate Volume at Month 12/ET 
(Evaluated at Baseline and Month 12) ........................................................................88 
6.2.2. 
Change from Baseline in HD-CAB Total Score (Sum of the Standardized 
Sub-Components) at Month 12/ET (Evaluated at Baseline and Months 6 and 
12) ...............................................................................................................................89 
6.2.2.1. 
Symbol Digit Modalities Test (SDMT) ......................................................................89 
6.2.2.2. 
Emotion Recognition ..................................................................................................89 
6.2.2.3. 
Trail Making Test .......................................................................................................89 
6.2.2.4. 
Hopkins Verbal Learning Test, revised (HVLT-R) ....................................................89 


 
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6.2.2.5. 
Paced Tapping at 3 Hz ................................................................................................90 
6.2.2.6. 
One Touch Stockings of Cambridge (OTS) ...............................................................90 
6.2.3. 
CIBIC-Plus Global Score at Month 12/ET (Evaluated at Months 6 and 12) as 
Compared to Baseline (Rated by an Independent Rater) ............................................90 
6.2.4. 
Change from Baseline in UHDRS- TFC at Month 12/ET (Evaluated at 
Baseline and Months 6 and 12) ..................................................................................91 
6.3. 
Exploratory Variables .................................................................................................92 
6.3.1. 
Change from Baseline in Brain Atrophy as Defined by the Percentage 
Change in Volume In: Whole Brain Volume and White-Matter Volume at 
Month 12/ET and Absolute Change in Ventricular Volume at Month 12/ET 
(Evaluated at Baseline and Month 12) ........................................................................92 
6.3.2. 
Change from baseline in UHDRS- FA at Month 12/ET (evaluated at baseline 
and Months 6 and 12) .................................................................................................92 
6.3.3. 
Change from baseline in Q-Motor assessments at Month 12/ET (evaluated at 
baseline and Months 1, 3, 6 and 12) ...........................................................................92 
6.3.3.1. 
Digitomotography (Speeded Index Finger Tapping) ..................................................92 
6.3.3.2. 
Dysdiadochomotography (Pronation/Supination Hand Tapping) ..............................93 
6.3.3.3. 
Manumotography and Choreomotography (Grip Force and Chorea Analysis) .........93 
6.3.3.4. 
Pedomotography (Speeded Foot Tapping) .................................................................93 
6.3.4. 
Change from baseline in mPPT at Month 12/ET (evaluated at baseline and 
Months 6 and 12) ........................................................................................................93 
6.3.5. 
Change from baseline in HD QoL and EQ-5D-5L at Month 12/ET 
(evaluated at baseline and Month 12) .........................................................................94 
6.3.5.1. 
HD-QoL ......................................................................................................................94 
6.3.5.2. 
EQ-5D-5L ...................................................................................................................94 
6.3.6. 
Change from baseline in WLQ at Month 12/ET (evaluated at baseline and 
Month 12) ...................................................................................................................94 
6.3.7. 
Change from baseline in HD-CAB sub-components at Month 12/ET 
(evaluated at baseline and Months 6 and 12) ..............................................................95 
6.3.8. 
Change from baseline in CDR-SB at Month 12/ET (evaluated at baseline 
and Month 12) .............................................................................................................95 
6.3.9. 
Change from baseline in HADS at Month 12/ET (evaluated at baseline and 
Month 12) ...................................................................................................................96 
6.3.10. 
Change from Baseline in Problem Behaviors Assessment-Short Form (PBA-
s) at Month 12/ET (Evaluated at Baseline and Month 12) .........................................96 
6.4. 
Methods and Timing of Assessing, Recording, and Analyzing Efficacy Data ..........96 
7. 
ASSESSMENT OF SAFETY .....................................................................................97 


 
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7.1. 
Adverse Events ...........................................................................................................97 
7.1.1. 
Definition of an Adverse Event ..................................................................................97 
7.1.2. 
Recording and Reporting Adverse Events ..................................................................98 
7.1.3. 
Severity of an Adverse Event .....................................................................................99 
7.1.4. 
Relationship of an Adverse Event to the Study Drug ...............................................100 
7.1.5. 
Serious Adverse Events ............................................................................................100 
7.1.5.1. 
Definition of a Serious Adverse Event .....................................................................100 
7.1.5.2. 
Expectedness .............................................................................................................101 
7.1.5.3. 
Reporting a Serious Adverse Event ..........................................................................101 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting ....................................103 
7.1.7. 
Withdrawal Due to an Adverse Event ......................................................................103 
7.1.8. 
Medical Emergencies ................................................................................................104 
7.1.9. 
Medication Error and Special Situations ..................................................................104 
7.1.10. 
Protocol Deviations Because of an Adverse Event ..................................................104 
7.2. 
Pregnancy .................................................................................................................105 
7.3. 
Clinical Laboratory Tests .........................................................................................106 
7.3.1. 
Serum Chemistry ......................................................................................................106 
7.3.2. 
Hematology ...............................................................................................................107 
7.3.3. 
Anemia panel ............................................................................................................107 
7.3.4. 
Urgent Safety Laboratory Panel ...............................................................................108 
7.3.5. 
Urinalysis ..................................................................................................................108 
7.3.6. 
Human Chorionic Gonadotrophin Tests ...................................................................108 
7.4. 
Vital Signs ................................................................................................................109 
7.5. 
Electrocardiography ..................................................................................................109 
7.6. 
Physical Examinations ..............................................................................................109 
7.7. 
Estimated Creatinine Clearance Calculation ............................................................110 
7.8. 
Cardiovascular Risk Assessment and Management .................................................110 
7.9. 
Other Safety Measures and Variables .......................................................................110 
7.9.1. 
Concomitant Therapy or Medication ........................................................................110 
7.9.2. 
Columbia Suicide Severity Rating Scale (C-SSRS) .................................................110 
7.9.3. 
Abdominal Computed Tomography Scan ................................................................111 
7.10. 
Methods and Timing of Assessing, Recording, and Analyzing Safety Data ............111 


 
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8. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACOGENOMICS/OTHER ANCILLARY STUDIES ...............................112 
8.1. 
Pharmacokinetic Variables .......................................................................................112 
8.1.1. 
Blood Sampling and Handling..................................................................................112 
8.1.2. 
Shipment of Samples ................................................................................................113 
8.2. 
Pharmacodynamic Variables ....................................................................................113 
8.2.1. 
Sampling and Handling ............................................................................................113 
8.2.2. 
Shipment and Analysis of Samples ..........................................................................114 
8.2.3. 
Magnetic Resonance Spectroscopy (MRS) ..............................................................114 
8.2.4. 
PET Scan ..................................................................................................................115 
8.2.4.1. 
Collection of Genotyping Samples ...........................................................................116 
8.2.4.2. 
Scanning Procedures .................................................................................................116 
8.3. 
Pharmacogenomic Variables ....................................................................................117 
8.3.1. 
Methods and Timing of Pharmacogenomic Blood Sampling ...................................117 
8.3.2. 
Shipment of Samples ................................................................................................117 
9. 
STATISTICS ............................................................................................................118 
9.1. 
Study Design and Randomization ............................................................................118 
9.2. 
Sample Size and Power Considerations ...................................................................118 
9.3. 
Analysis Sets/Populations .........................................................................................118 
9.3.1. 
Intent-to-Treat Population ........................................................................................119 
9.3.2. 
Safety Population ......................................................................................................119 
9.3.3. 
Full Analysis Set (FAS) ............................................................................................119 
9.4. 
Data Handling Conventions ......................................................................................119 
9.5. 
Study Population .......................................................................................................119 
9.5.1. 
Patient Disposition ....................................................................................................119 
9.5.2. 
Demographic and Baseline Characteristics ..............................................................119 
9.6. 
Efficacy Analyses .....................................................................................................120 
9.6.1. 
Efficacy Variables ....................................................................................................120 
9.6.1.1. 
Primary Efficacy Variable and Endpoint ..................................................................120 
9.6.1.2. 
Secondary Efficacy Variables and Endpoints ...........................................................120 
9.6.1.3. 
Exploratory Efficacy Variables and Endpoints ........................................................120 
9.6.1.4. 
Pharmacodynamic Analyses .....................................................................................121 
9.6.2. 
Planned Method of Analysis .....................................................................................121 


 
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9.6.2.1. 
Primary Efficacy Endpoint Analysis ........................................................................121 
9.6.2.2. 
Secondary Efficacy Endpoints Analyses ..................................................................121 
9.6.2.3. 
Exploratory Efficacy Endpoints Analyses ................................................................122 
9.6.2.4. 
Sensitivity Analysis ..................................................................................................122 
9.6.2.5. 
Pooling of Small Centers ..........................................................................................122 
9.7. 
Multiple Comparisons and Multiplicity....................................................................122 
9.8. 
Safety Variables and Analysis ..................................................................................122 
9.8.1. 
Safety Variables ........................................................................................................122 
9.8.2. 
Safety Analysis .........................................................................................................123 
9.9. 
Pharmacokinetic and Pharmacodynamic Analysis ...................................................123 
9.9.1. 
Pharmacokinetics (PK) Ancillary Study ...................................................................123 
9.9.2. 
Population PK (PPK) Study......................................................................................124 
9.10. 
Planned Interim Analysis ..........................................................................................124 
9.11. 
Reporting Deviations from the Statistical Plan ........................................................124 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................125 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................126 
11.1. 
Protocol Amendments and Protocol Deviations and Violations ..............................126 
11.1.1. 
Protocol Amendments ..............................................................................................126 
11.1.2. 
Protocol Deviations ..................................................................................................126 
11.2. 
Information to Study Personnel ................................................................................126 
11.3. 
Study Monitoring ......................................................................................................127 
11.4. 
Clinical Product Complaints .....................................................................................127 
11.4.1. 
Product Complaint Information Needed from the Investigational Center ................128 
11.4.2. 
Handling the Study Drug at the Investigational Center ............................................128 
11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................129 
11.4.4. 
Documenting a Product Complaint ..........................................................................129 
11.5. 
Audit and Inspection .................................................................................................129 
12. 
ETHICS ....................................................................................................................130 
12.1. 
Informed Consent .....................................................................................................130 
12.2. 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .......................................................................................................................130 
12.3. 
Confidentiality Regarding Study Patients ................................................................130 


 
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12.4. 
Declaration of the End of the Clinical Study ............................................................130 
12.5. 
Registration of the Clinical Study.............................................................................131 
13. 
DATA HANDLING, DATA QUALITY ASSURANCE, AND RECORD 
KEEPING .................................................................................................................132 
13.1. 
Data Collection .........................................................................................................132 
13.2. 
Data Quality Assurance ............................................................................................132 
13.3. 
Archiving of Case Report Forms and Source Documents ........................................133 
13.3.1. 
Investigator Responsibilities .....................................................................................133 
13.3.2. 
Sponsor Responsibilities ...........................................................................................133 
14. 
FINANCING AND INSURANCE ...........................................................................134 
15. 
REPORTING AND PUBLICATION OF RESULTS ..............................................135 
16. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENTS........................136 
16.1. 
GLOBAL PROTOCOL AMENDMENT 04 DATED 16 FEBRUARY 2016 .........136 
16.2. 
ADMINISTRATIVE LETTER 07 DATED 05 NOVEMBER 2015 .......................168 
16.3. 
ADMINISTRATIVE LETTER 06 DATED 22 OCTOBER 2015 ...........................169 
16.4. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03 
DATED 24 SEPTEMBER 2015 ...............................................................................170 
16.5. 
ADMINISTRATIVE LETTER 05 DATED 29 APRIL 2015 ..................................188 
16.6. 
ADMINISTRATIVE LETTER 04 DATED 21 APRIL 2015 ..................................189 
16.7. 
ADMINISTRATIVE LETTER 03 DATED 18 FEBRUARY 2015 ........................190 
16.8. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 02 
DATED 16 FEBRUARY 2015 ................................................................................191 
16.9. 
SUMMARY OF CHANGES FOR LOCAL PROTOCOL AMENDMENT 
02 FOR ETHICS COMMITTEE SUBMISSION IN THE UNITED 
KINGDOM DATED 25 JANUARY 2015 ...............................................................222 
16.10. 
ADMINISTRATIVE LETTER 02 DATED 14 NOVEMBER 2014 .......................225 
16.11. 
SUMMARY OF CHANGES FOR LOCAL PROTOCOL AMENDMENT 
01 FOR ETHICS COMMITTEE SUBMISSION IN THE UNITED 
KINGDOM ...............................................................................................................226 
16.12. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 
DATED 10 SEPTEMBER 2014 ...............................................................................231 
16.13. 
ADMINISTRATIVE LETTER 01 DATED 18 JULY 2014 ....................................234 
APPENDIX A. GUIDANCE ON SAFETY MONITORING ...................................................236 
APPENDIX B. LIST OF DISALLOWED MEDICATIONS PRIOR TO AND 
DURING STUDY ....................................................................................................242 


 
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APPENDIX C. LIST OF OTHER CONCOMITANT MEDICATION/THERAPIES .............244 
APPENDIX D. MAGNETIC RESONANCE IMAGING ........................................................246 
17. 
REFERENCES .........................................................................................................247 
 


 
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LIST OF TABLES 
Table 1: 
Tabulated List of Adverse Reactions ..........................................................................41 
Table 2: 
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for ALT, AST and GGT Tests .........................................................................42 
Table 3: 
TV5600-CNS-20007 (LEGATO-HD) - Study Procedures and Assessments ............66 
Table 4: 
A Partial List of Moderate/Strong CYP3A4 Inhibitors Disallowed 2 Weeks 
Prior to Study, During Study and 30 Days After Last Study Dose. .........................242 
Table 5: 
A Partial List of CYP3A4 Inducers ..........................................................................243 
Table 6: 
A Partial List of Cytochrome P450 3A4 Substrates with a Narrow 
Therapeutic Index .....................................................................................................244 
Table 7: 
A Partial List of Drugs That Are Mainly Metabolized by CYP1A2. .......................244 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Schema (prior to 10 January 2016) .....................................................55 
Figure 2: 
Overall Study Schema (from 10 January 2016) .........................................................56 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
βHCG 
beta human chorionic gonadotropin  
AD 
Alzheimer's disease 
ADME 
Absorption, distribution, metabolism, and excretion 
AhR 
Aryl Hydrocarbon Receptor 
AKI 
Acute kidney injury 
ALT 
alanine aminotransferase (SGPT) 
ALS 
amyotrophic lateral sclerosis  
ANCOVA 
analysis of covariance 
AR(1) 
Autoregressive(1)  
ARH(1) 
Heterogeneous Autoregressive(1) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma drug concentration by time curve 
AUC0–τ 
area under the plasma drug concentration by time curve for 1 dosing interval of a 
multiple-dose regimen 
BMI 
body mass index 
BSI 
Boundary Shift Integral 
BBSI 
Brain Boundary Shift Integral 
BUN 
Blood urea nitrogen 
CAB 
Cognitive Assessment Battery  
CAG 
cytosine-adenosine-guanine repeat 
CBC 
Complete Blood Count 
CBSI 
Caudate Boundary Shift Integral 
CD 
Crohn's Disease 
CDMS 
clinical data management system  
CDR-SB 
Clinical Dementia Rating - Sum of Boxes 
CDT 
Carbohydrate deficient transferrin 
CFR 
Code of Federal Regulations 
CIBIC 
Clinician’s Interview-Based Impression of Change 
CIBIS 
Clinician's Interview-Based Impression of Severity 
CIOMS 
Council for International Organizations of Medical Sciences  


 
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Abbreviation 
Term 
Cmax 
maximum observed plasma drug concentration 
Cmin  
minimum observed plasma drug concentration 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
Cr 
Creatine 
CrCl 
Creatinine Clearance 
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 
CS 
Compound Symmetry 
CSC 
Clinical Supply Chain  
CSH 
Heterogeneous Compound Symmetry 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computed tomography 
CYP 
Cytochrome P450 
DLCs 
Dioxin-like compounds 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DSM–IV 
Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition Text Revision 
DSMB 
Data and Safety Monitoring Board 
EAE 
experimental autoimmune encephalomyelitis 
ECG 
electrocardiography, electrocardiogram 
EHDN 
European Huntington's Disease Network 
EQ VAS 
EQ visual analogue scale 
ET 
Early Termination 
EU 
European Union 
FAS 
full analysis set  
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
Glu 
Glutamate 
HAB 
High affinity binding 


 
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Abbreviation 
Term 
HADS 
Hospital Anxiety and Depression Scale 
HCG 
human chorionic gonadotropin 
HD 
Huntington's Disease 
HD- CAB 
Huntington’s Disease Cognitive Assessment Battery 
HDL 
High density lipoprotein 
HDPE 
High-density polyethylene 
HD-QoL 
Huntington’s Disease Quality of Life 
Hgb 
haemoglobin 
HIV 
Human Immunodeficiency Virus 
HPLC 
High performance liquid chromatography 
HVLT-R 
Hopkins Verbal Learning Test, revised 
IB 
Investigator's Brochure 
iCRO 
Imaging Contract Research Organization 
I3C 
Indole-3-carbinol 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
INR 
International Normalized Ratio  
IOI 
Inter onset intervals 
IPI 
Inter peak intervals 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISCED 
International Standard Classification of Education 
ITI 
Inter tap intervals 
ITT 
intent-to-treat  
LAB 
Low affinity binding 
LDL 
Low density lipoprotein 
LOCF 
Last Observation Carried Forward 
LSO 
local safety officer  
MAB 
Mixed affinity binding 
Max 
maximum 
mPPT 
Modified Physical Performance Test 


 
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Abbreviation 
Term 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Myo-inositol 
ML 
Maximum Likelihood 
MoA 
Mechanism of action 
MPV 
Mean platelet volume 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
MS 
Multiple Sclerosis 
MTD 
Maximal Tolerated Dose 
Na2EDTA 
Disodium ethylenediamine tetraacetate  
NAA 
N-acetyl-aspartate 
NF-кB 
Nuclear Factor-KappaB 
OTC 
over-the-counter 
OTS 
One Touch Stockings of Cambridge 
PBA-s 
Problem Behaviors Assessment-Short form 
PBMC 
Peripheral Blood Mononuclear Cells 
PD  
Parkinson's disease 
PET  
Positron Emission Tomography 
PGx 
pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PPK 
Population Pharmacokinetics 
PT 
Preferred Term 
qd 
once daily 
Q-Motor 
Quantitative Motor Assessments 
QoL 
Quality of Life 
RBC 
red blood cell 
RDW 
Red Cell Distribution Width 
REML 
Restricted Maximum-Likelihood 
RNA 
Ribonucleic Acid 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
SAP 
Statistical Analysis Plan 


 
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Abbreviation 
Term 
SD 
standard deviation 
SDMT 
Symbol Digit Modalities Test 
SDV 
source document verification 
SLE 
Systemic lupus erythematosus 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to maximal plasma drug concentration 
tCho 
total Choline 
TCDD 
2,3,7,8-Tetrachlorodibenzo-p-dioxin 
TD 
Tap duration 
TE 
Echo Time 
TF 
Tapping forces 
TNFα 
Tumor Necrosis Factor α 
TR 
Repetition Time 
TSH 
thyroid stimulating hormone 
TSPO 
Translocator Protein 
UHDRS-FA 
Unified Huntington’s Disease Rating Scale Functional Assessment 
UHDRS-TFC 
Unified Huntington’s Disease Rating Scale Total Functional Capacity 
UHDRS-TMS 
Unified Huntington’s Disease Rating Scale Total Motor Score 
ULN 
upper limit of the normal range 
US(A) 
United States (of America) 
VBSI 
Ventricular Boundary Shift Integral 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO Drug 
World Health Organization (WHO) drug dictionary 
WLQ 
Work Limitations Questionnaire 


 
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1. 
BACKGROUND INFORMATION 
1.1. 
Introduction  
The aim of this clinical study is investigate the efficacy and safety of laquinimod as a potential 
treatment for patients with Huntington’s disease (HD). 
Laquinimod is developed by Teva Pharmaceutical Industries, Ltd. for Multiple Sclerosis (MS) 
and HD. The mechanism of action (MoA) of laquinimod includes modulation of the peripheral 
inflammation and central nervous system (CNS)-resident inflammatory response resulting in 
down regulation of myelin and axonal damage. These effects are compatible with interference of 
NF-κB activation and may represent a novel protective mechanism which down regulates 
peripheral inflammation, CNS inflammation, tissue damage, and neurodegeneration in CNS 
diseases that involve microglia and astrocytic activation, like MS and HD. Recently performed 
studies show that the aryl hydrocarbon receptor (AhR) pathway is involved in the efficacy of 
laquinimod in the experimental autoimmune encephalomyelitis (EAE) model. Further 
investigations are ongoing, assessing the role of AhR in the MoA of laquinimod.  
Further, laquinimod was shown to cause a weak decrease of CYP3A4 activity and is a strong 
inducer of CYP1A enzymes. CYP1A induction is a biomarker of activation of the AhR 
transcription factor; activation of this pathway by laquinimod has been demonstrated. 
Given laquinimod’s suggested mode of action as an immunomodulator, its penetrance to the 
CNS in animals with an intact blood-brain-barrier, and its downregulation of activated microglia 
and astrocytes in the cuprizone induced demyelination model, its potential as a drug slowing 
disease progression in HD is being explored by Teva. 
Huntington's disease is a hereditary disorder causing degeneration of neurons in the brain leading 
to uncontrolled movements, progressive loss of controlled motor function, cognitive decline, and 
emotional disturbance. The onset and progression varies but the most common age of onset is 
between 30 and 40 years. The illness generally lasts 15-20 years, and has fatal outcome. 
HD manifests in 4 domains; motor impairment, cognitive decline, psychiatric problems, and loss 
of function, all assessed by various rating scales. A number of medications are used off-label to 
control motor and emotional problems arising from HD. The scientific evidence for these drugs 
in HD is poor and most of these drugs have significant side effects. None of the drugs used today 
has an effect on disease progression. One drug, tetrabenazine, is approved to treat chorea 
associated with HD.  
It is believed that inflammatory processes in the CNS contribute to the pathogenesis of HD, via 
neuronal disturbances and cell death. Microglia, the major intrinsic immunocompetent cell in the 
CNS, are normally present in a quiescent state. Upon exposure to neuronal insults such as 
infection, ischaemia or the presence of abnormal protein aggregations (including mutant 
huntingtin aggregation), microglia become activated and release pro-inflammatory cytokines and 
cytotoxic mediators. In addition, it has been shown that microglia hyperreactivity is an 
autonomous feature in HD, as the expression of mutant Huntingtin in microglia promotes pro-
inflammatory transcriptional activity in the absence of proinflammatory stimuli. (Crotti et al, 
2014). This inflammatory activation may contribute to neuronal death. Microglia activation was 


 
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evident post-mortem in HD patients (Sapp et al, 2001) as well as in-vivo in pre-symptomatic and 
symptomatic HD gene carriers, demonstrated by positron emission tomography (PET) tracer 
ligands to activation markers on microglia (Tai et al, 2007). In-vivo microglia activation was 
shown in correlation with striatal neuronal dysfunction. These findings indicate that microglial 
activation is an early event in the pathogenic processes of HD and is associated with subclinical 
progression of disease. Elevated levels of inflammatory cytokines have been detected both in 
serum and cerebral spinal fluid in patients with HD. Specifically interleukin (IL)-6 levels were 
increased in the plasma of premanifest HD gene carriers. In addition, monocytes from HD 
patients as well as macrophages and microglia from the YAC128 HD model, were hyperactive in 
response to stimulation. In in vitro experiments, utilizing monocytes from patients with HD and 
microglia cells from YAC128 mice, reduced levels of this aberrant IL-6 production was observed 
after incubation with laquinimod.  
Moreover, in a post-mortem analysis of HD patients striatum, RNA Levels of IL-6, IL-8, and 
tumor necrosis factor α (TNF-α) were significantly increased (Björkqvist et al, 2008). IL- 6 
release is triggered by activation of the NF-κB pathway. The increased cytokine release, in 
particular IL-6, correlates with the interesting finding that the NF-κB activity is upregulated in 
several HD cell models and transgenic mouse models, possibly by direct interaction of mutant htt 
and IKK (Khoshnan et al, 2004).  
Further, cleavage of the mutant huntingtin protein by caspase-6 is believed to contribute to the 
pathogenesis of HD (Graham et al, 2011). In vitro studies have indicated that primary cortical 
neurons show reduced caspase 6 activity when treated with laquinimod, and laquinimod showed 
protective effects on axonal degeneration driven by caspase 6 activity. 
In human HD studies, astrocytosis is observed in affected regions of the brain of patients with 
HD. The mutated huntingtin protein co-localizes with these reactive astrocytes in specific 
regions (Singhrao et al, 1998). Astrocytes from HD mice has been shown to have an aberrant 
activation of NF-κB, and peripheral monocytes from HD patients express a hyper-reactive 
phenotype. Investigation on the effect of laquinimod on human activated astrocytes demonstrates 
that laquinimod inhibits astrocyte morphological changes in response to inflammatory cytokines 
and decreases their production of pro-inflammatory compounds.  
No clinical studies with laquinimod in patients with HD have been performed, and the potential 
benefits of laquinimod treatment for individual patients participating in this study is not known. 
The study is designed to investigate potential beneficial effects after treatment with laquinimod 
in patients with HD. The rationale for this is based on the immunomodulatory effects in CNS 
associated with treatment with laquinimod, findings indicating that laquinimod downregulates 
aberrant cytokine production from HD monocytes and microglia, and reports in the scientific 
literature that aberrant inflammatory phenotypic changes are an intrinsic feature in patients with 
HD and animal models for HD.  
1.2. 
Name and Description of Investigational Product  
Laquinimod (International Non-proprietary Name), 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 name sodium 5-chloro-3-
(ethyl(phenyl)carbamoyl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-olate.  


 
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The laquinimod investigational medicinal product is available as capsules containing laquinimod 
sodium equivalent to 0.5 mg laquinimod.  
Laquinimod capsules and corresponding placebo are supplied as white opaque cap and body, 
hard gelatine capsules filled with white to off-white granulate. The capsules are packed in high-
density polyethylene (HDPE) bottles equipped with child-resistant caps 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. 
1.3. 
Findings from Nonclinical and Clinical Studies  
1.3.1. 
Nonclinical Studies  
Laquinimod is rapidly absorbed resulting in high oral bioavailability of 80-90% in all animal 
species tested and its exposure was shown to increase proportionally with dose 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 biotransformations 
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 weak 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 absorption, distribution, metabolism, and excretion (ADME)-
pharmacokinetic (PK) program of laquinimod, please refer to the Laquinimod Investigator’s 
Brochure (IB).  
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 indices. In general, the severity of these effects was dose-
related and toxicity was mostly reversible upon drug discontinuation. The nature of these toxic 


 
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events allows adequate monitoring in the clinical setting (for details please refer to current 
edition of the laquinimod Investigator’s Brochure).  
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 
females (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-5211) 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-5842). 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 0.5 mg/day based on exposure. A slight delay in puberty and 
reduction in fertility were noted in rat offspring exposed in utero to laquinimod at doses slightly 
 
                                                 
1 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. 
 
2 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. 


 
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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. In a pre- and 
post-natal toxicity study in monkeys, the high dose level was associated with higher incidence of 
prenatal loss which limited the number of monkeys that could be evaluated, but there were no 
treatment-related malformations at doses up to 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. 
A complete overview of the safety pharmacology and non-clinical safety program of laquinimod 
is presented in Laquinimod IB. 
In the planned clinical study, potential risks will be mitigated by careful screening of patients and 
monitoring of patients and appropriate stopping rules for certain potential AEs related to the 
toxicology target organs. Furthermore, an independent data safety monitoring board (DSMB) 
will be assigned to assess the data in an unblinded manner (see Section 7). The body of existing 
clinical safety data for the doses studied to date suggests that laquinimod is safe and well-
tolerated. 
1.3.2. 
Clinical Studies 
1.3.2.1. 
Clinical Pharmacology Studies  
Laquinimod is considered to have high oral bioavailability with linear, time independent and 
predictable PK that is characterized by high plasma protein binding (>98%), high oral 
bioavailability (~90%), low oral clearance (~0.09 L/h), low apparent volume of distribution (~10 
L), and long half-life (~80 h). Absorption under fasting conditions is rapid and maximal plasma 
levels attained generally within 1 hour after laquinimod administration. Concomitant 
administration with a high-fat high-calorie meal results in reduction of the absorption rate 
reflected by prolongation of the time to maximal plasma drug concentration (Tmax) to 
approximately 5 hours and reduction of the maximum plasma concentration (Cmax) by 30%. Food 
however did not significantly affect the overall extent of absorption AUC. 
Laquinimod is extensively metabolized predominantly by CYP3A4. Laquinimod metabolites 
levels in plasma are very low and parent laquinimod is the main systemically circulating entity. 
Laquinimod PK is affected by moderate and strong CYP3A4 inhibitors (2.5- and 3.1-fold 
increase in laquinimod systemic exposure, respectively) and strong CYP3A4 inducers and 
moderate hepatic impairment. Studies have shown that laquinimod is a strong inducer of 
CYP1A2 and a weak inhibitor of CYP3A4. Therefore, co-administration of laquinimod may 
affect the systemic exposure of drugs metabolized by CYP450 1A2 or CYP3A4. 
Plasma levels of drugs that are CYP1A2 substrates may decrease when combined with 
laquinimod and within 30 days after the last laquinimod dose, rendering these drugs less 
effective.  
In general, it is recommended to avoid the use of CYP1A2 substrates in clinical trials of 
laquinimod. Therapeutic alternatives may be considered in context. 


 
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For additional information on concomitant use of laquinimod with CYP1A2 substrates, please 
refer to Section 5.3.2.  
Studies in subjects with mild or moderate hepatic impairment resulted in an increase of 
laquinimod exposure by approximately 1.3- and 2.3-fold, respectively. In subjects with moderate 
renal impairment, laquinimod exposure was increased by 1.4-fold. A physiologically based 
pharmacokinetic model was further used to predict the effect of hepatic impairment and renal 
impairment on the pharmacokinetics of laquinimod after single and multiple doses of 0.6 to 
1.5 mg in comparison with 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 0.6mg 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 or severe hepatic impairment (3.41- and 6.51-fold, respectively) or 
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 1.5mg 
dose range following single- or multipledose administration, demonstrating that the 
doseproportional 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  
No clinical data on the effects of laquinimod in patients with HD is available. However, clinical 
data from patients with relapsing remitting MS show a benefit of laquinimod treatment on brain 
atrophy and disability progression after 1 year of treatment, also in patients without relapses 
during this period. A disproportionally large effect on disability compared to relapses was also 
observed. The results suggest that in addition to peripheral inflammatory modulating effects, 
laquinimod could also have neuroprotective effects, and a mode of affecting CNS inflammatory 
processes beyond the classical MS dogma of active T cell driven lesions. 
Detailed information concerning all clinical studies with laquinimod is presented in the IB. For a 
brief overview on these studies, see also Section 1.5. 
1.4. 
Known and Potential Risks and Benefits to Human Subjects  
1.4.1. 
Known and Potential Risks and Benefits for Laquinimod  
1.4.1.1. 
Potential Risk Based on Non Clinical Safety Findings 
Laquinimod has been extensively studied in a battery of non clinical safety studies. The data and 
major findings have been described in Section 1.3.1, and in the current IB. The toxicities 
identified are pro-inflammatory effects (including thyroiditis), mild liver toxicity, and mild 
reductions of red blood cell indices. The severity of these effects was dose-related and toxicity 
was mostly reversible upon drug discontinuation.  
As these events are addressed in the clinical setting by frequent monitoring of relevant clinical 
laboratory assessments (described in Section 7.3), and were all reversible, it is judged that these 
non-clinical findings should not preclude administration of laquinimod to patients with HD as 
described in this protocol. Careful screening of patients and appropriate stopping rules for 


 
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specific AEs related to the toxicology target organs, as described in Appendix A, will further 
minimize any potential risk.  
1.4.1.2. 
Potential Risk Based on Clinical Safety Findings 
This is the first clinical study with laquinimod in HD. Therefore, no clinical data on the effects of 
laquinimod in patients with Huntington’s disease is available, and a wide dose range exploration 
is warranted. 
Unless noted otherwise, characterization of the safety profile (important risks and ADRs) 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 haematological changes [Hemoglobin (Hgb) decreased/anaemia, white blood cells 
(WBC) increased, platelets decreased] and elevation of blood C-reactive protein (CRP) or 
fibrinogen levels; these laboratory changes are generally mild and asymptomatic. 
The safety profile of laquinimod is provided in detail below: 
Table 1 presents the list of adverse drug reactions. 
The following definitions apply to the frequency terminology used hereafter: 
Very common (≥ 1/10) 
Common (≥ 1/100 to < 1/10) 
Uncommon (≥ 1/1000 to < 1/100) 
Rare (≥ 1/10000 to < 1/1000) 
Very rare (< 1/10000) 
Not known (cannot be estimated from the available data) 
Note: The table has been updated in line with the updated Reference Safety Information; 
myocardial infarction and cerebrovascular accident are now included. 
 


 
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Table 1: 
Tabulated List of Adverse Reactions  
Cardiac disorders 
Uncommon:  Myocardial infarction 
Infections and infestations  
Common:   
Urinary tract infection, skin infections 
Uncommon:  
Appendicitis*, furuncle 
Blood and lymphatic system disorders 
Common:   
Anaemia* 
Very common:  Decreased platelets*, Increased white blood cells* 
Psychiatric disorders 
Common:   
Anxiety 
Nervous system disorders 
Very Common:  Headache  
Rare:  
 
 
Cerebrovascular accident 
Respiratory, thoracic and mediastinal disorders 
Common:   
Cough, bronchospasm  
Uncommon:  
Asthma 
Gastrointestinal disorders 
Very Common:  Abdominal pain  
Common:   
Constipation, toothache, abdominal distension , nausea, and vomiting 
Uncommon:  
Dry mouth 
Hepatobiliary disorders  
Common:  
Liver enzymes increased*: (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 
Renal and urinary disorders 
Uncommon:  
Micturition urgency 
Reproductive system and breast disorders  
Common:   
Menstruation disorders and uterine bleeding  
General disorders and administration site conditions 
Common:   
Peripheral oedema  
Investigations  
Common:  
Blood fibrinogen increased*, C-reactive protein (CRP) increased *, blood amylase 
increased, creatinine decreased 
* An asterisk (*) indicates that additional information is provided under section Description of Selected Adverse 
Reactions below.  
Description of selected adverse drug reactions: 
1.4.1.2.1. Liver enzyme elevations: 
Treatment with laquinimod has been associated with mostly mild, reversible, asymptomatic liver 
enzyme elevations that generally occur within 6 months after initiation of treatment (see 
Table 2). 


 
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In clinical trials, laquinimod was discontinued if elevation of liver enzymes exceeded 5 times the 
upper limit of the normal range (ULN) for more than two weeks in the absence of a clear 
alternative explanation; if the elevation exceeded 8 times the ULN laquinimod was discontinued 
without further delay.  
Table 2: 
ALLEGRO and BRAVO: Shift from Normal Test at Baseline to Highest 
Value for ALT, AST and GGT Tests 
Test 
Range of Increase 
Placebo 
Laquinimod 0.6 mg 
AST 
(IU/L) 
 
Subjects with Normal Test at Baseline: 
N = 977 
Subjects 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) 
 
Subjects with Normal Test at Baseline: 
N = 930 
Subjects 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) 
 
Subjects with Normal Test at Baseline: 
N = 930 
Subjects with Normal Test at Baseline: 
N = 906 
>1 and <3x ULN 
90 (9.7%) 
147 (16.2%) 
> 3 and <5x ULN 
11 (1.2%) 
22 (2.4%) 
> 5 and <8x ULN 
1 (0.1%) 
6 (0.7%) 
ULN = Upper limit of normal range; AST = aspartate aminotransferase; ALT = alanine aminotransferase;  
IU/L = international units/L 
1.4.1.2.2. Elevated blood fibrinogen level 
Treatment with laquinimod has been associated with an increased incidence (43% vs. 34%; 
laquinimod vs. placebo) of shifts of blood fibrinogen to levels that are above normal, without 
clinical manifestations. Maximal fibrinogen did not exceed 2.5x> ULN; maximal fibrinogen 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. 
1.4.1.2.3. Elevated blood CRP level  
An increase in blood CRP level has not been found in clinical studies in subjects treated with 
laquinimod at a dose of 0.6 mg/day. In the phase III trials, until month 15, the proportion of 
patients with elevations in both CRP and fibrinogen was slightly higher in the laquinimod group 
compared to placebo. An increase of CRP and fibrinogen was seen in the dose-escalating studies 
with higher doses than 0.6 mg.  


 
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1.4.1.2.4. Back and neck pain  
Treatment with laquinimod has been associated with an increased incidence of back and neck 
pain. Back and neck pains usually occur during the first three months of treatment, are generally 
of mild severity, but may sometimes occur at a later time point, be of longer duration or require 
symptomatic treatment. 
1.4.1.2.5. Appendicitis 
Treatment with laquinimod has been associated with an increased incidence of appendicitis. 
There is 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. 
1.4.1.2.6. Haematological changes 
Hgb decrease/Anaemia:  
Treatment with laquinimod has been associated with a mild, asymptomatic, non-progressive 
decrease of the haemoglobin level, which occurs early after initiation of treatment and is usually 
transient without cessation of therapy or need for anti-anaemic 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 is consistent across white blood cell subtypes, without clinical 
manifestations.  
As per the current protocol, regular monitoring of liver enzymes, complete blood count (CBC), 
blood fibrinogen and CRP levels will be performed (described in Section 7.3), and patients will 
be followed regularly for adverse events. The sponsor considers these means as adequate to 
address laquinimod-related safety concerns. To further mitigate any potential risks, patients with 
unstable medical conditions will be excluded from the study. In addition, an independent DSMB 
will be assigned to assess the data in unblinded manner (see Section 7). 
1.4.1.2.7. Cardiovascular Events (in the high-dose treatment arms of the ongoing MS 
studies)  
In December 2015, the Data Monitoring Committee (DMC) for the Teva-sponsored MS studies, 
LAQ-MS-305 (CONCERTO) and TV5600-CNS-20006 (ARPEGGIO), found an imbalance in 
serious cardiovascular events in the high-dose treatment arms of these studies (1.2 mg in 
CONCERTO, 1.5 mg in ARPEGGIO). Six cases of myocardial infarction occurred in the 
CONCERTO 1.2 mg treatment arm, compared with no events in the 0.6 mg or placebo treatment 
arms, along with a cerebral infarction in a 31-yearold man in 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 


 
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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 the high-dose treatment arms (1.2 mg/day 
and 1.5 mg/day) 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 recommended that study subjects continuing on laquinimod 
0.6 mg be reconsented with information about the cardiovascular risk seen at higher doses.  
On 07 January 2016, the LEGATO-HD Data Safety Monitoring Board (DSMB) was called by 
Teva to review and discuss the recommendations of the DMC for the CONCERTO and 
ARPEGGIO MS trials and their implications on LEGATO-HD. The DSMB confirmed that no 
cardiovascular events had been observed to date for any dose of the LEGATO-HD trial and 
concurred with the Sponsor’s recommendation that the high-dose (ie, 1.5 mg) arm in this trial be 
discontinued as a proactive safety measure. The DSMB approved the continuation of the 0.5 
mg/day and 1.0 mg/day arms with enhanced monitoring and safety precautions.  
Teva notified LEGATO-HD investigators on 10 January 2016 to immediately contact patients 
randomized to the high dose of 1.5 mg laquinimod and instruct them to discontinue study 
medication as a proactive measure to protect the safety of patients (endorsed by DSMB as noted 
above).  
Currently, the mechanism of the cardiovascular events remains unknown. Although no specific 
time-to-event patterns have been identified in the MS studies, 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 investigations into 
potential predictors and the potential causality are ongoing. 
1.4.1.3. 
Other Potential Safety Issues with Laquinimod  
1.4.1.3.1. Pregnancy 
Studies in rats have shown reproductive toxicity including teratogenicity (urogenital 
malformations) at doses similar to the clinical dose of 0.5 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 (see Section 1.3.1). 
The relevance to humans of these findings is not known, but cannot be excluded.  
Exposure to laquinimod during pregnancy must be avoided.  
To prevent such exposure, female patients who are of child-bearing potential (for example 
women who are not postmenopausal or surgically sterilized) must practice an acceptable method 
of birth control (see Section 7.2) for 30 days before initiation of treatment, and 2 acceptable 
methods of birth control throughout treatment and for 30 days after cessation of treatment. Use 
of acceptable contraception will be ascertained at every study visit.  
In addition, regular pregnancy testing is required during the study. If pregnancy is suspected 
despite all recommended precautions (based on a positive pregnancy test, delay in menses or any 


 
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other reason to suspect pregnancy), treatment should be discontinued immediately. The patient 
will be reminded of the potential risk to the fetus, and all options, including discontinuation of 
pregnancy, should be discussed.  
All female patients should be counseled by the investigator about the potential risks of exposure 
to laquinimod during pregnancy and the need to use acceptable contraception and avoid 
pregnancy throughout treatment with laquinimod and for 30 days after cessation of treatment. 
1.4.1.3.2. Cancer 
An increase in the incidence of uterine and oral cancers was observed in rats (see Section 1.3.1). 
It is the sponsor’s position that these findings are likely related to species-specific mechanisms. 
While a connection to humans cannot be entirely excluded, these mechanisms are likely not 
relevant to humans. Currently available clinical data does not suggest that laquinimod at a dose 
of 0.6 mg/day is associated with an increased risk of cancer.  
1.4.1.3.3. Cardiotoxicity and Systemic Inflammation 
In clinical studies performed with laquinimod's predecessor, roquinimex, pericarditis/pleuritis 
and ischaemic 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 incuding 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 non-clinical 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 MS 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 signal for laquinimod in doses up to 0.6 mg/day. However, at doses of 1.2 and 
1.5 mg, laquinimod manifested a potential clinical signal of myocardial infarction in the MS 
trials. 
1.4.1.3.4. QT Prolongation 
Even though laquinimod in doses up to 1.2 mg once daily (qd) did not prolong the QTcF 
interval, (based on the thorough QT study TQT-LAQ-122), and pre-clinical data do not indicate 
a potential for laquinimod to influence the QT interval, higher doses of laquinimod have not been 
studied for potential QT prolongation effects. ECG monitoring is implemented in this protocol, 
as described in Section 7.5.  
1.4.1.4. 
Justification for Using Placebo 
There are no standard treatments in HD, and no registered drugs known to slow disease 
progression are available for patients with HD. The only approved drug for treatment of HD is 
Tetrabenazine, which is indicated for treatment of chorea in patients with HD. A number of 
medications are used off-label to control motor and emotional problems arising from HD. All of 
these drugs are symptomatic, and the scientific evidence for their use in patients with HD is poor. 


 
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In addition, many of the drugs that have been used are fraught with significant side effects, 
including worsening of parkinsonian symptoms, and cognitive decline. No drugs are available 
that target the underlying pathogenesis of HD. In this context, a placebo controlled study to 
investigate laquinimod’s potential benefits in patients with HD is deemed acceptable. 
1.4.1.5. 
Potential Benefits 
No clinical studies with laquinimod in patients with HD have been performed, and the potential 
benefits of laquinimod treatment for individual patients participating in this study is not known. 
The study is designed to investigate potential beneficial effects after treatment with laquinimod 
in patients with HD. The rationale for this is based on the immunomodulatory effects in CNS 
associated with treatment with laquinimod, and reports in scientific literature that aberrant 
inflammatory phenotypic changes are an intrinsic feature in patients with HD and animal models 
for HD (see Section 1.1). 
1.4.1.6. 
Overall Benefit-Risk Assessment 
An imbalance in serious cardiovascular events in the high-dose treatment arms (1.2 mg/day and 
1.5 mg/day) in the Teva-sponsored CONCERTO and ARPEGGIO studies in MS was identified 
(6 cases of myocardial infarction in the CONCERTO 1.2 mg treatment arm, compared with no 
events in the 0.6 mg or placebo treatment arms, along with a cerebral infarction in a 31-year-old 
man in the 1.2 mg treatment arm. In the ARPEGGIO study, 1 myocardial infarction event was 
identified in the laquinimod 1.5 mg treatment arm. Due to these events, the DMC recommended 
stopping higher-dose laquinimod treatment (1.2 and 1.5 mg) in the laquinimod MS trials (see 
Section 1.4.1.2.7). 
No cardiovascular events have been observed to date for any dose in the LEGATO-HD trial. 
On 07 January 2016, the LEGATO-HD DSMB met and approved the Sponsor's proposal to 
discontinue the 1.5 mg arm of the study as a proactive safety measure, and approved the 
continuation of the 0.5 mg/day and 1.0 mg/day arms with enhanced monitoring and safety 
precautions.  
Teva notified LEGATO-HD investigators on 10 January 2016 to immediately contact patients 
randomized to the high dose of 1.5 mg laquinimod and instruct them to discontinue study 
medication as a proactive measure to protect the safety of patients currently participating in the 
LEGATO-HD study. This action was endorsed by the DSMB as noted above. Patients in the 1.5 
mg/day (high dose) treatment arm, whose treatment with laquinimod was discontinued, were 
asked to continue all scheduled visits for safety assessment after study drug discontinuation. 
Appropriate risk mitigation procedures have been implemented via this protocol amendment to 
restrict excess drug exposure due to impairment of liver or kidney function, as well as to assure 
evaluation and management of cardiovascular risk factors.  
LEGATO-HD is the first "proof of concept" study in the HD patient population, which 
represents a disease with a fatal outcome and a severe unmet medical need (no current available 
medications). Based on data accumulated to date, the LEGATO-HD study aims for disease 
modification beyond symptomatic treatment. 
Thus, the LEGATO study in the HD patient population represents different benefit/risk 
considerations. 


 
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Based on the above described risks and means for their mitigation, it is judged that potential 
benefit from administration of laquinimod to patients with HD outweighs the risks based on 
currently available information, supporting investigation of its role in the Huntington’s disease 
patient population. 
For an overall risk benefit assessment of laquinimod treatment in human patients, additional 
information may be found in the current Investigator’s Brochure. 
1.5. 
Selection of Drugs and Dosages  
The dosages of laquinimod to be evaluated in this double-blind study (i.e. 0.5, 1.0 and 
1.5 mg/day) were selected on the basis of an extensive clinical program evaluating 
pharmacokinetics, safety, tolerability and efficacy in healthy volunteers, and patients with MS, 
Crohn’s Disease (CD) and systemic lupus erythematosus (SLE).  
Two studies to evaluate the MTD of laquinimod in healthy volunteers and MS patients have been 
performed. One early ascending-dose study in healthy volunteers and MS patients (Study 
99506202) established the 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 CRP and fibrinogen]. A subsequent 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 reproduce study 99506202 results and did not reveal 
dose-dependent AEs, laboratory or electrocardiography (ECG) findings up to and including the 
dose of 2.7 mg/day. 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, the 
sponsor considers study MS-LAQ-101 as more adequately representing the safety profile of 
higher doses of laquinimod. The last cohort of patients received 2.7 mg laquinimod with no dose 
limiting adverse events (AEs) or laboratory findings (see Section 1.5). The study’s safety 
committee recommended further dose escalation; however the sponsor has instead decided to 
perform dose escalation above 2.7 mg laquinimod, if needed, under a new, more comprehensive 
protocol. Hence, 2.7 mg/day is the highest multiple dose administered to humans to date. 
Laquinimod 1.5 mg was selected as the maximal dose to be tested for the current study based on 
the existing MTD study (up to 2.7 mg).  
Daily doses of 0.1 mg and 0.3 mg were originally assessed in MS patients in a phase II study 
(01506203), which showed that laquinimod 0.3 mg reduced the cumulative number of active 
lesions at week 24 while laquinimod 0.1 mg did not demonstrate an effect. A new phase II study 
(LAQ/5062) assessed the efficacy, tolerability, and safety of 0.3 mg/day and 0.6 mg/day of 
laquinimod in MS patients, and demonstrated a statistically significant effect on the primary 
endpoint for the laquinimod 0.6 mg dose. However, in contrast to study 01506203, a significant 
effect on the primary endpoint could not be demonstrated after treatment with laquinimod 
0.3 mg. This discrepancy is considered by the sponsor to be likely explained by methodological 
differences in measuring the MS lesions. None of the studies identified significant safety or 
tolerability concerns. 
Two Phase III studies with laquinimod 0.6 mg dose/day have been completed in patients with 
MS (ALLEGRO and BRAVO). Both studies used annualized relapse rate as the primary 


 
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endpoint. In ALLEGRO, significant effect of laquinimod treatment was shown on the primary 
endpoint and 3 key secondary endpoints. The BRAVO study did not show a statistically 
significant effect on the primary endpoint, but a post hoc corrected analysis showed that results 
were comparable to those of ALLEGRO. In addition, it was demonstrated that the suggested 
effect of laquinimod on disease progression and brain atrophy is consistent and robust. Both 
studies showed a benign safety profile of laquinimod at the dose tested. 
In light of the dose-dependent clinical effect detailed above and absence of safety concerns in the 
MS-LAQ-101 study, the sponsor has initiated a clinical program in MS patients to investigate 
whether a 1.2 mg qd dose of laquinimod is associated with greater efficacy while retaining the 
adequate safety and tolerability profile that was evident for the 0.6 mg qd dose. This program is 
currently ongoing. 
The safety and efficacy of laquinimod given 0.5, 1.0, 1.5, or 2.0 mg/day have been investigated 
in 180 patients with CD for 8 weeks (study CD-LAQ-201). Significant effect on the primary 
endpoint (Crohn’s Disease Activity Index) was seen after treatment with laquinimod 0.5 mg/day; 
laquinimod 1 mg had a lower magnitude effect that was also less robust than the effect of 
laquinimod 0.5 mg. Laquinimod 1.5 mg and 2.0 mg did not have an overall clinical effect 
compared to the pooled placebo. However, when evaluating reduction in calprotectin levels, an 
objective marker of disease activity, similar efficacy was observed across the laquinimod doses. 
Laquinimod showed an overall favorable safety and tolerability profile in this study. Laquinimod 
is no longer being developed as a treatment for CD. 
The safety and efficacy of laquinimod given 0.5 or 1.0 mg/day have also been investigated in 
two studies in SLE patients [with lupus nephritis (LN-LAQ-201) and with lupus arthritis 
(LA-LAQ-202)] for 24 and 12 weeks, respectively. In LN-LAQ-201, 46 patients were enrolled: 
15 received placebo, 16 received laquinimod 0.5 mg and 15 received laquinimod 1 mg. In 
LA-LAQ-202, 82 patients were enrolled: 26 were randomized to receive placebo, and 28 patients 
were randomized to each of the laquinimod arms (0.5 mg, and 1 mg). Overall laquinimod was 
safe and well tolerated in these studies. No clinically meaningful effect of laquinimod treatment 
could be seen in patients with LA. Beneficial effect of laquinimod was seen in patients with LN 
with both doses investigated, with the 0.5 mg dose showing a greater improvement in several 
efficacy variables. Laquinimod is no longer being developed as a treatment for SLE. 
The described data indicates that 0.6 mg/day is the minimal clinically effective dose in MS 
patients, whereas data from patients with CD and lupus nephritis indicated that also 0.5 mg/day 
is efficacious in treating the inflammatory condition in these diseases. The maximal tolerated 
dose has not formally been established, but the maximum tested repeated dosing is 2.7 mg/day in 
humans. Data from animal models for CNS inflammation, show a clear dose response of 
laquinimod's inhibition of disease (for additional information, please refer to the IB). Hence, 
3 doses of laquinimod, ranging from 0.5 mg/day, believed to be a minimal effective dose, to 
1.5 mg/day, providing a reasonable margin to the highest dose tested in humans over a short time 
period, were chosen for investigation. Also, given the available data on the 0.5 and 1.0 mg doses 
of laquinimod, a parallel (rather than sequential) design was deemed appropriate. 
Note: On 30 December 2015, the DMC for the LAQ-MS-305 (CONCERTO) and TV5600-CNS-
20006 (ARPEGGIO) studies held an unscheduled meeting to review cardiovascular events. The 
DMC found an imbalance in serious cardiovascular events in the high-dose treatment arms 
(1.2 mg in CONCERTO, 1.5 mg in ARPEGGIO). Iin CONCERTO there were 6 such cases in 


 
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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 high-dose 
laquinimod treatment arms (1.2 mg/day and 1.5 mg/day) in the MS trials; accordingly, the high-
dose arms were discontinued in both trials as of 01 January 2016. 
On 07 January 2016, the LEGATO-HD DSMB was called urgently by Teva to review and 
discuss new information regarding the occurrence of an imbalance in cardiovascular events from 
the high-dose laquinimod arms in the multiple sclerosis trials CONCERTO and ARPEGGIO 
(1.2 mg in CONCERTO, 1.5 mg in ARPEGGIO).  
The most recent study data for LEGATO-HD were also reviewed in open and closed sessions. 
No cardiovascular signal was detected from the LEGATO-HD study as of 10 January 2016. The 
DSMB agreed with the plan to discontinue the 1.5 mg arm of the LEGATO-HD study as a 
proactive safety measure, and approved the continuation of the 0.5 mg/day and 1.0 mg/day arms 
with enhanced monitoring and safety precautions. Therefore, these treatment arms will be 
continued with updated informed consent and an amended protocol while the sponsor closely 
monitors cardiovascular events in all laquinimod studies for emergence of any potential 
cardiovascular signal. 
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 (e.g., 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 investigator is 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 Investigator’s Brochure or prescribing information.  
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. 


 
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1.7. 
Population To Be Studied  
Based on the anticipated mode of action (MoA) of laquinimod in HD, an intervention to reduce 
CNS inflammation as early as possible would be desirable to prevent further neuronal 
dysfunction and death. However, the rate of progression in signs and symptoms makes it difficult 
to detect slowing of disease in a feasible way in terms of treatment length in patients without 
signs of disease. Therefore, patients with clinical symptoms that are measurable, but with a 
retained functional capacity will be selected. Further, concomitant medications with 
antipsychotic drugs may confound the data due to side effects in the motor and cognitive domain, 
and thus these drugs will be disallowed in the study. It is also known that cytosine-adenosine-
guanine (CAG) repeat length in the mutant huntingtin gene influence disease progression and 
course. To reduce variability in the study, patients will be selected from a pre-defined range of 
CAG repeat lengths frequently observed in the clinic. 
Thus, the target patient population will be adult patients, with a CAG repeat length between 36 
and 49, and the basic eligibility criteria will select a patient population with symptoms of HD, as 
assessed by a Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS) >5, 
but with a largely retained functional capacity, as assessed with a HDRS-Total Functional 
Capacity (UHDRS-TFC) score ≥8. This will recruit a symptomatic early HD patient population. 
The criteria for study eligibility are described in Section 4.1 and Section 4.2, respectively.  
1.8. 
Relevant Literature and Data 
Relevant literature is cited above. Further literature and data may be found in the current 
Investigator’s Brochure. 


 
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2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1. 
Purpose of the Study  
The purpose of this Phase II clinical study is to investigate the efficacy and safety of multiple 
doses of laquinimod (0.5, 1.0 and 1.5 mg/day) as a potential treatment for patients with 
Huntington's disease (HD). 
As no drug is currently available to treat HD disease progression, the study will be placebo 
controlled. 
Prior to 10 January 2016, a total of 400 patients were planned to be equally randomized in a 
1:1:1:1 ratio (100 patients within each treatment arm) to receive laquinimod 0.5, 1.0, 1.5 mg/day, 
or matching placebo for 52 weeks.  
As of 10 January 2016, following the decision to discontinue treatment of the laquinimod 1.5 mg 
dose arm, additional eligible patients who are enrolled will be randomized in a 1:1:1 ratio to 
receive laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo for 52 weeks. Approximately 
300 patients (100 patients within each study arm), plus the 30 patients who were already 
randomized to the laquinimod 1.5 mg treatment arm, are planned to be enrolled in the study. 
This is the first clinical study with laquinimod in HD. Therefore, no clinical data on the effects of 
laquinimod in patients with Huntington’s disease is available, and a wide dose range exploration 
is warranted.  
Clinical data from patients with relapsing remitting multiple sclerosis (RRMS) show a benefit of 
laquinimod treatment of 0.6 mg/day on brain atrophy and disability progression after 1 year of 
treatment, also in patients without relapses during this period. A disproportionally large effect on 
disability compared to relapses was also observed. The results suggest that in addition to 
peripheral inflammatory modulating effects, laquinimod could also have neuroprotective effects, 
and a mode of affecting central nervous system (CNS) inflammatory processes beyond the 
classical MS dogma of active T-cell driven lesions. This is important in Huntington’s disease 
where intrinsic CNS inflammatory phenotypes are observed to correlate with disease 
progression. 
The study aims to detect potential beneficial effects in deteriorating clinical signs and symptoms 
of HD. Based on previous studies in patients with HD, the UHDRS-TMS has been shown to be 
one of the more sensitive clinical measures to detect decline in symptoms of HD, and hence 
TMS has been chosen as primary endpoint. 
2.2. 
Study Objectives  
2.2.1. 
Primary Study Objective  
The primary objective of this study is to assess the efficacy of laquinimod 0.5 and 1.0 mg qd in 
patients with HD after 12 months of treatment using the Unified Huntington’s Disease Rating 
Scale (UHDRS) Total Motor Score (TMS).  
Due to the decision from 10 January 2016 to discontinue treatment of the laquinimod 1.5 mg 
dose arm, and the low number of enrolled patients compared to the target at this time, data from 


 
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the laquinimod 1.5 mg treatment arm will be presented descriptively only, and will not be 
included in any inferential analyses for efficacy or safety. 
2.2.2. 
Secondary Study Objectives:  
• To assess the effect of laquinimod on brain atrophy in patients with HD after 12 
months of treatment using MRI measures of caudate volume. 
• To assess the effect of laquinimod on the cognitive capacity in patients with HD after 
12 months of treatment using the cognitive assessment battery (CAB) for patients 
with HD [comprised of: Symbol Digit Modalities Test (SDMT), Emotion 
Recognition, Trail Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), 
Paced Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 
trial version]. 
• To assess the effect of laquinimod on the clinical global impression in patients with 
HD after 12 months of treatment using the Clinician’s Interview-Based Impression of 
Change plus Caregiver Input (CIBIC-Plus)  
• To assess the effect of laquinimod on the functional capacity in patients with HD after 
12 months of treatment using the UHDRS-TFC scale 
2.2.3. 
Exploratory Study Objectives:  
• To assess the effect of laquinimod on brain atrophy in patients with HD after 
12 months of treatment using MRI measures of whole brain volume, white-matter 
volume and ventricular volume. 
• To assess the effect of laquinimod on the functional capacity in patients with HD after 
12 months of treatment using the UHDRS-functional assessment (FA) scale 
• To assess the effect of laquinimod on motor function in patients with HD after 
12 months of treatment using the objective instrument Q-Motor 
• To assess the effect of laquinimod on physical performance in patients with HD after 
12 months of treatment using the modified Physical Performance Test (mPPT). 
• To assess the effect of laquinimod on the quality of life in patients with HD after 
12 months of treatment using the Huntington’s Disease Quality of Life (HD-QoL) 
and EQ-5D-5L instruments 
• To assess the effect of laquinimod on work productivity in patients with HD after 
12 months of treatment. 
• To assess the effect of laquinimod on functional impairment due to cognitive decline 
in patients with HD after 12 months of treatment using the Clinical Dementia Rating - 
Sum of Boxes (CDR-SB) 
• To assess the effect of laquinimod on depression and anxiety in patients with HD 
after 12 months of treatment using the Hospital Anxiety and Depression Scale 
(HADS)  
• To assess the effect of laquinimod on behavioral signs and symptoms in patients with 
HD after 12 months of treatment using the Problem Behaviors Assessment-Short 
form (PBA-s) 
• To evaluate the pharmacokinetics of laquinimod and its metabolites in patients with 
HD 


 
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• To investigate the relationship between exposure to laquinimod and its metabolites 
and outcome measures (eg, clinical effect and toxicity parameters).  
2.2.4. 
Safety and Tolerability Study Objectives: 
• To evaluate safety and tolerability of laquinimod in patients with HD during 12 
months of treatment by evaluating adverse events (AEs), electrocardiography (ECG), 
and clinical laboratory parameters, vital signs, physical examinations, and premature 
discontinuations from the study.  
2.2.5. 
Ancillary Study Objectives: 
• To explore potential correlation between genetic polymorphisms in deoxyribonucleic 
acid (DNA) and pharmacokinetics, clinical response to laquinimod, and/or adverse 
drug reactions, if these occur 
• To explore potential correlation between ribonucleic acid (RNA) expression profile in 
blood cells and clinical response to laquinimod 
• To evaluate changes in cytokines and other soluble protein levels following treatment 
with laquinimod as potential biomarkers for laquinimod mechanism of action and/or 
response predictive factors 
• To explore gene expression and/or protein profile in monocytes in response to 
laquinimod treatment 
• To explore change in microglial activation state in response to treatment with 
laquinimod 
• To assess the correlation between microglial activation state at baseline and the 
clinical characteristics of HD patients (age, gender, number of triplets, disease onset, 
disease duration, motor and behavioral scores). 
• To explore changes in MRS metabolite levels in response to treatment with 
laquinimod that reflect neuronal integrity (NAA) and astrocytosis (myo-inositol) in 
the putamen and frontal white matter. 


 
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3. 
STUDY DESIGN 
3.1. 
General Design and Study Schema  
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of laquinimod treatment at dosages of 0.5, 1.0, and 1.5 mg/day in 
adults with Huntington’s Disease.  
The study will consist of a screening period (2 weeks up to 5 weeks), followed by a 52-week 
double-blind treatment period and a follow-up visit (one month after end of treatment). Prior to 
10 January 2016, a total of 400 patients were planned to be equally randomized in a 1:1:1:1 ratio 
(100 patients within each treatment arm) to receive laquinimod 0.5, 1.0, 1.5 mg/day, or matching 
placebo for 52 weeks. A total of 123 patients were randomized prior to 10 January 2016. 
As of 10 January 2016, following the decision to discontinue treatment of the laquinimod 1.5 mg 
dose arm, additional eligible patients who are enrolled will be randomized in a 1:1:1 ratio to 
receive laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo for 52 weeks. Approximately 
300 patients (100 patients within each study arm), plus the 30 patients who were already 
randomized to the laquinimod 1.5 mg treatment arm, are planned to be enrolled in the study. 
After signing the informed consent, including consent to provide a blood sample for genetic 
analyses including CAG repeat length analysis, patients will be screened for a period of 2 weeks 
up to 5 weeks in order to determine whether they are eligible to participate in the study. Patients 
with a legal guardian should be consented according to local requirements. 
The procedures and assessments performed during each of the study visits are detailed in 
Section 3.11.  
During the visits, vital sign measurements, physical examinations and ECG should preferably be 
performed prior to the blood draw for clinical laboratory tests and pharmacokinetic sampling. 
Further, the efficacy assessments (TMS, HD-CAB, CIBIC-plus and TFC) should be done prior to 
the exploratory assessments.  
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the final visit (Visit 8, Month 12). Patients who withdraw from the study before completing 
the 52-week evaluation period will have Visit 8 procedures and assessments performed at their 
last visit.  
An independent DSMB will oversee the study. The DSMB will review unblinded accumulating 
safety data on a regular basis to ensure the continuing safety of the study patients and study 
conduct issues. 
The study schema is presented in Figure 1 (prior to 10 January 2016) and in Figure 2 (from 10 
January 2016).  
 


 
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Figure 1: Overall Study Schema (prior to 10 January 2016) 
 
 


 
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Figure 2: 
Overall Study Schema (from 10 January 2016) 


 
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3.2. 
Primary, Secondary and Exploratory Measures and Endpoints  
3.2.1. 
Primary Efficacy Measure and Endpoints 
The primary efficacy variable and endpoint for this study is the change from baseline in the 
UHDRS-TMS (defined as the sum of the scores of all UHDRS-TMS subitems) at Month 12/ ET 
(evaluated at baseline and Months 1, 3, 6 and 12). 
3.2.2. 
Secondary Efficacy Measures and Endpoints 
The secondary efficacy variables and endpoints for this study are: 
• Percent change from baseline in caudate volume at Month 12/ET (evaluated at 
baseline and Month 12) 
• Change from baseline in HD-CAB total score (sum of the standardized sub-
components) at Month 12/ET (evaluated at baseline and Months 6 and 12)  
• CIBIC-Plus global score at Month 12/ET (evaluated at Months 6 and 12) as compared 
to baseline (rated by an independent rater) 
• Change from baseline in UHDRS- TFC at Month 12/ET (evaluated at baseline and 
Months 6 and 12) 
3.2.3. 
Exploratory Efficacy Measures and Endpoints 
The exploratory efficacy variables and endpoints for this study are: 
• Change from baseline in brain atrophy as defined by the percentage change in volume 
in: whole brain volume and white-matter volume at Month 12/ET and absolute 
change in ventricular volume at Month 12/ET (evaluated at baseline and Month 12) 
• Change from baseline in UHDRS- FA at Month 12/ET (evaluated at baseline and 
Months 6 and 12)  
• Change from baseline in Q-Motor assessments at Month 12/ET (evaluated at baseline 
and Months 1, 3, 6 and 12) 
• Change from baseline in mPPT at Month 12/ET (evaluated at baseline and Months 6, 
and 12) 
• Change from baseline in HD QoL and EQ-5D-5L at Month 12/ET (evaluated at 
baseline and Month 12) 
• Change from baseline in WLQ at Month 12/ET (evaluated at baseline and Month 12) 
• Change from baseline in HD-CAB sub-components at Month 12/ET (evaluated at 
baseline and Months 6 and 12):  
Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail Making Test, 
Hopkins Verbal Learning Test, revised (HVLT-R), Paced Tapping at 3 Hz, One 
Touch Stockings of Cambridge (OTS, abbreviated 10 trial version) 
• Change from baseline in CDR-SB at Month 12/ET (evaluated at baseline and 
Month12)  
• Change from baseline in HADS at Month 12/ET (evaluated at baseline and Month 
12) 
• Change from baseline in PBA-s at Month 12/ET (evaluated at baseline and Month 12) 


 
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3.2.4. 
Safety Measures and Endpoints 
The safety of laquinimod will be assessed throughout the study by evaluating adverse events, 
clinical laboratory test results, vital signs measurements, electrocardiography (ECG), physical 
examination results, and suicidality (as assessed by changes from baseline in C-SSRS scores).  
3.2.5. 
Tolerability Measures and Endpoints 
Tolerability variables and endpoints will include the following: 
• Proportion of subjects (%) who prematurely discontinued from the study, reason of 
discontinuation and the time to ET 
• Proportion of subjects (%) who prematurely discontinued from the study due to AEs 
and the time to ET  
3.2.6. 
Pharmacokinetic Measures and Endpoints  
3.2.6.1. 
Pharmacokinetics (PK) Ancillary Study 
 
PK samples of laquinimod and its metabolites will be collected from approximately 15 patients 
per each of the three continuing treatment groups (at selected sites at Month 1), for a total of 
approximately 45 patients. Additionally, PK samples were collected from 2 patients in the 
laquinimod 1.5 mg/day treatment group when the treatment was stopped; no further PK samples 
will be collected from the laquinimod 1.5 mg/day treatment group. 
The time of the previous dose as well as deviations from the blood sampling times will be 
recorded in the appropriate eCRF. Patients performing the 24-hour PK profile will come to the 
clinic after an overnight fast (minimum of 8 hours) and will be given breakfast 4 hours after drug 
administration. 
Samples will be collected at pre-dose, 15, 30 min and 1, 2, 3, 6 and 24 hours post dose.  
Steady state pharmacokinetic parameters for laquinimod (AUCtau, Cmax and Cmin, tmax), will be 
calculated for each patient. Additional parameters for laquinimod and pharmacokinetic 
parameters for its metabolites may be calculated if data permit. 
For patients participating in this ancillary study, the morning dose and the 24 hours dose 
administration (the day after) will take place at the clinic. 
3.2.6.2. 
Population PK (PPK) Study 
A single blood sample will be collected from all patients at Months 1, 3, 6 and 12 for evaluation 
of laquinimod and its metabolites. 
Pharmacokinetics of laquinimod will be evaluated using a Population PK approach. The effect of 
covariates on the PK of laquinimod will be evaluated. Possible covariates will include 
demographic variables (e.g., age, gender, body weight and ethnicity), clinical variables (e.g. 
CAG repeat length), concomitant medications, blood and urine chemistry variables and markers 
of renal (creatinine clearance and serum creatinine) or hepatic function.Pharmacokinetic 
parameters for laquinimod metabolites may be calculated if data permit. 


 
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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 eCRF. 
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 for safety 
(see Section 8.1).  
3.2.7. 
Pharmacodynamic Measures and Endpoints  
Biomarker assessment will include the following: 
• Cytokines, Soluble protein (or any other soluble marker) levels will be determined at 
baseline, Months 6 and 12.  
• Monocyte gene expression and/or protein profile will be explored at baseline and 
Month 12. This study will be performed only at selected sites in a subgroup of 
patients. 
• PET scans and imaging analysis of microglial activation marker TSPO will be 
performed at baseline and Month 12. This study will be performed only in a subgroup 
of patients. 
• MRI scans for MRS to explore the potential effect on metabolic changes in the 
putamen and frontal white matter will be done in a subgroup of patients at baseline 
and Month 12. 
3.2.8. 
 Pharmacogenomic Measures and Endpoints 
Pharmacogenomic (PGx) assessment will include CAG repeats analysis in the huntingtin gene 
and might include other DNA variations and RNA expression patterns potentially associated 
with clinical treatment responses to laquinimod (e.g. 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 in 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 CAG repeat length in the huntingtin gene will be established by a central laboratory for all 
patients, as part of the screening process to determine eligibility for the study. This will be done 
also for patients where a historical CAG repeat length result is available. If during this screening 
process a CAG repeat length result that differs from the patient’s historical result is obtained, the 
central laboratory results should be used for determining eligibility. The exact CAG repeat length 
will not be available to the sites, only to the Sponsor. The central laboratory report will only note 
if the patient is within the eligibility criteria range (36-49 inclusive) or not. This will be explicitly 
explained and noted in the ICF of the patient. In either case, the investigator should review the 
CAG repeat results with the patient at the baseline visit, or at an unscheduled visit if a baseline 
visit will not take place.  


 
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3.3. 
Randomization and Blinding  
This is a randomized, double-blind, placebo-controlled study. Prior to 10 January 2016, eligible 
patients were randomly assigned to receive treatment with laquinimod at a dosage of 0.5, 1.0 or 
1.5 mg qd or a matching placebo in a 1:1:1:1 ratio. 
As of 10 January 2016, following a decision to discontinue treatment of the laquinimod 1.5 mg 
dose arm, future eligible patients will be randomized in a 1:1:1 ratio to receive laquinimod 0.5 
mg/day or 1.0 mg/day or matching placebo for 52 weeks. No change was performed to the 
original randomization list except that the patient numbers assigned to laquinimod 1.5 mg/day 
were removed from the list by the interactive response technology (IRT) vendor.  
All patients who discontinued the 1.5 mg/day dose have been unblinded. No attempts will be 
made to re-randomize patients whose 1.5 mg treatment was stopped to a lower dose of 
laquinimod. The remaining ongoing patients retained their originally randomized treatment 
assignments. 
Patients and investigators will remain blinded to treatment assignment during the study.  
The randomization code will be generated by the Clinical Supply Chain (CSC) department 
following specifications from the Biostatistics Department.  
In addition, the sponsor’s clinical personnel involved in the study will be blinded to the study 
drug identity until the database is locked for analysis and the treatment assignment revealed. 
However, in case a prioritized sample analysis is needed, bioanalytical personnel may not be 
blinded. A statistician not assigned to the study will be responsible for reviewing the 
randomization code, and the final randomization code will be maintained by the CSC 
department.  
Patients will be randomly assigned to treatment through a qualified randomization service 
provider (e.g., IRT). This system is used to ensure a balance across treatment groups.  
3.4. 
Study Drugs and Dosage  
Patients will be randomized to receive laquinimod 0.5, 1.0, or 1.5 mg qd or matching placebo 
(prior to 10 January 2016), or randomly assigned to receive treatment with laquinimod at a 
dosage of 0.5 mg/day, 1.0 mg/day or placebo in a 1:1:1 ratio (from 10 January 2016). Every 
patient will take 3 capsules once daily, at the same time of the day, during the entire study 
period. Study drug will be administered as described in Section 3.4.1 and Section 3.4.2 below. 
The capsules will be taken orally and must be swallowed whole with a glass of water. The 
capsule should not be opened. Laquinimod can be taken with or without food. 
3.4.1. 
Investigational Product and Dosage 
Laquinimod will be provided as off-white, opaque, hard gelatin capsules. The capsules should be 
swallowed whole with water.  
• Patients randomized to the laquinimod 1.5 mg qd treatment arm received 3 capsules 
of 0.5 mg laquinimod (Note: The treatment of this high dose arm was discontinued as of 
10 January 2016). 
• Patients randomized to the laquinimod 1.0 mg qd treatment arm will receive 2 
capsules of 0.5 mg laquinimod and 1 capsule of matching placebo. 


 
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• Patients randomized to the laquinimod 0.5 mg qd treatment arm will receive 1 capsule 
of 0.5 mg laquinimod and 2 capsules of matching placebo. 
A more detailed description of administration procedures is given in Section 5.1.  
3.4.2. 
Other Study Drugs and Dosage - Placebo 
Matching placebo for laquinimod capsules will be provided as off-white opaque, hard gelatin 
capsules. Patients randomized to the placebo treatment arm will receive 3 capsules of matching 
placebo capsules. 
A more detailed description of administration procedures is given in Section 5.1.  
3.5. 
Duration of Patient Participation  
Subjects are expected to participate in this study for approximately 14 months, consisting of a 
screening period of 2 weeks up to 5 weeks, a double-blind treatment period of 12 months and a 1 
month follow-up period.  
3.6. 
Stopping Rules and Discontinuation Criteria  
Safety stopping rules are detailed in Appendix A (Guidance on Safety Monitoring).  
These include: 
• Elevated liver enzymes (as detailed in Appendix A) 
• Pregnancy 
• Need for concomitant treatment with moderate and strong CYP3A4 inhibitors 
• Patients that are diagnosed with a malignant solid or liquid tumor while participating in 
the study  
• Acute coronary syndrome, myocardial infarction or any major cardiovascular event 
Female subjects will be reminded to continue using 2 methods of acceptable contraception 
throughout treatment duration, and up to 30 days from the date from the last dose of the study 
drug, and about the need to stop treatment immediately if pregnancy is suspected. During the 
conduct of the study, serious adverse events will be reviewed (see Section 7.1.5) as they are 
reported from the investigational center to identify safety concerns. The study may be terminated 
by the sponsor at any time. 
A patient may discontinue participation in the study at any time for any reason (e.g., lack of 
efficacy, consent withdrawn, and adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (e.g., protocol violation or deviation as defined 
in Section 11.1.1, noncompliance, adverse event). 
Liver Impairment 
To avoid exposures to higher levels of laquinimod (see Section 1.3.2.1), a stopping rule 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. 
Renal Impairment 


 
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To avoid exposures to higher levels of laquinimod (see Section 1.3.2.1), a stopping rule related 
to renal impairment has been introduced. Patients who develop chronic renal disease associated 
with moderate or severe functional impairment, defined as estimated creatinine clearance (CrCl) 
<60 mL/min/1.73 m2, while participating in the study should stop study medication temporarily, 
and the assessment of estimated CrCl should be repeated. If the development of renal impairment 
is confirmed (estimated CrCl <60 mL/min/1.73 m2), the patient should stop study medication 
permanently. 
3.6.1. 
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. 
The reasons for temporary study drug discontinuation should be recorded in the appropriate 
section of the study drug dispensing and compliance log in the electronic Case Report Form 
(eCRF).  
The subject will report any temporary discontinuation to the investigator and will be instructed 
by the investigator regarding continuation of treatment. 
3.6.2. 
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). 
Early termination refers to the study drug termination and not termination of the patient from the 
study. Patients will be asked to continue all scheduled visits and safety asessements after study 
drug discontinuation (with the exception of drug dispensing and accountability, pregnancy 
testing, and pharmacokinetic sampling). 
Patients in the 1.5 mg/day (high dose) treatment arm, whose treatment with laquinimod was 
discontinued, were invited to attend an early termination visit (to return study medication and 
perform drug accountability). At this visit, only safety assessments were to be completed. These 
included vital signs, clinical laboratory tests, pregnancy test, adverse event inquiry, drug 
accountability, review of concomitant medication, and C-SSRS (see also Section 3.11.3.1.5). 
Patients were asked to continue scheduled follow up safety visits per the current schedule. 
Women of child bearing potential should continue using 2 acceptable contraception methods up 
to 30 days after the last dose of study medication has been administered. 
Moderate/strong CYP3A4 inhibitors are disallowed during the 30 days after the last laquinimod 
dose has been administered (see Appendix B).  
Plasma levels of drugs that are CYP1A2 substrates may decrease when combined with 
laquinimod and within 30 days after the last laquinimod dose, rendering these drugs less 
effective (see Appendix C). 


 
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3.7. 
Study Drug Supply and Accountability  
3.7.1. 
Study Drug Storage and Security 
Laquinimod and matching placebo capsules must be stored at room temperature (15-25°C), in a 
dry place, and in a securely locked, substantially constructed cabinet or enclosure. 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. Maintenance of a temperature 
log (manual or automated) is required and should be available for review by the monitor for the 
duration of the study. The temperature shall be recorded daily and the max/min thermometer 
reset after each reading. Complete instructions on receipt, storage, and handling of study drugs 
will be detailed in the Pharmacy Manual. 
3.7.2. 
Study Drug Accountability  
Each study drug shipment will include a packing slip, listing the contents of the shipment and 
any applicable forms. 
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. 
Study drugs accountability records must be maintained at the site at all times.  
During the study, all used and 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, with account given for any discrepancies. 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 Subject Number, the date, batch code/batch number, pack 
number and quantity of study drugs returned by the subject will be checked for correctness and 
recorded on the appropriate accountability forms, to be provided by the sponsor.  
The monitor will use the IRT to record the returns. 
3.8. 
Maintenance of Randomization and Blinding 
The randomization code will be maintained by the CSC department. At the time of analysis, 
when treatment codes are revealed, the CSC department will provide the randomization code to 
the statistician assigned to this study. 
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 blinded manner (i.e., 
a dummy subject identifier will be linked to an individual subject’s concentration data). 
For information about personnel who may be aware of treatment assignments, see Section 3.3. 
These individuals will not be involved in conduct of any study procedures or assessment of any 
adverse events. 
For a serious adverse event considered related and unexpected (ie, reasonable possibility; see 
Section 7.1.4) to the study drug, the sponsor’s Global Patient Safety & Pharmacovigilance 


 
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64 
Department may independently request that the treatment code be revealed (on a case-by-case 
basis). If this occurs, the investigator will remain blinded to treatment.  
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) and/or pharmacist(s) at the study center via the IRT, both via telephone and 
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. 
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. 
In blinded studies, 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. If this occurs, the investigator will 
remain blinded to treatment. 
As of 10 January 2016, treatment with laquinimod was discontinued for all patients in the 1.5 mg 
dose group; all these discontinued patients have been unblinded. No attempts will be made to re-
randomize patients whose 1.5 mg treatment was stopped to a lower dose of laquinimod.  
However, the blinding was maintained for the patients in the remaining ongoing 3 treatment 
arms (0.5 mg/day, 1.0 mg/day, and placebo). 
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 will not be considered as source data unless the study center obtains written 
documentation from the sponsor, prior to the beginning of the study, indicating which data are 
permitted to be recorded directly on to the CRF.  
Source data, including test results and/or assessments (e.g., clinical laboratory test results, ECG 
data, diary 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).  
The CRFs are filed in the sponsor’s central file.  
3.10. 
Time Schedule  
The study started in Q4 2014 (first patient randomized) and is expected to be completed in Q1 
2018 (last patient last visit).  


 
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65 
As of 10 January 2016, treatment with laquinimod was discontinued for all patients in the 1.5 
mg/day dose arm.  
Approximately 300 patients (100 patients within each study arm), plus the 30 patients who were 
already randomized to the laquinimod 1.5 mg dose arm, from ~51 investigational centers in 
North America, Europe and Russia are planned to be enrolled in the study.  
3.11. 
Study Procedures  
Study procedures and assessments with their timing are summarized in Table 3.  


 
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Table 3: 
TV5600-CNS-20007 (LEGATO-HD) - Study Procedures and Assessments 
TV5600-CNS-20007  
(LEGATO-HD) 
Pre-
treatment 
Baseline 
(Dosing) 
Double-blind Treatment Period 
Follow-Up Unscheduled 
Visit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 - 
Termination Visita 
Visit 9 
- 
Time (Weeks) 
Screening 
Baseline 
Week 4 
Week 13 
Week 19 
Week 26 
Week 39 
Week 52 
Week 56 
- 
Time (Months) 
 
Month 0 
Month 1 
Month 3 
Month 6 
Month 9 
Month 12 (or ET) 
 
 
Visit Window 
2 weeks up to 5 weeks 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±5 days 
 
Informed consent 
Xb 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
Xc 
Xc 
 
 
 
 
 
 
 
 
Medical and psychiatric history / 
demographics 
X 
 
 
 
 
 
 
 
 
 
Cardiovascular risk factor assessment 
and managementd e 
X 
 
 
 
 
 
 
 
 
 
ISCED 
X 
 
 
 
 
 
 
 
 
 
HD history 
X 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
Drug test and/or CDT testf 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsg 
Xh 
X 
X 
X 
 
X 
X 
X 
X 
Xi 
Clinical hematology 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Anemia panelj 
 
X 
Anemia panel is performed if there is a confirmed hemoglobin decrease of >1 g/dL from baseline 
Lipid profileg 
 
X 
 
 
 
 
 
X 
 
 
Thyroid function (T3, T4, TSH) 
 
X 
 
 
 
X 
 
X 
 
 
Blood collection for soluble biomarkers 
(cytokines)  
 
X 
 
 
 
X 
 
X 
 
Xi 
Blood collection for gene expression 
analysis 
 
X 
 
 
 
X 
 
X 
 
 
Blood sample for genomic analysis 
(including CAG analysis) 
X 
 
 
 
 
 
 
 
 
 
Blood sample for TSPO genotype 
X 
 
 
 
 
 
 
 
 
 


 
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TV5600-CNS-20007  
(LEGATO-HD) 
Pre-
treatment 
Baseline 
(Dosing) 
Double-blind Treatment Period 
Follow-Up Unscheduled 
Visit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 - 
Termination Visita 
Visit 9 
- 
Time (Weeks) 
Screening 
Baseline 
Week 4 
Week 13 
Week 19 
Week 26 
Week 39 
Week 52 
Week 56 
- 
Time (Months) 
 
Month 0 
Month 1 
Month 3 
Month 6 
Month 9 
Month 12 (or ET) 
 
 
Visit Window 
2 weeks up to 5 weeks 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±5 days 
 
analysisk 
Blood sample for monocyte analysisk l 
 
X 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Physical examination, including weight 
Xm 
X 
X 
X 
 
X 
X 
X 
X 
 
ECG n 
X 
X  
X  
X  
 
X  
 
X  
X  
 
Vital signs measurements  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Serum β-HCG in women of 
childbearing potential 
Xo 
Xo 
X 
X 
 
X 
X 
X 
X 
 
Urine β-HCG in women of child-
bearing potential 
 
Xp 
X 
X 
 
X 
X 
Xp 
X 
 
Ascertaining use of acceptable 
contraception 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Home urine pregnancy test 
 
 
Starting after Month1 (Visit 3), a urine β-hCG test will be performed at home in 
women of child-bearing potential every 28 (±2) days.  
 
 
Site call to patient for result inquiry 
 
 
A telephone call will be scheduled to be performed within 72 hours of the urine 
test date to inquire about the results.  
 
 
C-SSRS (baseline screening version) 
X 
 
 
 
 
 
 
 
 
 
C-SSRS (since last visit version) 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
MRI scanq 
Xn 
Xr 
 
 
 
 
 
Xs 
 
 
Estimated creatinine clearance 
calculationt 
X 
X 
X 
X 
 
X 
X 
X 
X 
Xi 
MRS scank  
 
X 
 
 
 
 
 
X 
 
 
PET scank u v  
 
Xp 
 
 
 
 
 
Xp 
 
 


 
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68 
TV5600-CNS-20007  
(LEGATO-HD) 
Pre-
treatment 
Baseline 
(Dosing) 
Double-blind Treatment Period 
Follow-Up Unscheduled 
Visit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 - 
Termination Visita 
Visit 9 
- 
Time (Weeks) 
Screening 
Baseline 
Week 4 
Week 13 
Week 19 
Week 26 
Week 39 
Week 52 
Week 56 
- 
Time (Months) 
 
Month 0 
Month 1 
Month 3 
Month 6 
Month 9 
Month 12 (or ET) 
 
 
Visit Window 
2 weeks up to 5 weeks 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±5 days 
 
UHDRS-TMS 
Xw 
X 
X 
X 
 
X 
 
X 
 
 
UHDRS-TFC 
Xw 
X 
 
 
 
X 
 
X 
 
 
UHDRS-FA 
 
X 
 
 
 
X 
 
X 
 
 
mPPT 
 
X 
 
 
 
X 
 
X 
 
 
PBA-sx 
 
X 
 
 
 
 
 
X 
 
 
CIBISx 
 
X 
 
 
 
 
 
 
 
 
CIBIC-plusx 
 
 
 
 
 
X 
 
X 
 
 
HD-QoLy 
 
X 
 
 
 
 
 
X 
 
 
EQ-5D-5Lz 
 
X 
 
 
 
 
 
X 
 
 
WLQz 
 
X 
 
 
 
 
 
X 
 
 
Q-Motor Assessments 
X 
X 
X 
X 
 
X 
 
X 
 
 
HD-CABaa  
Xbb 
X 
Xcc 
Xcc 
 
X 
 
X 
 
 
CDR-SBx 
 
X 
 
 
 
 
 
X 
 
 
HADS 
 
X 
 
 
 
 
 
X 
 
 
PK (drug and metabolites 
concentration) sampling 
 
 
Xy 
X 
 
X 
 
X 
 
Xi 
24-hour PK profilingdd for drug and 
metabolites 
 
 
X 
 
 
 
 
 
 
 
Review study compliance 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study Drug Dispensing 
 
X 
X 
X 
 
X 
X 
 
 
 
Study Drug Collection and 
Reconciliation 
 
 
X 
X 
 
X 
X 
X 
 
X 


 
Placebo-Controlled Study – Huntington's Disease 
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69 
TV5600-CNS-20007  
(LEGATO-HD) 
Pre-
treatment 
Baseline 
(Dosing) 
Double-blind Treatment Period 
Follow-Up Unscheduled 
Visit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 - 
Termination Visita 
Visit 9 
- 
Time (Weeks) 
Screening 
Baseline 
Week 4 
Week 13 
Week 19 
Week 26 
Week 39 
Week 52 
Week 56 
- 
Time (Months) 
 
Month 0 
Month 1 
Month 3 
Month 6 
Month 9 
Month 12 (or ET) 
 
 
Visit Window 
2 weeks up to 5 weeks 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±5 days 
 
Concomitant Medication Inquiry 
 
Concomitant medication will be monitored throughout the treatment and follow-up periods. 
Adverse events inquiry 
 
Adverse events will be monitored throughout the treatment and follow-up periods. 
a For patients in the high dose group (1.5 mg/day) who were discontinued, only safety and no efficacy assessments had to be performed at the Early Termination 
visit. The patients will be asked to continue all scheduled visits for safety assessment only after study drug discontnuation. 
b Patients with a legal guardian should be consented according to local requirements. 
c Inclusion/exclusion criteria should be met at screening and reviewed at baseline (Visit 2) before the patient is randomized. 
d Including smoking history. In addition, an evaluation of cardiovascular risk factors should take place as soon as possible for patients already in the study, 
following approval of Global Amendment 04. 
e Assessment of changes in cardiovascular risk and appropriate cardiovascular risk management with appropriate medical follow-up, if clinically indicated, 
should be performed during the scheduled and unscheduled visits. 
f When applicable, patients will be screened for drug substances in urine and/or CDT level in blood at screening to confirm abstinence in former (more than 12 
months from screening) alcohol and/or drug abusers.  
g For visits 2 through 9, Patients must have fasted no less than 8 hours prior to the blood draw.  
h When applicable per local requirements, patients will undergo an HIV test at screening.  
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 Anemia panel includes B12, 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. 
k Only at selected sites in a subgroup of patients 
l Blood sample for monocyte collection and analysis has to be done in accordance with the laboratory manual. For UK patients, the sample can be drawn prior to 
the baseline or Month 12 visit, as it coincides with the PET scan visits 
m Height will be assessed during the physical exam at screening (Visit 1) 
n ECG will be performed in triplicate at baseline (approximately 10±5 minutes apart). All other visits will have a single ECG performed. 
o At the screening visit, only serum β-HCG test will be performed. For the baseline visit - urine pregnancy test (beta human chorionic gonadotropin [β-hCG]) 
result is required for women of child-bearing potential prior to randomization. The urine test should be conducted at the site to allow randomization. A serum β-
HCG test should also be used to confirm the urine test; however, the randomization should be performed based on the results of the urine pregnancy test.  


 
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p An additional urine β-HCG test will be performed at the PET facilities at Imperial College in London at the Baseline visit and at Visit 8 for women of child-
bearing potential participating in the PET substudy. Its result will be available on site prior to any procedures involving ionizing radiation and will be 
considered accordingly. 
q If anxiolysis is required in order to perform the MRI scan, the scan should be performed at the end of the study visit day. 
r The baseline MRI can be performed at the screening visit, but no later than 7 days prior to baseline. If performed at the screening visit, as many screening 
assessements as possible should be conducted prior to the MRI scan in order to assess eligibility.  
s If a patient terminates within 3 months of the baseline visit, they will not undergo an Early Termination scan. If a patient terminates prior to Month 12, the 
Early termination scans should be performed as soon as possible, but not more than 7 days after discontinuation of study drug. Month 12 scans should be 
performed 7 days prior to the Termination Visit. The early termination MRI scan was not to be done for the patients in the discontinued 1.5 mg/day treatment 
arm .  
t Estimated creatinine clearance will be calculated at all in clinic study visits. Patients who develop chronic renal disease associated with moderate or severe 
functional impairment, defined as estimated creatinine clearance (CrCl) <60 mL/min/1.73 m2, while participating in the study should stop study medication 
temporarily and the creatinine clearance assessment should be repeated. If the renal impairment is confirmed (estimated CrCl <60 mL/min/1.73 m2), the patient 
should stop study medication permanently. 
u The PET scan can be done at any time prior to the date of the baseline visit, after eligibility of the patient has been confirmed. It can also be done 2 to 5 weeks 
prior to the Month 12 visit. 
v Patients taking benzodiazepines should be instructed to stop taking them for 3 days prior to having the PET scan. 
w UHDRS-TMS>5 and UHDRS-TFC≥8 are required for study eligibility 
x Where possible, the same person should act as a patient’s caregiver/informant throughout the study. If this is not possible, a patient should have no more than 2 
caregivers throughout the study. All possible attempts should be made to assure that caregiver will attend the clinical visits in person together with the patient. 
If the caregiver/informant is not available to attend the clinic visit, the interview can be done over phone.  
y HD-QoL will be assessed by both caregiver/informant and patient. All possible attempts should be made to assure that caregiver/informant will attend the 
clinical visits in person together with the patient. If the caregiver/informant is not available to attend the clinic visit, the caregiver/informant form should be 
omitted. 
z The WLQ/EQ-5D-5L could be completed by the patients with caregiver/informant assistance if needed.  
aa Includes Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced Tapping 
at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 trial version). 
bb The HD-CAB is performed at screening to reduce practice effects during the treatment phase.  
cc Reduced battery (only SDMT and Trail Making Test). 
dd Only at selected sites in a subgroup of patients (approximately 15 patients per each of the three continuing treatment groups, for a total of approximately 45 
patients) at Month 1. Patients participating in the 24-hour PK profiling will not have the single PK sample drawn at Visit 3. Additionally, PK samples were 
collected from 2 patients in the laquinimod 1.5 mg/day treatment group when the treatment was stopped; no further PK samples will be collected from the 
laquinimod 1.5 mg/day treatment group.  
Abbreviations: ET = early termination; CDT = carbohydrate deficient transferrin; ECG = electrocardiogram; C-SSRS = Columbia-Suicide Severity Rating Scale; 
UHDRS = Unified Huntington’s Disease Rating Scale; CIBIS = Clinician’s Interview-Based Impression of Severity; CIBIC-Plus = Clinician’s Interview-Based 
Impression of Change plus Caregiver Input; HD-CAB = HD Cognitive Assessment Battery; HD-QoL = Huntington’s disease Quality of Life; HIV = human 
immunodeficiency virus; CAG = cytosine-adenine-guanine; TMS = Total Motor Score; PBA-s = Problem Behaviors Assessment-Short form; SDMT = Symbol 
Digit Modalities Test.TFC = Total Functional Capacity; Q-Motor = Quantitative motor; CDR-SB = Clinical Dementia Rating – Sum of Boxes; HADS = Hospital 
Anxiety and Depression Scale 


 
Placebo-Controlled Study – Huntington's Disease 
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Study TV5600-CNS-20007 
71 
3.11.1. 
Procedures for Screening and Enrollment (Visit 1)  
A signed and dated informed consent form will be obtained before screening procedures 
commence. Evaluations obtained as part of routine medical care and performed during the 
screening period may be used in place of the protocol-specific evaluations. Patients will 
acknowledge and agree to the possible use of this information for the study by giving informed 
consent. Patients with a legal guardian should be consented according to local requirements. 
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
permanent identification number such that all patients from each investigational center are given 
consecutive identification numbers in successive order of inclusion. The first 2 digits of the 
screening number will be the number assigned to the country where the investigational center is 
located, the next 3 digits will be the designated investigator center number, and the last 3 digits 
will be assigned at the investigator center (e.g., if the number assigned to the country is 01, the 
3rd patient screened at center 5 would be given the number of 01005003). 
For patients for whom a unique HD-ID number is available, this identification number will be 
collected in the CRF. 
The International Standard Classification of Education (ISCED) will also be administered at 
screening as part of a panel of demographic measures including date of birth and gender. The 
ISCED is a scale that ranges from 0 to 8 (pre-primary school to doctoral level) that is used to 
establish education level equivalence across different countries/educational systems. Education 
levels are determined by using informal questioning of the patient, and then scores on the 0-6 
scale are assigned using country-specific tables that establish international education level 
equivalence (UNESCO, 2012). 
A patient who is screened but not randomized, e.g., because entry criteria were not met or 
enrollment did not occur within the specified time, may be considered for screening again if, e.g., 
there is a change in the patient’s medical background or a modification of study entry criteria.  
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 new Subject Number will be assigned to the subject. 
The screening visit (Visit 1) will take place up to 5 weeks before the baseline visit. The 
following procedures will be performed at Visit 1: 
• obtain written informed consent before any other study-related procedures are 
performed 
• review inclusion/exclusion criteria  
• review medical and psychiatric history/demographics  
• 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. 
• ISCED 
• HD history  
• review prior medication history 
• blood sample for genomic analysis including CAG analysis  


 
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• when applicable, patients will be screened for drug substances in urine and/or CDT 
level in blood to confirm abstinence in former (more than 12 months from screening) 
alcohol and/or drug abusers 
• perform clinical laboratory tests 
• when applicable per local requirements, patients will undergo an HIV test  
• clinical hematology 
• perform urinalysis 
• perform vital signs measurements  
• perform single electrocardiography (ECG) 
• perform full physical examination (including weight and height) 
• serum β-HCG in women of childbearing potential  
• blood sample for TSPO genotype analysis (Only at selected sites in a subgroup of 
patients) 
• C-SSRS (baseline screening version) 
• UHDRS-TMS (required for study eligibility) 
• UHDRS-TFC (required for study eligibility) 
• Estimated creatinine clearance calculation based on laboratory results (for inclusion 
in study).  
• Q-Motor assessments 
• HD-CAB 
o Includes Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail 
Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced 
Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 
trial version) 
o The HD-CAB is performed at screening to reduce practice effects during the 
treatment phase.  
• MRI scan 
o The baseline MRI can be performed at the screening visit, but no later than 7 
days prior to baseline. If performed at the screening visit, as many screening 
assessements as possible should be conducted prior to the MRI scan in order 
to assess eligibility. If the screening period is extended by up to 30 days, the 
MRI scan does not have to be repeated. 
• inform patients of study restrictions and compliance requirements 
3.11.2. 
Procedures Before Study Drug Treatment and Randomization (Baseline 
[Visit 2]) 
Patients who meet the inclusion/exclusion criteria at Visit 1 will continue to Visit 2, when 
baseline evaluations will be conducted. 
The following procedures will be performed at Visit 2 in patients who continue to meet the 
inclusion/exclusion criteria: 
• review inclusion/exclusion criteria 
• perform clinical laboratory tests 
• estimated creatinine clearance calculation 
• clinical hematology 


 
Placebo-Controlled Study – Huntington's Disease 
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• 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) and B12 
• lipid profile 
• thyroid function (T3, T4, TSH) 
• blood sample for soluble biomarkers (cytokines)  
• blood sample for gene expression analysis 
• blood sample for monocyte analysis (Only at selected sites in a subgroup of 
patients) 
o Blood sample for monocyte collection and analysis has to be done in 
accordance with the laboratory manual; 
o For UK patients, the sample can be drawn prior to the baseline visit, as it 
coincides with the PET scan visits 
• perform full physical examination (including weight) 
• perform vital signs measurements  
• ECG – in triplicate (approximately 10±5 minutes apart) 
• urine β-HCG in women of child-bearing potential 
o The urine test should be conducted at the site to allow randomization. A serum 
β-HCG test should also be used to confirm the urine test; however, the 
randomization should be performed based on the results of the urine 
pregnancy test.  
• serum β-HCG in women of child-bearing potential 
• additional urine β-HCG in women of child-bearing potential at PET facilities (Only 
in a subgroup of patients) 
• Ascertaining use of acceptable contraception 
• C-SSRS (since last visit version) 
• MRI scan 
o The baseline MRI can be performed at the screening visit, but no later than 7 
days prior to baseline. 
o If anxiolysis is required in order to perform the MRI scan, the scan should be 
performed at the end of the study visit day. 
• MRS scan (Only at selected sites in a subgroup of patients) 
• PET scan (Only in a subgroup of patients) 
o The PET scan can be done at any time prior to the date of the baseline visit, 
after eligibility of the patient has been confirmed.  
o Patients taking benzodiazepines should be instructed to stop taking them for 3 
days prior to having the PET scan. 
• UHDRS-TMS  
• UHDRS-TFC 
• UHDRS-FA  
• mPPT 
• PBA-s 
• CIBIS 
• HD-QoL 
• EQ-5D-5L 


 
Placebo-Controlled Study – Huntington's Disease 
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• WLQ 
• Q-Motor assessments 
• HD-CAB 
o Includes Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail 
Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced 
Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 
trial version) 
• CDR-SB 
• HADS 
• Review study compliance  
• Review of concomitant medications 
• Adverse event inquiry 
• Randomization  
• Study drug dispensing 
In case an unscheduled visit is performed, all mandatory activities according to the protocol, for 
this visit, should be performed. 
A patient who does not meet the inclusion/exclusion criteria may be considered for screening 
again if there is a change in the patient’s medical background, a modification of study entry 
criteria, or other relevant change.  
Patients who continue to meet the inclusion/exclusion criteria will be assigned a permanent 
unique randomization number and a treatment number (kit, bottle) using an IRT. These two 
newly assigned numbers will be entered into the CRF, and study drug will be dispensed. 
3.11.3. 
Procedures During Study Drug Treatment  
3.11.3.1. Double-Blind Treatment Period (Weeks 4 Through 52 [Visits 3 Through 8]) 
3.11.3.1.1. Months 1 and 3 (Visits 3 and 4) 
The following procedures/assessments will be performed at Months 1 and 3 (Visits 3 and 4): 
• Review of concomitant medications 
• Adverse events inquiry 
• perform full physical examination (including weight) 
• perform vital signs measurements  
• perform single ECG  
• perform clinical laboratory tests 
• estimated creatinine clearance calculation 
• clinical hematology 
• serum β-HCG in women of child-bearing potential 
• urine β-HCG in women of child-bearing potential 
o Starting after Month 1 (Visit 3), a urine β-hCG test will be performed at home 
in women of child-bearing potential every 28 (±2) days. A telephone call will 
be scheduled to be performed within 72 hours of the urine test date. 
• Ascertaining use of acceptable contraception 


 
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• C-SSRS (since last visit version) 
• UHDRS-TMS 
• Q-Motor assessments 
• Reduced cognitive battery (only SDMT and Trail Making Test)  
• PK drug concentration sampling  
• 24-hour PK profiling (only at selected sites in a subgroup of patients) – at Visit 3 
only 
o Patients participating in the 24-hour PK profiling will not have the single PK 
sample drawn at Visit 3. 
• Review study compliance 
• Study drug collection and reconciliation 
• Study drug dispensing 
3.11.3.1.2. Week 19 (Visit 5) – Phone Call 
Patients will be contacted by telephone at Week 19 to evaluate tolerability to the study drug 
through assessment of adverse events and concomitant medication usage, and to review study 
compliance. 
Use of acceptable contraception will be ascertained.  
The home urine β-hCG test will be performed in women of child-bearing potential, and a 
telephone call will be scheduled to be performed within 72 hours of the urine test date to inquire 
about the results.  
3.11.3.1.3. Month 6 (Visit 6) 
The following procedures/assessments will be performed at Month 6 (Visit 6): 
• Review of concomitant medications 
• Adverse events inquiry 
• perform full physical examination (including weight) 
• perform vital signs measurements  
• perform single ECG  
• perform clinical laboratory tests 
• estimated creatinine clearance calculation 
• clinical hematology 
• thyroid function (T3, T4, TSH) 
• blood sample for soluble biomarkers (cytokines) 
• blood sample for gene expression analysis 
• serum β-HCG in women of child-bearing potential 
• urine β-HCG in women of child-bearing potential 
• Ascertaining use of acceptable contraception 
• C-SSRS (since last visit version) 
• UHDRS-TMS  
• UHDRS-TFC 
• UHDRS-FA  


 
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• mPPT 
• CIBIC-plus 
• Q-Motor assessments 
• HD-CAB 
o Includes Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail 
Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced 
Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 
trial version) 
• PK drug concentration sampling 
• Review study compliance  
• Study drug collection and reconciliation  
• Study drug dispensing 
3.11.3.1.4. Month 9 (Visit 7) 
The following procedures/assessments will be performed at Month 9 (Visit 7): 
• Review of concomitant medications 
• Adverse events inquiry 
• perform full physical examination (including weight) 
• perform vital signs measurements  
• perform clinical laboratory tests 
• estimated creatinine clearance calculation  
• clinical hematology 
• serum β-HCG in women of child-bearing potential 
• urine β-HCG in women of child-bearing potential 
• Ascertaining use of acceptable contraception 
• C-SSRS (since last visit version) 
• Review study compliance 
• Study drug collection and reconciliation  
• Study drug dispensing 
3.11.3.1.5. Month 12 (Visit 8) –or Early Termination 
The following procedures/assessments will be performed at Month 12 (Visit 8) or early 
termination: 
• Review of concomitant medications 
• Adverse events inquiry 
• perform full physical examination (including weight) 
• perform vital signs measurements  
• perform single ECG  
• perform clinical laboratory tests 
• estimated creatinine clearance calculation  
• clinical hematology 
• lipid profile 
• thyroid function (T3, T4, TSH) 


 
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• blood sample for soluble biomarkers (cytokines) 
• blood sample for gene expression analysis 
• blood sample for monocyte analysis (Only at selected sites in a subgroup of 
patients) 
o Blood sample for monocyte collection and analysis has to be done in 
accordance with the laboratory manual 
o For UK patients, the sample can be drawn prior to the Month 12 visit, as it 
coincides with the PET scan visits 
• serum β-HCG in women of child-bearing potential 
• urine β-HCG in women of child-bearing potential 
• additional urine β-HCG in women of child-bearing potential at PET facilities (Only 
in a subgroup of patients) 
• Ascertaining use of acceptable contraception 
• PK drug concentration sampling 
• C-SSRS (since last visit version) 
• MRI scan 
o If anxiolysis is required in order to perform the MRI scan, the scan should be 
performed at the end of the study visit day. 
• MRS scan (Only at selected sites in a subgroup of patients) 
• PET scan (Only in a subgroup of patients) 
o The PET scan can be done 2 to 5 weeks prior to the Month 12 visit. 
o Patients taking benzodiazepines should be instructed to stop taking them for 3 
days prior to having the PET scan. 
• UHDRS-TMS  
• UHDRS-TFC 
• UHDRS-FA  
• mPPT 
• PBA-s 
• CIBIC-plus 
• HD-QoL 
• EQ-5D-5L 
• WLQ 
• Q-Motor assessments 
• HD-CAB 
o Includes Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail 
Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced 
Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 
trial version) 
• CDR-SB 
• HADS 
• Review study compliance  
• Study drug collection and reconciliation 


 
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Moderate/strong CYP3A4 inhibitors are disallowed during the 30 days after the last laquinimod 
dose has been administered (see Appendix B).  
Plasma levels of drugs that are CYP1A2 substrates may decrease when combined with 
laquinimod and within 30 days after the last laquinimod dose, rendering these drugs less 
effective (see Appendix C).  
Early termination refers to the study drug termination and not termination of the patient from the 
study. Patients in the 1.5 mg/day (high dose) treatment arm, whose treatment with laquinimod 
was discontinued, were invited to attend an early termination safety visit to return study 
medication and perform drug accountability. At this visit, only safety assessments (vital signs, 
clinical laboratory tests, pregnancy test, adverse event inquiry, drug accountability, review of 
concomitant medication, and C-SSRS) were to be conducted (see Section 3.6.2), and none of the 
efficacy assessments. Patients were asked to continue all scheduled visits for safety assessment 
after study drug discontinuation. 
Patients in the high dose group (1.5mg/day) who were requested to discontinue study drug before 
week 52, but who continue to attend scheduled study visits for safety assessment, are not 
considered to have completed the study. 
3.11.4. 
Procedures After Study Drug Treatment  
3.11.4.1. Follow-Up (Week 56, Visit 9) 
The following procedures/assessments will be performed at the follow up visit (Week 56, 
Visit 9): 
• Review of concomitant medications 
• Adverse events inquiry 
• perform clinical laboratory tests 
• estimated creatinine clearance calculation  
• clinical hematology 
• perform full physical examination (including weight) 
• perform vital signs measurements  
• perform single ECG  
• serum β-HCG in women of child-bearing potential 
• urine β-HCG in women of child-bearing potential 
• Ascertaining use of acceptable contraception 
• C-SSRS (since last visit version) 
Patients who participate in the study in compliance with the protocol for the entire duration of 
the double-blind treatment will be considered to have completed the study.  
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at the end-of-treatment visit or as soon as possible thereafter. Procedures for patients 
who withdraw prematurely from the study are described in Section 4.3.  
If it is not possible to schedule the ET visit within 2 weeks after end of treatment, only the safety 
evaluations for that visit (vital signs, clinical laboratory tests, pregnancy test, adverse event 


 
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inquiry, drug accountability, review of concomitant medication, and C-SSRS, see Section 3.6.2) 
need to be performed.  
Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 7.1.2 and Section 7.3, 
respectively.  
3.11.5. 
Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the subject’s request or 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (e.g., adverse events, concomitant 
medications and treatments, and results from procedures or tests). 
Mandatory Unscheduled Visit Procedures (except for subjects that perform the unscheduled visit 
for repeat MRI scan):  
• Vital signs 
• Evaluation of AEs 
• Review of concomitant medications 
• Review of study drug accountability 
• Compliance 
• Ascertaining use of acceptable contraception 
Other procedures may be performed at the discretion of the investigator, 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) 
• estimated creatinine clearance calculation  
• collection of unscheduled pharmacokinetic blood sample 
collection of sample for potential biomarker analysis 


 
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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: 
a.  [New criterion] Documentation of prior positive genetic testing for HD, or a clinical 
diagnosis of symptomatic HD (Diagnostic Confidence Level 4).  
b.  [Revision 1] Presence of 36-49 CAG repeats, inclusive, in the huntingtin gene based on 
centralized CAG testing during screening.  
c. Male or female between 21-55 years of age, inclusive, with an onset of HD at or after 
18 years of age. 
d. [Revision 1] Women of child-bearing potential (women who are not post menopausal or 
who have not undergone surgical sterilization) must practice an acceptable method of 
birth control for 30 days before taking the study treatment, and 2 acceptable methods of 
birth control during all study duration and until 30 days after the last dose of treatment 
was administered. Acceptable methods of birth control in this study include: Intrauterine 
device, barrier method (condom or diaphragm with spermicide) and hormonal methods of 
birth control (e.g., oral contraceptive, contraceptive patch, long-acting injectable 
contraceptive).  
e. A sum of >5 points on the UHDRS-TMS at the screening visit 
f. UHDRS-TFC ≥ 8 at the screening visit. 
g. Able and willing to provide written informed consent prior to any study related procedure 
being performed at the screening visit. Patients with a legal guardian should be consented 
according to local requirements. 
h. Willing to provide a blood sample for genomic CAG analysis at the screening visit. 
i. Willing and able to take oral medication and able to comply with the study specific 
procedures.  
j. Ambulatory, being able to travel to the study centre, and judged by the investigator as 
likely to be able to continue to travel for the duration of the study  
k. Availability and willingness of a caregiver, informant, or family member to provide input 
at study visits assessing CIBIC-Plus, CDR-SB, PBA-s and HD-QoL. A caregiver is 
recommended to be someone who attends to the patient at least 2 to 3 times per week for 
at least 3 hours per occasion, and the suitability of the caregiver should be judged by the 
investigator. 
l. For patients taking allowed antidepressant medication, the dosing of medication must 
have been kept constant for at least 30 days before baseline and must be kept constant 
during the study.  
 


 
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4.2. 
Patient Exclusion Criteria  
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and 
azathioprine within 12 months prior to screening 
b. Previous use of laquinimod 
c. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to randomization. 
d. Use of inducers of CYP3A4 within 2 weeks prior to randomization.  
e. Pregnant or breastfeeding. 
f. [Revision 1] Serum levels ≥2xULN of either ALT or AST at screening. 
g. [Revision 1] Serum direct bilirubin which is ≥1.5xULN at screening.  
h. [Revision 2] Estimated creatinine clearance <60 mL/min at screening, calculated using 
the Cockcroft Gault equation:  
(140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL)  
i. [Revision 1] Subjects with a clinically significant or unstable medical or surgical 
condition that may put the patient at risk when participating in the study or may influence 
the results of the study or affect the patient's ability to take part in the study, as 
determined by medical history, physical examinations, ECG, or laboratory tests. Such 
conditions may include: 
1. A major cardiovascular event (e.g. myocardial infarction, acute coronary syndrome, 
de-compensated congestive heart failure, pulmonary embolism, coronary 
revascularization, angina) that occurred prior to randomization. 
2. Significant cardiovascular risk factors (such as, but not limited to, uncontrolled 
hypertension, uncontrolled diabetes), per investigator discretion. 
3. Any acute pulmonary disorder 
4. A CNS disorder other than HD that may jeopardize the subject's participation in the 
study, including such disorders that are demonstrated on the baseline MRI (based 
on local read). 
5. A gastrointestinal disorder that may affect the absorption of study medication. 
6. Acute or chronic renal disease including acute kidney injury (AKI). 
7. Any form of acute or chronic liver disease. 
8. Known human immunodeficiency virus positive status. Patients will undergo an 
HIV test at screening per local requirements, if applicable. 
9. Any malignancies, excluding basal cell carcinoma, in the 5 years prior to 
randomization. 


 
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j. Any clinically significant, abnormal, screening laboratory result which in the opinion of 
the investigator, affects the patients’ suitability for the study or puts the patient at risk if 
he/she enters the study 
k. Unsuitable for MRI (e.g., claustrophobia, metal implants) 
l. Alcohol and/or drug abuse within the 12 months prior to screening, as defined by 
Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition Text Revision 
(DSM-IV TR) criteria for substance abuse. For former alcohol and/or drug abusers, the 
abstinence should be confirmed by laboratory tests (drug testing and/or carbohydrate 
deficient transferrin (CDT) level in blood). 
m. Patients with active suicidal ideation during the past month as measured by a most severe 
suicide ideation score of 4 (Active Suicidal Ideation with Some Intent to Act, without 
Specific Plan) or 5 (Active Suicidal Ideation with Specific Plan and Intent) on the 
baseline screening Columbia-Suicide Severity Rating Scale (C-SSRS) or subjects who 
answer “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts, or behavior) if the attempt or acts 
were performed within 1 year of screening, or subjects who, in the opinion of the 
investigator, present a serious risk of suicide. 
n. Patients with known intracranial neoplasms, vascular malformations, or intracranial 
hemorrhage 
o. Known drug hypersensitivity that would preclude administration of laquinimod or 
placebo, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate. 
p. Swallowing difficulties that would preclude administration of laquinimod or placebo 
capsules. 
q. [Revision 1] Treatment with any investigational product within 30 days of screening or 
patients planning to participate in another clinical study assessing any investigational 
product during the study. Patients in non-interventional and/or observational studies will not be 
excluded from participating in this study. 
r. Treatment with tetrabenazine within 30 days of the study baseline visit 
s. Treatment with antipsychotic medication within 30 days of the study baseline visit 
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 in the event of intercurrent illness, adverse 
events, pregnancy (see Section 7.3.3), or other reasons concerning the health or well-being of the 
patient, or in the event of lack of cooperation. In addition, a patient may be withdrawn from the 
study as described in Sections 3.6, 3.8, 3.11.4, 5.4, and 7.1.7.  
Specific safety reasons for withdrawing a patient from the study are described in detail in 
Appendix A and Section 3.6. These include: 
• Elevated liver enzymes (as detailed in Appendix A)  
• Pregnancy 


 
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• Need for concomitant treatment with moderate and strong CYP3A4 inhibitors 
• Patients that are diagnosed with a malignant solid or liquid tumor 
• Acute coronary syndrome, myocardial infarction or any major cardiovascular event 
 
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 (including all Visit 8 procedures) should be made and an explanation given 
as to why the patient is withdrawing or being withdrawn from the study. 
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 (e.g., 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. If it is not possible to schedule the ET visit within 2 
weeks after end of treatment, only the safety evaluations for that visit need to be performed.  
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’. 


 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Study Drugs Administered  
Until 10 January 2016, at the baseline visit, patients were randomly assigned in a 1:1:1:1 ratio to 
1 of 3 laquinimod treatment groups or to the placebo treatment group. Three capsules will be 
administered orally once each day, at the same time of the day, as follows: 
• Oral laquinimod 0.5 mg: 3 capsules, 1 containing 0.5 mg laquinimod and 2 capsules 
containing matching placebo, to be administered orally qd.  
• Oral laquinimod 1.0 mg: 3 capsules, 2 containing 0.5 mg laquinimod and 1 capsule 
containing matching placebo, to be administered orally qd.  
• Oral laquinimod 1.5 mg: 3 capsules containing 0.5 mg laquinimod (Note: The treatment 
of this high dose arm was discontinued as of 10 January 2016) 
• Matching placebo: 3 capsules, containing 0.5 mg matching placebo, to be administered 
orally qd. 
As of 10 January 2016, following the decision to discontinue treatment of the laquinimod 1.5 mg 
dose arm, additional eligible patients who are enrolled will be randomized in a 1:1:1 ratio to 
receive laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo for 52 weeks. 
The capsules will be taken orally and must be swallowed whole with a glass of water. The 
capsule should not be opened. Laquinimod can be taken with or without food. 
The time of the dosing will be recorded on the CRF. 
Compliance to study drug administration will be monitored. See Section 5.4 for additional 
information. 
Study drug will be packaged in bottles and provided for patients to take at home (see 
Section 3.4). Study drug exposure will be measured and compliance to study drug administration 
will be monitored. 
5.2. 
Restrictions  
There are no restrictions in this study. 
However, regarding fasting prior to in-clinic visits that will require fasting blood draws: 
For visits 2 through 9, patients must have fasted (no food or beverages) no less than 8 hours prior 
to each morning visit that will require fasting blood draws (i.e. a blood draw for the lipid profile, 
or for the safety laboratory panels which include clinical chemistries and hormone 
concentrations). 
Patients will be permitted to have water up until 1 hour before blood draws. 
For patients participating in the PK-profiling ancillary study, the fasting conditions will be held 
up to 4 hours after the dosing. 


 
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5.3. 
Prior and Concomitant Therapy or Medication  
Any prior or concomitant therapy, medication, or procedure a patient has had within 3 months 
before study drug administration and up to the end of the study period, including follow-up, will 
be recorded on the CRF. Generic or trade name, indication, and dosage will be recorded. The 
sponsor will encode all therapy and medication according to the World Health Organization 
(WHO) drug dictionary (WHO Drug). 
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. 
5.3.1. 
Disallowed Previous Medications/Therapies Prior to and During the Study 
The following medications will not be allowed prior to and during this study: 
• Use of tetrabenazine within 30 days prior to baseline and during the study; 
• Use of antipsychotic medication within 30 days prior to baseline and during the 
study; 
• Use of moderate/strong inhibitors of CYP3A4, such as erythromycin and 
ketoconazole (more examples listed in Appendix B), within 2 weeks prior to 
randomization, during the study and until 30 days after the last study dose has been 
administered. 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. 
• Use of inducers of CYP3A4 within 2 weeks prior to randomization and during the 
study;  
• Immunosuppressive or immunomodulating agents, or cytotoxic agents, including 
cyclophosphamide and azathioprine within 12 months prior to screening and during 
the study; 
• Use of experimental or investigational drugs and/or participation in drug clinical 
studies within 30 days of screening and during the study. 
For patients taking antidepressant medication, the dose has to be kept constant for at least 
30 days prior to randomization and during the whole study period. 
Appendix B provides a list of medications disallowed prior to and during the study. 
Patients who for their safety and well-being, according to the treating physician, are in need of 
antipsychotic medication or changed dose of antidepressant medication during the study, will be 
allowed to continue in the study, and the change in concomitant medication will be recorded in 
the CRF. 


 
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5.3.2. 
 Other Concomitant Medications/Therapies 
Studies have shown that laquinimod is a strong inducer of CYP1A2 and a weak inhibitor of 
CYP3A4. Therefore, co-administration of laquinimod may affect the systemic exposure of drugs 
metabolized by CYP450 1A2 or CYP3A4. 
5.3.2.1. 
CYP1A2 
Laquinimod 0.6 mg/day reduced the systemic exposure of caffeine (a compound mainly 
metabolized by CYP1A2) 5-fold. Laquinimod doses higher than 0.6 mg/day may further increase 
CYP1A2 induction and decrease exposure of CYP1A2 substrates.  
Plasma levels of drugs that are CYP1A2 substrates may decrease when combined with 
laquinimod. Also, during a period of 30 days following the last laquinimod dose these CYP1A2 
substrates are potentially less effective due to decreased plasma levels. 
Table 7 (Appendix C) presents a partial list of drugs that are mainly metabolized by CYP1A2, 
i.e. CYP1A2 plays a major role in their biotransformation. The systemic exposure of these drugs 
is expected to be significantly reduced by laquinimod co-administration. Drugs that are mainly 
metabolized by CYP1A2 and have a narrow therapeutic index are of special concern and appear 
in bolded text.  
In general, as a precautionary measure, it is recommended to avoid the use of CYP1A2 
substrates in clinical trials of laquinimod. Therapeutic alternatives may be considered in the 
appropriate clinical context. 
5.3.2.2. 
CYP3A4 
Laquinimod 0.6 mg/day increases the systemic exposure of midazolam (a sensitive CYP3A4 
substrate) 1.5-fold and for the 1.2 mg/day dose 1.7 fold. Therefore, plasma levels of drugs that 
are CYP3A4 substrates may increase when combined with laquinimod. Patients taking drugs that 
are metabolized by CYP3A4, specifically those with a Narrow Therapeutic Index (Table 6, 
Appendix C) should be advised that plasma levels of these drugs could increase when combined 
with laquinimod.  
5.4. 
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. 
5.5. 
Total Blood Volume  
The total amount of blood to be drawn throughout the entire study for serum chemistry, 
hematology, pharmacokinetic, biomarker and pharmacogenomic measurements is approximately 
350 mL/patient.  
Patients who will participate in the PK profiling ancillary study will have approximately 32 mL 
extra blood drawn throughout the study.  


 
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Patients who will participate in the monocyte ancillary study will have approximately 50 mL 
extra blood drawn throughout the entire study.  


 
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6. 
ASSESSMENT OF EFFICACY  
6.1. 
Primary Efficacy Variables  
The primary efficacy variable and endpoint for this study is the change from baseline in the 
UHDRS-TMS (defined as the sum of the scores of all UHDRS-TMS subitems) at Month 12/ ET 
(evaluated at baseline and Months 1, 3, 6 and 12). 
The TMS component of UHDRS comprises 31 assessments of different motor signs, including 
eye movements, hand motor coordination, speech, involuntary movements, gait and posture. 
Each assessment is rated on a 5-point scale from 0 (normal) to 4 (maximally abnormal). All 
UHDRS-TMS raters have to be certified by the European Huntington's Disease Network 
(EHDN) UHDRS-TMS online certification (Reilmann et al, 2009).  
6.2. 
Secondary Efficacy Variables  
6.2.1. 
Percent Change from Baseline in Caudate Volume at Month 12/ET (Evaluated 
at Baseline and Month 12) 
Participants will undergo 3T MRI at baseline and Month 12 following unaccelerated volumetric 
T1-weighted acquisition protocols developed during the ADNI study (www.adni-info.org). 
Change in caudate volume over the scanning interval will be calculated using the Boundary Shift 
Integral (BSI) technique (Hobbs et al, 2009; Freeborough and Fox, 1997; Leung et al, 2010). 
Change in whole brain and ventricular volume will also be calculated using this approach (see 
Section 6.3.1). The BSI is an intensity-driven technique within the MIDAS software 
(Freeborough et al, 1997) which measures change over time in the brain directly from within-
subject registered (aligned) MR scan pairs. This technique has been optimised to provide robust 
measures of brain-volume change from multi-site data (Leung et al, 2010) and has been shown to 
be sensitive to HD-related pathology over a 12-month interval in the multi-site TRACK-HD 
study (Tabrizi et al, 2011). Details of how the BSI has been implemented for this study are 
described in the Imaging Review Charter. 
White-matter volume change (see Section 6.3.1) will be estimated using a non-linear registration 
approach.Voxel-level volume change derived from within-subject non-linear registration will be 
summed over an automated baseline white-matter mask, to estimate within-subject volume 
change over the interval. This analysis is detailed in the Imaging Review Charter. 
End-point quality control will be performed by trained analysts to ensure accuracy.  
Longitudinal change in caudate, whole-brain and white-matter volume will be measured in mls 
and converted to a percentage of their baseline value for subsequent analysis. Longitudinal 
change in ventricular volume will be measured and analysed in absolute terms (ml). 
MRI scans may be evaluated locally for any incidental pathology (ie, pathology unrelated to, or 
inconsistent with, the subject’s known HD) according to locally determined procedures. If such 
pathology is found, the Treating Neurologist/Physician should be notified. The MRI reading 
center will evaluate the scans only for the purpose of performing quantitative measurements. In 
order not to compromise blinding of the study, the MRI Reading Center will not report 
quantitative MRI findings back to the clinical site. 


 
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Patients who develop unsuitability for MRI measures after baseline visit, will be allowed to 
continue in the study without performing the MRI assessment. 
6.2.2. 
Change from Baseline in HD-CAB Total Score (Sum of the Standardized Sub-
Components) at Month 12/ET (Evaluated at Baseline and Months 6 and 12) 
The following sections describe the tests that will are included in the HD-CAB. 
The CAB assessments will be performed only in those sites that have access to the devices 
needed to perform the assessments and, where this is the case, only in those patients who are 
capable of performing the assessments. 
To avoid variability due to different operating systems, hardware and computer accessories (i.e. 
mouse), sites will be provided with standardized equipment (tablets) to perform the 
computerized cognitive assessments. 
6.2.2.1. 
Symbol Digit Modalities Test (SDMT) 
The SDMT is a paper-and-pencil test of attention, psychomotor speed and working memory. 
Participants view a ‘key’ at the top of the page containing symbols paired with numbers. The 
remainder of the page displays rows of symbols, and the participant has 90 seconds to write in 
the corresponding number that matches each symbol. 
6.2.2.2. 
Emotion Recognition 
Recognition of facial expressions of emotions is examined using computerized images of faces 
depicting 6 basic emotions or a neutral expression. Participants are asked to indicate the emotion 
expressed in each photograph by selecting from the words fear, disgust, happy, sad, surprise, 
angry, and neutral (10 stimuli per emotion). 
6.2.2.3. 
Trail Making Test 
Visual attention and task switching are assessed using the Trail Making test, which consists of 
25 circles on a standard sheet of paper. For Trails A, participants are required to connect, as 
quickly as possible, circles containing numbers in ascending numerical order. For Trails B, 
participants are to connect, as quickly as possible, circles containing numbers and letters, 
alternating between numbers and letters in ascending order (e.g., 1, A, 2, B, 3, C, etc.) (Bowie 
and Harvey, 2006) Trail A is administered first, followed by Trail B to ensure preparedness for 
Trail B; however, only the Trail B score is used as an outcome measure in the HD-CAB. 
6.2.2.4. 
Hopkins Verbal Learning Test, revised (HVLT-R) 
The HVLT-R is a paper-based instrument that offers a brief assessment of verbal learning and 
memory (recall). It is easy to administer and score and is well tolerated even by significantly 
impaired individuals. 
Its use has been validated with brain-disordered populations (e.g., Alzheimer's disease, HD, 
amnestic disorders) as a measure of verbal learning and memory. There are six alternate forms 
available, but 3 of the 6 forms, which have relatively greater equivalence with each other (Forms 
4, 5, and 6) will be used, in randomized order. Each form consists of a list of 12 nouns (targets) 
with 4 words drawn from each of 3 semantic categories. The semantic categories differ across 


 
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the 6 forms, but the forms are very similar in their psychometric properties. Only the three 
learning trials (Trials 1-3) and the delayed recall trial (Trial 4) will be administered as part of the 
HD-CAB. The primary scores that will be examined as part of the HD-CAB is the sum of Trials 
1-4; however, the sum of Trials 1-3 and separately Trial 4 will also be examined in exploratory 
analyses. The HVLT-R has high test-retest reliability, and its construct, concurrent, and 
discriminant validity have been well established. 
6.2.2.5. 
Paced Tapping at 3 Hz 
Psychomotor function is assessed in a computerized Paced Tapping test. Participants tap on left 
and right mouse buttons, alternating between thumbs, at 3.0 Hz. They first listen to a tone 
presented at the 3.0 Hz rate, and then begin tapping in time with the tone. After 11 taps with the 
tone, the repetition tone is discontinued, and participants attempt to continue tapping at the same 
rate until the end of the trial (31 taps later). Four trials are administered. 
6.2.2.6. 
One Touch Stockings of Cambridge (OTS) 
OTS is a computerized spatial planning task which gives a measure of frontal lobe function. OTS 
is a variant of the Stockings of Cambridge task, and places greater demands on working memory 
as the participant has to visualize the solution. As with Stockings of Cambridge, the participant is 
shown 2 displays containing 3 colored balls. The displays are presented in such a way that they 
can easily be perceived as stacks of colored balls held in stockings or socks suspended from a 
beam.  
Along the bottom of the screen, there is a row of numbered boxes. The test administrator first 
demonstrates to the participant how to use the balls in the lower display to copy the pattern in the 
upper display, and completes 1 demonstration problem, where the solution requires 1 move. The 
participant must then complete 3 further problems, 1 each of 2 moves, 3 moves, and 4 moves. 
Next, the participant is shown further problems, and must work out in their head how many 
moves the solutions to these problems require, then select the appropriate box at the bottom of 
the screen to indicate their response. 
6.2.3. 
CIBIC-Plus Global Score at Month 12/ET (Evaluated at Months 6 and 12) as 
Compared to Baseline (Rated by an Independent Rater) 
Global change in HD will be measured using the CIBIS scale at baseline and the CIBIC-Plus 
scale at subsequent time points. The CIBIC-Plus (version ADCS-CGIC) was developed, 
validated, and is commonly used in studies of anti-dementia drugs in Alzheimer’s disease 
(Joffres et al, 2000). 
An independent rater whose only role in the study is to conduct these global assessments will 
evaluate the patient’s overall disease severity during the baseline visit (Visit 2) prior to the 
administration of study drug. This assessment, known as the CIBIS, rates the patient on a 7-point 
Likert scale from extremely severe HD to no symptoms of HD. 
At each subsequent visit in which the evaluation is performed (Months 6 and 12; Visits 6 and 8), 
the CIBIC-Plus will be preferentially administered by the same independent rater, but without 
knowledge of other endpoint assessments or the AEs experienced by the patient during the study 
(so as not to confound the rating of CIBIC-Plus as an efficacy measure or to unblind the study). 


 
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The independent rater is not permitted to discuss the medical condition of the patient with the 
treating physician. Instead, the independent rater exclusively will consider observations of the 
patient’s cognitive, functional, and behavioral performance obtained through interviewing the 
patient and the caregiver. The rater then compares those findings to the baseline assessment. The 
overall impression of change from baseline (CIBIC-Plus) is rated on a 7-point scale: 1 = marked 
improvement; 2 = moderate improvement; 3 = minimal improvement; 4 = no change; 
5 = minimal worsening; 6 = moderate worsening; 7 = marked worsening; all assessments were 
relative to baseline. A higher score indicates a worsening of global function. 
In HD, the inclusion of caregiver input is particularly critical for a global assessment as previous 
studies have demonstrated that patients have limited awareness and recognition of their deficits. 
Where possible, the same person should act as a patient’s caregiver/informant throughout the 
study. If this is not possible, a patient should have no more than 2 caregivers throughout the 
study. All possible attempts should be made to assure that caregiver will attend the clinical visits 
in person together with the patient. If the caregiver/informant is not available to attend the clinic 
visit, the interview can be done over phone. 
6.2.4. 
Change from Baseline in UHDRS- TFC at Month 12/ET (Evaluated at Baseline 
and Months 6 and 12) 
The Unified Huntington’s Disease Rating Scale (UHDRS) motor section (see Section 6.1) and 
Total Functional Capacity will be used as measures of disease severity. The UHDRS is a 
research tool, which has been developed by the Huntington Study Group to provide a uniform 
measure of clinical performance and course of HD. The UHDRS has undergone extensive 
reliability and validity testing and has been used in many research studies as a primary outcome 
measure (Huntington Study Group, 1996).  
The TFC scale of the UHDRS assesses 5 functional domains associated with disability 
(occupation, finances, domestic chores, activities of daily living, and care level) and is rated from 
0-13 (maximum functionality). 


 
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6.3. 
Exploratory Variables 
6.3.1. 
Change from Baseline in Brain Atrophy as Defined by the Percentage Change in 
Volume In: Whole Brain Volume and White-Matter Volume at Month 12/ET 
and Absolute Change in Ventricular Volume at Month 12/ET (Evaluated at 
Baseline and Month 12) 
For a description of the MRI procedure and analysis, see Section 6.2.1.  
6.3.2. 
Change from baseline in UHDRS- FA at Month 12/ET (evaluated at baseline 
and Months 6 and 12)  
The FA scale of the UHDRS assesses several functional domains associated with disability 
(occupation, finances, capability to drive a car, ability to take care of children, ability to make a 
phone call, etc.) and is rated from 0-25 (maximum functionality). 
6.3.3. 
Change from baseline in Q-Motor assessments at Month 12/ET (evaluated at 
baseline and Months 1, 3, 6 and 12) 
Motor deficits can be objectively assessed using different Q-Motor assessments (Reilmann, 
2012). All Q-Motor assessments are based on the application of precalibrated and temperature 
controlled force transducers and 3-dimensional position sensors with very high sensitivity and 
test-retest reliability across sessions and sites in a multicenter clinical study. Q-Motor measures 
thus aim to reduce the limited sensitivity of categorical clinical rating scales, the intra- and inter-
rater variability, and placebo effects observed in scales such as UHDRS-TMS. In addition, Q-
Motor assessments allow for the objective monitoring of unintended motor side-effects in 
clinical studies. 
Tasks detailed in the sections below have been selected for use in the current study. Data transfer 
will be performed using a secure web based platform, allowing continuous centralized data 
monitoring and quality control. Data analysis will be performed blinded and automated as 
described in the statistical analysis plan (SAP). 
Q-Motor assessments will be performed only in those sites that have access to the devices 
needed to perform the assessments and, where this is the case, only in those patients who are 
capable of performing the assessments. 
6.3.3.1. 
Digitomotography (Speeded Index Finger Tapping) 
The patient will place their hand on a hand rest with their index finger positioned above a force-
transducer. Recordings will start after practice runs. The patient will be instructed to finger tap as 
fast as possible between 2 auditory cues. The beginning of a tap is defined as a rise of the force 
by 0.05 N above maximal baseline level. The tap ends when it drops to 0.05 N before the 
maximal baseline level is reached again. The duration and variability of tap durations (TD), 
inter-onset intervals (IOI), inter peak intervals (IPI), and inter tap intervals (ITI) are the 
exploratory outcome measures for speeded tapping. In addition, variability of peak tapping 
forces (TF) will be calculated, and the tapping frequency (Freq), ie, the number of taps between 
the onsets of the first and the last tap divided by the time in between, will be determined. Five 
trials of 10 seconds duration are performed with each hand (Bechtel et al, 2010).  


 
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6.3.3.2. 
Dysdiadochomotography (Pronation/Supination Hand Tapping) 
This task assesses the regularity of hand taps performed when alternating between the palm and 
dorsal surface of the hand performing a repetitive pronation/supination movement. The force and 
duration of the hand taps are recorded similarly to the speeded tapping task. A tone cues the start 
and end of an assessment. Five trials of 10 seconds duration are performed with each hand. 
6.3.3.3. 
Manumotography and Choreomotography (Grip Force and Chorea Analysis) 
This task assesses the coordination of isometric grip forces in the precision grip between the 
thumb and index finger (Reilmann et al, 2001, Reilmann et al, 2010). Grip forces are assessed 
during grip initiation, object transport, and in a static holding phase. Patients are instructed to 
grasp and lift a device equipped with a force transducer and 3-dimensional position sensor in the 
precision grip between thumb and index finger and hold it stable adjacent to a marker 10-cm 
high. Grip forces and 3-dimensional position and orientation of the object are recorded. Mean 
isometric grip forces and grip force variability in the static phase (expressed as coefficient of 
variation = standard deviation [SD]/mean × 100) (GFV-C) are calculated during a 15-second 
period prior to the second cueing tone. 
Five trials of 20 seconds duration are performed with each hand. Chorea is assessed calculating a 
“position-index” and “orientation-index” (Reilmann et al, 2011). Start and end of assessment are 
signaled by a cueing tone. 
6.3.3.4. 
Pedomotography (Speeded Foot Tapping) 
The patient will place a foot on the foot device such that the ball of the foot is positioned above a 
force-transducer. Recordings will start after practice runs. The patient will be instructed to tap 
with the foot as fast as possible between 2 auditory cues. The beginning of a tap is defined as a 
rise of the force by 0.05 N above maximal baseline level. The tap ends when it dropped to 0.05 N 
before the maximal baseline level is reached again. The duration and variability of TD, IOI, IPI, 
and ITI are the exploratory outcome measures for speeded foot tapping. In addition, variability of 
peak TF will be calculated , and the tapping Freq, ie, the number of taps between the onsets of 
the first and the last tap divided by the time in between, will be determined. Five trials of 10 
seconds duration are performed with each foot. 
6.3.4. 
Change from baseline in mPPT at Month 12/ET (evaluated at baseline and 
Months 6 and 12) 
The modified PPT quantifies the patient’s performance in physical tasks (Brown et al, 2000). It 
is a standardized 9-item test that measures the patient’s performance on functional tasks. 
Assistive devices are permitted for the tasks that require a standing position. Both the speed and 
accuracy at which the patients complete the items are taken into account during scoring. The 
maximum score of the test is 36, with higher scores indicating better performance. 


 
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6.3.5. 
Change from baseline in HD QoL and EQ-5D-5L at Month 12/ET (evaluated at 
baseline and Month 12) 
6.3.5.1. 
HD-QoL 
The HD-QoL is a standardized instrument for measuring health-related quality of life (Hocaoglu 
et al, 2012). It is a validated disease-specific measure designed for HD, and can provide a 
summary score of overall health-related quality of life, as well as scores on several discrete 
scales. HD-QoL is for people who are living with HD; this includes people who are at risk for 
HD, people who have tested positive for the huntingtin gene but do not have symptoms, and also 
for people at early through to late stages of disease. HD-QoL can be used across the full 
spectrum of HD. 
HD-QoL will be assessed by both caregiver/informant and patient. All possible attempts should 
be made to assure that caregiver/informant will attend the clinical visits in person together with 
the patient. If the caregiver/informant is not available to attend the clinic visit, the 
caregiver/informant form should be omitted. 
6.3.5.2. 
EQ-5D-5L 
The EQ-5D 3 level version (EQ-5D-3L) was introduced in 1990 (EuroQoL Group, 1990). It 
essentially consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ 
VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. In developing the 5L, the 5-
dimensional structure of the original EQ-5D-3L was retained but the levels on each dimension 
were expanded to 5-levels based on qualitative and quantitative studies conducted by the 
EuroQol Group. The labels for each of the dimensions are: no problems, slight problems, 
moderate problems, severe problems and unable to/extreme problems. The EQ-VAS is still an 
integral part of the EQ-5D-5L but has been adapted to make it more user friendly. The 
respondent is asked to indicate his/her health state by ticking (or placing a cross) in the box 
against the most appropriate statement in each of the 5 dimensions. The EQ VAS records the 
respondent’s self-rated health on a vertical, visual analogue scale where the endpoints are 
labelled ‘Best imaginable health state’ and ‘Worst imaginable health state’. This information can 
be used as a quantitative measure of health outcome as judged by the individual respondents. It 
should be noted that the numerals 1-5 have no arithmetic properties and should not be used as a 
cardinal score. 
The EQ-5D-5L could be completed by the patients with caregiver assistance if needed. 
6.3.6. 
Change from baseline in WLQ at Month 12/ET (evaluated at baseline and 
Month 12) 
Huntington’s Disease imposes a substantial burden on patients in the form of impaired ability to 
perform productive activity such as paid employment, domestic household activity, or schooling. 
The WLQ captures a multidimensional look at work productivity. It is designed to measure 
productivity among workers who are employed, but may be performing at less than full capacity. 
It measures the degree to which health problems interfere with specific aspects of job 
performance and the productivity impact of these work limitations. The eight-item version will 
be used to reduce respondent burden (Lerner et al, 2001).  


 
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The work productivity will be assessed in all patients, also those with milder disease. 
However, if the patient is unemployed, this questionnaire will not be completed.  
The WLQ could be completed by the patients with caregiver assistance if needed.  
6.3.7. 
Change from baseline in HD-CAB sub-components at Month 12/ET (evaluated 
at baseline and Months 6 and 12) 
For a description of the HD-CAB sub-components, see Section 6.2.2. 
6.3.8. 
Change from baseline in CDR-SB at Month 12/ET (evaluated at baseline and 
Month 12) 
The Clinical Dementia Rating – Sum of Boxes (CDR-SB) is a widely used scale that has 
demonstrated validity and reliability in the longitudinal assessment of patients with cognitive and 
functional deficits that do not rise to the level of a diagnosis of overt dementia3. 
The utilization of CDR-SB scores for staging dementia severity offers several advantages over 
the global score because the optimal characteristics of both scores can be combined into a single 
score. First, CDR-SB scores are much simpler to calculate than the global score and they do not 
require an algorithm for computation, which will ultimately result in fewer calculation errors for 
those not using the online system. Second, CDR-SB scores can be treated as interval data in 
statistical analyses, whereas global CDR scores are ordinal by the nature of the algorithm 
approach to condensing the data. Finally, the most significant advantage to using CDR-SB scores 
for staging of dementia severity is the increased precision afforded for tracking changes across 
time (O'Bryant et al, 2008). 
The CDR is obtained through semistructured interviews of patients and informants, and 
cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and 
problem solving, community affairs, home and hobbies, and personal care. Each domain is rated 
on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, 
mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on 
a 4-point scale without a 0.5 rating available). The global CDR score is computed via an 
algorithm (Morris, 1993). The CDR-SB score is obtained by summing each of the domain box 
scores, with scores ranging from 0 to 18. 
Where possible, the same person should act as a patient’s caregiver/informant throughout the 
study. If this is not possible, a patient should have no more than 2 caregivers throughout the 
study. All possible attempts should be made to assure that caregiver/informant will attend the 
clinical visits in person together with the patient. If the caregiver/informant is not available to 
attend the clinic visit, the interview can be done over phone. 
 
                                                 
3 Food and Drug Administration (FDA) Guidance for Industry: Alzheimer's Disease: Developing Drugs for the 
Treatment of Early Stage Disease. Center for Drug Evaluation and Research (CDER). February 2013. 


 
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6.3.9. 
Change from baseline in HADS at Month 12/ET (evaluated at baseline and 
Month 12) 
The HADS (Zigmond and Snaith, 1983) is a 14 item (each item scored 0-3), self-administered 
rating scale that consists of two subscales assessing the presence and severity of depression (0–
21) and anxiety (0–21), with a global score of 0–42. It was designed to diminish the influence of 
somatic symptoms and consequently does not include items relating to the physical symptoms of 
depression and has a medium overall cognitive complexity. Completion time: 5–10 min. It has 
been validated in a study comprised of 50 patients with HD (De Souza et al, 2001).  
6.3.10. 
Change from Baseline in Problem Behaviors Assessment-Short Form (PBA-s) at 
Month 12/ET (Evaluated at Baseline and Month 12) 
Because of the prominence of psychiatric symptoms in HD, it is recommended that the PBA-s 
form be used in all HD studies with any need for behavioral assessment as a comprehensive 
screen for the most common psychiatric symptoms in HD (Craufurd et al, 2001; Kingma et al, 
2008). The PBA-s also includes questions concerning suicidal behavior, a particular concern in 
HD. The PBA-s is based on the same set of core behavioral symptoms as the UHDRS Behavioral 
questions, which were used previously as the global psychiatric measure in most HD studies. The 
PBA-s has more detailed questions and more specific guidance on administration and scoring. 
The PBA-s is a brief semi-structured interview with both the patient and the informant covering 
the most common behavioral and psychiatric manifestations of HD. The interview is not 
restricted to a single construct, but rather covers several broad symptom domains relevant to HD, 
comprising 11 items: low mood, suicidal ideation, anxiety, irritability, anger/aggressive 
behavior, loss of motivation, perseverative thinking or behavior, obsessive-compulsive 
behaviors, paranoid thinking, hallucinations, behavior suggestive of disorientation.  
Each symptom is rated for severity on a 5-point scale according to detailed scoring criteria which 
roughly correspond to the following: 0 = “not at all”; 1 = trivial; 2 = mild; 3 = moderate 
(disrupting everyday activities) and 4 = severe or intolerable. 
Each symptom is also scored for frequency on a 5-point scale as follows: 0 = symptom absent; 1 
= less than once weekly; 2 = at least once a week; 3 = most days (up to and including some part 
of every day); and 4 = all day, every day. Severity and frequency scores are multiplied to 
produce an overall ‘PBA score’ for each symptom. 
Where possible, the same person should act as a patient’s caregiver/informant throughout the 
study. If this is not possible, a patient should have no more than 2 caregivers throughout the 
study. All possible attempts should be made to assure that caregiver/informant will attend the 
clinical visits in person together with the patient. If the caregiver is not available to attend the 
clinic visit, the interview can be done over phone. 
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 9.6.2.  


 
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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 (including body weight and height measurements), and suicidality 
(as assessed by changes from baseline in C-SSRS scores) and premature discontinuations from 
the study. 
During the conduct of the study, an independent DSMB will review unblinded accumulating 
safety data on a regular basis to ensure the continuing safety of the study patients and study 
conduct issues. 
The DSMB will meet monthly until 40 patients from each study group (i.e. a total of 160 
patients) will have been exposed to their respective full dose for at least 3 months. Conditional 
on the absence of significant emerging safety concerns, enrolment in all the study arms will be 
approved to continue by the DSMB. The DSMB will then continue to meet at least bi-monthly, 
or as decided by the DSMB, throughout the study. The DSMB can call a meeting at any time 
based on safety concerns, and decisions about discontinuing patients, should that happen, will be 
explained in a report to all sites and patients.  
The DSMB will be composed of independent physicians with expertise in the relevant 
therapeutic field and other relevant experts, such as a statistician. The DSMB will receive safety 
data periodically in an unblinded fashion. They will have the right to recommend discontinuation 
of the study for safety reasons.  
DSMB sessions can be open or closed. During open sessions, representatives of the sponsor and 
the Steering Committee may be present and information is provided and discussed in a blinded 
fashion. During closed sessions, the only participants are members of the DSMB and the 
designated unblinded statistician (if approved to be present).  
The DSMB 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 subject 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 


 
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are present before study entry and do not worsen during the study will not be considered adverse 
events.  
New symptoms of HD or deterioration of previously existing symptoms 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 subject. 
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• 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 [e.g., 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 times the ULN, plus either bilirubin ≥2 times the ULN or 
International Normalized Ratio [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 1 month following the last dose of study medication 
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 


 
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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. 
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 
 


 
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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. 
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. 


 
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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 
Investigator’s Brochure. 
The sponsor’s Global Patient Safety & 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 
investigator within 24 hours of becoming aware of 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 subjects for adverse events once the study has 
ended. Serious adverse events occurring to a patient after the defined study period should be 
reported to the sponsor only 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 & Pharmacovigilance Department. 
The following information should be provided to record the event accurately and completely: 
• study number TV5600-CNS-20007 (LEGATO-HD) 


 
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• 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 sex 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) 
The investigator is responsible for ensuring that the IEC/IRB is also informed of the event, in 
accordance with local regulations. 
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.  
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 & 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.  


 
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The blinding will be maintained for the people who are involved directly in the study. Therefore, 
in case of a suspected unexpected serious adverse reaction (SUSAR), only the LSO/CRO 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 
similar to that for reporting a serious adverse event (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 (and 
IEC/IRB, if appropriate).  
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
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), cerebrovascular events (such as cerebral arterial occlusion, cerebral ischemia, 
etc), and deaths should be reported to the sponsor within 24 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 discontinue treatment at any time at the 
discretion of the investigator. If a patient discontinues treatment wholly or in part because of an 
adverse event, both the adverse events page and termination page of the CRF will be completed 
at that time.  
A complete final evaluation at the time of the patient’s withdrawal (Visit 8 procedures) should be 
made. In addition, a blood sample will be obtained for the measurement of study drug 
concentrations. The patient will be monitored at the discretion of the investigator (e.g., 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 clinical project physician/clinical leader (CPP/CL) 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 discontinues treatment for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 


 
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An exception to this requirement will be the occurrence of an adverse event which in the opinion 
of the investigator is not severe enough to warrant discontinuation but which 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 laquinimod or 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. 
Medication Error and Special Situations 
Any administration of study medication that is not in accordance with the study protocol should 
be reported on the CRF either as a violation, if it meets the violation criteria according to the 
protocol (Section 11.1.2), or as a deviation in the patients source documents, regardless of 
whether an adverse event occurs as a result. All instances of incorrect medication administration 
should be categorized as 'Non-Compliance to IMP'. 
Types of Medication Errors and/or special situations: 
1. Medication error - Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient or consumer. 
2. Overdose - Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. 
3. Misuse - Situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the authorized product information. 
4. Abuse - Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects. 
5. Off-label use - Situations where a medicinal product is intentionally used for a medical 
purpose not in accordance with the authorized product information. 
6. Occupational exposure- Exposure to a medicinal product, as a result of one’s professional 
or non-professional occupation. 
7.1.10. 
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 


 
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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  
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 occurs despite all recommended measures, all women of child-bearing 
potential (for example women who are not postmenopausal or have not undergone surgical 
sterilization) and not using acceptable methods of contraception, will be instructed about the 
teratogenicity and potential delayed risks for a child exposed in utero to laquinimod. These 
subjects will be counseled about the importance of using 2 acceptable methods of contraception 
throughout the entire study 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. 
Patients who are women of child-bearing potential must use 2 acceptable methods of 
contraception for 30 days prior to initiation of treatment, 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 (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. 
Additionally, monthly pregnancy tests (urine dipstick and/or serum pregnancy β-hCG test, as 
applicable per the relevant time point) will be performed. Early terminated subjects who are in 
the study for the purpose of follow-up will not be required to take the pregnancy tests if the last 
study drug dose was taken more than 30 days prior to the visit. 
All pregnancies of women participating in study and that occur during the study, or within 
30 days after the last dose of treatment was administered, are to be reported immediately to the 
individual identified in the clinical study personnel contact information section of this protocol, 
and the investigator must provide the LSO/CRO with the pregnancy form. The process for 
reporting a pregnancy is the same as that for reporting a serious adverse event (see 
Section 7.1.5.3).  
Any woman who becomes pregnant during the study will discontinue treatment. Subjects who 
become pregnant will be monitored for the outcome of the pregnancy (including spontaneous or 
voluntary termination. If the pregnancy continues to term, the outcome (health of the infant up to 
8 weeks of age), details of birth, and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the sponsor. Any 
complication of pregnancy during the study and any complication of pregnancy that the 
investigator becomes aware of after termination from the study will be reported as an adverse 
event or serious adverse event, as appropriate. 
If the pregnancy does not continue to term, 1 of the following actions will be taken: 


 
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• 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. 
7.3. 
Clinical Laboratory Tests  
All clinical laboratory test results outside of the reference range will be interpreted by the 
investigator as belonging to 1 of the following categories: 
• abnormal but not a clinically significant worsening 
• abnormal and a clinically significant worsening 
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up. 
Clinical laboratory tests (serum chemistry and hematology) will be performed at Visits 1-4 and 
6-9. Urinalysis will be performed at screening. When applicable per local requirements, patients 
will undergo an HIV test at screening. Also when applicable, patients will be screened for drug 
substances in urine and/or CDT level in blood at screening to confirm abstinence in former 
alcohol and/or drug abusers.  
Specific laboratory tests to be performed are listed below.  
7.3.1. 
Serum Chemistry 
The following serum chemistry tests will be performed at all scheduled visits: 
• calcium 
• phosphorus 
• sodium 
• potassium 
• chloride 
• bicarbonate and carbon dioxide 
• glucose 
• blood urea nitrogen (BUN) 
• creatinine (Note: Estimated creatinine clearance will be calculated at all in-clinic 
study visits.)  
• uric acid 
• ALT 
• AST 
• lactic dehydrogenase (LDH) 
• gamma-glutamyl transpeptidase (GGT) 
• alkaline phosphatase 


 
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• creatine phosphokinase (CPK) 
- In case of CPK results >ULN, troponin and creatine kinase MB isoenzyme 
(CK-MB) 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. 
• total protein 
• albumin 
• Fibrinogen 
• CRP  
• pancreatic amylase 
− Lipase will be tested in case of abnormal pancreatic amylase results 
• total bilirubin 
o Only if total bilirubin is elevated, the following tests will be performed: 
 direct bilirubin 
 indirect bilirubin 
• lipid profile [total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL), triglycerides] - at baseline and Month 12 only 
• thyroid function (T3, T4, TSH) – at baseline, Months 6 and 12 only 
7.3.2. 
Hematology 
The following hematology tests will be performed: 
• Hemoglobin 
• hematocrit 
• red blood cell (RBC) count  
• mean corpuscular volume (MCV) 
• red cell distribution width (RDW)  
• Mean platelet volume (MPV) 
• Reticulocytes (percentage and absolute count) 
• platelet count 
• white blood cell (WBC) count and differential count 
− polymorphonuclear leukocytes (neutrophils) 
− lymphocytes 
− eosinophils 
− monocytes 
− 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 


 
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• At baseline: B12, 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 >1g/dL from the patient's hemoglobin level at 
baseline: 
− - Subject will be re-tested to ascertain true 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. 
Urinalysis 
Urinalysis, performed at the screening visit, will include testing for the following: 
• protein 
• glucose 
• ketones 
• erythrocytes 
• leukocytes 
• pH 
7.3.6. 
Human Chorionic Gonadotrophin Tests  
Human chorionic gonadotropin (β-hCG) serum test will be performed for all women of child-
bearing potential (women who are not post menopausal or who have not undergone surgical 
sterilization) at screening (Visit 1) and at all subsequent study visits. Age-appropriate normal 
ranges for HCG should be used. If the reading for the serum pregnancy test is indeterminate, the 
test should be repeated after 3-4 days to see whether there is an increase in β-hCG or whether it 
is a stable elevation. If no increase is observed, the patient will not be considered to be pregnant. 
However, no study drug will be administered until this is resolved.  


 
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Urine β-hCG tests will be performed for all women of child-bearing potential at baseline (Visit 
2), and at all subsequent visits, and if clinically indicated at any other time. 
In addition, starting after Visit 3, a urine β-hCG test will be performed in women of child-
bearing potential every 28 (±2) days, by the patient at home, and recorded in the patient's 
medical records. The patient will be contacted by telephone within 72 hours after the scheduled 
test is to be performed and asked specific questions regarding the test. In case of suspected 
pregnancy (positive urine β-hCG test result), absence of menstruation or any other reason 
suggesting pregnancy), the caller will make sure that the study drug has been discontinued and 
the subject will be instructed to arrive to the site as soon as possible (within 10 days) with all 
remaining study drugs capsules. 
Any patient who becomes pregnant during the study will be withdrawn. Procedures for reporting 
the pregnancy are provided in Section 7.2.  
7.4. 
Vital Signs  
Vital signs will be measured at all in-clinic visits (Visits 1-4 and 6-9). Vital signs include the 
following: 
• pulse 
• blood pressure  
• body temperature 
Before pulse and blood pressure are measured, the patient must be in a supine position and 
resting for at least 5 minutes. The same position and arm should be used each time vital signs are 
measured for a given patient. For any abnormal vital sign finding, the measurement should be 
repeated as soon as possible. Any vital sign value that is judged by the investigator as a clinically 
significant change (worsening) from a baseline value will be considered an adverse event, 
recorded on the source documentation and transcribed onto the CRF, and monitored as described 
in Section 7.1.2. 
7.5. 
Electrocardiography  
A single 12-lead ECG will be conducted at screening (Visit 1), and at the following in-clinic 
visits: Week 4, Week 13, Week 26, Week 52 and follow-up (Visits 3, 4, 6, 8 and 9). During the 
baseline visit (Visit 2) a 12-lead ECG will be conducted in triplicate (approximately 10±5 
minutes apart). A qualified physician at a central diagnostic center will be responsible for 
interpreting the ECG. Any ECG finding that is judged by the site investigator as a clinically 
significant change (worsening) compared with a baseline value will be considered an adverse 
event, recorded on the source documentation and transcribed onto the CRF, and monitored as 
described in Section 7.1.2. 
7.6. 
Physical Examinations  
Physical examinations, including height (to be obtained at the screening visit only) and weight 
will be performed at all in-clinic visits (Visits 1-4 and 6-9). Any physical examination finding 
that is judged by the investigator as a clinically significant change (worsening) compared with a 


 
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baseline value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2.  
7.7. 
Estimated Creatinine Clearance Calculation 
Significant changes in laquinimod exposure, in particular in terms of unbound drug fraction, are 
predicted in patients with renal impairment (see Section 1.3.2.1). Consequently, estimated CrCl 
will be calculated at all visits to monitor chronic renal function in the study in order to identify 
patients with potentially impaired laquinimod clearance. Patients with a confirmed CrCl 
<60 mL/min/1.73 m2 should stop study medication temporarily, and the CrCl assessment should 
be repeated. If the renal impairment is confirmed (estimated CrCl <60 mL/min/1.73 m2), the 
patient should stop study medication permanently (see Section 3.6). 
Following recent findings connecting Gd-based contrast agents and nephrogenic systemic 
fibrosis, the estimated CrCl result should be available prior to the baseline MRI scan. Estimated 
CrCl calculation will be done in accordance with the central laboratory creatinine value 
measurement performed at the screening visit. The central laboratory will report calculated 
estimated CrCl; however, if the result is not available prior to the baseline MRI scan, estimated 
CrCl may be calculated using the Cockcroft-Gault equation (eg, available online CrCl calculator: 
http://reference.medscape.com/calculator/creatinine-clearance-cockcroft-gault). 
7.8. 
Cardiovascular Risk Assessment and Management 
Evaluation of major modifiable cardiac risk factors (eg, body mass index [BMI], diabetes, high 
blood pressure, hyperlipidemia, tobacco smoking) will be performed at the time points indicated 
in Table 3. In addition, an evaluation of cardiovascular risk factors should take place as soon as 
possible for patients already in the study, following approval of Global Amendment 04. 
Assessment of changes in cardiovascular risk and appropriate cardiovascular risk management 
with appropriate medical follow-up, if clinically indicated, should be performed during the 
scheduled and unscheduled visits. 
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  
7.9.1. 
Concomitant Therapy or Medication 
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3. 
7.9.2. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be used to rate the patient’s degree of suicidal ideation on a scale ranging from 
“no suicidal ideation” to “active suicidal ideation with specific plan and intent” (Posner et al, 
2011). The baseline screening version of the C-SSRS will be completed at screening (Visit 1). 
On subsequent visits (Visits 2-4 and Visits 6-9) The C-SSRS since last visit version will be 
completed. 


 
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Patients with active suicidal ideation, as measured by a score of 4 or 5 on the C-SSRS at the 
screening visit, will not be eligible for the study. 
A referral for psychiatric evaluation is required for any increase in the scale from baseline.  
In any event of suspected active suicidality (e.g. active suicidal ideation or intent, significant 
suicidal behavior) or clinical findings suggesting that the patient is dangerous to himself or 
herself, the patient should be referred for immediate psychiatric evaluation. 
7.9.3. 
Abdominal Computed Tomography Scan 
In case of pancreatitis or suspected pancreatitis, an abdominal computed tomography (CT) scan 
should be performed as soon as possible in order to clarify the diagnosis and enable assessment 
of severity of this condition.  
For complete guidance on monitoring subjects with elevated pancreatic amylase levels, see 
Appendix A (Section 7). 
7.10. 
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data  
Methods and timing of assessing safety data are discussed in Section 3.11. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
Section 9.8.2.  
Furthermore, all adverse events will be reviewed on a periodic basis (e.g., scheduled safety 
reviews for laquinimod) as safety data becomes available (see Section 7). 


 
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8. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACOGENOMICS/OTHER ANCILLARY STUDIES  
8.1. 
Pharmacokinetic Variables 
Samples will be analyzed for laquinimod and its metabolites using appropriate validated 
methods. Incurred sample reanalysis may be performed.  
8.1.1. 
Blood Sampling and Handling 
Whole blood samples (4 mL) will be collected via venipuncture in the morning for plasma 
concentration measurements of laquinimod and its metabolites as follows: 
PPK samples will be collected at visits at Months 1, 3, 6 and 12 from all subjects.  
PK samples of laquinimod and its metabolites will be collected from approximately 15 patients 
per each of the three continuing treatment groups (at selected sites at Month 1), for a total of 
approximately 45 patients, at the following timepoints – pre-dose, 15, 30 min and 1, 2, 3, 6 and 
24 hours post dose. Additionally, PK samples were collected from 2 patients in the laquinimod 
1.5 mg/day treatment group when the treatment was stopped; no further PK samples will be 
collected from the laquinimod 1.5 mg/day treatment group. 
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 for safety. 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.  
Samples will be collected into disodium ethylenediamine tetraacetate (Na2EDTA) Vacutainer 
tubes, inverted slowly 6 to 8 times to mix the contents, and placed on water/ice (~0-5°C). Blood 
samples will be centrifuged (2000g, ~10 minutes, 0°C-5°C) between 5 minutes and 1 hour after 
sampling. If a refrigerated centrifuge is not available, samples should be chilled before 
centrifugation. Other measures should be taken as appropriate to prevent samples from any 
heating during centrifugation. Separated plasma will be placed on water/ice (~0-5°C) and 
transferred in 3 portions (1 aliquot of 300 uL for laquinimod analysis and 2 approximately equal 
portions of ~750 uL for metabolite analysis) into 3 opaque, labeled, polypropylene tubes (sets A , 
B, and C respectively). Tubes will be placed in an upright position into frozen storage at nominal 
-70ºC (if -70ºC storage is not possible at the site, store at -20ºC) within 1 hour from the start of 
the centrifugation.  
Sample labels should include the study number, patient randomization number, period, nominal 
collection time, set (A B, or C), indication that they are pharmacokinetic samples, and an 
indication of storage conditions at the site (-70ºC or -20ºC).  


 
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8.1.2. 
Shipment of Samples 
Plasma samples for all patients will be shipped from the investigational center to the central 
coordinating laboratory, where they will be stored at nominal -70°C until shipped to 
Bioanalytical Laboratory of Teva Pharmaceutical Works Private Ltd. Co., Debrecen, Hungary 
for analysis. The bioanalytical laboratory will be notified before the shipment of the samples. 
Shipping information will be sent when the samples are shipped. 
Set A and B samples will be transported, frozen with sufficient dry ice for 4 days, by next-day 
courier to the bioanalytical laboratory.  
Set C samples will be sent to the same laboratory as that for sets A and B on subsequent days by 
next-day courier,.  
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend. 
8.2. 
Pharmacodynamic Variables 
Biomarker assessment will include the following: 
Cytokines, and other soluble proteins (or any other soluble marker) levels will be determined in 
plasma in order to better understand laquinimod mechanism of action and explore response 
predictive markers. 
Monocytes, which were shown to play an important role in laquinimod mechanism of action in 
preclinical studies, will be isolated from patients’ blood using cell separation method. Monocyte 
gene expression and/or protein profile will be explored. This experiment will help us understand 
the molecular mechanism of laquinimod in patients. This study will be performed only at 
selected sites in a subgroup of patients. 
TSPO is highly expressed in activated microglia which have been found to contribute to 
neuroinflammation in many types of CNS disorders. Change in microglial activation state, will 
be investigated. PET scans and imaging analysis of microglial activation marker TSPO will be 
performed. This study will be performed only at selected sites in a subgroup of patients. 
MRS will be performed in order to explore the potential effect on metabolic changes in the 
putamen and frontal white matter that are associated with the earliest stages of Huntington’s 
Disease. This study will be performed only at selected sites in a subgroup of patients. 
The above biological markers will also be used to aim to identify responders to laquinimod 
treatment, and explore response predictive markers, to potentially identify patients in which 
clinical benefits could be further investigated. 
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. 
8.2.1. 
Sampling and Handling 
Blood samples for Biomarker assessment:  


 
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• 8.5 mL blood samples for plasma cytokine and protein analysis will be collected from all 
subjects at Baseline, Months 6 and 12. 
• 50 mL whole blood samples for monocyte isolation will be collected at baseline and 
Month 12 only at selected sites in a subgroup of patients (aiming at 25 per treatment 
arm). The sample collection has to be done in accordance with the laboratory manual. For 
UK patients, the sample can be drawn prior to the baseline or Month 12 visit, as it 
coincides with the PET scan visits. 
Biomarker samples will be stored for a period of up to 15 years and then destroyed. 
8.2.2. 
Shipment and Analysis of Samples 
Plasma samples will be collected in BD P800 tubes (or equivalent) and will be transferred to -
70ºC within maximum 4 hours (if -70ºC storage is not possible at the site, store at -20ºC). Tubes 
will be sent to the central laboratory on dry ice. 
Analysis will be performed if and when required. Since new biomarker techniques continue to be 
developed, the method and laboratory that will be recommended for cytokine and protein 
analysis will be determined at a later stage. 
For monocyte isolation experiments - whole blood samples will be sent at ambient temperature 
as specified in the laboratory manual to the CRO.  
8.2.3. 
Magnetic Resonance Spectroscopy (MRS) 
The principal motivation for including MRS as an endpoint in this study will be to assess the 
potential effect of Laquinimod on metabolic changes in the putamen and frontal white matter that 
are associated with the earliest stages of Huntington’s Disease. The biochemical changes 
measured by MRS may be reversible and responsive to pharmacological intervention, making 
them a promising biomarker in HD.  
Previous studies by the Vancouver site investigators have demonstrated that the neuronal marker 
metabolite NAA exhibited significantly decreased concentrations in the putamen between 
controls and pre-HD, and between pre-HD and early-HD, and that these changes were robust, 
consistent, and had a low degree of variability when followed longitudinally over 24 months. 
The concentration of Myo-inositol (MI), a glial cell marker in the putamen was substantially 
increased in early HD vs pre-HD and controls (Sturrock et al, 2010).  
At selected sites, the MRS analysis will add two single voxel acquisitions to the MRI protocol in 
this study. The putamen and frontal white matter voxels will be collected using the same protocol 
that was used in the MRS study for the TRACK-HD study and will be described in detail in a 
separate imaging manual. The magnetic resonance (MR) spectra will be obtained using a single-
voxel PRESS localization sequence with a Repetition time (TR) of 2000ms, an Echo time (TE) 
of 35ms and 1024 points will be acquired. Sites with 3.0T Philips MRI scanners will be provided 
with a standardized ‘Exam Card’ (a precise specification of MR pulse sequence parameters). 
Two MRS voxels will be acquired. The first voxel will be the previous in the left putamen with a 
voxel size of 35 mm x 10 mm x 15 mm (5250 mm3). The second voxel will be placed in frontal 
white matter and will have a voxel size of 15 mm x 15 mm x 10 mm (2250 mm3).  
The MRS results will be analysed using LCModel, which is the most commonly used MRS data 
analysis package. Its advantages include the fact it is almost completely objective, it provides a 


 
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measure of confidence in the resulting concentrations and because it is used by so many groups 
worldwide, the analysed results are easier to compare with results from other MRS studies.  
Metabolite concentrations will be normalized to the unsuppressed water spectrum. Where 
possible, results will be corrected for T1 and T2 (uncoupled spins) relaxation using published 
times from the literature on normal brain, although at TE 35ms and TR 2000ms, these 
corrections are small. LCModel estimates the reliability of a “concentration” measurement and 
returns a standard deviation (%SD) for each metabolite. Standard deviations less than 20% are 
considered reliable and therefore any metabolite with a %SD greater than 20% will be excluded 
from further analysis. From the MR spectra, at least five metabolites of interest will examined: 
N-acetyl aspartate (NAA, a marker of neuronal integrity), Creatine (Cr, a marker of brain energy 
metabolism), total Choline (tCho, a marker for neuronal membrane turnover), Glutamate (Glu, a 
major CNS excitatory neurotransmitter) and Myo-inositol (MI, an astrocyte marker). 
Mean metabolite concentrations will be compared between treatment groups.  
8.2.4. 
PET Scan 
At selected sites, patients will be referred to the Imperial College in London, where PET Imaging 
will be performed at the Imanova Imaging Centre on the Hammersmith Hospital site. The PET 
imaging will be performed at baseline and after treatment with laquinimod over a 12–month 
period of time. 
All patients participating in the PET arm of the study will be exposed to additional ionizing 
radiation due to the PET/CT scans. There are no alternatives methods available to explore 
neuroinflammation in vivo. While any ionizing radiation exposure increases the risk of future 
malignancy, for the radiation exposure in this study such exposure is small and the increased risk 
is minimal. Patients who recently took part in clinical studies or underwent medical procedures 
involving ionizing radiation, such that participation in this study would lead to an exposure of 
>10mSv in the last 12 months, will be excluded from participation in this ancillary study. This 
will not affect the patient's participation in the main study. 
The 18-kDa TSPO is expressed within microglia and macrophages and has been used as a target 
for PET ligands to study neurodegenerative disease processes that involve microglial activation, 
such as HD, Parkinson’s disease (PD) and Alzheimer's disease (AD) (Politis et al, 2012). The 
PET radioligand 11C-PK11195 has been used most frequently for this purpose, but signal 
quantification is limited by poor specific signal-to-background ratio.  
11C-PBR28 is a second generation radioligand with high affinity to TSPO, favourable in vivo 
kinetics, and greater signal-to-noise ratio than 11C-(R)-PK 11195 (Fujita et al, 2008; Imaizumi et 
al, 2008; Kreisl et al, 2010; Kreisl et al, 2013). 
One limitation of 11C-PBR28, shared by all tested second generation TSPO radioligands 
(including 11C-DAA1106), is differential affinity for the target protein (Owen et al, 2011). This 
differential affinity is caused by the rs6971 polymorphism on the TSPO gene that causes a non-
conservative amino acid substitution, resulting in three patterns of TSPO binding (Owen et al, 
2012). Subjects without the polymorphism (HH) have high affinity binding for PBR28, 
homozygotes (LL) have low affinity binding, and heterozygotes (HL) express both high and low 
affinity TSPO (mixed-affinity binding). Low affinity subjects are easily identified by PET due to 
negligible 11C-PBR28 binding in vivo; however, PET cannot easily resolve the difference 


 
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between high and mixed-affinity subjects. Previous work demonstrated that correcting in vitro 
binding data for rs6971 genotype improves the ability of 3H-PBR28 to detect differences in 
TSPO density (Kreisl et al, 2013). This simple strategy of TSPO genotype correction to PET 
imaging will be used in the present study. 
This will be the first trial to assess in vivo changes in TSPO following a treatment aimed to 
reduce microglia activation. As such it will be an exploratory, ancillary, study. Previous PET 
studies looking at baseline increases of microglia activation in HD patients compared to normal 
volunteers have found significant differences even in small groups of patients (11 HD vs 10 
normal volunteers, striatal differences in TSPO binding p=0.001). 
Not all benzodiazepines have been tested for TSPO binding. Patients taking benzodiazepines 
should be instructed to stop taking them for 3 days prior to having the PET scan. 
8.2.4.1. 
Collection of Genotyping Samples 
Genomic DNA will be collected at the screening visit as described in Section 8.3.1 and used to 
genotype the rs6971 polymorphism within the TSPO gene on chromosome 22q13.2 (Owen et al, 
2011; Kreisl et al, 2013). 
Patients who have A/A genotype for rs6971 polymorphism on the TSPO gene, which has been 
shown to result in low affinity binding (LAB) of the 11C-PBR28 radioligand, will be excluded 
from the PET ancillary study. Patients with LAB for TSPO can participate in the main study 
even if they are excluded from the PET ancillary study. Patients with G/G and A/G rs6971 
genotype have been shown to have high (HAB) and mixed (MAB) affinity binding, respectively, 
and will be included in the PET ancillary study. 
8.2.4.2. 
Scanning Procedures 
For women of child-bearing potential, a urine pregnancy test will be performed on the same day, 
and prior to, the PET scan at Imperial College in London. If the result of this test is positive, the 
PET procedure will not be performed and the patient will be monitored as outlined in 
Section 7.2.  
Specific activity, chemical purity, and radiochemical purity of 11C-PBR28 will be determined by 
radio high performance liquid chromatography (HPLC) coupled with a gamma detector. Specific 
activity will be determined by counting an aliquot in a dose calibrator and determining the mass 
by HPLC against a calibration curve of the cold standard. Identity will be confirmed by co-
injecting the standard.  
Approximately 400 MBq of 11C-PBR28 as intravenous bolus will be injected, and an 
approximately 90 minutes emission PET-CT scan will be acquired on a Siemens HiRez 6 
PET/CTI scanner (Siemens Healthcare, Erlanger, Germany). A low dose CT scan of the head 
will be performed immediately before each PET study for subsequent attenuation and scatter 
correction of PET signal. Imaging data will be reconstructed with filter backprojection (direct 
inversion Fourier transform) with a 128 matrix, a zoom of 2.6, a transaxial Gaussian filter of 5 
mm, scatter correction and attenuation correction. All subjects will have a volumetric T1-
weighted MR sequence for co-registration purpose with PET images. 
Patients will be advised that they should not participate in further research studies involving 
ionizing radiation for a year following the last performed scan.  


 
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8.3. 
Pharmacogenomic Variables 
It is recognized that genomic variation within the population can be an important contributory 
factor to inter-individual differences in drug response. Pharmacogenomic (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. PGx assessment will include CAG repeats analysis in huntingtin gene and 
might also include other DNA variations and RNA expression patterns potentially associated 
with clinical treatment responses to laquinimod (e.g. 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 in 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. 
PGx assessment will be performed if variability in response measurements is observed and 
attributable to genomic parameters. Samples might be used for investigations related to CNS 
disorders diseases and/or response to laquinimod or related investigational drugs. 
8.3.1. 
Methods and Timing of Pharmacogenomic Blood Sampling 
PGx assessment will be performed using blood samples.  
• Blood samples for DNA extraction will be collected at screening (or if not possible, at 
the next possible visit) in two 5.0 mL K3 EDTA Vacutainer plastic tubes (or 
equivalent).  
• Blood samples for gene expression analysis (RNA extraction) will be collected at 
baseline, Month 6 and Month 12 from all subjects in PAXgene RNA 10 mL tubes (or 
equivalent). 
PGx samples will be stored for a period of up to 15 years from patient last visit in the main study 
and then destroyed. 
8.3.2. 
Shipment of Samples 
PGx samples will be stored at -70ºC (if -70ºC storage is not possible at the site, store at -20ºC) 
and sent to the central laboratory on dry ice. Following DNA and RNA extractions, the samples 
will be stored at–70ºC and labeled with a new code, so genomic data will not be recorded with 
subject number or initials. Data will be kept confidential and stored separately. 
The PGx sample analyses will be performed if and when required. Since new PGx techniques 
continue to be developed, we cannot anticipate the method and laboratory that will be 
recommended for the DNA/RNA analysis. 


 
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9. 
STATISTICS  
9.1. 
Study Design and Randomization 
This is a double-blind, randomized, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of laquinimod (0.5 mg and 1.0 mg qd) treatment in patients with HD. Prior to 
10 January 2016, eligible patients were randomly assigned to receive treatment with laquinimod 
at a dosage of 0.5 mg, 1.0 mg, or 1.5 mg/day or a matching placebo in a 1:1:1:1 ratio. 
Randomization will be as described in Section 3.3. 
As of 10 January 2016, following a decision to discontinue treatment of the laquinimod 1.5 mg 
dose arm, future eligible patients will be randomized in a 1:1:1 ratio to receive laquinimod 0.5 
mg/day or 1.0 mg/day or matching placebo for 52 weeks.  
No change was performed to the original randomization list except that the patient numbers 
assigned to laquinimod 1.5 mg/day were removed from the list by the IRT vendor. Patients and 
investigators will remain blinded to treatment assignment during the study.  
All patients who discontinued the 1.5 mg/day dose have been unblinded. No attempts will be 
made to re-randomize patients whose 1.5 mg treatment was stopped to a lower dose of 
laquinimod. The remaining ongoing patients retained their originally randomized treatment 
assignments. 
9.2. 
Sample Size and Power Considerations 
The study aims to detect potential beneficial effects in deteriorating clinical signs and symptoms. 
Based on previous studies in patients with HD, the UHDRS-TMS has been shown to be one of 
the more sensitive clinical measures to detect decline in symptoms of HD. It is estimated that 
approximately 100 patients per arm will enable a power of 80% to detect a beneficial effect 
compared to placebo, of 2.5 points or more in the change from baseline in UHDRS-TMS of an 
active laquinimod arm, assuming SD of 6.2 and type I error of 5%. 
As the intention is to investigate laquinimod as a treatment with the potential to slow disease 
progression and prohibit neuronal death in the CNS, the study should also be sized to be able to 
detect changes in brain atrophy rate after treatment with laquinimod. One of the most sensitive 
measures to detect brain atrophy over time in patients with HD is change in the caudate volume.  
It is estimated that approximately 100 patients per arm will enable a power of 80% to detect a 
beneficial effect of 0.95 (30% of the estimated decline in placebo) or more in the percent change 
from baseline in caudate brain atrophy of an active laquinimod arm compared to placebo, 
assuming SD of 2.36 and type I error of 5%. 
9.3. 
Analysis Sets/Populations  
Due to the decision from 10 January 2016 to discontinue treatment of the laquinimod 1.5 mg 
dose arm, and the low number of enrolled patients compared to the target at this time, data from 
the laquinimod 1.5 mg dose arm will be presented descriptively only and will not be included in 
any inferential analyses for efficacy or safety. 


 
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9.3.1. 
Intent-to-Treat 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. 
Safety Population 
The safety 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.  
9.3.3. 
Full Analysis Set (FAS) 
The full analysis set (FAS) will include all patients in the ITT population who receive at least 
1 dose of study drug and have at least 1 post-baseline efficacy assessment.  
9.4. 
Data Handling Conventions 
For all variables, only the observed data from the patients will be used in the by visit summary.  
For efficacy endpoints that are measured at baseline and at month 12 only, the Last Observation 
Carried Forward (LOCF) method will be applied for early terminated patient observation. 
Detailed data imputation rule will be specified in the statistical analysis plan. 
9.5. 
Study Population 
The ITT population will be used for all study population summaries unless otherwise noted. 
Summaries will be presented by treatment group and for all patients.  
The Safety population will be used for safety variables.  
The FAS will be used for efficacy variables. 
9.5.1. 
Patient Disposition 
Data from patients screened, patients screened but not treated, patients in the safety population 
and FAS, patients who complete the study, and patients who withdraw from the study will be 
summarized using descriptive statistics. Data from patients who withdraw from the study will 
also be summarized by reason for withdrawal using descriptive statistics. 
9.5.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics will be examined to assess the comparability of 
the treatment groups and will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number, mean, SD, 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. 


 
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9.6. 
Efficacy Analyses  
9.6.1. 
Efficacy Variables 
9.6.1.1. 
Primary Efficacy Variable and Endpoint 
The primary efficacy variable and endpoint for this study is the change from baseline in the 
UHDRS-TMS (defined as the sum of the scores of all UHDRS-TMS subitems) at Month 12/ ET 
(evaluated at baseline and Months 1, 3, 6 and 12) 
9.6.1.2. 
Secondary Efficacy Variables and Endpoints 
The secondary efficacy variables and endpoints for this study are: 
• Percent change from baseline in caudate volume at Month 12/ET (evaluated at 
baseline and Month 12) 
• Change from baseline in HD-CAB total score (sum of the standardized sub-
components) at Month 12/ET (evaluated at baseline and Months 6 and 12)  
• CIBIC-Plus global score at Month 12/ET (evaluated at Months 6 and 12) as compared 
to baseline (rated by an independent investigator) 
• Change from baseline in UHDRS- TFC at Month 12/ET (evaluated at baseline, 
Months 6 and 12) 
9.6.1.3. 
Exploratory Efficacy Variables and Endpoints 
• Change from baseline in brain atrophy as defined by the percentage change in volume 
in: whole brain volume and white-matter volume at Month 12/ET and absolute 
change in ventricular volume at Month 12/ET (evaluated at baseline and Month 12) 
• Change from baseline in UHDRS- FA at Month 12/ET (evaluated at baseline and 
Months 6 and 12)  
• Change from baseline in Q-Motor assessments at Month 12/ET (evaluated at baseline 
and Months 1, 3, 6 and 12) 
• Change from baseline in mPPT at Month 12/ET (evaluated at baseline and Months 6 
and 12) 
• Change from baseline in HD QoL and EQ-5D-5L at Month 12/ET (evaluated at 
baseline and Month 12) 
• Change from baseline in WLQ at Month 12/ET (evaluated at baseline and Month 12) 
• Change from baseline in HD-CAB sub-components at Month 12/ET (evaluated at 
baseline and Months 6 and 12):  
Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail Making Test, 
Hopkins Verbal Learning Test, revised (HVLT-R), Paced Tapping at 3 Hz, One 
Touch Stockings of Cambridge (OTS, abbreviated 10 trial version) 
• Change from baseline in CDR-SB at Month 12/ET (evaluated at baseline and Month 
12)  
• Change from baseline in HADS at Month 12/ET (evaluated at baseline and Month12) 
• Change from baseline in PBA-s at Month 12/ET (evaluated at baseline and Month 12) 


 
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9.6.1.4. 
Pharmacodynamic Analyses  
• Change from baseline in microglial activation marker TSPO at Month 12/ET  
• Change from baseline in brain MRS metabolite markers of neuronal integrity (NAA) 
and striatal astrocytosis (myo-inositol) at Month 12 in putamen and frontal white 
matter 
• Change from baseline in soluble biomarkers at Months 6 and 12  
• Change from baseline in monocyte gene expression and/or proteomic profile at 
Month12. 
9.6.2. 
Planned Method of Analysis 
The full analysis set (see Section 9.3) will be used for all efficacy analyses. Summaries will be 
presented by treatment group.  
9.6.2.1. 
Primary Efficacy Endpoint Analysis 
The change from baseline in UHDRS-TMS, will be analyzed using a Repeated Measures model 
(SAS® MIXED procedure with REPEATED sub-command). The model will include the 
following fixed effects: categorical week in trial by treatment interaction, center, and 
UHDRS-TMS at baseline. The unstructured covariance matrix for repeated observations within 
patients will be used. In case that the model will not converge, the Maximum-Likelihood (ML) 
estimation method will be used instead of the default Restricted ML (REML). If the model still 
does not converge then a simpler covariance structures with less parameters will be used, 
according to the following order: Heterogeneous Autoregressive(1) [ARH(1)], Heterogeneous 
Compound Symmetry (CSH), Autoregressive(1) [AR(1)], and Compound Symmetry (CS). The 
estimated mean changes from baseline at the Month 12//Early Termination visit will be 
compared between the active treatment arms and the placebo arm. 
The Hochberg’s Step-Up method for multiple comparisons between treatment arms will be used 
to control inflation in type I error rate. 
9.6.2.2. 
Secondary Efficacy Endpoints Analyses 
According to the hierarchical method to control inflation in type I error rate for multiple 
endpoints, any statistically significant dose that will be observed in the primary analysis will 
continue to be tested for the secondary endpoints at an alpha level of 5%, according to the 
secondary endpoints order. 
The secondary efficacy endpoints: change from baseline in HD-CAB total score and change 
from baseline in UHDRS- TFC, will be analyzed in the same way as the primary efficacy 
endpoint except that the efficacy endpoint evaluation at baseline will be included in the model 
instead of baseline UHDRS-TMS.  
The CIBIC-Plus will be analyzed in the same way as the primary efficacy endpoint except that 
the baseline CIBIS (Clinician’s Interview-Based Impression of Severity) will be included in the 
model as the efficacy measure at baseline. 
The percent change from baseline to Month 12/Early Termination in caudate volume will be 
analyzed using an Analysis Of Covariance (ANCOVA) model (SAS® MIXED procedure). The 
model will include the following fixed effects: treatment, center, and caudate volume at baseline. 


 
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The estimated means at the Month 12 visit will be compared between the active treatment arms 
and the placebo arm. Early terminated patient observation will have their Last Observation 
Carried Forward (LOCF). 
9.6.2.3. 
Exploratory Efficacy Endpoints Analyses 
The exploratory efficacy endpoints will be analyzed in the same way as the primary efficacy 
endpoint except that the efficacy endpoint evaluation at baseline will be included in the model 
instead of baseline UHDRS-TMS. 
The change from baseline to Month 12/Early Termination of continuous efficacy endpoints that 
are measured at baseline and at month 12 only, will be analyzed using an ANCOVA model 
(SAS® MIXED procedure). The model will include the following fixed effects: treatment, 
center, and the efficacy measure at baseline. The estimated means at the Month 12 visit will be 
compared between the active treatment arms and the placebo arm. Early terminated patient 
observation will have their Last Observation Carried Forward (LOCF). 
9.6.2.4. 
Sensitivity Analysis 
No sensitivity analyses are planned for this study.  
9.6.2.5. 
Pooling of Small Centers 
Centers with low number of patients will be pooled according to geographical region. 
Details will be provided in the Statistical Analyses Plan (SAP). 
The pooled center variable will be used in all statistical models that include center as covariate. 
9.7. 
Multiple Comparisons and Multiplicity 
The Hochberg’s Step-Up method for multiple comparisons between treatment arms in 
combination with the hierarchical method between the primary efficacy endpoint and the 
secondary efficacy endpoints, will be used to maintain the experiment wise type I error of 5% 
level. First, the Hochberg method will be applied for the comparisons of the 2 active doses to 
placebo in the primary endpoint analysis. Then, using the hierarchical method, any statistically 
significant dose will continue to be tested for the secondary endpoints at an alpha level of 5% 
and according to the order of the secondary endpoints. 
9.8. 
Safety Variables and Analysis 
9.8.1. 
Safety Variables 
Safety variables and endpoints will include the following:  
• Adverse events reports throughout the study 
• ECG findings throughout the study 
• Clinical safety laboratory tests throughout the study 
• Vital signs measurements throughout the study 
• Physical examination findings throughout the study 
• Changes from baseline suicidality (C-SSRS) scores throughout the study 


 
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Tolerability variables:  
• Proportion of subjects (%) who prematurely discontinued from the study, reason of 
discontinuation and the time to ET 
• Proportion of subjects (%) who prematurely discontinued from the study due to AEs 
and the time to ET 
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 
withdrawal from the study. Summaries will be presented by treatment group and for all patients. 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented. 
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. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug. 
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. 
Descriptive summaries of serious adverse events, patient withdrawals due to adverse events, and 
potentially clinically significant abnormal values (clinical laboratory or vital signs) based on 
predefined criteria will also 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 and Pharmacodynamic Analysis 
9.9.1. 
Pharmacokinetics (PK) Ancillary Study 
 
PK samples of laquinimod and its metabolites will be collected from approximately 15 patients 
per each of the three continuing treatment groups (at selected sites at Month 1), for a total of 
approximately 45 patients. Additionally, PK samples were collected from 2 patients in the 
laquinimod 1.5 mg/day treatment group when the treatment was stopped; no further PK samples 
will be collected from the laquinimod 1.5 mg/day treatment group. 
Samples will be collected at pre-dose, 15, 30 min and 1, 2, 3, 6 and 24 hours post dose.  
Steady state pharmacokinetic parameters for laquinimod (AUCtau, Cmax and Cmin, tmax), will be 
calculated for each patient. 


 
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Additional parameters for laquinimod and pharmacokinetic parameters for its metabolites may 
be calculated if data permit. 
The time of the previous dose as well as deviations from the blood sampling times will be 
recorded in the appropriate eCRF. Patients performing the 24 hours PK profile will come to the 
clinic after an overnight fast (minimum of 8 hours) and will be given breakfast 4 hours after drug 
administration. 
The morning dose and the 24 hours dose administration (the day after) will take place at the 
clinic. 
9.9.2. 
Population PK (PPK) Study 
A single blood sample will be collected from all patients at months 1, 3, 6 and 12 for evaluation 
of laquinimod and its metabolites.  
Pharmacokinetics of laquinimod will be evaluated using a Population PK approach. The effect of 
covariates on the PK of laquinimod will be evaluated. Possible covariates will include 
demographic variables (e.g. age, gender, body weight and ethnicity), clinical variables (e.g. CAG 
repeat length), concomitant medications, blood and urine chemistry variables and markers of 
renal function (creatinine clearance and serum creatinine). 
Pharmacokinetic parameters for laquinimod metabolites may be calculated if data permit. 
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 for safety 
(see Section 8.1). 
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 eCRF. 
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. 


 
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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 (e.g., medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with local requirements. 
Each investigator must maintain, at all times, the original records (ie, source documents) of each 
patient’s data. 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, diary data, protocol required worksheets, and CRFs that 
are used as the source (see Section 3.9). 
Each 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. 


 
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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 and local competent 
authorities as applicable, 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 documented approval 
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 (e.g., 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. 


 
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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 SOPs, the protocol, and other written instructions and regulatory 
guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor are to visit the 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 monitor will contact the 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. The 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 


 
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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 


 
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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. 


 
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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. 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. Patients with a legal guardian should be 
consented according to local requirements. 
Patients participating in ancillary studies will provide written informed consent specific to that 
study. 
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 personal 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 recorded on 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, such as Canada, local regulations will be followed. 


 
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12.5. 
Registration of the Clinical Study  
This clinical study will be registered on clinical trials registry websites according to local 
regulations and in compliance with Teva standard procedures. 


 
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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 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. Subsequent to the training, the users will be provided with 
individual system access rights. 
Data will be collected at the study center by appropriately designated and trained personnel, and 
CRFs must be completed for each patient who provided informed consent according to the data 
source. The patient’s 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 study center. This approval acknowledges the investigator’s 
review and acceptance of the data as being complete and accurate.  
If data are processed from other institutions (e.g., central laboratory, central image center, 
electronic diary data), the results should be sent to the study center, where they are 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 added to 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 worldwide regulatory guidelines (e.g., 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 ad needed. Data from external sources will be compared with the 
information available in the CDMS. Discrepancies found will be queried. 


 
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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. The system 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 [Section 3.9], data 
results from other institutions [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 case 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 (e.g., 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 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 prior to 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 study centers for archiving.  


 
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14. 
FINANCING AND INSURANCE  
A separate financial agreement will be made between the principal investigator and/or institution 
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.  


 
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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 and regulations 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. 


 
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16. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENTS 
16.1. 
GLOBAL PROTOCOL AMENDMENT 04 DATED 16 FEBRUARY 
2016 
The primary reason for this global amendment was to discontinue treatment for patients 
receiving 1.5 mg laquinimod as a proactive safety measure, and to implement additional safety 
measures to help ensure the safety of patients (both ongoing patients and those still to be 
enrolled) receiving 0.5 mg/day or 1.0 mg/day laquinimod or placebo. To avoid increased 
exposure to laquinimod, stopping rules have been introduced for renal impairment and hepatic 
impairment, with additional assessments of estimated creatinine clearance introduced for 
increased monitoring of renal function.  
Table 3 (Study Procedures and Assessments) has been revised to reflect changes described 
below. An additional study schema (Figure 2) has been included to reflect the amended study 
design. 
The statistical analysis sections were updated accordingly, and the risks and benefits sections of 
the protocol have also been updated to reflect the new findings observed in the MS trials.  
Additional clarifications related to study conduct were implemented in this amendment. These 
include (not all inclusive) clarifications regarding determination of eligibility of patients with 
exclusionary variance from historical CAG repeat results, testing of both troponin and CK-MB in 
case of creatine phosphokinase levels above the upper limit of the normal range to provide 
additional cardiovascular assessment, and adjustment of blood volume collected to allow for 
unscheduled visits. 
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 by the sponsor’s 
Authorized Representative will be dependent on the region and will be indicated in the covering 
letter or application form that accompanies the amendment in that region. 
A comparison table showing substantive changes from Amendment 03 to Amendment 04 is 
provided below. Previous text is presented in the column titled “Original text with changes 
shown", and the revised or new text is presented in the column titled "New wording". Revised or 
new text is shown in bold italics and deletions are shown in strikethrough. A few formatting and 
editing changes have also been made but are not detailed below. 
Where appropriate, the informed consent form will be amended to reflect the changes introduced 
into the protocol. 
The administrative letters #6 (dated 22 October 2015) and #7 (dated 05 November 2015) have 
also been added to the summary of changes section. The content of the administrative letters has 
been implemented in protocol Amendment 03 as applicable. 
 
 


 
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Original text with changes shown 
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Reason/Justification 
for change 
TITLE PAGE  
Sponsor’s Medical Expert  
  
Teva Branded Pharmaceutical Products R&D, Inc. 
 
Sponsor’s Medical Expert  
Teva Branded Pharmaceutical Products R&D, Inc. 
 
Change of personnel 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
USA 
Change of personnel 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AKI – Acute kidney injury 
AKI – Acute kidney injury 
New abbreviation. 
CrCl – Creatinine Clearance 
CrCl – Creatinine Clearance 
New abbreviation. 
qd – once daily 
qd – oncedaily 
New abbreviation. 
BMI – body mass index 
BMI – body mass index 
New abbreviation 
DMC– Data Monitoring Committee 
DMC– Data Monitoring Committee 
New abbreviation 
MoA- Mode Mechanism of Action 
MoA- Mechanism of Action 
Correction of 
terminology. 
1 BACKGROUND INFORMATION 
Section 1.1 
Laquinimod is developed by Teva Pharmaceutical Industries, Ltd. for 
Multiple Sclerosis (MS), Crohn’s Disease (CD), and Systemic Lupus 
Erythematosus (SLE) and HD. The precise mechanism of action of 
laquinimod in MS is still under investigation. Available data support that 
laquinimod, is an immunomodulator that acts both on the peripheral immune 
system and within the central nervous system (CNS) on resident 
immunocompetent cells. The data collected to date suggests that laquinimod 
(i) reduces the levels of proinflammatory cytokines such as TNFα; (ii) 
reduces inflammation within the CNS; (iii) down regulates genes involved 
in inflammation and antigen presentation; and (iv) modulates T cell 
responses via a direct effect on antigen presenting cells, and skews 
Laquinimod is developed by Teva Pharmaceutical Industries, 
Ltd. for Multiple Sclerosis (MS) and HD. The mechanism of 
action (MoA) of laquinimod includes modulation of the 
peripheral inflammation and central nervous system (CNS)-
resident inflammatory response resulting in down regulation 
of myelin and axonal damage. These effects are compatible 
with interference of NF-κB activation and may represent a 
novel protective mechanism which down regulates peripheral 
inflammation, CNS inflammation, tissue damage, and 
neurodegeneration in CNS diseases that involve microglia 
and astrocytic activation, like MS and HD. Recently 
The CD and SLE 
indications are no 
longer pursued.  
 
Introduction revised 
for consistency with 
the IB. 


 
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monocytes to a regulatory phenotype. The presumed mechanism by which 
laquinimod exerts this effect is down regulation of both astrocytic and 
microglial pro inflammatory response mediated by interference with the 
NF κB pathway, investigated in experimental autoimmune 
encephalomyelitis (EAE) and the Cuprizone models of demyelination 
(Wegner et al, 201045; Bruck et al, 201246; Aharoni et al, 201247). The 
mechanism of action (MoA) of laquinimod includes modulation of the 
peripheral inflammation and central nervous system (CNS)-resident 
inflammatory response resulting in down regulation of myelin and axonal 
damage. These effects are compatible with interference of NF-κB 
activation and may represent a novel protective mechanism which down 
regulates peripheral inflammation, CNS inflammation, tissue damage, 
and neurodegeneration in CNS diseases that involve microglia and 
astrocytic activation, like MS and HD. Recently performed studies show 
that the aryl hydrocarbon receptor (AhR) pathway is involved in the 
efficacy of laquinimod in the experimental autoimmune encephalomyelitis 
(EAE) model. Further investigations are ongoing, assessing the role of 
AhR in the MoA of laquinimod. 
Further, laquinimod was shown to cause a weak decrease of CYP3A4 
activity and is a strong inducer of CYP1A enzymes. CYP1A induction is a 
biomarker of activation of the AhR transcription factor; activation of this 
pathway by laquinimod has been demonstrated. 
Studies investigating laquinimod’s mode of action have suggested that 
treatment with laquinimod interferes with the NF kB pathway results in 
immunomodulation, including modulation of the cytokine balance and 
reduction of inflammation. Laquinimod is not a general immunosupressor, 
nor immunotoxic, but treatment with laquinimod results in a shift in the 
cytokine balance towards reduced pro inflammatory cytokine production, 
induction of regulatory monocytes, reduced astrogliosis, and reduced 
infiltration to inflammatory target tissues, as demonstrated in animal models 
of MS and CD.  
... 
performed studies show that the aryl hydrocarbon receptor 
(AhR) pathway is involved in the efficacy of laquinimod in 
the experimental autoimmune encephalomyelitis (EAE) 
model. Further investigations are ongoing, assessing the role 
of AhR in the MoA of laquinimod. 
Further, laquinimod was shown to cause a weak decrease of 
CYP3A4 activity and is a strong inducer of CYP1A enzymes. 
CYP1A induction is a biomarker of activation of the AhR 
transcription factor; activation of this pathway by laquinimod 
has been demonstrated. 
... 
 
Section 1.3.1. 
Laquinimod was shown to cause a weak decrease of CYP3A4 activity and is 
a strong inducer of CYP1A enzymes. 
Laquinimod was shown to cause a weak decrease of CYP3A4 
activity and is a strong inducer of CYP1A enzymes.  
Clarification 
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 pharmacology studies in the rat and dog did not 
demonstrate significant effects of laquinimod on the function 
of cardiovascular, respiratory, central nervous, renal and 
Reflecting that 1.5 mg 
is no longer an 
intended clinical dose 


 
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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. 
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. 
(changed 
several other times in 
this section) 
In addition, an increase in the incidence of oral cavity tumors was noted in 
mid and high dose females (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 with 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-5211) 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-5842). 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., including industrial chemicals (such as 2,3,7,8
tetrachlorodibenzo p dioxin [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. 
In addition, an increase in the incidence of oral cavity tumors 
was noted in mid and high dose females (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-5211) 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-5842). No increased incidence of oral 
tumors was seen in humans exposed to TCDD, indicating a 
species specific response in rats. Therefore, oral cavity tumors 
induced by laquinimod in rats after a lifelong exposure do not 
imply an elevated carcinogenicity risk in humans. Humans, in 
general, also seem to be less sensitive to AhR activation by 
laquinimod than rats, as shown by the differential gene 
expression profiles discussed in the IB.  
Section updated in 
accordance 
with Investigator’s 
Brochure 


 
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for change 
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-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. 
Reference to report in 
newly-added text in 
the non-clinical 
section. 
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. 
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. 
Reference to report in 
newly-added text in 
the non-clinical 
section. 
Section 1.3.2.1 
Laquinimod is extensively metabolized predominantly by CYP3A4. 
Laquinimod metabolites levels in plasma are very low and parent 
laquinimod is the main systemically circulating entity. Laquinimod PK is 
affected by moderate and strong CYP3A4 inhibitors (2.5- and 3.1-fold 
increase in laquinimod systemic exposure, respectively,) and strong 
CYP3A4 inducers and moderate hepatic impairment. Studies have shown 
that laquinimod is a strong inducer of CYP1A2 and a weak inhibitor of 
CYP3A4. Therefore, co-administration of laquinimod may affect the 
systemic exposure of drugs metabolized by CYP450 1A2 or CYP3A4. 
... 
Studies in subjects with mild and moderate hepatic impairment resulted in 
an increase of laquinimod exposure by approximately 1.3- and 2.3-fold, 
respectively. In subjects with moderate renal impairment, laquinimod 
exposure was increased by 1.4-fold. A physiologically based 
pharmacokinetic model was further used to predict the effect of hepatic 
impairment and renal impairment on the pharmacokinetics of laquinimod 
after single and multiple doses of 0.6 to 1.5 mg in comparison with 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 
Laquinimod is extensively metabolized predominantly by 
CYP3A4. Laquinimod metabolites levels in plasma are very 
low and parent laquinimod is the main systemically 
circulating entity. Laquinimod PK is affected by moderate 
and strong CYP3A4 inhibitors (2.5- and 3.1-fold increase in 
laquinimod systemic exposure, respectively) and strong 
CYP3A4 inducers and moderate hepatic impairment. Studies 
have shown that laquinimod is a strong inducer of CYP1A2 
and a weak inhibitor of CYP3A4. Therefore, co-
administration of laquinimod may affect the systemic 
exposure of drugs metabolized by CYP450 1A2 or CYP3A4. 
... 
Studies in subjects with mild and moderate hepatic 
impairment resulted in an increase of laquinimod exposure by 
approximately 1.3- and 2.3-fold, respectively. In subjects with 
moderate renal impairment, laquinimod exposure was 
increased by 1.4-fold. A physiologically based 
pharmacokinetic model was further used to predict the effect 
of hepatic impairment and renal 
impairment on the pharmacokinetics of laquinimod after 
single and multiple doses of 0.6 to 1.5 mg in comparison with 
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 
Added text on hepatic 
and 
renal impairment as 
background for new 
stopping rules. 


 
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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. 
(1.71-fold and 1.65-fold, respectively). More significant 
increases in laquinimod exposure, in particular in terms of 
unbound drug fraction, are predicted in patients with 
moderate and severe hepatic impairment (3.41- and 6.51-fold, 
respectively) and severe renal impairment (1.86-fold). The 
model predictions indicated similar increases in systemic 
laquinimod exposure with a given stage of organ impairment 
across the 0.6- to 1.5-mg dose range following single- or 
multiple-dose administration, demonstrating that the dose-
proportional pharmacokinetics of laquinimod is maintained in 
subjects with hepatic impairment (mild to severe) and renal 
impairment (moderate to severe) across this dose range. 
Section 1.4.1. 
Note: The table has been updated in line with the updated Reference 
Safety Information; myocardial infarction and cerebrovascular accident 
are now included. 
 
Table 1: Tabulated List of Adverse Reactions in the Pooled ALLEGRO and 
BRAVO Studies 
 
Cardiac disorders 
Uncommon: Myocardial infarction 
 
Nervous system disorders 
Very Common: Headache 
Rare:               Cerebrovascular accident 
Note: The table has been updated in line with the updated 
Reference Safety Information; myocardial infarction and 
cerebrovascular accident are now included. 
 
Table 1: Tabulated List of Adverse Reactions  
 
Cardiac disorders 
Uncommon: Myocardial infarction 
 
Nervous system disorders 
Very Common: Headache 
Rare:               Cerebrovascular accident 
Updated in line with 
changes to the IB 
Section 1.4.1.2.7 
Cardiovascular Events (in the high-dose treatment arms of the ongoing 
MS studies)  
In December 2015, the Data Monitoring Committee (DMC) for the Teva-
sponsored MS studies LAQ-MS-305 (CONCERTO) and TV5600-CNS-
20006 (ARPEGGIO) found an imbalance in serious cardiovascular events 
in the high-dose treatment arms of these studies (1.2 mg in CONCERTO, 
1.5 mg in ARPEGGIO). Six cases of myocardial infarction occurred in the 
CONCERTO 1.2 mg treatment arm, compared with no events in the 0.6 
mg or placebo treatment arms, along with a cerebral infarction in a 31-
year-old man in the 1.2 mg treatment arm. In the ARPEGGIO study, 1 
myocardial infarction event was identified in the laquinimod 1.5 mg 
Cardiovascular Events (in the high-dose treatment arms of the 
ongoing MS studies)  
In December 2015, the Data Monitoring Committee (DMC) 
for the Teva-sponsored MS studies LAQ-MS-305 
(CONCERTO) and TV5600-CNS-20006 (ARPEGGIO) 
found an imbalance in serious cardiovascular events in the 
high-dose treatment arms of these studies (1.2 mg in 
CONCERTO, 1.5 mg in ARPEGGIO). Six cases of 
myocardial infarction occurred in the CONCERTO 1.2 mg 
treatment arm, compared with no events in the 0.6 mg or 
placebo treatment arms, along with a cerebral infarction in a 
New text added to 
reflect 
cardiovascular 
findings in the high 
dose treatment arms 
of the ongoing 
CONCERTO and 
ARPEGGIO MS 
studies. 
 
 


 
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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 the high-dose 
treatment arms (1.2 mg/day and 1.5 mg/day) 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 recommended that study subjects 
continuing on laquinimod 0.6 mg be reconsented with information about 
the cardiovascular risk seen at higher doses.  
On 07 January 2016, the LEGATO-HD Data Safety Monitoring Board 
(DSMB) was called by Teva to review and discuss the recommendations of 
the DMC for the CONCERTO and ARPEGGIO MS trials and their 
implications on LEGATO-HD. The DSMB confirmed that no 
cardiovascular events had been observed to date for any dose of the 
LEGATO-HD trial and concurred with the Sponsor’s recommendation 
that the high-dose (ie, 1.5 mg) arm in this trial be discontinued as a 
proactive safety measure. The DSMB approved the continuation of the 0.5 
mg/day and 1.0 mg/day arms with enhanced monitoring and safety 
precautions. Teva notified LEGATO-HD investigators on 10 January 
2016 to immediately contact patients randomized to the high dose of 1.5 
mg laquinimod and instruct them to discontinue study medication as a 
proactive measure to protect the safety of patients (endorsed by DSMB as 
noted above).  
Currently, the mechanism of the cardiovascular events remains unknown. 
Although no specific time-to-event patterns have been identified in the MS 
studies, 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 patients exhibited 
signs of myocardial tissue injury, the cardiac work-up in these cases 
revealed heterogeneous etiologies. Of note, the patients all had some 
established cardiovascular risk factors, including patients with probable 
myocarditis or with probable familial hypercholesterolemia. Further 
investigations into potential predictors and the potential causality are 
ongoing. 
31-year-old man in 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 the 
high-dose treatment arms (1.2 mg/day and 1.5 mg/day) 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 recommended that study subjects 
continuing on laquinimod 0.6 mg be reconsented with 
information about the cardiovascular risk seen at higher 
doses.  
On 07 January 2016, the LEGATO-HD Data Safety 
Monitoring Board (DSMB) was called by Teva to review and 
discuss the recommendations of the DMC for the 
CONCERTO and ARPEGGIO MS trials and their 
implications on LEGATO-HD.The DSMB confirmed that no 
cardiovascular events had been observed to date for any dose 
of the LEGATO-HD trial and concurred with the Sponsor’s 
recommendation that the high-dose (ie, 1.5 mg) arm in this 
trial be discontinued as a proactive safety measure. The 
DSMB approved the continuation of the 0.5 mg/day and 
1.0 mg/day arms with enhanced monitoring and safety 
precautions.  
Teva notified LEGATO-HD investigators on 10 January 2016 
to immediately contact patients randomized to the high dose 
of 1.5 mg laquinimod and instruct them to discontinue study 
medication as a proactive measure to protect the safety of 
patients (endorsed by DSMB as noted above).  
Currently the mechanism of the cardiovascular events 
remains unknown. Although no specific time-to-event 
patterns have been identified in the MS studies, 
cardiovascular risk factors and demographics may play a role. 
Different pre-existing risk factors were noted, including 


 
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for change 
hypertension, high cholesterol, and/or smoking history. While 
all patients exhibited signs of myocardial tissue injury, the 
cardiac work-up in these cases revealed heterogeneous 
etiologies. Of note, the patients all had some established 
cardiovascular risk factors, including patients with probable 
myocarditis or with probable familial hypercholesterolemia. 
Further investigations into potential predictors and the 
potential causality are ongoing. 
Section 1.4.1.3.1 
Studies in rats have shown reproductive toxicity including teratogenicity 
(urogenital malformations) at doses similar to the clinical dose of 
0.5 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 (see 
Section 1.3.1). The relevance to humans of these findings is not known, but 
cannot be excluded. 
Studies in rats have shown reproductive toxicity including 
teratogenicity (urogenital malformations) at doses similar to 
the clinical dose of 0.5 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 (see 
Section 1.3.1). The relevance to humans of these findings is 
not known, but cannot be excluded. 
Reflecting that 1.5 mg 
is no longer an 
intended clinical dose.  
1.4.1.3.2 Cancer 
An increase in the incidence of uterine and oral cancers was observed in rats 
(see Section 1.3.1). It is the sponsor’s position that these findings are likely 
related to the administration procedure or to species-specific mechanisms. 
While a connection to humans cannot be entirely excluded, these 
mechanisms are likely not relevant to humans. Currently available clinical 
data does not suggest that laquinimod at a dose of 0.6 mg/day is associated 
with an increased risk of cancer.  
1.4.1.3.2 Cancer 
An increase in the incidence of uterine and oral cancers was 
observed in rats (see 1.3.1). It is the sponsor’s position that 
these findings are likely related to species-specific 
mechanisms. While a connection to humans cannot be 
entirely excluded, these mechanisms are likely not relevant to 
humans. Currently available clinical data does not suggest 
that laquinimod at a dose of 0.6 mg/day is associated with an 
increased risk of cancer.  
Administration 
procedure no longer 
considered a factor. 
Section 1.4.1.3.3 
14.1.3.3 Cardiotoxicity and Systemic Inflammation 
In clinical studies performed with laquinimod’s predecessor, roquinimex, 
pericarditis/pleuritis and ischemic heart disorders were identified as 
important safety concerns. Roquinimex demonstrated clinical efficacy in 
MS in Phase II studies. However, sSerious toxicities (including myocardial 
infarction, pericarditis and pleuritis) occurring that occurred during Phase 
III 3 trials led to early termination 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 
1.4.1.3.3 Cardiotoxicity and Systemic Inflammation 
In clinical studies performed with laquinimod’s predecessor, 
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 
Updated following 
recent findings in the 
multiple sclerosis 
studies. 


 
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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 MS patient-
years,. as well as the patients exposed to 0.6 mg in the CONCERTO and 
ARPEGGIO studies, This analysis analyses showed that these safety issues 
do not constitute a 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 a 
potential clinical signal of myocardial infarction in the MS trials. 
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 MS 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 
signal for laquinimod in doses up to 0.6 mg/day. However, at 
doses of 1.2 and 1.5 mg, laquinimod manifested a potential 
clinical signal of myocardial infarction in the MS trials. 
Section 1.4.1.6 
An imbalance in serious cardiovascular events in the high-dose treatment 
arms (1.2 mg/day and 1.5 mg/day) in the Teva-sponsored CONCERTO 
and ARPEGGIO studies in MS was identified (6 cases of myocardial 
infarction in the CONCERTO 1.2 mg treatment arm, compared with 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. Due to these events, the DMC 
recommended stopping higher-dose laquinimod treatment arms (1.2 and 
1.5 mg) in the laquinimod MS trials (see Section 1.4.1.2.7). 
No cardiovascular events have been observed to date for any dose in the 
LEGATO-HD trial. 
On 07 January 2016, the LEGATO-HD DSMB met and approved the 
Sponsor's proposal to discontinue the 1.5 mg arm of the study as a 
proactive safety measure, and approved the continuation of the 0.5 mg/day 
and 1.0 mg/day arms with enhanced monitoring and safety precautions.  
Teva notified LEGATO-HD investigators on 10 January 2016 to 
immediately contact patients randomized to the high dose of 1.5 mg 
laquinimod and instruct them to discontinue study medication as a 
proactive measure to protect the safety of patients currently participating 
in the LEGATO-HD study. This action was endorsed by DSMB as noted 
above. Patients in the 1.5 mg/day (high dose) treatment arm, whose 
treatment with laquinimod was discontinued, were asked to continue all 
scheduled visits for safety assessment after study drug discontinuation. 
Appropriate risk mitigation procedures have been implemented via this 
An imbalance in serious cardiovascular events in the high-
dose treatment arms (1.2mg/day and 1.5mg/day) in the Teva-
sponsored CONCERTO and ARPEGGIO studies in MS was 
identified (6 cases of myocardial infarction in the 
CONCERTO 1.2 mg treatment arm, compared with 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. Due to 
these events, the DMC recommended stopping higher-dose 
laquinimod treatment arms (1.2 and 1.5 mg) in the 
laquinimod MS trials (see Section 1.4.1.2.7). 
No cardiovascular events have been observed to date for any 
dose in the LEGATO-HD trial. 
On 07 January 2016, the LEGATO-HD DSMB met and 
approved the Sponsor's proposal to discontinue the 1.5 mg 
arm of the study as a proactive safety measure, and approved 
the continuation of the 0.5 mg/day and 1.0 mg/day arms with 
enhanced monitoring and safety precautions.  
Teva notified LEGATO-HD investigators on 10 January 2016 
to immediately contact patients randomized to the high dose 
of 1.5 mg laquinimod and instruct them to discontinue study 
medication as a proactive measure to protect the safety of 
patients currently participating in the LEGATO-HD study. 
This action was endorsed by DSMB as noted above. Patients 
Updated overall 
risk/benefit 
assessment following 
recent findings in the 
multiple sclerosis 
studies. 


 
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protocol amendment to restrict excess drug exposure due to impairment of 
liver or kidney function, as well as to assure evaluation and management 
of cardiovascular risk factors.  
LEGATO-HD is the first "proof of concept" study in the HD patient 
population, which represents a disease with a fatal outcome and a severe 
unmet medical need (no current available medications). Based on data 
accumulated to date, the LEGATO-HD study aims for disease 
modification beyond symptomatic treatment. 
Thus, the LEGATO study in the HD patient population represents 
different benefit/risk considerations. 
Based on the above described risks and means for their mitigation, it is 
judged that potential benefit from administration of laquinimod to patients 
with HD outweighs the risks based on currently available information, 
supporting investigation of its role in this the Huntington’s disease patient 
population. 
For an overall risk benefit assessment of laquinimod treatment in human 
patients, additional information may be found in the current Investigator’s 
Brochure. 
in the 1.5 mg/day (high dose) treatment arm, whose treatment 
with laquinimod was discontinued, were asked to continue all 
scheduled visits for safety assessment after study drug 
discontinuation. 
Appropriate risk mitigation procedures have been 
implemented via this protocol amendment to restrict excess 
drug exposure due to impairment of liver or kidney function, 
as well as to assure evaluation and management of 
cardiovascular risk factors.  
LEGATO-HD is the first "proof of concept" study in the HD 
patient population, which represents a disease with a fatal 
outcome and a severe unmet medical need (no current 
available medications). Based on data accumulated to date, 
the LEGATO-HD study aims for disease modification beyond 
symptomatic treatment. 
Thus, the LEGATO study in the HD patient population 
represents different benefit/risk considerations. 
Based on the above described risks and means for their 
mitigation, it is judged that potential benefit from 
administration of laquinimod to patients with HD outweighs 
the risks based on currently available information, supporting 
investigation of its role in the Huntington’s disease patient 
population. 
For an overall risk benefit assessment of laquinimod 
treatment in human patients, additional information may be 
found in the current Investigator’s Brochure. 
Section 1.5 
The safety and efficacy of laquinimod given 0.5, 1.0, 1.5, or 2.0 mg/day 
have been investigated in 180 patients with CD for 8 weeks (study CD-
LAQ-201). Significant effect on the primary endpoint (Crohn’s Disease 
Activity Index) was seen after treatment with laquinimod 0.5 mg/day; 
laquinimod 1 mg had a lower magnitude effect that was also less robust than 
the effect of laquinimod 0.5 mg. Laquinimod 1.5 mg and 2.0 mg did not 
have an overall clinical effect compared to the pooled placebo. However, 
when evaluating reduction in calprotectin levels, an objective marker of 
disease activity, similar efficacy was observed across the laquinimod doses. 
Laquinimod showed an overall favorable safety and tolerability profile in 
this study. Laquinimod is no longer being developed as a treatment for 
The safety and efficacy of laquinimod given 0.5, 1.0, 1.5, or 
2.0 mg/day have been investigated in 180 patients with CD 
for 8 weeks (study CD-LAQ-201). Significant effect on the 
primary endpoint (Crohn’s Disease Activity Index) was seen 
after treatment with laquinimod 0.5 mg/day; laquinimod 1 mg 
had a lower magnitude effect that was also less robust than 
the effect of laquinimod 0.5 mg. Laquinimod 1.5 mg and 
2.0 mg did not have an overall clinical effect compared to the 
pooled placebo. However, when evaluating reduction in 
calprotectin levels, an objective marker of disease activity, 
similar efficacy was observed across the laquinimod doses. 
These indications are 
no longer pursued. 


 
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CD. 
Laquinimod showed an overall favorable safety and 
tolerability profile in this study. 
Laquinimod is no longer being developed as a treatment for 
CD. 
The safety and efficacy of laquinimod given 0.5 or 1.0 mg/day have also 
been investigated in two studies in SLE patients [with lupus nephritis (LN-
LAQ-201) and with lupus arthritis (LA-LAQ-202)] for 24 and 12 weeks, 
respectively. In LN-LAQ-201, 46 patients were enrolled: 15 received 
placebo, 16 received laquinimod 0.5 mg and 15 received laquinimod 1 mg. 
In LA-LAQ-202, 82 patients were enrolled: 26 were randomized to receive 
placebo, and 28 patients were randomized to each of the laquinimod arms 
(0.5 mg, and 1 mg). Overall laquinimod was safe and well tolerated in these 
studies. No clinically meaningful effect of laquinimod treatment could be 
seen in patients with LA. Beneficial effect of laquinimod was seen in 
patients with LN with both doses investigated, with the 0.5 mg dose 
showing a greater improvement in several efficacy variables. Laquinimod is 
no longer being developed as a treatment for SLE. 
 
The safety and efficacy of laquinimod given 0.5 or 
1.0 mg/day have also been investigated in two studies in SLE 
patients [with lupus nephritis (LN-LAQ-201) and with lupus 
arthritis (LA-LAQ-202)] for 24 and 12 weeks, respectively. In 
LN-LAQ-201, 46 patients were enrolled: 15 received placebo, 
16 received laquinimod 0.5 mg and 15 received laquinimod 
1 mg. In LA-LAQ-202, 82 patients were enrolled: 26 were 
randomized to receive placebo, and 28 patients were 
randomized to each of the laquinimod arms (0.5 mg, and 
1 mg). Overall laquinimod was safe and well tolerated in 
these studies. No clinically meaningful effect of laquinimod 
treatment could be seen in patients with LA. Beneficial effect 
of laquinimod was seen in patients with LN with both doses 
investigated, with the 0.5 mg dose showing a greater 
improvement in several efficacy variables. Laquinimod is no 
longer being developed as a treatment for SLE. 
These indications are 
no longer pursued. 
Note: On 30 December 2015, the DMC for the LAQ-MS--305 
(CONCERTO) and TV5600-CNS-20006 (ARPEGGIO) studies held an 
unscheduled meeting to review cardiovascular events. The DMC found an 
imbalance in serious cardiovascular events in the high-dose treatment 
arms (1.2 mg in CONCERTO, 1.5 mg in ARPEGGIO). 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 high-dose laquinimod treatment arms 
(1.2 mg/day and 1.5 mg/day)in the MS trials; accordingly, the high-dose 
arms were discontinued in both trials as of 01 January 2016.  
On 07 January 2016, the LEGATO-HD DSMB was called urgently by 
Teva to review and discuss new information regarding the occurrence of 
an imbalance in cardiovascular events from the high-dose laquinimod 
arms in the multiple sclerosis trials CONCERTO and ARPEGGIO (1.2 mg 
in CONCERTO, 1.5 mg in ARPEGGIO).  
The most recent study data for LEGATO-HD were also reviewed in open 
Note: On 30 December 2015, the DMC for the LAQ-MS-305 
(CONCERTO) and TV5600-CNS-20006 (ARPEGGIO) 
studies held an unscheduled meeting to review cardiovascular 
events. The DMC found an imbalance in serious 
cardiovascular events in the high-dose treatment arms (1.2 mg 
in CONCERTO, 1.5 mg in ARPEGGIO). 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 
high-dose laquinimod treatment arms (1.2mg/day and 
1.5mg/day)in the MS trials; accordingly, the high-dose arms 
were discontinued in both trials as of 01 January 2016 
On 07 January 2016 the LEGATO-HD DSMB was called 
urgently by Teva to review and discuss new information 
regarding the occurrence of an imbalance in cardiovascular 
events from the high-dose laquinimod arms in the multiple 
New text added 
following recent 
findings in the 
multiple sclerosis 
studies. 


 
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New wording 
Reason/Justification 
for change 
and closed sessions. No cardiovascular signal was detected from the 
LEGATO-HD study as of 10 January 2016. The DSMB agreed with the 
plan to discontinue the 1.5 mg arm of LEGATO-HD as a proactive safety 
measure and approved the continuation of the 0.5 mg/day and 1.0 mg/day 
arms with enhanced monitoring and safety precautions. Therefore, these 
treatment arms will be continued with updated informed consent and an 
amended protocol while the sponsor closely monitors cardiovascular 
events in all laquinimod studies for emergence of any potential 
cardiovascular signal. 
A more detailed description of study drug administration is presented in 
Section 5.1. 
sclerosis trials CONCERTO and ARPEGGIO (1.2 mg in 
CONCERTO, 1.5 mg in ARPEGGIO).  
The most recent study data for LEGATO-HD were also 
reviewed in open and closed sessions. No cardiovascular 
signal was detected from the LEGATO-HD study as of 10 
January 2016. The DSMB agreed with the plan to discontinue 
the 1.5 mg arm of LEGATO-HD as a proactive safety 
measure and approved the continuation of the 0.5 mg/day and 
1.0 mg/day arms with enhanced monitoring and safety 
precautions. Therefore, these treatment arms will be 
continued with updated informed consent and an amended 
protocol while the sponsor closely monitors cardiovascular 
events in all laquinimod studies for emergence of any 
potential cardiovascular signal. 
A more detailed description of study drug administration is 
presented in Section 5.1. 
2 PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
Section 2.1 
The purpose of this Phase II clinical study is to investigate the efficacy and 
safety of multiple doses of laquinimod (0.5, 1.0 and 1.5 mg/day) as a 
potential treatment for patients with Huntington's disease (HD). 
As no drug is currently available to treat HD disease progression, the study 
will be placebo controlled. 
Prior to 10 January 2016, a total of 400 patients were planned to be 
equally randomized in a 1:1:1:1 ratio (100 patients within each treatment 
arm) to receive laquinimod 0.5, 1.0, 1.5 mg/day, or matching placebo for 
52 weeks.  
As of 10 January 2016, following the decision to discontinue treatment of 
the laquinimod 1.5 mg dose arm, additional eligible patients who are 
enrolled will be randomized in a 1:1:1 ratio to receive laquinimod 0.5 
mg/day, 1.0 mg/day, or matching placebo for 52 weeks. Approximately 300 
patients (100 patients within each study arm), plus the 30 patients who 
were already randomized to the laquinimod 1.5 mg treatment arm, are 
planned to be enrolled in the study. 
... 
The purpose of this Phase II clinical study is to investigate the 
efficacy and safety of multiple doses of laquinimod (0.5, 1.0 
and 1.5 mg/day) as a potential treatment for patients with 
Huntington's disease (HD). 
As no drug is currently available to treat HD disease 
progression, the study will be placebo controlled. 
Prior to 10 January 2016, a total of 400 patients were planned 
to be equally randomized in a 1:1:1:1 ratio (100 patients 
within each treatment arm) to receive laquinimod 0.5, 1.0, 
1.5 mg/day, or matching placebo for 52 weeks.  
As of 10 January 2016, following the decision to discontinue 
treatment of the laquinimod 1.5 mg dose arm, additional 
eligible patients who are enrolled will be randomized in a 
1:1:1 ratio to receive laquinimod 0.5 mg/day, 1.0 mg/day, or 
matching placebo for 52 weeks. Approximately 300 patients 
(100 patients within each study arm), plus the 30 patients who 
were already randomized to the laquinimod 1.5 mg treatment 
arm, are planned to be enrolled in the study. 
... 
Clarification of the 
study randomization 
following the 
discontinuation of the 
laquinimod 1.5 
mg/day treatment 
arm. 
Section 2.2.1 (Other section affected by this change: 9.3) 


 
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The primary objective of this study is to assess the efficacy of laquinimod 
0.5, and 1.0, and 1.5 mg qd on in patients with HD after 12 months of 
treatment using the Unified Huntington’s Disease Rating Scale (UHDRS) 
Total Motor Score (TMS).  
 
Due to the decision from 10 January 2016 to discontinue treatment of the 
laquinimod 1.5 mg dose arm, and the low number of enrolled patients 
compared to the target at this time, data from the laquinimod 1.5 mg 
treatment arm will be presented descriptively only, and will not be 
included in any inferential analyses for efficacy or safety. 
The primary objective of this study is to assess the efficacy of 
laquinimod 0.5, and 1.0 mg qd in patients with HD after 12 
months of treatment using the Unified Huntington’s Disease 
Rating Scale (UHDRS) Total Motor Score (TMS).  
 
Due to the decision from 10 January 2016 to discontinue 
treatment of the laquinimod 1.5 mg dose arm, and the low 
number of enrolled patients compared to the target at this 
time, data from the laquinimod 1.5 mg treatment arm will be 
presented descriptively only, and will not be included in any 
inferential analyses for efficacy or safety. 
Clarification 
following the 
discontinuation of the 
laquinimod 1.5 
mg/day treatment 
arm. 
Section 2.2.3 
... 
• 
To evaluate the pharmacokinetics of laquinimod and its 
metabolites in patients with HD 
• 
To investigate the relationship between exposure to laquinimod 
and its metabolites and outcome measures (e.g., clinical effect and 
toxicity parameters).  
... 
• 
To evaluate the pharmacokinetics of laquinimod and 
its metabolites in patients with HD 
• 
To investigate the relationship between exposure to 
laquinimod and its metabolites and outcome 
measures (e.g., clinical effect and toxicity 
parameters). 
Assessment of 
laquinimod 
metabolites was 
added to the overall 
exploratory PK 
assessment for better 
characterization of 
laquinimod 
disposition. 
3 STUDY DESIGN 
Section 3.1 
This is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of laquinimod 
treatment at dosages of 0.5, 1.0, and 1.5 mg/day in adults with Huntington’s 
Disease.  
The study will consist of a screening period (2 weeks up to 5 weeks), 
followed by a 52-week double-blind treatment period and a follow-up visit 
(one month after end of treatment). Prior to 10 January 2016, A a total of 
400 patients are were planned to be equally randomized in a 1:1:1:1 ratio 
(100 patients within each treatment arm) to receive laquinimod 0.5, 1.0, 
1.5 mg/day, or matching placebo for 52 weeks. A total of 123 patients were 
randomized prior to 10 January 2016. 
As of 10 January 2016, following the decision to discontinue treatment of 
the laquinimod 1.5 mg dose arm, additional eligible patients who are 
enrolled will be randomized in a 1:1:1 ratio to receive laquinimod 0.5 
mg/day, 1.0 mg/day, or matching placebo for 52 weeks. Approximately 300 
This is a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of laquinimod treatment at dosages of 0.5, 
1.0, and 1.5 mg/day in adults with Huntington’s Disease.  
The study will consist of a screening period (2 weeks up to 5 
weeks), followed by a 52-week double-blind treatment period 
and a follow-up visit (one month after end of treatment). Prior 
to 10 January 2016, a total of 400 patients were planned to be 
equally randomized in a 1:1:1:1 ratio (100 patients within 
each treatment arm) to receive laquinimod 0.5, 1.0, 
1.5 mg/day, or matching placebo for 52 weeks. A total of 123 
patients were randomized prior to 10 January 2016. 
As of 10 January 2016, following the decision to discontinue 
treatment of the laquinimod 1.5 mg dose arm, additional 
eligible patients who are enrolled will be randomized in a 
Clarification of the 
study randomization 
following the 
discontinuation of the 
laquinimod 1.5 
mg/day treatment 
arm. 


 
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patients (100 patients within each study arm), plus the 30 patients who 
were already randomized to the laquinimod 1.5 mg treatment arm, are 
planned to be enrolled in the study. 
... 
1:1:1 ratio to receive laquinimod 0.5 mg/day, 1.0 mg/day, or 
matching placebo for 52 weeks. Approximately 300 patients 
(100 patients within each study arm), plus the 30 patients who 
were already randomized to the laquinimod 1.5 mg treatment 
arm, are planned to be enrolled in the study. 
... 
The study schema is presented in Figure 1 (prior to 10 January 2016), and 
in Figure 2 (from 10 January 2016).  
The study schema is presented in Figure 1 (prior to 
10 January 2016), and in Figure 2 (from 10 January 2016). 
Clarification 
regarding the study 
schemas. 
(Newly added Figure 2) 
(Newly added Figure 2) 
Reflects the removal 
of the 1.5 mg/day 
treatment group. 
Section 3.2.6.1. (Other sections affected by this change: 8.1.1; 9.9.1) 
Blood samples for PK evaluation of laquinimod and its metabolites will be 
collected at selected sites at Month 1 from a total of 60 patients (15 patients 
per treatment group). PK samples of laquinimod and its metabolites will be 
collected from approximately 15 patients per each of the three continuing 
treatment groups (at selected sites at Month 1), for a total of 
approximately 45 patients. Additionally, PK samples were collected from 2 
patients in the laquinimod 1.5 mg/day treatment group when the treatment 
was stopped; no further PK samples will be collected from the laquinimod 
1.5 mg/day treatment group. 
... 
Steady state pharmacokinetic parameters for laquinimod (AUCtau, Cmax and 
Cmin, tmax), will be calculated for each patient. Additional parameters for 
laquinimod and pharmacokinetic parameters for its metabolites may be 
calculated if data permit. 
For patients participating in this ancillary study, the morning dose and the 
24 hours dose administration (the day after) will take place at the clinic. 
... 
PK samples of laquinimod and its metabolites will be 
collected from approximately 15 patients per each of the three 
continuing treatment groups (at selected sites at Month 1), for 
a total of approximately 45 patients. Additionally, PK 
samples were collected from 2 patients in the laquinimod 1.5 
mg/day treatment group when the treatment was stopped; no 
further PK samples will be collected from the laquinimod 1.5 
mg/day treatment group. 
... 
Steady state pharmacokinetic parameters for laquinimod 
(AUCtau, Cmax and Cmin, tmax), will be calculated for each 
patient. Additional parameters for laquinimod and 
pharmacokinetic parameters for its metabolites may be 
calculated if data permit. 
... 
Revision following 
discontinuation of 1.5 
mg treatment arm. 
Assessment of 
laquinimod 
metabolites was 
added to the overall 
exploratory PK 
assessment for better 
characterization of 
laquinimod 
disposition. 
Section 3.2.6.2 (Other sections affected by this change: 8.1; 9.9.2) 
A single blood sample will be collected from all patients at Months 1, 3, 6 
and 12 for evaluation of laquinimod and its metabolites. 
Pharmacokinetic parameters for laquinimod metabolites may be 
calculated if data permit. 
… 
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 eCRF. 
A single blood sample will be collected from all patients at 
Months 1, 3, 6 and 12 for evaluation of laquinimod and its 
metabolites. 
... 
Pharmacokinetic parameters for laquinimod metabolites may 
be calculated if data permit. 
The date and time of the blood sample, as well as the date and 
PPK analysis can 
include 
the newly added 
unscheduled PK 
samples. 


 
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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).  
time of the last study drug dose prior to the sample will be 
recorded on the eCRF. 
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).  
Section 3.3 
This is a randomized, double-blind, placebo-controlled study. Prior to 
10 January 2016, eligible Ppatients will be were randomly assigned to 
receive treatment with laquinimod at a dosage of 0.5, 1.0 , or 1.5 mg qd or a 
matching placebo in a 1:1:1:1ratio. 
As of 10 January 2016, following the decision to discontinue treatment of 
the laquinimod 1.5 mg dose arm, future eligible patients will be 
randomized in a 1:1:1 ratio to receive laquinimod 0.5 mg/day or 1.0 
mg/day or matching placebo for 52 weeks. 
No change was performed to the original randomization list except that 
the patient numbers assigned to laquinimod 1.5 mg/day were removed 
from the list by the interactive response technology (IRT) vendor.  
All patients that discontinued the 1.5 mg/day dose have been unblinded. 
No attempts will be made to re-randomize patients whose 1.5 mg treatment 
was stopped to a lower dose of laquinimod. The remaining ongoing 
patients retained their originally randomized treatment assignments. 
Patients and investigators will remain blinded to treatment assignment 
during the study. 
…  
This is a randomized, double-blind, placebo-controlled study. 
Prior to 10 January 2016, eligible patients were randomly 
assigned to receive treatment with laquinimod at a dosage of 
0.5, 1.0, or 1.5 mg qd or a matching placebo in a 1:1:1:1 ratio. 
As of 10 January 2016, following the decision to discontinue 
treatment of the laquinimod 1.5 mg dose arm, future eligible 
patients will be randomized in a 1:1:1 ratio to receive 
laquinimod 0.5 mg/day or 1.0 mg/day or matching placebo 
for 52 weeks. 
No change was performed to the original randomization list 
except that the patient numbers assigned to laquinimod 1.5 
mg/day were removed from the list by the interactive 
response technology (IRT) vendor. 
All patients that discontinued the 1.5 mg/day dose have been 
unblinded. No attempts will be made to re-randomize patients 
whose 1.5 mg treatment was stopped to a lower dose of 
laquinimod. The remaining ongoing patients retained their 
originally randomized treatment assignments.  
Patients and investigators will remain blinded to treatment 
assignment during the study. 
… 
1.5 mg/day treatment 
arm has been 
discontinued and 
patients in that arm 
unblinded. 
Section 3.4 
Patients will be randomized to receive laquinimod 0.5, 1.0, or 1.5 mg qd or 
matching placebo (prior to 10 January 2016), or randomly assigned to 
receive treatment with laquinimod at a dosage of 0.5 mg/day, 1.0 mg/day 
or placebo in a 1:1:1 ratio (from 10 January 2016). Every patient will take 
3 capsules once daily, at the same time of the day, during the entire study 
period. Study drug will be administered as described in Section 3.4.1 and 
Section 3.4.2. below. The capsules will be taken orally and must be 
swallowed whole with a glass of water. The capsule should not be opened. 
Laquinimod can be taken with or without food. 
Patients will be randomized to receive laquinimod 0.5, 1.0, or 
1.5 mg qd or matching placebo (prior to 10 January 2016), or 
randomly assigned to receive treatment with laquinimod at a 
dosage of 0.5 mg/day, 1.0 mg/day or placebo in a 1:1:1 ratio 
(from 10 January 2016). Every patient will take 3 capsules 
once daily, at the same time of the day, during the entire study 
period. Study drug will be administered as described in 
Section 3.4.1 and Section 3.4.2. below. The capsules will be 
taken orally and must be swallowed whole with a glass of 
1.5 mg/day treatment 
arm has been 
discontinued. 


 
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water. The capsule should not be opened. Laquinimod can be 
taken with or without food. 
Section 3.4.1 
Laquinimod will be provided as off-white, opaque, hard gelatin capsules. 
The capsules should be swallowed whole with water.  
• 
Patients randomized to the laquinimod 1.5 mg qd treatment arm 
will received 3 capsules of 0.5 mg laquinimod (Note: The 
treatment of this high dose arm was discontinued as of 10 
January 2016).  
... 
Laquinimod will be provided as off-white, opaque, hard 
gelatin capsules. The capsules should be swallowed whole 
with water.  
• 
Patients randomized to the laquinimod 1.5 mg qd 
treatment arm received 3 capsules of 0.5 mg 
laquinimod (Note: The treatment of this high dose 
arm was discontinued as of 10 January 2016). 
... 
Updated following the 
discontinuation of the 
1.5 mg/day treatment 
arm. 
Section 3.6 (Other sections affected by change: 4.3; APPENDIX A) 
Safety stopping rules are detailed in Appendix A (Guidance on Safety 
Monitoring).  
These include: 
• 
Elevated liver enzymes (as detailed in Appendix A)  
• 
Pregnancy 
• 
Need for concomitant treatment with moderate and strong CYP3A4 
inhibitors 
• 
Patients that are diagnosed with invasive cancer a malignant solid 
or liquid tumor while participating in the study 
• 
Acute coronary syndrome, myocardial infarction or any major 
cardiovascular event  
Safety stopping rules are detailed in Appendix A (Guidance 
on Safety Monitoring).  
These include: 
• 
Elevated liver enzymes (as detailed in Appendix A)  
• 
Pregnancy 
• 
Need for concomitant treatment with moderate and 
strong CYP3A4 inhibitors 
• 
Patients that are diagnosed with a malignant solid or 
liquid tumor while participating in the study 
• 
Acute coronary syndrome, myocardial infarction or 
any major cardiovascular event 
Correction of 
terminology. 
 
Newly added 
cardiovascular 
stopping rule. 
Section 3.6 (Other sections affected by change: APPENDIX A) 
... 
Liver Impairment 
To avoid exposures to higher levels of laquinimod (see Section 1.3.2.1), a 
stopping rule 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. 
 
Renal Impairment 
To avoid exposures to higher levels of laquinimod (see Section 1.3.2.1), a 
stopping rule related to renal impairment has been introduced. Patients 
who develop chronic renal disease associated with moderate or severe 
functional impairment, defined as estimated creatinine clearance (CrCl) 
<60 mL/min/1.73 m2, while participating in the study should stop study 
... 
Liver Impairment 
To avoid exposures to higher levels of laquinimod (see 
Section 1.3.2.1), a stopping rule 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. 
 
Renal Impairment 
To avoid exposures to higher levels of laquinimod (see 
Section 1.3.2.1), a stopping rule related to renal impairment 
has been introduced. Patients who develop chronic renal 
disease associated with moderate or severe functional 
New stopping rules 
implemented to avoid 
increased exposure to 
laquinimod in cases 
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medication temporarily and the assessment of estimated CrCl should be 
repeated. If the development of renal impairment is confirmed (estimated 
CrCl <60 mL/min/1.73 m2), the patient should stop study medication 
permanently. 
 
impairment, defined as estimated creatinine clearance (CrCl) 
<60 mL/min/1.73 m2, while participating in the study should 
stop study medication temporarily and the assessment of 
estimated CrCl should be repeated. If the development of 
renal impairment is confirmed (estimated CrCl 
<60 mL/min/1.73 m2), the patient should stop study 
medication permanently. 
Section 3.6.2 (Other sections affected by change: 3.11.3.1.5) 
3.6.2 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). 
Early termination refers to the study drug termination and not termination 
of the patient from the study. Patients will be asked to continue all 
scheduled visits and safety assessments after study drug discontinuation 
(with the exception of drug dispensing and accountability, pregnancy 
testing, and pharmacokinetic sampling). 
Patients in the 1.5 mg/day (high dose) treatment arm, whose treatment 
with laquinimod was discontinued, were invited to attend an early 
termination visit (to return study medication and perform drug 
accountability). At this visit, only safety assessments were to be completed. 
These included vital signs; clinical laboratory tests; pregnancy test; 
adverse event inquiry; drug accountability; review of concomitant 
medication, and C-SSRS (see also Section 3.11.3.1.5) . Subjects were 
asked to continue scheduled follow up safety visits per the current 
schedule. 
Women of child bearing potential should continue using 2 acceptable 
contraception methods up to 30 days after the last dose of study 
medication has been administered. 
Moderate/strong CYP3A4 inhibitors are disallowed during the 30 days 
after the last laquinimod dose has been administered (see Appendix B).  
Plasma levels of drugs that are CYP1A2 substrates may decrease when 
combined with laquinimod and within 30 days after the last laquinimod 
dose, rendering these drugs less effective (see Appendix C). 
3.6.2 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). 
Early termination refers to the study drug termination and not 
termination of the patient from the study. Patients will be 
asked to continue all scheduled visits and safety assessments 
after study drug discontinuation (with the exception of drug 
dispensing and accountability, pregnancy testing, and 
pharmacokinetic sampling). 
Patients in the 1.5 mg/day (high dose) treatment arm, whose 
treatment with laquinimod was discontinued, were invited to 
attend an early termination visit (to return study medication 
and perform drug accountability). At this visit, only safety 
assessments were to be completed. These included vital signs; 
clinical laboratory tests; pregnancy test; adverse event 
inquiry; drug accountability; review of concomitant 
medication, and C-SSRS (see also Section 3.11.3.1.5) . 
Subjects were asked to continue scheduled follow up safety 
visits per the current schedule. 
Women of child bearing potential should continue using 
2 acceptable contraception methods up to 30 days after the 
last dose of study medication has been administered. 
Moderate/strong CYP3A4 inhibitors are disallowed during 
the 30 days after the last laquinimod dose has been 
administered (see Appendix B).  
Plasma levels of drugs that are CYP1A2 substrates may 
decrease when combined with laquinimod and within 30 days 
after the last laquinimod dose, rendering these drugs less 
effective (see Appendix C). 
New section added 
for clarification 
regarding the early 
termination visit. 


 
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Section 3.8 
... 
As of 10 January 2016, treatment with laquinimod was discontinued for 
all patients in the 1.5 mg dose group; all these discontinued patients have 
been unblinded. No attempts will be made to re-randomize patients whose 
1.5 mg treatment was stopped to a lower dose of laquinimod.  
 
However, the blinding was maintained for the patients in the remaining 
ongoing 3 treatment arms (0.5 mg/day, 1.0 mg/day, and placebo). 
 
... 
As of 10 January 2016, treatment with laquinimod was 
discontinued for all patients in the 1.5 mg dose group; all 
these discontinued patients have been unblinded. No attempts 
will be made to re-randomize patients whose 1.5 mg 
treatment was stopped to a lower dose of laquinimod.  
 
However, the blinding was maintained for the patients in the 
remaining ongoing 3 treatment arms (0.5 mg/day, 1.0 mg/day, 
and placebo). 
Clarification 
regarding 
maintenance of the 
blinding for the 
remaining treatment 
arms. 
Section 3.10 
The study is expected to started in Q3 Q4 2014 (first patient randomized) 
and is expected to be completed in Q4 2016 Q1 2018 (last patient last visit).  
 
As of 10 January 2016, treatment with laquinimod was discontinued for 
all patients in the 1.5 mg/day dose arm.  
 
Approximately 400 300 patients (100 patients within each study arm), plus 
the 30 patients that were already randomized to the laquinimod 1.5 mg 
dose arm from ~51 investigational centers in North America, Europe and 
Russia are planned to be enrolled in the study.  
 
 
The study started in Q4 2014 (first patient randomized) and is 
expected to be completed in Q1 2018 (last patient last visit).  
 
As of 10 January 2016, treatment with laquinimod was 
discontinued for all patients in the 1.5 mg/daydose arm. 
 
Approximately 300 patients (100 patients within each study 
arm), plus the 30 patients that were already randomized to the 
laquinimod 1.5 mg dose arm, from ~51 investigational centers 
in North America, Europe and Russia are planned to be 
enrolled in the study.  
Revised to reflect 
actual start date and 
planned completion.  
 
Number of patients 
updated following the 
discontinuation of the 
1.5 mg/day treatment 
arm. 
Section 3.11 – Table 3 
Estimated creatinine clearance calculation 
Estimated creatinine clearance calculation 
Name of procedure 
clarified. 
PK (drug and metabolites concentration) sampling 
PK (drug and metabolites concentration) sampling 
Name of procedure 
clarified. 
24-hour PK profiling for drug and metabolites 
24-hour PK profiling for drug and metabolites 
Name of procedure 
clarified. 
Footnote a. For patients in the high dose group (1.5 mg/day) who were 
discontinued, only safety and no efficacy assessments had to be performed 
at the Early Termination visit. The patients will be asked to continue all 
scheduled visits for safety assessment only after study drug discontinuation. 
Footnote a. For patients in the high dose group (1.5 mg/day) 
who were discontinued, only safety and no efficacy 
assessments had to be performed at the Early Termination 
visit. The patients will be asked to continue all scheduled 
visits for safety assessment only after study drug 
discontinuation. 
Newly added footnote 
for clarification 
regarding the 
discontinued 1.5 
mg/day dose arm. 
Footnote d. Including smoking history. In addition, an evaluation of 
Footnote d. Including smoking history. In addition, an 
Newly added footnote 


 
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cardiovascular risk factors should take place as soon as possible for 
patients already in the study, following approval of Global Amendment 04. 
evaluation of cardiovascular risk factors should take place as 
soon as possible for patients already in the study, following 
approval of Global Amendment 04. 
for cardiovascular risk 
factor assessment and 
management. 
Footnote e. Assessment of changes in cardiovascular risk and appropriate 
cardiovascular risk management with appropriate medical follow-up, if 
clinically indicated, should be performed during the scheduled and 
unscheduled visits. 
Footnote e. Assessment of changes in cardiovascular risk and 
appropriate cardiovascular risk management with appropriate 
medical follow-up, if clinically indicated, should be 
performed during the scheduled and unscheduled visits. 
Newly added footnote 
for cardiovascular risk 
factor assessment and 
management. 
Footnote 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. 
Footnote 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. 
Newly added footnote 
for clarification 
regarding urgent 
samples that may be 
collected during the 
study. 
Footnote r. If a patient terminates within 3 months of the baseline visit, they 
will not undergo an Early Termination scan. If a patient terminates prior to 
Month 12, the Early termination scans should be performed as soon as 
possible, but not more than 7 days after discontinuation of study drug. 
Month 12 scans should be performed 7 days prior to the Termination Visit. 
The early termination MRI scan was not to be done for the patients in the 
discontinued 1.5 mg/day treatment arm .  
Footnote r. If a patient terminates within 3 months of the 
baseline visit, they will not undergo an Early Termination 
scan. If a patient terminates prior to Month 12, the Early 
termination scans should be performed as soon as possible, 
but not more than 7 days after discontinuation of study drug. 
Month 12 scans should be performed 7 days prior to the 
Termination Visit. The early termination MRI scan was not to 
be done for the patients in the discontinued 1.5 mg/day 
treatment arm .  
Clarification. 
Footnote t. Estimated Ccreatinine clearance will be calculated based on 
laboratory results at screening (for inclusion in study) at every in-clinic 
study visit. Patients who develop chronic renal disease associated with 
moderate or severe functional impairment, defined as estimated creatinine 
clearance (CrCl) <60 mL/min/1.73 m2, while participating in the study 
should stop study medication temporarily and the creatinine clearance 
assessment should be repeated. If the renal impairment is confirmed 
(estimated CrCl <60 mL/min/1.73 m2), the patient should stop study 
medication permanently. 
Footnote t. Estimated creatinine clearance will be calculated 
at every in-clinic visit. Patients who develop chronic renal 
disease associated with moderate or severe functional 
impairment, defined as estimated creatinine clearance (CrCl) 
<60 mL/min/1.73 m2, while participating in the study should 
stop study medication temporarily and the creatinine 
clearance assessment should be repeated. If the renal 
impairment is confirmed (estimated CrCl <60 mL/min/1.73 
m2), the patient should stop study medication permanently. 
Extra monitoring 
added in case of 
decrease in renal 
function. 
Footnote dd. Only at selected sites in a subgroup of patients, N=60 (15 from 
each treatment arm), (approximately 15 patients per each of the three 
continuing treatment groups, for a total of approximately 45 patients) at 
Month 1. Patients participating in the 24-hour PK profiling will not have the 
single PK sample drawn at Visit 3. Additionally, PK samples were collected 
from 2 patients in the laquinimod 1.5 mg/day treatment group when the 
Footnote dd. Only at selected sites in a subgroup of patients 
(approximately 15 patients per each of the three continuing 
treatment groups, for a total of approximately 45 patients) at 
Month 1. Patients participating in the 24-hour PK profiling 
will not have the single PK sample drawn at Visit 3. 
Additionally, PK samples were collected from 2 patients in 
Revised following the 
discontinuation of the 
1.5 mg/day treatment 
arm. 


 
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treatment was stopped; no further PK samples will be collected from the 
laquinimod 1.5 mg/day treatment group. 
the laquinimod 1.5 mg/day treatment group when the 
treatment was stopped; no further PK samples will be 
collected from the laquinimod 1.5 mg/day treatment group. 
Section 3.11.1 
... 
The screening visit (Visit 1) will take place up to 5 weeks before the 
baseline visit. The following procedures will be performed at Visit 1: 
• 
obtain written informed consent before any other study-related 
procedures are performed 
• 
review inclusion/exclusion criteria  
• 
review medical and psychiatric history/demographics 
• 
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. 
• 
... 
• 
Estimated cCreatinine clearance calculation based on laboratory 
results (for inclusion in study).  
• 
... 
• 
MRI scan 
o 
The baseline MRI can be performed at the screening visit, but no 
later than 7 days prior to baseline. If performed at the screening 
visit, as many screening assessements as possible should be 
conducted prior to the MRI scan in order to assess eligibility. If the 
screening period is extended by up to 30 days, the MRI scan does 
not have to be repeated.  
• 
inform patients of study restrictions and compliance requirements  
... 
The screening visit (Visit 1) will take place up to 5 weeks 
before the baseline visit. The following procedures will be 
performed at Visit 1: 
• 
obtain written informed consent before any other 
study-related procedures are performed 
• 
review inclusion/exclusion criteria  
• 
review medical and psychiatric 
history/demographics 
• 
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. 
• 
... 
• 
Estimated creatinine clearance calculation based on 
laboratory results (for inclusion in study).  
• 
MRI scan 
o 
The baseline MRI can be performed at the screening 
visit, but no later than 7 days prior to baseline. If 
performed at the screening visit, as many screening 
assessements as possible should be conducted prior 
to the MRI scan in order to assess eligibility. If the 
screening period is extended by up to 30 days, the 
MRI scan does not have to be repeated.  
• 
inform patients of study restrictions and compliance 
requirements  
As an enhanced 
monitoring and safety 
precaution, data on 
patient's smoking 
habits will now be 
collected and 
evaluation of cardiac 
risk factors will be 
performed.  
 
Clarification 
regarding other 
procedures and 
assessments. 
Section 3.11.2 (Other sections affected by this change: 3.11.3.1.1; 3.11.3.1.3-5; 3.11.4.1) 
Patients who meet the inclusion/exclusion criteria at Visit 1 will continue to 
Visit 2, when baseline evaluations will be conducted. 
The following procedures will be performed at Visit 2 in patients who 
continue to meet the inclusion/exclusion criteria: 
• 
review inclusion/exclusion criteria 
Patients who meet the inclusion/exclusion criteria at Visit 1 
will continue to Visit 2, when baseline evaluations will be 
conducted. 
The following procedures will be performed at Visit 2 in 
patients who continue to meet the inclusion/exclusion criteria: 
Extra creatinine 
clearance monitoring 
added in case of 
decrease 
in renal function. 


 
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• 
perform clinical laboratory tests 
• 
estimated creatinine clearance calculation 
• 
clinical hematology 
... 
• 
review inclusion/exclusion criteria 
• 
perform clinical laboratory tests 
• 
estimated creatinine clearance calculation 
• 
clinical hematology 
... 
Section 3.11.3.1.5  
... 
Early termination refers to the study drug termination and not termination 
of the patient from the study. Patients in the 1.5 mg/day (high dose) 
treatment arm, whose treatment with laquinimod was discontinued, were 
invited to attend an early termination safety visit to return study 
medication and perform drug accountability. At this visit, only safety 
assessments (vital signs, clinical laboratory tests, pregnancy test, adverse 
event inquiry, drug accountability, review of concomitant medication, and 
C-SSRS) were to be conducted (see Section 3.6.2), and none of the efficacy 
assessments. Patients were asked to continue all scheduled visits for safety 
assessment after study drug discontinuation. 
 
Patients in the high dose group (1.5mg/day) who were requested to 
discontinue study drug before week 52 but continue to attend scheduled 
study visits for safety assessment are not considered to have completed the 
study . 
Early termination refers to the study drug termination and not 
termination of the patient from the study. Patients in the 1.5 
mg/day (high dose) treatment arm, whose treatment with 
laquinimod was discontinued, were invited to attend an early 
termination safety visit to return study medication and 
perform drug accountability. At this visit, only safety 
assessments (vital signs, clinical laboratory tests, pregnancy 
test, adverse event inquiry, drug accountability, review of 
concomitant medication, and C-SSRS) were to be conducted 
(see Section 3.6.2), and none of the efficacy assessments. 
Patients were asked to continue all scheduled visits for safety 
assessment after study drug discontinuation. 
 
Patients in the high dose group (1.5mg/day) who were 
requested to discontinue study drug before week 52 but 
continue to attend scheduled study visits for safety assessment 
are not considered to have completed the study . 
Clarification 
regarding end-of-
treatment assessments 
of discontinued 
patients. 
Section 3.11.4.1 (Other sections affected by this change: 4.3) 
... 
For patients who complete the study or withdraw prematurely, final 
evaluations will be performed at the end-of treatment visit or as soon as 
possible thereafter. Procedures for patients who withdraw prematurely from 
the study are described in Section 4.3.  
If it is not possible to schedule the ET visit within 2 weeks after end of 
treatment, only the safety evaluations for that visit (vital signs; clinical 
laboratory tests; pregnancy test; adverse event inquiry; drug 
accountability; review of concomitant medication, and C-SSRS; see 
Section 3.6.2) need to be performed.  
 
... 
For patients who complete the study or withdraw 
prematurely, final evaluations will be performed at the end-of 
treatment visit or as soon as possible thereafter. Procedures 
for patients who withdraw prematurely from the study are 
described in Section 4.3 If it is not possible to schedule the 
ET visit within 2 weeks after end of treatment, only the safety 
evaluations for that visit (vital signs; clinical laboratory tests; 
pregnancy test; adverse event inquiry; drug accountability; 
review of concomitant medication, and C-SSRS; see Section 
3.6.2) need to be performed.  
Clarification. 
Section 3.11.5 
... 
Other procedures may be performed at the discretion of the investigator, and 
Other procedures may be performed at the discretion of the 
investigator, and must be recorded in the source 
Clarification. 
Additional 


 
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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) 
• 
estimated creatinine clearance calculation 
• 
collection of unscheduled pharmacokinetic blood sample 
• 
collection of sample for potential biomarker analysis 
 
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) 
• 
estimated creatinine cleaerance calculation 
• 
collection of unscheduled pharmacokinetic blood 
sample 
• 
collection of sample for potential biomarker analysis 
assessmens for 
monitoring of cardiac 
risk.  
4 SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.2 
f. [Revision 1] Serum levels ≥3 2xULN of either ALT or AST at screening. 
f. [Revision 1] Serum levels ≥2xULN of either ALT or AST 
at screening. 
More stringent 
exclusion criterion for 
hepatic parameters. 
g. [Revision 1] Serum direct bilirubin which is ≥2 1.5xULN at screening.  
g. [Revision 1] Serum direct bilirubin which is ≥1.5xULN at 
screening.  
More stringent 
exclusion criterion for 
hepatic parameters 
h. [Revision 1 2] Estimated cCreatinine clearance <60 mL/min at screening, 
calculated using the Cockcroft Gault equation:  
(140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL)  
h. [Revision 2] Estimated creatinine clearance <60 mL/min at 
screening, calculated using the Cockcroft Gault equation:  
(140 - age) × mass (kg) × [0.85 if female] / 72 × serum 
creatinine (mg/dL)  
Correction of 
terminology. 
i. [Revision 1] Subjects with a clinically significant or unstable medical or 
surgical condition that may put the patient at risk when participating in the 
study or may influence the results of the study or affect the patient's ability 
to take part in the study, as determined by medical history, physical 
examinations, ECG, or laboratory tests. Such conditions may include: 
1. A major cardiovascular event (e.g. myocardial infarction, acute coronary 
syndrome, de-compensated congestive heart failure, pulmonary embolism, 
coronary revascularization, angina) that occurred during the past 6 months 
prior to randomization. 
2. Significant cardiovascular risk factors (such as, but not limited to, 
uncontrolled hypertension, uncontrolled diabetes), per investigator 
discretion. 
2 3. Any acute pulmonary disorder 
34. A CNS disorder other than HD that may jeopardize the subject's  
participation in the study, including such disorders that are demonstrated on 
the baseline MRI (based on local read). 
4 5. A gastrointestinal disorder that may affect the absorption of study 
i. [Revision 1] Subjects with a clinically significant or 
unstable medical or surgical condition that may put the 
patient at risk when participating in the study or may 
influence the results of the study or affect the patient's ability 
to take part in the study, as determined by medical history, 
physical examinations, ECG, or laboratory tests. Such 
conditions may include: 
1. A major cardiovascular event (e.g. myocardial infarction, 
acute coronary syndrome, de-compensated congestive heart 
failure, pulmonary embolism, coronary revascularization, 
angina) that occurred prior to randomization. 
2. Significant cardiovascular risk factors (such as, but not 
limited to, uncontrolled hypertension, uncontrolled diabetes), 
per investigator discretion. 
3. Any acute pulmonary disorder 
4. A CNS disorder other than HD that may jeopardize the 
subject's participation in the study, including such disorders 
More stringent 
criterion for exclusion 
of patients with 
significant cardiac 
events or conditions 
in their medical 
history. 
 
 


 
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medication. 
5 6. Acute or chronic rRenal disease including acute kidney injury (AKI). 
6 7. Cirrhotic patients with moderate or severe hepatic impairment Any 
form of acute or chronic liver disease. 
7 8. Known human immunodeficiency virus positive status. Patients will 
undergo an HIV test at screening per local requirements, if applicable. 
8 9. Any malignancies, excluding basal cell carcinoma, in the 5 years prior 
to randomization. 
that are demonstrated on the baseline MRI (based on local 
read). 
5. A gastrointestinal disorder that may affect the absorption of 
study medication. 
6. Acute or chronic renal disease including acute kidney 
injury (AKI). 
7. Any form of acute or chronic liver disease. 
8. Known human immunodeficiency virus positive status. 
Patients will undergo an HIV test at screening per local 
requirements, if applicable. 
9. Any malignancies, excluding basal cell carcinoma, in the 5 
years prior to randomization. 
Section 4.3 
 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’. 
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 TREATMENT OF PATIENTS 
Section 5.1 
Until 10 January 2016, aAt the baseline visit, patients will be were 
randomly assigned in a 1:1:1:1 ratio to 1 of 3 laquinimod treatment groups 
or to the placebo treatment group. Three capsules will be administered 
orally once each day, at the same time of the day, as follows: 
• 
Oral laquinimod 0.5 mg: 3 capsules, 1 containing 0.5 mg 
laquinimod and 2 capsules containing matching placebo, to be 
administered orally qd.  
• 
Oral laquinimod 1.0 mg: 3 capsules, 2 containing 0.5 mg 
laquinimod and 1 capsule containing matching placebo, to be 
administered orally qd.  
• 
Oral laquinimod 1.5 mg: 3 capsules containing 0.5 mg laquinimod 
(Note: The treatment of this high dose arm was discontinued as 
of 10 January 2016) 
• 
Matching placebo: 3 capsules, containing 0.5 mg matching 
placebo, to be administered orally qd. 
As of 10 January 2016, following the decision to discontinue treatment of 
the laquinimod 1.5 mg dose arm, additional eligible patients who are 
enrolled will be randomized in a 1:1:1 ratio to receive laquinimod 0.5 
mg/day, 1.0 mg/day, or matching placebo for 52 weeks. 
... 
Until 10 January 2016, at the baseline visit, patients were 
randomly assigned in a 1:1:1:1 ratio to 1 of 3 laquinimod 
treatment groups or to the placebo treatment group. Three 
capsules will be administered orally once each day, at the 
same time of the day, as follows: 
• 
Oral laquinimod 0.5 mg: 3 capsules, 1 containing 
0.5 mg laquinimod and 2 capsules containing 
matching placebo, to be administered orally qd.  
• 
Oral laquinimod 1.0 mg: 3 capsules, 2 containing 
0.5 mg laquinimod and 1 capsule containing 
matching placebo, to be administered orally qd.  
• 
Oral laquinimod 1.5 mg: 3 capsules containing 
0.5 mg laquinimod (Note: The treatment of this high 
dose arm was discontinued as of 10 January 2016) 
• 
Matching placebo: 3 capsules, containing 0.5 mg 
matching placebo, to be administered orally qd. 
As of 10 January 2016, following the decision to discontinue 
treatment of the laquinimod 1.5 mg dose arm, additional 
eligible patients who are enrolled will be randomized in a 
1:1:1 ratio to receive laquinimod 0.5 mg/day, 1.0 mg/day, or 
Revision following 
discontinuation of 1.5 
mg treatment arm. 
 


 
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matching placebo for 52 weeks. 
... 
Section 5.3.1 
The following medications will not be allowed prior to and during this 
study: 
• 
Use of tetrabenazine within 30 days prior to baseline and during the 
study; 
• 
Use of antipsychotic medication within 30 days prior to baseline 
and during the study; 
• 
Use of moderate/strong inhibitors of CYP3A4, such as 
erythromycin and ketoconazole (more examples listed in 
Appendix B), within 2 weeks prior to randomization, during the 
study and until 30 days after the last study dose has been 
administered. 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. 
... 
The following medications will not be allowed prior to and 
during this study: 
• 
Use of tetrabenazine within 30 days prior to baseline 
and during the study; 
• 
Use of antipsychotic medication within 30 days prior 
to baseline and during the study; 
• 
Use of moderate/strong inhibitors of CYP3A4, such 
as erythromycin and ketoconazole (more examples 
listed in Appendix B), within 2 weeks prior to 
randomization, during the study and until 30 days 
after the last study dose has been administered. 
Laquinimod is extensively metabolized 
predominantly by CYP3A4, and ketoconazole and 
fluconazole, strong and moderate inhibitors of 
CYP3A4, were found to inhibit the metabolism, 
leading to 2.5- and 3.1-fold increases in laquinimod 
exposure, respectively. 
... 
Clarification. 
 
Rationale for 
disallowed 
medication added 
 
 
 
Section 5.5 
The total amount of blood to be drawn throughout the entire study for serum 
chemistry, hematology, pharmacokinetic, biomarker and pharmacogenomic 
measurements is approximately 300 350 mL/patient.  
The total amount of blood to be drawn throughout the entire 
study for serum chemistry, hematology, pharmacokinetic, 
biomarker and pharmacogenomic measurements is 
approximately 350 mL/patient.  
Adjustment to allow 
for unscheduled 
visits. 
7 ASSESSMENT OF SAFETY 
Section 7.1.6 
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), cerebrovascular events (such as cerebral 
arterial occlusion, cerebral ischemia, etc) and deaths should be reported to 
the sponsor within 24 hours, including completion of the corresponding 
dedicated CRF. 
Ischemic cardiac events (such as myocardial infarction, 
unstable angina, acute coronary syndrome etc), 
cerebrovascular events (such as cerebral arterial occlusion, 
cerebral ischemia, etc) and deaths should be reported to the 
sponsor within 24 hours, including completion of the 
corresponding dedicated CRF. 
 
Due to cardiovascular 
findings at higher 
dose levels, adverse 
events for expedited 
reporting have 
been identified. 
Section 7.3.1 (Other sections affected by this change: APPENDIX A) 


 
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The following serum chemistry tests will be performed at all scheduled 
visits: 
• 
calcium 
• 
phosphorus 
• 
... 
• 
creatinine (Note: Estimated creatinine clearance will be 
calculated at all in-clinic study visits)  
• 
… 
• 
creatine phosphokinase (CPK) 
-In case of CPK results >ULN, troponin or and creatine kinase MB 
isoenzyme (CK-MB) 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. 
... 
The following serum chemistry tests will be performed at all 
scheduled visits: 
• 
calcium 
• 
phosphorus 
• 
... 
• 
creatinine (Note: Estimated creatinine clearance will 
be calculated at all in-clinic study visits)  
• 
... 
• 
creatine phosphokinase (CPK) 
-In case of CPK results >ULN, troponin and creatine 
kinase MB isoenzyme (CK-MB) 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. 
... 
Clarification 
regarding estimated 
creatinine clearance 
cacluation. 
 
In case of CPK 
>ULN, both troponin 
and CK-MB will be 
tested to give 
additional 
cardiovascular 
assessment. 
Section 7.3.4 (Other sections affected by this change: Table 3; 3.11.5) 
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 
7.3.4 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 
Unscheduled 
laboratory test 
samples may be 
collected to allow 
further investigation 
of events of interest.  
Numbering of 
subsequent headings 
has changes. 
Section 7.7 (Other sections affected by change: 3.11) 
7.7 Estimated Creatinine Clearance Calculation 
Significant changes in laquinimod exposure, in particular in terms of 
unbound drug fraction, are predicted in patients with renal impairment 
(see Section 1.3.2.1). Consequently, estimated CrCl will be calculated at all 
7.7 Estimated Creatinine Clearance Calculation 
Significant changes in laquinimod exposure, in particular in 
terms of unbound drug fraction, are predicted in patients with 
renal impairment (see Section 1.3.2.1). Consequently, 
New section - Extra 
creatinine clearance 
monitoring 
added in case of 


 
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visits to monitor chronic renal function in the study in order to identify 
patients with potentially impaired laquinimod clearance. Patients with a 
confirmed CrCl <60 mL/min/1.73 m2 should stop study medication 
temporarily and the CrCl assessment should be repeated. If the renal 
impairment is confirmed (estimated CrCl <60 mL/min/1.73 m2), the 
patient should stop study medication permanently (see Section 3.6). 
Following recent findings connecting Gd-based contrast agents and 
nephrogenic systemic fibrosis, the estimated CrCl result should be 
available prior to the baseline MRI scan. Estimated CrCl calculation will 
be done in accordance with the central laboratory creatinine value 
measurement performed at the screening visit. The central laboratory will 
report calculated CrCl; however, if the result is not available prior to the 
baseline MRI scan, estimated CrCl may be calculated using the Cockcroft-
Gault equation (eg available online CrCl calculator): 
http://reference.medscape.com/calculator/creatinine-clearance-cockcroft-
gault 
estimated CrCl will be calculated at all visits to monitor 
chronic renal function in the study in order to identify patients 
with potentially impaired laquinimod clearance. Patients with 
a confirmed CrCl <60 mL/min/1.73 m2 should stop study 
medication temporarily and the CrCl assessment should be 
repeated. If the renal impairment is confirmed (estimated 
CrCl <60 mL/min/1.73 m2), the patient should stop study 
medication permanently (see Section 3.6). 
Following recent findings connecting Gd-based contrast 
agents and nephrogenic systemic fibrosis, the estimated CrCl 
result should be available prior to the baseline MRI scan. 
Estimated CrCl calculation will be done in accordance with 
the central laboratory creatinine value measurement 
performed at the screening visit. The central laboratory will 
report calculated CrCl; however, if the result is not available 
prior to the baseline MRI scan, estimated CrCl may be 
calculated using the Cockcroft-Gault equation (eg available 
online CrCl calculator): 
http://reference.medscape.com/calculator/creatinine-
clearance-cockcroft-gault 
decrease in renal 
function. 
Section 7.8 (Other sections affected by change: 3.11. Study Procedures) 
Evaluation and management of major modifiable cardiac risk factors (eg, 
body mass index [BMI], diabetes, high blood pressure, hyperlipidemia, 
tobacco smoking) will be performed at the time points indicated in Table 3. 
In addition, an evaluation of cardiovascular risk factors should take place 
as soon as possible for patients already in the study, following approval of 
Global Amendment 04. 
Assessment of changes in cardiovascular risk and appropriate 
cardiovascular risk management with appropriate medical follow-up, if 
clinically indicated, should be performed during the scheduled and 
unscheduled visits. 
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. 
Evaluation and management of major modifiable cardiac risk 
factors (eg, body mass index [BMI], diabetes, high blood 
pressure, hyperlipidemia, tobacco smoking) will be performed 
at the time points indicated in Table 3. In addition, an 
evaluation of cardiovascular risk factors should take place as 
soon as possible for patients already in the study, following 
approval of Global Amendment 04. 
Assessment of changes in cardiovascular risk and appropriate 
cardiovascular risk management with appropriate medical 
follow-up, if clinically indicated, should be performed during 
the scheduled and unscheduled visits. 
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 ASSESSMENT OF PHARMACOKINETICS/PHARMACOGENOMICS/OTHER ANCILLARY STUDIES 
Section 8.1. 


 
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Samples will be analyzed for laquinimod and its metabolites using an 
appropriate validated methods. Incurred sample reanalysis may be 
performed.  
Samples will be analyzed for laquinimod and its metabolites 
using appropriate validated methods. Incurred sample 
reanalysis may be performed.  
Clarification. 
Section 8.1.1  
 
 
Whole blood samples (4 mL) will be collected via venipuncture in the 
morning for plasma concentration measurements of laquinimod and its 
metabolites as follows: 
PPK samples will be collected at visits at Months 1, 3, 6 and 12 from all 
subjects.  
PK samples at Month 1 from a total of 60 patients (15 patients per dose 
group) at the following timepoints  pre dose, 15, 30 min and 1, 2, 3, 6 and 
24 hours post dose. PK samples of laquinimod and its metabolites will be 
collected from approximately 15 patients per each of the three continuing 
treatment groups (at selected sites at Month 1), for a total of 
approximately 45 patients, at the following timepoints – pre-dose, 15, 30 
min and 1, 2, 3, 6 and 24 hours post dose. Additionally, PK samples were 
collected from 2 patients in the laquinimod 1.5 mg/day treatment group 
when the treatment was stopped; no further PK samples will be collected 
from the laquinimod 1.5 mg/day treatment group. 
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 for safety. 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. 
... 
Other measures should be taken as appropriate to prevent samples from any 
heating significantly during centrifugation. Separated plasma will be will be 
placed on water/ice (~0-5°C) and transferred in 3 portions (1 aliquot of 
300uL for laquinimod analysis, and 2 approximately equal portions of 
~750 uL for metabolites analysis) into 3 opaque, labeled, polypropylene 
tubes (sets A , B and C respectively). transferred in approximately equal 
portions into 2 opaque, labeled, polypropylene tubes (sets A and B) and 
Tubes will be placed in an upright position into frozen storage at nominal -
70ºC (if -70ºC storage is not possible at the site, store at -20ºC) (at nominal 
20°C) within 21 hours from the start of the centrifugation.  
Whole blood samples (4 mL) will be collected via 
venipuncture in the morning for plasma concentration 
measurements of laquinimod and its metabolites as follows: 
PPK samples will be collected at visits at Months 1, 3, 6 and 
12 from all subjects.  
PK samples of laquinimod and its metabolites will be 
collected from approximately 15 patients per each of the three 
continuing treatment groups (at selected sites at Month 1), for 
a total of approximately 45 patients, at the following 
timepoints – pre-dose, 15, 30 min and 1, 2, 3, 6 and 24 hours 
post dose. Additionally, PK samples were collected from 2 
patients in the laquinimod 1.5 mg/day treatment group when 
the treatment was stopped; no further PK samples will be 
collected from the laquinimod 1.5 mg/day treatment group. 
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 for 
safety. 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. 
... 
Other measures should be taken as appropriate to prevent 
samples from any heating during centrifugation. Separated 
plasma will be will be placed on water/ice (~0-5°C) and 
transferred in 3 portions (1 aliquot of 300uL for laquinimod 
analysis, and 2 approximately equal portions of ~750 uL for 
metabolites analysis) into 3 opaque, labeled, polypropylene 
tubes (sets A , B and C respectively). Tubes will be placed in 
an upright position into frozen storage at nominal -70ºC (if -
70ºC storage is not possible at the site, store at -20ºC) within 
1 hour from the start of the centrifugation.  
Revision following 
discontinuation of 1.5 
mg treatment arm. 
 
Details regarding 
metabolites PK 
sampling and 
handling added.  
 
Unscheduled samples 
may be collected to 
allow further 
investigation of 
events of interest. 


 
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Sample labels should include the study number, patient randomization 
number, period, nominal collection time, set (A, or B, or C), andindication 
that they are pharmacokinetic samples, and an indication of storage 
conditions at the site (-70ºC or -20ºC).  
  
Sample labels should include the study number, patient 
randomization number, period, nominal collection time, set 
(A, B, or C), indication that they are pharmacokinetic 
samples, and an indication of storage conditions at the site (-
70ºC or -20ºC).  
Section 8.1.2 
... 
Set A and B samples will be transported, frozen with sufficient dry ice for 
4 days, by next-day courier to the bioanalytical laboratory. 
 
Set BC samples will either be sent to the same laboratory as that for sets A 
and B on asubsequent days by next-day courier,or be retained at the central 
laboratory until the study is completed and the clinical study report has been 
issued (unless shipment to another facility is requested by the sponsor). 
Instructions as to the disposition of the B samples will be provided by the 
sponsor. 
 
Sample shipments should be sent no later in the week than Wednesday 
morning for next-day delivery. Samples are not to arrive on the weekend. 
... 
Set A and B samples will be transported, frozen with 
sufficient dry ice for 4 days, by next-day courier to the 
bioanalytical laboratory. 
 
Set C samples will be sent to the same laboratory as that for 
sets A and B on subsequent days by next-day courier. 
 
Sample shipments should be sent no later in the week than 
Wednesday morning for next-day delivery. Samples are not to 
arrive on the weekend. 
Details regarding 
metabolites PK 
sample shipment 
added.  
 
  
Section 8.2 
... 
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 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. 
New text -
Unscheduled samples 
may be collected to 
allow further 
investigation of 
events of interest. 
9 STATISTICS 
Section 9.1 
This is a double-blind, randomized, placebo-controlled, parallel-group study 
to evaluate the efficacy and safety of laquinimod (0.5 mg and 1.0 mg, or 
1.5 mg qd) treatment in patients with HD. Randomization will be as 
described in Section 3.3.  
Prior to 10 January 2016, eligible Ppatients will bewere randomly assigned 
to receive treatment with laquinimod at a dosage of 0.5 mg, 1.0 mg, or 
1.5 mg/day or a matching placebo in a 1:1:1:1 ratio. Randomization will be 
as described in Section 3.3.  
As of 10 January 2016, following a decision to discontinue treatment of 
This is a double-blind, randomized, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of 
laquinimod (0.5 mg and 1.0 mg qd) treatment in patients with 
HD. Randomization will be as described in Section 3.3.  
Prior to 10 January 2016, eligible patients were randomly 
assigned to receive treatment with laquinimod at a dosage of 
0.5 mg, 1.0 mg, or 1.5 mg/day or a matching placebo in a 
1:1:1:1 ratio. As of 10 January 2016, following a decision to 
discontinue treatment of the laquinimod 1.5 mg dose arm, 
Revised following the 
discontinuation of the 
1.5 mg/day treatment 
arm. 


 
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the laquinimod 1.5 mg dose arm, future eligible patients will be 
randomized in a 1:1:1 ratio to receive laquinimod 0.5 mg/day or 1.0 
mg/day or matching placebo for 52 weeks.  
No change was performed to the original randomization list except that 
the patient numbers assigned to laquinimod 1.5 mg/day were removed 
from the list by the IRT vendor. Patients and investigators will remain 
blinded to treatment assignment during the study.  
All patients that discontinued the 1.5 mg/day dose have been unblinded. 
No attempts will be made to re-randomize patients whose 1.5 mg treatment 
was stopped to a lower dose of laquinimod. The remaining ongoing 
patients retained their originally randomized treatment. 
future eligible patients will be randomized in a 1:1:1 ratio to 
receive laquinimod 0.5 mg/day or 1.0 mg/day or matching 
placebo for 52 weeks.  
No change was performed to the original randomization list 
except that the patient numbers assigned to laquinimod 1.5 
mg/day were removed from the list by the IRT vendor. 
Patients and investigators will remain blinded to treatment 
assignment during the study.  
All patients that discontinued the 1.5 mg/day dose have been 
unblinded. No attempts will be made to re-randomize patients 
whose 1.5 mg treatment was stopped to a lower dose of 
laquinimod. The remaining ongoing patients retained their 
originally randomized treatment. 
Section 9.3 
Due to the decision from 10 January 2016 to discontinue treatment of the 
laquinimod 1.5 mg treatment arm, and the low number of enrolled 
patients compared to the target at this time, data from the laquinimod 
1.5 mg treatment arm will be presented descriptively only, and will not be 
included in any inferential analyses for efficacy or safety. 
Due to the decision from 10 January 2016 to discontinue 
treatment of the laquinimod 1.5 mg treatment arm, and the 
low number of enrolled patients compared to the target at this 
time, data from the laquinimod 1.5 mg treatment arm will be 
presented descriptively only, and will not be included in any 
inferential analyses for efficacy or safety. 
Newly-added text for 
clarification following 
the discontinuation of 
the 1.5 mg/day 
treatment arm. 
Section 9.7 
 
 
First, the Hochberg method will be applied for the comparisons of the 3 
2 active doses to placebo in the primary endpoint analysis. 
First, the Hochberg method will be applied for 
the comparisons of the 2 active doses to placebo in the 
primary endpoint analysis. 
Revised following the 
discontinuation of the 
1.5 mg/day treatment 
arm. 
Section 9.9.1 
Blood samples for PK evaluation of laquinimod will be collected at selected 
sites at month 1 from 60 patients in total (15 patients per treatment group). 
PK samples of laquinimod and its metabolites will be collected from 
approximately 15 patients per each of the three continuing treatment 
groups (at selected sites at Month 1), for a total of approximately 45 
patients. Additionally, PK samples were collected from 2 patients in the 
laquinimod 1.5 mg/day treatment group when the treatment was stopped; 
no further PK samples will be collected from the laquinimod 1.5 mg/day 
treatment group. 
Samples will be collected at pre-dose, 15, 30 min and 1, 2, 3, 6 and 24 hours 
post dose.  
Steady state pharmacokinetic parameters for laquinimod (AUCtau, Cmax and 
PK samples of laquinimod and its metabolites will be 
collected from approximately 15 patients per each of the three 
continuing treatment groups (at selected sites at Month 1), for 
a total of approximately 45 patients. Additionally, PK 
samples were collected from 2 patients in the laquinimod 1.5 
mg/day treatment group when the treatment was stopped; no 
further PK samples will be collected from the laquinimod 1.5 
mg/day treatment group. 
Samples will be collected at pre-dose, 15, 30 min and 1, 2, 3, 
6 and 24 hours post dose.  
Steady state pharmacokinetic parameters for laquinimod 
(AUCtau, Cmax and Cmin, tmax), will be calculated for each 
Assessment of 
laquinimod 
metabolites was 
added to the overall 
exploratory PK 
assessment for better 
characterization of 
laquinimod 
disposition. 
Revised following the 
discontinuation of the 
1.5 mg/day treatment 


 
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Cmin, tmax), will be calculated for each patient. 
Additional parameters for laquinimod and pharmacokinetic parameters 
for metabolites may be calculated if data permit. 
... 
patient. 
Additional parameters for laquinimod and pharmacokinetic 
parameters for metabolites may be calculated if data permit. 
... 
arm. 
Section 9.9.2 
A single blood sample will be collected from all patients at months 1, 3, 6 
and 12 for evaluation of laquinimod and its metabolites.  
... 
Pharmacokinetic parameters for laquinimod metabolites may be 
calculated if data permit. 
 
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 for safety (see Section 8.1). 
... 
 
A single blood sample will be collected from all patients at 
months 1, 3, 6 and 12 for evaluation of laquinimod and its 
metabolites.  
...  
Pharmacokinetic parameters for laquinimod metabolites may 
be calculated if data permit. 
 
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 for safety (see Section 8.1). 
... 
Assessment of 
laquinimod 
metabolites was 
added to the overall 
exploratory PK 
assessment for better 
characterization of 
laquinimod 
disposition. 
Clarification 
regarding the PPK 
model. 
APPENDIX A – GUIDANCE ON SAFETY MONITORING 
6. Cancer 
Patients who are diagnosed with invasive cancer a malignant solid or liquid 
tumor while participating in the study should be discontinued from the 
study. 
6. Cancer 
Patients who are diagnosed with a malignant solid or liquid 
tumor while participating in the study should be discontinued 
from the study. 
Correction of 
terminology. 
7. Guidance on monitoring subjects with elevated pancreatic amylase 
levels  
... 
Necessary medical procedures including repeat labs will be performed 
based on clinical needs determined by the treating physician’s judgement. 
7. Guidance on monitoring subjects with elevated 
pancreatic amylase levels  
... 
Necessary medical procedures including repeat labs will be 
performed based on clinical needs determined by the treating 
physician’s judgement. 
Clarification 
8. Guidance on monitoring subjects with hemoglobin decrease 
... 
Necessary medical procedures including repeat labs will be performed 
based on clinical needs determined by the treating physician’s judgement. 
8. Guidance on monitoring subjects with hemoglobin 
 Decrease 
... 
Necessary medical procedures including repeat labs will be 
performed based on clinical needs determined by the treating 
physician’s judgement. 
Clarification 
10. Acute Coronary Syndrome, Myocardial Infarction or Any Major 
Cardiovascular Event 
Patients who experience acute coronary syndrome, myocardial infarction 
or any major cardiovascular event will permanently discontinue treatment 
10. Acute Coronary Syndrome, Myocardial Infarction or Any 
Major Cardiovascular Event 
Patients who experience acute coronary syndrome, 
myocardial infarction or any major cardiovascular event will 
New stopping rule 
implemented for 
patients who 
experience 


 
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with study medication. 
Patients will be asked to continue all scheduled visits for safety 
assessment. 
permanently discontinue treatment with study medication. 
Patients will be asked to continue all scheduled visits for 
safety assessment. 
cardiovascular events. 
11. Liver Impairment 
Patients who develop liver disease associated with liver functional 
impairment while participating in the study should stop study medication. 
11. Liver Impairment 
Patients who develop liver disease associated with liver 
functional 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 
12. Renal Impairment 
Patients who develop chronic renal disease associated with moderate-
severe functional impairment, defined as estimated creatinine clearance 
(CrCl) <60 mL/min/1.73 m2, while participating in the study should stop 
study medication temporarily until normalization of renal function or 
confirmation of renal impairment diagnosis. In case moderate-severe 
renal impairment is diagnosed, the patient will permanently discontinue 
treatment with study medication. 
 
12. Renal Impairment 
Patients who develop chronic renal disease associated with 
moderate-severe functional impairment, defined as estimated 
creatinine clearance (CrCl) <60 mL/min/1.73 m2, while 
participating in the study should stop study medication 
temporarily until normalization of renal function or 
confirmation of renal impairment diagnosis. In case 
moderate-severe renal impairment is diagnosed, the patient 
will permanently discontinue treatment with study 
medication. 
New stopping rule 
implemented to avoid 
increased exposure to 
laquinimod in cases 
of organ impairment 
APPENDIX B – LIST OF DISALLOWED MEDICATIONS PRIOR TO AND DURING STUDY 
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. 
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. 
New text for 
clarification. 
REFERENCES 
Wegner C, Stadelmann C, Pförtner R, Raymond E, Feigelson S, Alon R et 
al. Laquinimod interferes with migratory capacity of T cells and reduces IL
17 levels, inflammatory demyelination and acute axonal damage in mice 
with experimental autoimmune encephalomyelitis. J Neuroimmunol. 
2010;227(1 2):133 43 
 
Brück W, Pförtner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V et al. 
Reduced astrocytic NF κB activation by laquinimod protects from 
cuprizone induced demyelination. Acta Neuropathol. 2012 Sep;124(3):411
(Deleted from list) 
These reference are 
no longer relevant 
following the revision 
of the text in Section 
1.1. 


 
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24 
 
Aharoni R, Saada R, Eilam R, Hayardeny L, Sela M, Arnon R. Oral 
treatment with laquinimod augments regulatory T cells and brain derived 
neurotrophic factor expression and reduces injury in the CNS of mice with 
experimental autoimmune encephalomyelitis. J Neuroimmunol. 2012;251(1
2):14 24. 


 
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16.2. 
ADMINISTRATIVE LETTER 07 DATED 05 NOVEMBER 2015 
 
 


 
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16.3. 
ADMINISTRATIVE LETTER 06 DATED 22 OCTOBER 2015 
 
 


 
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16.4. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03 
DATED 24 SEPTEMBER 2015 
The primary reason for this amendment is to update study eligibility requirements (i.e. shorter 
washout period from previous investigational product) and clarify various aspects of study 
conduct (i.e. option of MRI scan at screening was introducted and frequency of several scales 
was reduced to lessen patient burden, etc.). 
The revisions listed below have been made to the protocol, as appropriate, and are considered 
substantial by the sponsor’s Authorized Representative.  
 
A comparison table showing substantive changes from Amendment 02 to Amendment 03 is 
provided below. Previous text is presented in the column titled “Original text with changes 
shown",” and the revised or new text is presented in the column titled "new wording". Revised or 
new text is shown in bold italics and deletions are shown in strikethrough. Few formatting 
changes have also been made but are not detailed below. 
Changes to the synopsis are not detailed in the table but have been made according to the 
corresponding changes in the body of the protocol. 
Where appropriate, the informed consent form will be amended to reflect the changes introduced 
into the protocol. 
The administrative letters issued since the release of Amendment 02 have been added to the 
summary of changes section. Also, although already mentioned in the amendment history page, 
the administrative letters preceding Amendment 02 have also been added for revision history 
tracking purposes, in line with current Teva standards. 


 
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TITLE PAGE  
Clinical Study Protocol with Amendment 02 03 
Clinical Study Protocol with Amendment 03 
Revised to reflect 
amendment. 
Sponsor’s Safety Officer  
Teva Pharmaceutical Industries, Ltd. 
Sponsor’s Safety Officer  
Teva Pharmaceutical Industries, Ltd. 
 
Updated to reflect the 
identity and contact 
details of the new safety 
physician. 
1 BACKGROUND INFORMATION 
Section 1.1 (Other sections affected by this change: 1.3.1) 
Further, laquinimod was shown to cause a decrease of CYP3A4 
activity and is a potent strong inducer of CYP1A enzymes. 
Further, laquinimod was shown to cause a decrease of 
CYP3A4 activity and is a strong inducer of CYP1A enzymes. 
Language updated for 
consistency with other 
laquinimod protocols 
and Investigator’s 
Brochure. 
Section 1.2 
The capsules are packed in either high-density polyethylene (HDPE) 
bottles equipped with child-resistant caps or aluminium/aluminium 
blister cards and should be stored at room temperature (+15°C to 
+25°C), with excursions permitted to +15°C to +30°C. 
The capsules are packed in either high-density polyethylene 
(HDPE) bottles equipped with child-resistant caps and should 
be stored at room temperature (+15°C to +25°C). 
Clarification regarding 
the primary packaging 
configuration and 
storage. 
Section 1.4.1.3.1. 
To prevent such exposure, female patients who are of child-bearing 
potential (for example women who are not postmenopausal or 
surgically sterilized) must practice an acceptable method of birth 
control (see Section 7.2) are required to use effective contraception 
for 30 days before initiation of treatment, and 2 acceptable methods 
of effective (acceptable) contraception birth control throughout 
treatment and for 30 days after cessation of treatment. Use of 
effective acceptable contraception will be ascertained at every study 
visit.  
... 
All female patients should be counseled by the investigator about the 
potential risks of exposure to laquinimod during pregnancy and the 
need to use effective acceptable contraception and avoid pregnancy 
To prevent such exposure, female patients who are of child-
bearing potential (for example women who are not 
postmenopausal or surgically sterilized) must practice an 
acceptable method of birth control (see Section 7.2) for 30 
days before initiation of treatment, and 2 acceptable methods 
of birth control throughout treatment and for 30 days after 
cessation of treatment. Use of acceptable contraception will 
be ascertained at every study visit.  
... 
All female patients should be counseled by the investigator 
about the potential risks of exposure to laquinimod during 
pregnancy and the need to use acceptable contraception and 
avoid pregnancy throughout treatment with laquinimod and 
Language updated for 
consistency with other 
laquinimod protocols. 


 
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throughout treatment with laquinimod and for 30 days after cessation 
of treatment. 
for 30 days after cessation of treatment. 
3 STUDY DESIGN 
Section 3.2.3 (Other sections affected by this change: 9.6.1.3) 
... 
• 
Change from baseline in CDR-SB at Month 12/ET 
(evaluated at baseline and Months 6 and 12)  
• 
Change from baseline in HADS at Month 12/ET 
(evaluated at baseline and Months 1, 3, 6, and 12) 
• 
Change from baseline in PBA-s at Month 12/ET 
(evaluated at baseline and Months 1, 3, 6, and 12) 
... 
• 
Change from baseline in CDR-SB at Month 
12/ET (evaluated at baseline and Month 12)  
• 
Change from baseline in HADS at Month 12/ET 
(evaluated at baseline and Month 12) 
• 
Change from baseline in PBA-s at Month 12/ET 
(evaluated at baseline and Month 12) 
To reduce patient 
burden, the CDR-SB, 
HADS and PBA-s scales 
will only be assessed at 
baseline and at Month 
12/ET. 
Section 3.6 
Female subjects will be reminded to continue using an acceptable 
method of contraception 2 methods of acceptable contraception 
throughout treatment duration, and up to 30 days from the date 
from the last dose of the study drug, and about the need to stop 
treatment immediately if pregnancy is suspected.  
Female subjects will be reminded to continue using 2 
methods of acceptable contraception throughout treatment 
duration, and up to 30 days from the date from the last dose 
of the study drug, and about the need to stop treatment 
immediately if pregnancy is suspected.  
Language updated for 
consistency with other 
laquinimod protocols. 
Section 3.7.1 
Laquinimod and matching placebo capsules must be stored at room 
temperature (15-25°C), in a dry place, and in a securely locked, 
substantially constructed cabinet or enclosure. 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. Maintenance of a temperature log (manual or 
automated) is required and should be available for review by the 
monitor for the duration of the study. The temperature shall be 
recorded daily and the max/min thermometer reset after each 
reading. Complete instructions on receipt, storage, and handling of 
study drugs will be detailed in the Pharmacy Manual. 
Laquinimod and matching placebo capsules must be stored at 
room temperature (15-25°C), in a dry place, and in a securely 
locked, substantially constructed cabinet or enclosure. 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. Maintenance 
of a temperature log (manual or automated) is required and 
should be available for review by the monitor for the duration 
of the study. The temperature shall be recorded daily and the 
max/min thermometer reset after each reading. Complete 
instructions on receipt, storage, and handling of study drugs 
will be detailed in the Pharmacy Manual. 
Clarification. 
Section 3.7.2 
During the study, all used and 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 
During the study, all used and 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 
Clarification. 


 
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reconciliation and destruction, with account given for any 
discrepancies. A photocopy of these records must be kept at the study 
sites.  
basis for reconciliation and destruction, with account given 
for any discrepancies . A photocopy of these records must be 
kept at the study sites.  
Section 3.10 
Approximately 400 patients from ~35 51 investigational centers in 
North America and, Europe and Russia are planned to be enrolled in 
the study.  
Approximately 400 patients from ~51 investigational centers 
in North America, Europe and Russia are planned to be 
enrolled in the study.  
 
Updated number of and 
location of centers. 
Section 3.11 – Table 3 
No "X' in MRI scan row at the screening visit.  
"X" added to the MRI scan row at screening, and reference to 
footnote m.  
The option to perform 
the MRI scan at 
screening has been 
introduced to reduce 
patient burden. 
(Not applicable)  
A row for the anemia panel has been added to the table. 
Newly added procedure 
for consistency with 
other laquinimod 
protocols. 
Row name "Ascertaining use of effective acceptable contraception" 
Row name changed to "Ascertaining use of acceptable 
contraception" 
Language updated for 
consistency with other 
laquinimod protocols. 
PBA-s was assessed at baseline and at Months 1, 3, 6 and 12 
CDR-SB was assessed at baseline and at Months 6 and 12 
HADS was assessed at baseline and at Months 1, 3, 6 and 12 
PBA-s is assessed at baseline and at Month 12. 
CDR-SB is assessed at baseline and at Month 12. 
HADS is assessed at baseline and at Month 12. 
To reduce patient 
burden, these scales will 
only be assessed at 
baseline and at Month 
12/ET. 
(Not applicable) 
Footnote f: Anemia panel includes B12, 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. 
Newly added footnote 
for clarification 
regarding the anemia 
panel. 
Footnote i j: ECG will be performed in triplicate at baseline 
(approximately 10±5 minutes apart). All other visits will have a 
single ECG performed. 
Footnote j: ECG will be performed in triplicate at baseline 
(approximately 10±5 minutes apart). All other visits will have 
a single ECG performed. 
Clarification regarding 
ECG measurements. 
Footnote j k: At the screening visit, only serum β-HCG test will be 
Footnote k: At the screening visit, only serum β-HCG test 
Clarification that both 


 
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performed. For the baseline visit - Serum urine pregnancy test (beta 
human chorionic gonadotropin [β-hCG]) result is required for 
women of child-bearing potential within the 7 days prior to 
randomization. Whenever possible, this should be sent to the central 
laboratory for analysis. The sample may be sent to a local 
laboratory if timing does not permit sending to the central 
laboratory. The urine test may be conducted at the site to allow 
randomization. A serum β-HCG test should also be used to 
confirm the urine test; however, the randomization should be 
performed based on the results of the urine pregnancy test.  
 
will be performed. For the baseline visit - urine pregnancy 
test (beta human chorionic gonadotropin [β-hCG]) result is 
required for women of child-bearing potential prior to 
randomization. The urine test may be conducted at the site 
to allow randomization. A serum β-HCG test should also be 
used to confirm the urine test; however, the randomization 
should be performed based on the results of the urine 
pregnancy test.  
 
urine and pregnancy 
tests will be performed 
at baseline, and the 
randomization will be 
based on the results of 
urine pregnancy test.  
Footnote m n: The baseline MRI may be performed as soon as 
possible after confirmation of eligibility but not less than 7 days prior 
to baseline can be performed at the screening visit, but no later than 
7 days prior to baseline. If performed at the screening visit, as many 
screening assessements as possible should be conducted prior to the 
MRI scan.  
Footnote m n: The baseline MRI can be performed at the 
screening visit, but no later than 7 days prior to baseline. If 
performed at the screening visit, as many screening 
assessements as possible should be conducted prior to the 
MRI scan in order to assess eligibility.  
The time window for the 
baseline MRI has been 
changed to reduce 
patient burden but 
ensure quality baseline 
MRI scan prior to 
randomization. 
Section 3.11.1  
• 
... 
• 
perform full physical examination (including weight and 
height) 
• 
serum β-HCG in women of child-bearing potential 
within the 7 days prior to initiation of treatment 
• 
HD-CAB 
o 
Includes Symbol Digit Modalities Test 
(SDMT), Emotion Recognition, Trail Making 
Test, Hopkins Verbal Learning Test, revised 
(HVLT-R), Paced Tapping at 3 Hz, One 
Touch Stockings of Cambridge (OTS, 
abbreviated 10 trial version) 
o 
The HD-CAB is performed at screening to 
reduce practice effects during the treatment 
phase.  
• 
MRI scan 
o 
The baseline MRI can be performed at the 
• 
... 
• 
perform full physical examination (including 
weight and height) 
• 
serum β-HCG in women of child-bearing 
potential  
• 
HD-CAB 
o 
Includes Symbol Digit Modalities Test 
(SDMT), Emotion Recognition, Trail 
Making Test, Hopkins Verbal Learning 
Test, revised (HVLT-R), Paced 
Tapping at 3 Hz, One Touch Stockings 
of Cambridge (OTS, abbreviated 10 
trial version) 
o 
The HD-CAB is performed at 
screening to reduce practice effects 
during the treatment phase.  
• 
MRI scan 
The option to perform 
the MRI scan at 
screening has been 
introduced to reduce 
patient burden. 
 
Clarification regarding 
time frame of the serum 
β-HCG test.  


 
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screening visit, but no later than 7 days prior 
to baseline. If performed at the screening 
visit, as many screening assessements as 
possible should be conducted prior to the MRI 
scan in order to assess eligibility.  
• 
inform patients of study restrictions and compliance 
requirements 
• 
The baseline MRI can be performed at the 
screening visit, but no later than 7 days prior to 
baseline. If performed at the screening visit, as 
many screening assessements as possible should 
be conducted prior to the MRI scan in order to 
assess eligibility.  
• 
 inform patients of study restrictions and 
compliance requirements 
Section 3.11.2 
• 
review inclusion/exclusion criteria 
• 
perform clinical laboratory tests 
• 
clinical hematology 
• 
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) and B12 
... 
• 
perform vital signs measurements  
• 
ECG – in triplicate (approximately 10±5 minutes apart) 
• 
urine β-HCG in women of child-bearing potential 
o 
The urine test should be conducted at the site 
to allow randomization. A serum β-HCG test 
should also be used to confirm the urine test; 
however, the randomization should be 
performed based on the results of the urine 
pregnancy test.  
• 
serum β-HCG in women of child-bearing potential 
• 
Serum pregnancy test (β HCG) is performed by the central 
lab within 7 days prior to the baseline visit and result 
obtained prior to randomization no need for additional test 
in Baseline visit. The sample should be sent to the lab at 
least 48 hours prior to the baseline visit to ensure results are 
available.  
• 
Serum pregnancy test (β HCG) is performed by a local lab 
within 7 days prior to the baseline visit, or at the day of the 
baseline visit, and result obtained prior to randomization at 
• 
review inclusion/exclusion criteria 
• 
perform clinical laboratory tests 
• 
clinical hematology  
• 
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) and B12 
... 
• 
perform vital signs measurements  
• 
ECG – in triplicate (approximately 10±5 minutes 
apart) 
• 
urine β-HCG in women of child-bearing potential 
o 
The urine test should be conducted at 
the site to allow randomization. A 
serum β-HCG test should also be used 
to confirm the urine test; however, the 
randomization should be performed 
based on the results of the urine 
pregnancy test.  
• 
serum β-HCG in women of child-bearing potential 
• 
additional urine β-HCG in women of child-bearing 
potential at PET facilities (Only in a subgroup of 
patients) 
• 
Ascertaining use of acceptable contraception 
• 
C-SSRS (since last visit version) 
• 
MRI scan 
o 
The baseline MRI can be performed at 
Anemia panel added at 
baseline for consistency 
with other laquinimod 
protocols. 
Clarification regarding 
ECG measurement. 
The time window for the 
baseline MRI has been 
changed to reduce 
patient burden but 
ensure quality baseline 
MRI scan prior to 
randomization.  
Placement of urine 
pregnancy test in list 
modified. 
 
Clarification that both 
urine and pregnancy 
tests will be performed 
at baseline, and the 
randomization will be 
based on the results of 
urine pregnancy test. 
 
Statement on 
performance of 


 
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the baseline visit day. If the local lab sample is collected on 
the baseline visit day, a sample does not need to be sent to 
the central laboratory as well. 
Results must be obtained prior to randomizing the patient, 
documented in an official lab report and filed with patient’s 
source documents. In case an unscheduled visit is performed, 
all mandatory activities according to the protocol, for this 
visit, should be performed. 
• 
urine β HCG in women of child bearing potential 
• 
additional urine β-HCG in women of child-bearing potential 
at PET facilities (Only in a subgroup of patients) 
• 
Ascertaining use of effective acceptable contraception 
• 
C-SSRS (since last visit version) 
• 
MRI scan 
o 
The baseline MRI can be performed as soon as 
possible after confirmation of eligibility but not 
less than 7 days prior to baseline. can be 
performed at the screening visit, but no later 
than 7 days prior to baseline. 
o 
If anxiolysis is required in order to perform the 
MRI scan, the scan should be performed at the 
end of the study visit day. 
... 
• 
Randomization  
• 
Study drug dispensing 
In case an unscheduled visit is performed, all mandatory activities 
according to the protocol, for this visit, should be performed. 
 
A patient who does not meet the inclusion/exclusion criteria may be 
considered for screening again if there is a change in the patient’s 
medical background, a modification of study entry criteria, or other 
relevant change.  
... 
the screening visit, but no later than 7 
days prior to baseline.  
o 
If anxiolysis is required in order to 
perform the MRI scan, the scan should 
be performed at the end of the study 
visit day. 
... 
• 
Randomization  
• 
Study drug dispensing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In case an unscheduled visit is performed, all mandatory 
activities according to the protocol, for this visit, should be 
performed. 
 
A patient who does not meet the inclusion/exclusion criteria 
may be considered for screening again if there is a change in 
the patient’s medical background, a modification of study 
entry criteria, or other relevant change.  
... 
procedures in case of 
unscheduled visit moved 
below. 
Section 3.11.3.1.1 
.. 
• 
Ascertaining use of effective acceptable contraception 
• 
C-SSRS (since last visit version) 
.. 
• 
Ascertaining use of acceptable contraception 
• 
C-SSRS (since last visit version) 
Language updated for 
consistency with other 
laquinimod protocols. 


 
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• 
UHDRS-TMS 
• 
PBA s 
• 
Q-Motor assessments 
• 
HADS 
• 
Reduced cognitive battery (only SDMT and Trail Making 
Test)  
... 
• 
UHDRS-TMS 
• 
Q-Motor assessments 
• 
Reduced cognitive battery (only SDMT and Trail 
Making Test)  
... 
 
To reduce patient 
burden, the PBA-s and 
the HADS will only be 
assessed at baseline and 
at Month 12/ET. 
Section 3.11.3.1.2 
Use of effective acceptable contraception will be ascertained.  
Use of acceptable contraception will be ascertained.  
Language updated for 
consistency with other 
laquinimod protocols. 
Section 3.11.3.1.3 
... 
• 
Ascertaining use of effective acceptable contraception 
• 
C-SSRS (since last visit version) 
• 
UHDRS-TMS  
• 
UHDRS-TFC 
• 
UHDRS-FA  
• 
mPPT 
• 
PBA s 
• 
CIBIC-plus 
• 
Q-Motor assessments 
• 
HD-CAB 
• 
Includes Symbol Digit Modalities Test (SDMT), Emotion 
Recognition, Trail Making Test, Hopkins Verbal Learning 
Test, revised (HVLT-R), Paced Tapping at 3 Hz, One Touch 
Stockings of Cambridge (OTS, abbreviated 10 trial version) 
• 
CDR SB 
• 
HADS 
• 
PK drug concentration sampling 
... 
... 
• 
Ascertaining use of acceptable contraception 
• 
C-SSRS (since last visit version) 
• 
UHDRS-TMS  
• 
UHDRS-TFC 
• 
UHDRS-FA  
• 
mPPT 
• 
CIBIC-plus 
• 
Q-Motor assessments 
• 
HD-CAB 
o 
Includes Symbol Digit Modalities Test (SDMT), 
Emotion Recognition, Trail Making Test, Hopkins 
Verbal Learning Test, revised (HVLT-R), Paced 
Tapping at 3 Hz, One Touch Stockings of 
Cambridge (OTS, abbreviated 10 trial version) 
• 
PK drug concentration sampling 
... 
Language updated for 
consistency with other 
laquinimod protocols. 
 
To reduce patient 
burden, the PBA-s, the 
CDR-SB and the HADS 
will only be assessed at 
baseline and at Month 
12/ET. 
Section 3.11.3.1.4 (Other sections affected by this change: 3.11.3.1.5; 3.11.4.1; 3.11.5) 
... 
• 
Ascertaining use of effective acceptable contraception 
... 
... 
• 
Ascertaining use of acceptable contraception 
... 
Language updated for 
consistency with other 
laquinimod protocols. 


 
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4 SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.1 (Other sections affected by this change: 7.2; 7.3.5; Appendix A, Section 5) 
d. [Revision 1] Women of child-bearing potential (women who are 
not post menopausal or who have not undergone surgical 
sterilization) must practice an acceptable method of birth control for 
30 days before taking the study treatment, and 2 acceptable methods 
of birth control during all study duration and until 30 days after the 
last dose of treatment was administered. Acceptable methods of birth 
control in this study include: Intrauterine device, barrier method 
(condom or diaphragm with spermicide) and hormonal methods of 
birth control (e.g., oral contraceptive, contraceptive patch, long-acting 
injectable contraceptive). 
d. [Revision 1] Women of child-bearing potential (women 
who are not post menopausal or who have not undergone 
surgical sterilization) must practice an acceptable method of 
birth control for 30 days before taking the study treatment, 
and 2 acceptable methods of birth control during all study 
duration and until 30 days after the last dose of treatment was 
administered. Acceptable methods of birth control in this 
study include: Intrauterine device, barrier method (condom or 
diaphragm with spermicide) and hormonal methods of birth 
control (e.g., oral contraceptive, contraceptive patch, long-
acting injectable contraceptive). 
Corrected per 
Administrative Letter 05 
Issued 29 April 2015. 
Section 4.2 
q. [Revision 1] Treatment with any investigational product within 12 
weeks 30 days of screening or patients planning to participate in 
another clinical study assessing any investigational product during the 
study. Patients in non-interventional and/or observational studies 
will not be excluded from participating in this study. 
q. [Revision 1] Treatment with any investigational product 
within 30 days of screening or patients planning to participate 
in another clinical study assessing any investigational product 
during the study. Patients in non-interventional and/or 
observational studies will not be excluded from participating 
in this study. 
Washout time from 
previous investigational 
product shortened. 
 
Correction of the 
criterion to match the 
wording in the synopsis. 
5 TREATMENT OF PATIENTS 
Section 5.2 
Patients will begin to fast (no food or beverages) at approximately 
22:00 hours on the evening prior to each morning visit that will 
require fasting blood draws.  
For visits 2 through 9, patients must have fasted (no food or 
beverages) no less than 8 hours prior to each morning visit that will 
require fasting blood draws (i.e. a blood draw for the lipid profile, or 
for the safety laboratory panels which include clinical chemistries and 
hormone concentrations). 
For visits 2 through 9, patients must have fasted (no food or 
beverages) no less than 8 hours prior to each morning visit 
that will require fasting blood draws (i.e. a blood draw for the 
lipid profile, or for the safety laboratory panels which include 
clinical chemistries and hormone concentrations). 
Clarification regarding 
the required fasting prior 
to blood draws.  
Section 5.3.1. 
The following medications will not be allowed prior to and during 
this study: 
The following medications will not be allowed prior to and 
during this study: 
Clarification regarding 
time window for 


 
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• 
Use of tetrabenazine within 30 days prior to baseline 
and during the study; 
• 
Use of antipsychotic medication within 30 days prior to 
baseline and during the study; 
• 
Use of moderate/strong inhibitors of CYP3A4 within 2 
weeks prior to randomization, during the study and 
until 30 days after the last study dose has been 
administered. 
• 
Use of inducers of CYP3A4 within 2 weeks prior to 
randomization and during the study;  
• 
Immunosuppressive or immunomodulating agents, or 
cytotoxic agents, including cyclophosphamide and 
azathioprine within 12 months prior to screening and 
during the study;  
• 
Use of experimental or investigational drugs and/or 
participation in drug clinical studies within12 weeks 30 
days of screening 
• 
Use of tetrabenazine within 30 days prior to 
baseline and during the study; 
• 
Use of antipsychotic medication within 30 days 
prior to baseline and during the study; 
• 
Use of moderate/strong inhibitors of CYP3A4 
within 2 weeks prior to randomization, during 
the study and until 30 days after the last study 
dose has been administered. 
• 
Use of inducers of CYP3A4 within 2 weeks 
prior to randomization and during the study; 
• 
Immunosuppressive or immunomodulating 
agents, or cytotoxic agents, including 
cyclophosphamide and azathioprine within 12 
months prior to screening and during the study; 
• 
Use of experimental or investigational drugs 
and/or participation in drug clinical studies 
within 30 days of screening 
disallowed medications. 
Washout time from 
previous investigational 
product shortened. 
6 ASSESSMENT OF EFFICACY 
Section 6.3.8 
6.3.8. Change from baseline in CDR-SB at Month 12/ET 
(evaluated at baseline and Months 6 and 12) 
6.3.8. Change from baseline in CDR-SB at Month 12/ET 
(evaluated at baseline and Month 12) 
To reduce patient 
burden, the CDR-SB 
will only be assessed at 
baseline and at Month 
12/ET. 
Section 6.3.9 
6.3.9 Change from baseline in HADS at Month 12/ET (evaluated 
at baseline and Months 1, 3, 6 and 12) 
6.3.9 Change from baseline in HADS at Month 12/ET 
(evaluated at baseline and Month 12) 
To reduce patient 
burden, the HADS will 
only be assessed at 
baseline and at Month 
12/ET. 
Section 6.3.10 
6.3.10 Change from Baseline in Problem Behaviors Assessment-
Short Form (PBA-s) at Month 12/ET (Evaluated at Baseline and 
Months 1, 3, 6, and 12) 
6.3.10 Change from Baseline in Problem Behaviors 
Assessment-Short Form (PBA-s) at Month 12/ET 
(Evaluated at Baseline and Month 12) 
To reduce patient 
burden, the PBA-s will 
only be assessed at 
baseline and at Month 
12/ET. 


 
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7 ASSESSMENT OF SAFETY 
Section 7.1.5.3.1 
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 
… 
The sponsor or its designee must ensure that the IEC/IRB is also 
informed of the event, in accordance with local regulations.The 
investigator is responsible for ensuring that the IEC/IRB is also 
informed of the event, in accordance with local regulations. 
For all countries, the sponsor’s Global Patient Safety & 
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 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 
… 
The investigator is responsible for ensuring that the IEC/IRB 
is also informed of the event, in accordance with local 
regulations. 
For all countries, the sponsor’s Global Patient Safety & 
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. 
Text has been updated in 
line with current Teva 
standards 
Section 7.1.9 
(Not applicable) 
7.1.9 Medication Error and Special Situations 
Any administration of study medication that is not in 
accordance with the study protocol should be reported on the 
CRF either as a violation, if it meets the violation criteria 
according to the protocol (Section 11.1.2), or as a deviation in 
the patients source documents, regardless of whether an 
adverse event occurs as a result. All instances of incorrect 
medication administration should be categorized as 'Non-
Compliance to IMP'. 
Types of Medication Errors and/or special situations: 
1. Medication error - Any unintentional error in the 
prescribing, dispensing, or administration of a medicinal 
product while in the control of the healthcare professional, 
patient or consumer. 
New text added for 
clarification regarding 
medication errors and 
special situations. 


 
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2. Overdose - Administration of a quantity of a medicinal 
product given per administration or cumulatively which is 
above the maximum recommended dose according to the 
authorized product information. Clinical judgment should 
always be applied. 
3. Misuse - Situations where the medicinal product is 
intentionally and inappropriately used not in accordance with 
the authorized product information. 
4. Abuse - Persistent or sporadic, intentional excessive use of 
medicinal products which is accompanied by harmful 
physical or psychological effects. 
5. Off-label use - Situations where a medicinal product is 
intentionally used for a medical purpose not in accordance 
with the authorized product information. 
6. Occupational exposure- Exposure to a medicinal product, 
as a result of one’s professional or non-professional 
occupation. 
Section 7.2 (Other sections affected by this change: Appendix A, Section 5 
To further emphasize the importance of use of effective acceptable 
contraception and avoidance of pregnancy under laquinimod 
exposure, and to reduce as much as possible the exposure to 
laquinimod if a pregnancy occurs despite all recommended measures, 
all women of childbearing potential (for example women who are not 
postmenopausal or have not undergone surgical sterilization) and not 
using effective acceptable methods of contraception, will be 
instructed about the teratogenicity and potential delayed risks for a 
child exposed in utero to laquinimod. These subjects will be 
counseled about the importance of using effective 2 acceptable 
methods of contraception throughout the entire study 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. Patients who are women of childbearing potential must use 
2 effective acceptable methods of contraception for 30 days prior to 
initiation of treatment, throughout treatment duration and until 
30 days after the last dose of treatment. 
To further emphasize the importance of use of effective 
contraception and avoidance of pregnancy under laquinimod 
exposure, and to reduce as much as possible the exposure to 
laquinimod if a pregnancy occurs despite all recommended 
measures, all women of childbearing potential (for example 
women who are not postmenopausal or have not undergone 
surgical sterilization) and not using acceptable methods of 
contraception, will be instructed about the teratogenicity and 
potential delayed risks for a child exposed in utero to 
laquinimod. These subjects will be counseled about the 
importance of using 2 acceptable methods of contraception 
throughout the entire study 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. 
Patients who are women of childbearing potential must use 
2 acceptable methods of contraception for 30 days prior to 
initiation of treatment, throughout treatment duration and 
until 30 days after the last dose of treatment. 
 
Correction per 
Administrative Letter 05 
Issued 29 April 2015. 
 
Language updated for 
consistency with other 
laquinimod protocols. 


 
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Section 7.3.1 
... 
• 
creatine phosphokinase (CPK) 
o 
Troponin or CPK MB and will be tested in case of abnormal 
CPK results 
in case of CPK results >ULN, troponin or creatine kinase 
MB isoenzyme (CK-MB) will be tested by the central 
laboratory. 
o 
In case of CPK > 10 ULN Urine Myoglobin will be tested 
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. 
• 
total protein 
... 
... 
• 
creatine phosphokinase (CPK) 
o 
in case of CPK results >ULN, troponin or creatine 
kinase MB isoenzyme (CK-MB) will be tested by 
the central laboratory. 
o 
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. 
• 
total protein 
... 
Clarification regarding 
monitoring in case of 
increased CPK for 
consistency with other 
laquinimod protocols. 
Section 7.3.2 
The following hematology tests will be performed: 
• 
Hemoglobin 
• 
In case of hemoglobin decrease of >1g/dL from the 
subject's hemoglobin level at baseline: 
 Subject will be re tested to ascertain true decrease 
 If true decrease, a thorough anemia work up will be 
done including: 
o 
Directed medical history and physical 
examination 
o 
Blood smear, serum iron, ferritin, total iron 
binding capacity, folic acid, B12, haptoglobin, 
and serum sample for cytokines 
o 
Additional investigations and follow up per the 
investigator's discretion or Sponsor's request. 
• 
hematocrit 
... 
The following hematology tests will be performed: 
• 
Hemoglobin 
• 
hematocrit 
… 
Following the addition 
of the anemia panel to 
baseline, this section has 
been deleted from here, 
moved to a separate 
subsection (7.3.3) and 
clarified. 
Section 7.3.3 
(Previous wording from Section 7.3.2) 
The anemia panel is assessed at baseline (with B12) and also at 1 
7.3.3. Anemia Panel 
The anemia panel is assessed at baseline(with B12) and also 
Following the addition 
of the anemia panel to 


 
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subsequent time point if hemoglobin decrease of >1 g/dL from the 
patient’s hemoglobin level at baseline and the decrease is 
confirmed. 
• At baseline: B12, 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 >1g/dL from the subject's 
hemoglobin level at baseline 
- Subject will be re-tested to ascertain true decrease 
- If true decrease decrease confirmed, a thorough anemia work-up 
will be done including: 
o 
Directed medical history and physical examination 
o 
Anemia panel (Blood smear, serum iron, ferritin, total iron 
binding capacity, folic acid, B12, haptoglobin, and serum 
sample for cytokines IL-1, IL-6, IFN-γ, TNF-α, and 
hepcidin) and B12 
o 
Additional investigations and follow-up per the 
investigator's discretion or Sponsor's request 
at 1 subsequent time point if hemoglobin decrease of >1 g/dL 
from the patient’s hemoglobin level at baseline and the 
decrease is confirmed. 
• At baseline: B12, 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 ascertain true decrease 
− if decrease confirmed, a thorough anemia work-up will be 
done including: 
o 
Directed medical history and physical examination 
o 
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 
o 
additional investigations and follow-up per the 
investigator’s discretion or sponsor’s request 
baseline, newly created 
section with explanation 
and guidance regarding 
the anemia panel.  
Some text moved from 
Section 7.3.2 and 
clarified for consistency 
with other laquinimod 
protocols. 
Section 7.3.5 
(Previous wording from Section 7.3.4) 
Human chorionic gonadotropin (β-hCG) serum test will be performed 
for all women of childbearing potential (women who are not post 
menopausal or who have not undergone surgical sterilization) at 
screening (Visit 1) and at all subsequent study visits. An 
indeterminate reading for the serum pregnancy test should be checked 
twice (urine test) and the patient referred to a gynecologist if 
required; Age-appropriate normal ranges for HCG should be used. 
If the reading for the serum pregnancy test is indeterminate, the test 
should be repeated after 3-4 days to see whether there is an increase 
in β-hCG or whether it is a stable elevation. If no increase is 
observed, the patient will not be considered to be pregnant. 
However, no study drug will be administered until this is resolved.  
 
Urine β-hCG tests will be performed for all women of childbearing 
potential at baseline (Visit 2), and at all subsequent visits, and if 
clinically indicated at any other time. 
7.3.5. Human Chorionic Gonadotrophin Tests 
Human chorionic gonadotropin (β-hCG) serum test will be 
performed for all women of childbearing potential (women 
who are not post menopausal or who have not undergone 
surgical sterilization) at screening (Visit 1) and at all 
subsequent study visits. Age-appropriate normal ranges for 
HCG should be used. If the reading for the serum pregnancy 
test is indeterminate, the test should be repeated after 3-4 
days to see whether there is an increase in β-hCG or whether 
it is a stable elevation. If no increase is observed, the patient 
will not be considered to be pregnant. However, no study 
drug will be administered until this is resolved.  
 
Urine β-hCG tests will be performed for all women of 
childbearing potential at baseline (Visit 2), and at all 
subsequent visits, and if clinically indicated at any other time. 
Correction per 
Administrative Letter 05 
Issued 29 April 2015. 
Clarification regarding 
procedure in case of 
indeterminate serum β-
hCG test. 
A serum β-hCG test is 
performed at screening 
only; urine pregnancy 
tests at all other visits. 


 
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Section 7.5 
A single 12-lead ECG will be conducted at screening (Visit 1), and at 
the following in-clinic visits: Week 4, Week 13, Week 26, Week 52 
and follow-up (Visits 3, 4, 6, 8 and 9). During the baseline visit (Visit 
2) a 12-lead ECG will be conducted in triplicate (approximately 10±5 
minutes apart) 
.... 
A single 12-lead ECG will be conducted at screening (Visit 
1), and at the following in-clinic visits: Week 4, Week 13, 
Week 26, Week 52 and follow-up (Visits 3, 4, 6, 8 and 9). 
During the baseline visit (Visit 2) a 12-lead ECG will be 
conducted in triplicate (approximately 10±5 minutes apart). 
... 
Clarification regarding 
ECG measurements. 
APPENDIXA 
Section 1.1.1. 
... 
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 3,), and 28 (±2 3). On at least 1 of these 
days, the test should be performed centrally. (INR should be sent to a 
local laboratory only.) 
... 
Section 1.1.1. 
... 
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 (±3,), and 28 (±3). On at 
least 1 of these days, the test should be performed centrally. 
(INR should be sent to a local laboratory only.) 
... 
Time window increased 
to ±3 days for the Day 
14 and Day 28 
monitoring of liver 
enzyme elevation. 
5. Management of Pregnancy and Pregnancy Testing During the 
Study 
Exposure to laquinimod during pregnancy should be avoided.  
... 
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. 
 
To further emphasize the importance of use of effective acceptable 
contraception and avoidance of pregnancy under laquinimod 
exposure, and to reduce as much as possible the exposure to 
laquinimod if a pregnancy occurs despite all recommended measures, 
the following measures will be taken: 
1. Female subjects of child-bearing potential (women who are not 
post menopausal or who have not undergone surgical sterilization) 
will be reminded at each study visit about: 
a. The importance of using effective acceptable contraception. 
5. Management of Pregnancy and Pregnancy Testing 
During the Study 
Exposure to laquinimod during pregnancy should be avoided.  
... 
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. 
 
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 occurs despite all recommended 
measures, the following measures will be taken: 
1. Female subjects of child-bearing potential (women who are 
not post menopausal or who have not undergone surgical 
sterilization) will be reminded at each study visit about: 
a. The importance of using acceptable contraception. 
Language updated for 
consistency with other 
laquinimod protocols. 


 
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for change 
b. The importance of immediately stopping the study drug and 
informing the site in any case of suspected pregnancy (following a 
positive urine test, absence of menstruation or any other reason 
suggesting pregnancy). 
2. At each scheduled visit, female subjects of childbearing potential 
(women who are not post menopausal or who have not undergone 
surgical sterilization) will undergo a urine β-hCG test. In addition, a 
serum pregnancy β-hCG test will be performed at each visit. 
... 
b. The importance of immediately stopping the study drug 
and informing the site in any case of suspected pregnancy 
(following a positive urine test, absence of menstruation or 
any other reason suggesting pregnancy). 
2. At each scheduled visit, female subjects of childbearing 
potential (women who are not post menopausal or who have 
not undergone surgical sterilization) will undergo a urine β-
hCG test. In addition, a serum pregnancy β-hCG test will be 
performed at each visit. 
... 
(Not applicable) 
8. Guidance on monitoring subjects with hemoglobin 
decrease 
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: B12, 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 
Newly added section to 
appendix to clarify 
monitoring of subjects 
with hemoglobin 
decrease. 
(Not applicable) 
9. Guidance on monitoring subjects with CPK increase  
• 
 In case of CPK results >ULN, troponin or creatine 
kinase MB isoenzyme (CK-MB) will be tested by 
the central laboratory. 
• 
In case of CPK >10×ULN, an unscheduled visit to 
assess urine myoglobin will be required. The 
Newly added section to 
appendix to clarify 
monitoring of subjects 
with CPK increase. 


 
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for change 
following blood tests will be repeated at the 
unscheduled visit: CPK, blood urea nitrogen, 
creatinine, electrolytes including potassium, 
calcium, phosphate. 
APPENDIX B  
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. 
 
Table 4: A Partial List of Moderate/Strong CYP3A4 Inhibitors. These 
Drugs May Increase the Level of Laquinimod and Therefore Are 
Disallowed 2 Weeks Prior to Study, During Study and 30 Days After 
Last Study Dose. 
(additional CYP3A4 inhibitor added to the medication class antivirals 
[elvitegravir])  
 
Notes: 
• 
Interactions between drugs and grapefruit juice are 
documented for drugs with low bioavailability due to 
pre-systemic gut-wall metabolism. Based on the 
suggested high oral bioavailability of laquinimod in 
humans, we do not predict that such interactions are 
expected with laquinimod. 
• 
Moderate/strong CYP3A4 inhibitors are disallowed 
during 30 days after the last dose has been administered 
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. 
 
Table 4: A Partial List of Moderate/Strong CYP3A4 
Inhibitors Disallowed 2 Weeks Prior to Study, During Study 
and 30 Days After Last Study Dose. 
(see Appendix B for revised table) 
 
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. 
Language updated for 
consistency with other 
laquinimod protocols 
and Investigator’s 
Brochure. 
2nd note bullet deleted 
due to redundancy. 
CYP3A4 inducers are disallowed within 2 weeks of baseline and 
during the treatment period. 
Table 5: A Partial List of CYP3A4 Inducers. These Drugs May 
Decrease the Level of Laquinimod and Are Therefore Disallowed 2 
Weeks Prior to Study and During Study 
 
(additional CYP3A4 inducers added to the following medication 
classes: anticonvulsants [Oxcarbazepine] and antipsychotics 
[Thioridazine], and psychostimulants [armodafinil]. The following 
medication class was deleted: Alzheimer's Treatments 
[Semagacestat]) 
CYP3A4 inducers are disallowed within 2 weeks of baseline 
and during the treatment period. 
Table 5: A Partial List of CYP3A4 Inducers.  
 
(see Appendix C for revised table) 
Language updated for 
consistency with other 
laquinimod protocols 
and Investigator’s 
Brochure 


 
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APPENDIX C - LIST OF OTHER CONCOMITANT MEDICATION/THERAPIES 
Table 6: Partial List of Drugs with a Narrow Therapeutic Index That 
Are Metabolized by CYP3A4 (Plasma Levels of These Drugs Could 
Increase when Combined with Laquinimod) 
A Partial List of Cytochrome P450 3A4 Substrates with a Narrow 
Therapeutic Index 
 
Table 6: A Partial List of Cytochrome P450 3A4 Substrates 
with a Narrow Therapeutic Index 
 
List updated for 
consistency with other 
laquinimod protocols 
and Investigator’s 
Brochure 
Table 7: A Partial List of Drugs That Are Mainly Metabolized by 
CYP1A2. 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. 
Table 7: A Partial List of Drugs That Are Mainly 
Metabolized by CYP1A2.  
Deleted text is now table 
footnote and the referral 
to the IB has been added 
for consistency with 
other laquinimod 
protocols  
 


 
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16.5. 
ADMINISTRATIVE LETTER 05 DATED 29 APRIL 2015 
 


 
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16.6. 
ADMINISTRATIVE LETTER 04 DATED 21 APRIL 2015 
 
 


 
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16.7. 
ADMINISTRATIVE LETTER 03 DATED 18 FEBRUARY 2015 
 
 


 
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16.8. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 02 
DATED 16 FEBRUARY 2015 
 
The revisions listed below have been made to the protocol, as appropriate, and are considered 
substantial by the sponsor’s Authorized Representative.  
The primary reason for this amendment is to update study eligibility requirements and clarify 
various aspects of study conduct. An inclusion criterion requiring documentation of prior 
positive genetic testing for HD, or a clinical diagnosis of symptomatic HD (Diagnostic 
Confidence Level 4), was introduced. Also, the range of the CAG repeat length required for 
study eligibility was expanded (lower cut-off of 36 instead of 40).  
During the IND process of Laquinimod for Huntington’s disease trial, the FDA commented that 
given that laquinimod 0.6 mg/day leads to a 5- fold reduction in the systemic concentration of 
caffeine, a cytochrome P450 (CYP) 1A2 probe substrate, an even larger effect on CYP1A2 may 
be observed when the higher doses of 1.0 mg and 1.5 mg planned in the Huntington's Disease 
trial are administered. The FDA recommended that in view of this potential increased effect of 
laquinimod on the pharmacokinetics of CYP1A2 substrates, use of drugs metabolized by 
CYP1A2 should be avoided during the trial. Based on this recommendation, Teva has decided to 
modify all laquinimod protocols in which higher doses of laquinimod than 0.6 mg/day are 
administered and updated the guidance regarding the co-administration of laquinimod and drugs 
that are mainly metabolized by CYP1A2. 
In addition, following the LAQ-MS-305 (CONCERTO) Data Monitoring Committee (DMC) 
recommendation, this amendment includes a requirement to perform abdominal computed 
tomography (CT) as soon as possible when pancreatitis is suspected. Evaluation of pancreatitis is 
important in order to enable adequate or better medical treatment/care. The complete guidance 
for monitoring subjects with elevated pancreatic amylase levels were added to Appendix A. 
Typographical errors have been corrected throughout the protocol. 
Previous changes to the protocol include the Global Amendment 01 following VHP assessment 
and the local UK amendments for the PET sub-study. 
Substantive changes from the Local UK Amendment 01 to the Global Amendment 02 are 
provided below. 
New text is shown in bold italics; deleted text is marked by strikethrough. 


 
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COVER PAGE, INVESTIGATOR AGREEMENT, COORDINATING INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 01 and Local 
Amendment for Ethics Committee Submission in the 
United Kingdom 01 
Clinical Study Protocol with Amendment 0102 and Local 
Amendment for Ethics Committee Submission in the United 
Kingdom 01  
Updated to reflect 
amendment. 
Authorized Representative (Signatory) 
Teva Pharmaceutical Industries, Ltd. 
 
Authorized Representative (Signatory) 
Teva Pharmaceutical Industries, Ltd. 
Teva Branded Pharmaceutical Products R&D, Inc. 
Updated to reflect the 
identity of the new Sponsor 
Authorized Representative 
and Signatory. 
Sponsor’s Global Clinical Leader  
Teva Pharmaceutical Industries, Ltd. 
 
 
Sponsor’s Global Clinical Leader  
Teva Pharmaceutical Industries, Ltd. 
 
Sponsor's Medical Expert 
Teva Branded Pharmaceutical Products 
R&D, Inc. 
  
Updated to reflect the 
identity and contact details 
of the new study medical 
expert. 
Teva Pharmaceutical Industries, Ltd. 
 
 
Teva Pharmaceutical Industries, Ltd. 
 
Updated to reflect the 
identity and contact details 
of the new safety physician. 
Global Coordinating Investigator: 
  
Global Coordinating Investigator: 
 
 Germany
 
 
Modified title of the 
coordinating investigator. 


 
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Central Clinical Laboratory 
Quest Diagnostics 
Unit B1 Parkway West, Cranford Lane  
Heston, Middlesex, TW5 9QA 
UK 
 
Electronic Data Capture 
Pending: Information will be included in the Trial Master 
File. 
 
Central Institutional Review Board 
Pending: Information will be included in the Trial Master 
File. 
Central Electrocardiogram Evaluation 
Pending: Information will be included in the Trial Master 
File. 
Central Clinical Laboratory 
Quest Diagnostics 
Unit B1 Parkway West, Cranford Lane  
Heston, Middlesex, TW5 9QA 
UK 
Quest Diagnostics Clinical Laboratories, Inc.  
27027 Tourney Road 
Suite 2E Valencia, CA 91355  
USA  
 
Quest Diagnostics Limited Unit B1 
Parkway West Industrial Estate Cranford Lane – Heston 
Middlesex TW5 9QA  
UK  
 
Quest Diagnostics Nichols Institute 
33608 Ortega Highway  
San Juan Capistrano, CA 92675-2042  
USA  
Electronic Data Capture 
Pending: Information will be included in the Trial Master File. 
 
Central Institutional Review Board 
Pending: Information will be included in the Trial Master File. 
 
Central Electrocardiogram Evaluation 
Pending: Information will be included in the Trial Master File. 
Biomedical Systems Corporation 
77 Projgress Parkway 
St. Louis, MO 63053 
USA 
 
Web and Phone Integrated Interactive Response Technology 
PAREXEL International 
Lady Bay House 
Meadow Grove 
Nottingham 
Section updated to include 
the various vendors of this 
study. 


 
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NG2 3HF 
UK 
Computer-Based Rating System 
QuantiMedis GmbH 
Marientalstrasse 43 
48149 Münster 
Germany 
 
Stout Neuropsych Pty Ltd 
44 Stewart Street 
Ormond VIC 3204 
Australia 
 
Bioanalytical Laboratory  
Teva Pharm. Works Private Ltd. Co (TPW) 
Pallagi St 13 
4042 Debrecen 
Hungary 
 
Collaborator 
Huntington Study Group 
2604 Elmwood Avenue, Suite 335 
Rochester, NY 14618 
USA 
 
European Huntington’s Disease Network 
University of Ulm 
Oberer Eselsberg 45/1 
D-89081 Ulm 
Germany 
 
Central MRI Vendor 
IXICO Technologies Limited 
4th Floor, Griffin Court 
15 Long Lane 
London 
EC1A 9PN 


 
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United Kingdom 
 
Scale Management 
Bracket 
575 E. Swedesford Road, Suite 200 
Wayne, PA 19087 
USA 
 
MRS Analysis 
University of British Columbia MRI Research Centre 
Room M10 Purdy Pavilion 
2221 Wesbrook Mall 
Vancouver 
British Columbia 
V6T 2B5 
CANADA 
PET Substudy 
Imperial College London 
Hammersmith Hospital, Neurology Imaging Unit 
Du Cane Road 
London 
W12 0NN 
United Kingdom 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
Global/EU : 
  
ICON 
Germany 
 
US: 
 
ICON 
USA 
Global/EU: 
  
ICON 
Germany 
(Located in Germany) 
US: 
 
Updated contact information 
for medical monitors and 
CRO call center. 


 
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Reason/justification for 
change 
 
ICON 
USA 
 
In a study-related medical emergency situation, when assigned 
Medical Monitors for a study cannot be reached, an on-call 
Physician can be reached 24 hours per day, 7 days per week via an 
ICON Call-Center: 
  
[Toll (not free of charge) telephone number allowing a global 
reach from both landlines and mobile phones] 
 
On the following internet page (https://icophone.iconplc.com), a 
list of country-specific toll-free telephone numbers is provided. It 
should be noted that not all countries globally have access to toll-
free numbers as indicated on the “24/7 Medical Help desk” index. 
Countries without toll-free numbers need to dial the toll (not free 
of charge) number as indicated above. Toll-free numbers are 
unfortunately not available from mobile phones.  
SYNOPSIS 
Randomization will be performed by interactive response 
technology (IRT) using dynamic randomization to balance 
the treatment groups within centers. Subjects will be 
equally assigned to the 4 treatment groups of the study (3 
active treatment groups and placebo, allocation ratio of 
1:1:1:1). 
 
In case that the safety committee will not approve 
continuation of one or more doses of laquinimod, the 
dynamic randomization algorithm will be adjusted to apply 
an equal allocation ratio to all approved remaining 
treatment groups.  
Randomization will be performed by interactive response 
technology (IRT) using dynamic randomization to balance the 
treatment groups within centers. Subjects will be equally assigned to 
the 4 treatment groups of the study (3 active treatment groups and 
placebo, allocation ratio of 1:1:1:1). 
 
In case that the safety committee will not approve continuation of 
one or more doses of laquinimod, the dynamic randomization 
algorithm will be adjusted to apply an equal allocation ratio to all 
approved remaining treatment groups.  
Patients will be randomly assigned to receive treatment with 
laquinimod at a dosage of 0.5, 1.0, or 1.5 mg qd or a matching 
placebo in a 1:1:1:1 ratio.  
Clarification and correction 
of text to reflect the method 
of blinding and 
randomization as described 
in protocol. 


 
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Patients and investigators will remain blinded to treatment 
assignment during the study.  
 
The randomization code will be generated by the Clinical Supply 
Chain (CSC) department following specifications from the 
Biostatistics Department.  
 
In addition, the sponsor’s clinical personnel involved in the study 
will be blinded to the study drug identity until the database is 
locked for analysis and the treatment assignment revealed.  
o 
Urinalysis at the screening visit (dipstick). 
o 
Urinalysis at the screening visit (dipstick). 
Sample analysis will be 
performed at the central lab. 
1 BACKGROUND INFORMATION 
Section 1.1 (Other sections affected by this change: 1.3.1) 
Further, laquinimod was shown to cause a marked decrease 
of CYP3A4 activity and is a potent 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. 
Further, laquinimod was shown to cause a marked decrease of 
CYP3A4 activity and is a potent 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. 
Laquinimod 0.6 mg/day and 
1.2 mg/day increased the 
systemic exposure of 
midazolam (a sensitive 
CYP3A4 substrate) by 1.5 
and 1.7 fold, respectively; 
therefore laquinimod is 
considered a weak CYP3A4 
inhibitor. 
Section 1.3.1 
Finally, a small increase in the incidence of oral cavity 
squamous cell carcinomas was noted in mid and high dose 
female rats (2/60 in each group). It is the sponsor’s position 
that this finding is likely a result of direct contact of the rat 
oral mucosa with high concentrations of laquinimod in the 
dosing solution.  
Although the mechanism leading to the local effect is 
unknown, the possibility that the local effect may relate to 
the AhR activation by laquinimod cannot be excluded. Oral 
cavity tumors have been observed in rat carcinogenicity 
studies for some AhR agonists, but the incidence rate of 
these tumors was higher than the incidence rate observed 
for laquinimod. Regardless of the mechanism underlying 
Finally, a small increase in the incidence of oral cavity squamous 
cell carcinomas was noted in mid and high dose female rats (2/60 in 
each group). It is the sponsor’s position that this finding is likely a 
result of direct contact of the rat oral mucosa with high 
concentrations of laquinimod in the dosing solution.  
Although the mechanism leading to the local effect is unknown, the 
possibility that the local effect may relate to the AhR activation by 
laquinimod cannot be excluded. Oral cavity tumors have been 
observed in rat carcinogenicity studies for some AhR agonists, but 
the incidence rate of these tumors was higher than the incidence rate 
observed for laquinimod. Regardless of the mechanism underlying 
this local effect, whether non specific cytotoxicity or local AhR 
activation, a local effect on the rat oral mucosa is not considered 
Clarification regarding oral 
cavity tumors in non-clinical 
section. 


 
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this local effect, whether non-specific cytotoxicity or local 
AhR activation, a local effect on the rat oral mucosa 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 large safety margins. 
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 large safety margins. 
In addition, an increase in the incidence of oral cavity tumors was 
noted in mid and high dose females (2/60 in each group). The oral 
effects may relate to the AhR activation properties of laquinimod 
since similar lesions were seen with other AhR activators, 
including industrial chemicals (such as 2,3,7,8-tetrachlorodibenzo-
p-dioxin [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. 
Section 1.3.2.1 
Laquinimod is considered to have high oral bioavailability 
with linear, time independent and predictable PK that is 
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 
Laquinimod is considered to have high oral bioavailability with 
linear, time independent and predictable PK that is 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 
New text regarding 
concomitant use of CYP1A2 
substrates with laquinimod. 
 
This change was made In 
response to the FDA request 
to avoid the use of CYP1A2 
substrates in th study 


 
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administration with a high-fat high-calorie meal results in 
reduction of the absorption rate reflected by prolongation 
of the time to maximal plasma drug concentration (Tmax) to 
approximately 5 hours and reduction of the maximum 
plasma concentration (Cmax) by 30%. Food however did not 
significantly affect the overall extent of absorption AUC. 
 
Laquinimod is extensively metabolized predominantly by 
CYP3A4. Laquinimod metabolites levels in plasma are 
very low and parent laquinimod is the main systemically 
circulating entity. Laquinimod PK is affected by moderate 
and strong CYP3A4 inhibitors, strong CYP3A4 inducers 
and moderate hepatic impairment. Laquinimod 0.6 and 
1.2 mg dose is a weak inhibitor of CYP3A4 and a strong 
inducer of CYP1A2. 
For additional information, please refer to the IB. 
 
 
in reduction of the absorption rate reflected by prolongation of the 
time to maximal plasma drug concentration (Tmax) to approximately 
5 hours and reduction of the maximum plasma concentration (Cmax) 
by 30%. Food however did not significantly affect the overall extent 
of absorption AUC. 
 
Laquinimod is extensively metabolized predominantly by CYP3A4. 
Laquinimod metabolites levels in plasma are very low and parent 
laquinimod is the main systemically circulating entity. Laquinimod 
PK is affected by moderate and strong CYP3A4 inhibitors, strong 
CYP3A4 inducers and moderate hepatic impairment. Laquinimod 
0.6 and 1.2 mg dose is a weak inhibitor of CYP3A4 and a strong 
inducer of CYP1A2. Studies have shown that laquinimod is a 
strong inducer of CYP1A2 and a weak inhibitor of CYP3A4. 
Therefore, co-administration of laquinimod may affect the 
systemic exposure of drugs metabolized by CYP450 1A2 or 
CYP3A4. 
For additional information, please refer to the IB. 
Plasma levels of drugs that are CYP1A2 substrates may decrease 
when combined with laquinimod and within 30 days after the last 
laquinimod dose, rendering these drugs less effective.  
 
In general, it is recommended to avoid the use of CYP1A2 
substrates in clinical trials of laquinimod. Therapeutic alternatives 
may be considered in context. 
 
For additional information on concomitant use of laquinimod with 
CYP1A2 substrates, please refer to Section 5.3.2.  
Section 1.7 
Thus, the target patient population will be adult patients, 
with a CAG repeat length between 40 and 49, and the basic 
eligibility criteria will select a patient population with 
symptoms of HD, as assessed by a Unified Huntington’s 
Disease Rating Scale Total Motor Score (UHDRS-TMS) 
>5, but with a largely retained functional capacity, as 
assessed with a HDRS-Total Functional Capacity 
Thus, the target patient population will be adult patients, with a 
CAG repeat length between 40 36 and 49, and the basic eligibility 
criteria will select a patient population with symptoms of HD, as 
assessed by a Unified Huntington’s Disease Rating Scale Total 
Motor Score (UHDRS-TMS) >5, but with a largely retained 
functional capacity, as assessed with a HDRS-Total Functional 
Capacity (UHDRS-TFC) score ≥8. This will recruit a symptomatic 
Updated to reflect CAG 
repeat length required for 
study eligibility. 


 
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(UHDRS-TFC) score ≥8. This will recruit a symptomatic 
early HD patient population. 
early HD patient population. 
3 STUDY DESIGN 
Section 3.1 (Other sections affected by this change: 3.11.1; Table 3) 
After signing the informed consent, including consent to 
provide a blood sample for genetic analyses including 
CAG repeat length analysis, patients will be screened for a 
period of 2 weeks up to 5 weeks in order to determine 
whether they are eligible to participate in the study.  
After signing the informed consent, including consent to provide a 
blood sample for genetic analyses including CAG repeat length 
analysis, patients will be screened for a period of 2 weeks up to 5 
weeks in order to determine whether they are eligible to participate 
in the study. Patients with a legal guardian should be consented 
according to local requirements. 
Text added for clarification. 
Section 3.2.8 
 
 
The patient will be given the opportunity to decide whether 
the exact CAG repeat result will be disclosed to them or 
not. If not, the result will be reported only as within or 
outside of the eligibility range (40-49 inclusive).  
The patient will be given the opportunity to decide whether the exact 
CAG repeat result will be disclosed to them or not. If not, the result 
will be reported only as within or outside of the eligibility range (40
49 inclusive). The exact CAG repeat length will not be available to 
the sites, only to the Sponsor. The central laboratory report will 
only note if the patient is within the eligibility criteria range (36-49 
inclusive) or not.  
To correctly reflect the 
reporting from the central 
laboratory, and per the 
administrative letter dated 
14 November 2014, and 
updated to reflect CAG 
repeat length required for 
eligibility. 
Section 3.6 
(Not applicable) 
3.6.1 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. 
 
The reasons for temporary study drug discontinuation should be 
recorded in the appropriate section of the study drug dispensing 
and compliance log in the electronic Case Report Form (eCRF). 
 
The subject will report any temporary discontinuation to the 
investigator and will be instructed by the investigator regarding 
continuation of treatment. 
Addition of new sections 
regarding temporary 
discontinuation of study 
drug. 
Section 3.10 
The study is expected to start in Q3 2014 (first patient 
randomized) and be completed in Q3 2016 (last patient last 
The study is expected to start in Q3 2014 (first patient randomized) 
and be completed in Q3 Q4 2016 (last patient last visit). 
Updated planned study end 
date and number of 


 
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visit). 
Approximately 400 patients from ~30 investigational 
centers in North America and Europe are planned to be 
enrolled in the study.  
  
Approximately 400 patients from ~30 35 investigational centers in 
North America and Europe are planned to be enrolled in the study.  
investigational centers. 
Section 3.11 – Table 3 (Other sections affected by this change: 5.2)  
c. Patients must have fasted no less than 8 hours prior to 
the blood draw.  
c. For visits 2 through 9, Ppatients must have fasted no less than 8 
hours prior to the blood draw.  
Clarification that fasting is 
not needed for the laboratory 
tests taken at the screening 
visit. 
Section 3.11 – Table 3 (Other sections affected by this change 3.11.2; 3.11.3.1.5; 8.2.1)  
f. Blood sample for monocyte collection and analysis has 
to be done in the morning, at 12:00 (noon) at the latest.  
f. Blood sample for monocyte collection and analysis has to be done 
in the morning, at 12:00 (noon) at the latest in accordance with the 
laboratory manual. For UK patients, the sample can be drawn 
prior to the baseline or Month 12 visit, as it coincides with the PET 
scan visits. 
Reference to a specific time 
point for monocyte blood 
collection has been removed. 
 
Clarification added 
regarding monocyte testing 
for UK patients. 
Section 3.11 – Table 3 (Other sections affected by this change: 7.4) 
g. During the visits, vital sign measurements, physical 
examinations and ECG should be performed prior to the 
blood draw for clinical laboratory tests and 
pharmacokinetic sampling. 
g. During the visits, vital sign measurements, physical examinations 
and ECG should be performed prior to the blood draw for clinical 
laboratory tests and pharmacokinetic sampling. 
The prescribed order of 
laboratory tests, ECGs and 
vital signs has been deleted 
to simplify conduct of study 
procedures. 
Section 3.11 – Table 3 (Other sections affected by this change: 3.11; 7.4)  
j. Including postural BP changes. 
j.Including postural BP changes. 
Footnote deleted; All 
references to "postural blood 
pressure changes" have been 
removed. Only supine 
measurements will be 
captured. 
Section 3.11 – Table 3 (Other sections affected by this change: 3.11.2) 
j. At the screening visit, only serum β-HCG test will be 
performed. For the baseline visit - Serum pregnancy test 
(beta human chorionic gonadotropin [β-hCG]) result is 
required for women of child-bearing potential within the 
7 days prior to initiation of treatment.  
j. At the screening visit, only serum β-HCG test will be performed. 
For the baseline visit - Serum pregnancy test (beta human chorionic 
gonadotropin [β-hCG]) result is required for women of child-bearing 
potential within the 7 days prior to initiation of treatment 
randomization. Whenever possible, this should be sent to the 
central laboratory for analysis. The sample may be sent to a local 
Clarification regarding 
procedure for the β-HCG 
testing prior to 
randomization and 
acceptability of local 
laboratory. 


 
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laboratory if timing does not permit sending to the central 
laboratory. 
Section 3.11 – Table 3 
k. An additional urine β-HCG test will be performed at the 
PET facilities at Imperial College in London at the 
Baseline visit and at Visit 8. This is a requirement for 
women of child-bearing potential participating in the 
PET substudy. Its result will be available on site prior to 
any procedures involving ionizing radiation and will be 
considered accordingly. 
k. An additional urine β-HCG test will be performed at the PET 
facilities at Imperial College in London at the Baseline visit and at 
Visit 8. This is a requirement for women of child-bearing potential 
participating in the PET substudy. Its result will be available on 
site prior to any procedures involving ionizing radiation and will 
be considered accordingly. 
Clarification of footnote 
regarding the additional β-
HCG test prior to the PET 
scan. 
 
 
 
Section 3.11 – Table 3 (Other sections affected by this change: 3.11.2; 3.11.3.1.5) 
(Not applicable) 
l. If anxiolysis is required in order to perform the MRI scan, the scan 
should be performed at the end of the study visit day. 
Clarification regarding 
timing of MRI scan in case 
of anxiolysis. 
Section 3.11 – Table 3 
m. The MRI can be done +/- 5 days from the clinical visit – 
once the eligibility of the patient has been established at 
screening.  
m.The MRI can be done +/  5 days from the clinical visit  once the 
eligibility of the patient has been established at screening. The 
baseline MRI may be performed as soon as possible after 
confirmation of eligibility but not less than 7 days prior to baseline. 
The time window for the 
baseline MRI has been 
changed to ensure quality 
baseline MRI scan prior to 
treatment initiation. 
Section 3.11 – Table 3  
The PET scan can be done at any time within 14 days prior 
to the date of the baseline visit, after eligibility of the 
patient has been confirmed. It can also be done 14 days 
prior to the Month 12 visit. 
The PET scan can be done at any time within 14 days prior to the 
date of the baseline visit, after eligibility of the patient has been 
confirmed. It can also be done 14 days 2 to 5 weeks prior to the 
Month 12 visit. 
Revised time window for the 
PET scan prior to the 
baseline visit. 
Section 3.11 – Table 3 (Other sections affected by this change: 3.11.2; 3.11.3.1.5; 8.2.4) 
(Not applicable) 
Patients taking benzodiazepines should be instructed to stop taking 
them for 3 days prior to having the PET scan. 
New text to disallow 
benzodiazepines 3 days prior 
to the PET scan, as 
benzodiazepines could 
interfere with TSPO binding. 
Section 3.11 – Table 3 
(Not applicable) 
If a patient terminates within 3 months of the baseline visit, they 
will not undergo an Early Termination scan. If a patient 
terminates prior to Month 12, the Early termination scans should 
be performed as soon as possible, but not more than 7 days after 
Newly added footnote 
regarding the timing of the 
Month 12/Early Termination 
MRI scan. 


 
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discontinuation of study drug. Month 12 scans should be 
performed 7 days prior to the Termination Visit. 
Section 3.11 – Table 3 (Other sections affected by this change: 3.11.3.1.1) 
w. Only at selected sites in a subgroup of patients, N=60 
(15 from each treatment arm), at Month 1.  
w. Only at selected sites in a subgroup of patients, N=60 (15 from 
each treatment arm), at Month 1. Patients participating in the 24-
hour PK profiling will not have the single PK sample drawn at 
Visit 3. 
Clarification that patients 
participating in 24hr PK will 
not need the single PK 
sample drawn. 
Section 3.11.2 
… 
• 
blood sample for monocyte analysis (Only at 
selected sites in a subgroup of patients) 
o 
Blood sample for monocyte 
collection and analysis has to be 
done in the morning, at 12:00 (noon) 
at the latest 
• 
perform full physical examination (including 
weight) 
• 
perform vital signs measurements (including 
postural BP changes) 
• 
ECG – in triplicate 
• 
serum β-HCG in women of childbearing 
potential 
• 
urine β-HCG in women of childbearing 
potential 
• 
Ascertaining use of effective contraception 
• 
C-SSRS (since last visit version) 
• 
MRI scan 
• 
MRS scan (Only at selected sites in a 
subgroup of patients) 
... 
 
… 
• 
blood sample for monocyte analysis (Only at selected 
sites in a subgroup of patients) 
o 
Blood sample for monocyte collection and 
analysis has to be done in the morning, at 
12:00 (noon) at the latest in accordance with 
the laboratory manual. 
o 
For UK patients, the sample can be drawn 
prior to the baseline visit, as it coincides with 
the PET scan visit. 
• 
perform full physical examination (including weight) 
• 
perform vital signs measurements (including postural 
BP changes)  
• 
ECG – in triplicate 
• 
serum β-HCG in women of childbearing potential 
Women of child-bearing potential must have a serum 
β-hCG within 7 days prior to the initiation of 
treatment. Whenever possible, this sample should be 
sent to the central laboratory for analysis. The sample 
may be sent to a local laboratory if timing does not 
permit sending to the central laboratory. The 
scenarios are as follows: 
o 
Serum pregnancy test (β-HCG) is performed by 
the central lab within 7 days prior to the baseline 
visit and result obtained prior to randomization – 
no need for additional test in Baseline visit. The 
sample should be sent to the lab at least 48 hours 
prior to the baseline visit to ensure results are 
Clarifications regarding 
various baseline assessments 
and procedures. 
 
Reference to specific time 
points for monocyte analysis 
was omitted; clarification 
regarding analysis for 
patients participating in the 
PET study. 
 
All references to postural 
blood pressure changes were 
removed. Only supine 
measurements will be 
captured. 
 
Clarification regarding 
procedure for the β-HCG 
testing prior to 
randomization and 
acceptability of local 
laboratory. 
  
The time window for the 
baseline MRI has been 
changed to ensure quality 
baseline MRI scan prior to 
treatment initiation. 
 


 
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Reason/justification for 
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available.  
o 
Serum pregnancy test (β-HCG) is performed by a 
local lab within 7 days prior to the baseline visit, 
or at the day of the baseline visit, and result 
obtained prior to randomization at the baseline 
visit day. If the local lab sample is collected on 
the baseline visit day, a sample does not need to 
be sent to the central laboratory as well. 
Results must be obtained prior to randomizing the 
patient, documented in an official lab report and filed 
with patient’s source documents. In case an 
unscheduled visit is performed, all mandatory 
activities according to the protocol, for this visit, 
should be performed. 
• 
urine β-HCG in women of childbearing potential 
• 
additional urine β-HCG in women of childbearing 
potential at PET facilities (Only in a subgroup of 
patients) 
• 
Ascertaining use of effective contraception 
• 
C-SSRS (since last visit version) 
• 
MRI scan 
• 
 
o 
The baseline MRI can be performed as soon 
as possible after confirmation of eligibility 
but not less than 7 days prior to baseline. 
• 
MRS scan (Only at selected sites in a subgroup of 
patients) 
• 
PET scan (Only at selected sites in a subgroup of 
patients) 
o 
The PET scan can be done at any time prior 
to the date of the baseline visit, after 
eligibility of the patient has been confirmed.  
o 
Patients taking benzodiazepines should be 
instructed to stop taking them for 3 days 
prior to having the PET scan. 
• 
UHDRS-TMS 
Clarifications regarding 
performance of the PET 
scan. 


 
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Amended or new wording 
Reason/justification for 
change 
… 
Section 3.11.3.1.5 
... 
• 
blood sample for gene expression analysis 
• 
blood sample for monocyte analysis (Only at 
selected sites in a subgroup of patients) 
o 
Blood sample for monocyte 
collection and analysis has to be 
done in the morning, at 12:00 
(noon) at the latest 
• 
serum β-HCG in women of childbearing 
potential 
• 
urine β-HCG in women of childbearing 
potential 
• 
additional urine β-HCG in women of 
childbearing potential at PET facilities (Only 
in a subgroup of patients) 
• 
Ascertaining use of effective contraception 
• 
PK drug concentration sampling 
• 
C-SSRS (since last visit version) 
• 
MRI scan 
• 
MRS scan (Only at selected sites in a 
subgroup of patients) 
• 
PET scan (Only at selected sites in a 
subgroup of patients) 
• 
UHDRS-TMS  
... 
... 
• 
blood sample for gene expression analysis 
• 
blood sample for monocyte analysis (Only at selected 
sites in a subgroup of patients) 
o 
Blood sample for monocyte collection and 
analysis has to be done in the morning, at 
12:00 (noon) at the latest in accordance with 
the laboratory manual 
o 
For UK patients, the sample can be drawn 
prior to the Month 12 visit, as it coincides 
with the PET scan visit 
• 
serum β-HCG in women of childbearing potential 
• 
urine β-HCG in women of childbearing potential 
• 
additional urine β-HCG in women of childbearing 
potential at PET facilities (Only in a subgroup of 
patients) 
• 
Ascertaining use of effective contraception 
• 
PK drug concentration sampling 
• 
C-SSRS (since last visit version) 
• 
MRI scan 
o 
If anxiolysis is required in order to perform 
the MRI scan, the scan should be performed 
at the end of the study visit day. 
• 
MRS scan (Only at selected sites in a subgroup of 
patients) 
• 
PET scan (Only at selected sites in a subgroup of 
patients) 
o 
The PET scan can be done 2 to 5 weeks prior 
to the Month 12 visit. 
o 
Patients taking benzodiazepines should be 
instructed to stop taking them for 3 days 
prior to having the PET scan. 
• 
UHDRS-TMS 
Clarifications regarding 
various baseline assessments 
and procedures. 
 
Reference to specific time 
points for monocyte analysis 
was omitted; clarification 
regarding analysis for 
patients participating in the 
PET study. 
 
All references to postural 
blood pressure changes were 
removed. Only supine 
measurements will be 
captured. 
 
Clarifications regarding 
performance of the PET 
scan. 
 
Newly added text regarding 
CYP1A2 substrates and 
CYP3A4 inhibitors 
following the last dose of 
study drug. 


 
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...  
Moderate/strong CYP3A4 inhibitors are disallowed during the 
30 days after the last laquinimod dose has been administered (see 
Appendix B).  
Plasma levels of drugs that are CYP1A2 substrates may decrease 
when combined with laquinimod and within 30 days after the last 
laquinimod dose, rendering these drugs less effective (see 
Appendix C).  
4 SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.1 
(Not applicable) 
l. [New criterion] Documentation of prior positive genetic testing 
for HD, or a clinical diagnosis of symptomatic HD (Diagnostic 
Confidence Level 4). 
New inclusion criterion 
introduced. 
 
As a result, the lettering of 
the subsequent criteria have 
changed. 
 
a. Presence of 40-49 CAG repeats, inclusive, in the 
huntingtin gene based on centralized CAG testing during 
screening. 
ab. [Revision 1] Presence of 4036-49 CAG repeats, inclusive, in the 
huntingtin gene based on centralized CAG testing during screening. 
Modified number of CAG 
repeats in the huntingtin 
gene required for eligibility 
to only disallow patients 
with more than 49 CAG 
repeats. 
Section 4.2 
h. Creatinine clearance <60 mL/min at screening, 
calculated using the Cockcroft Gault equation: (140 - age) 
× mass (kg) × [0.85 if female] / 72 × serum creatinine 
(mg/dL) x 88.4 
h. [Revision 1] Creatinine clearance <60 mL/min at screening, 
calculated using the Cockcroft Gault equation: (140 - age) × mass 
(kg) × [0.85 if female] / 72 × serum creatinine (mg/dL) x 88.4 
 
Correction of the Cockcroft 
Gault equation. 
5 TREATMENT OF PATIENTS 
Section 5.2 
 
 
Patients must have fasted no less than 8 hours prior to a 
blood draw for the lipid profile, or for the safety laboratory 
panels which include clinical chemistries and hormone 
concentrations. 
For visits 2 through 9, Ppatients must have fasted no less than 8 
hours prior to a blood draw for the lipid profile, or for the safety 
laboratory panels which include clinical chemistries and hormone 
concentrations. 
Clarification that screening 
laboratory tests do not need 
to be done fasting. 
Section 5.3.1 
... 
• 
Use of inducers of CYP3A4 within 2 weeks 
... 
• 
Use of inducers of CYP3A4 within 2 weeks prior to 
Clarification regarding 
disallowed previous 


 
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prior to randomization  
• 
Immunosuppressive agents, or cytotoxic 
agents, including cyclophosphamide and 
azathioprine within 12 months prior to 
screening 
... 
randomization  
• 
Immunosuppressive or immunomodulating agents, or 
cytotoxic agents, including cyclophosphamide and 
azathioprine within 12 months prior to screening 
... 
medications prior to the 
study. 
Section 5.3.2 
5.3.2 Allowed Medications/Therapies During Study  
Clinical studies have shown laquinimod 0.6 mg/day to be a 
potent inducer of CYP1A2. Subjects taking drugs that are 
metabolized by CYP1A2 (examples listed in Appendix C ) 
should be advised that plasma levels of these drugs may 
need dose adjustment and more frequent clinical 
monitoring when treatment with laquinimod is initiated or 
stopped. 
 
Drug-Drug interaction studies have been performed with 
the laquinimod doses of 0.6 mg/day and 1.2 mg/day dose. 
These studies show that laquinimod at both doses is a weak 
inhibitor of CYP3A4. Subjects taking drugs that are 
metabolized by CYP3A4 (specifically those with a Narrow 
Therapeutic Index (listed in Appendix C) should be 
advised that plasma levels of these drugs could increase 
when combined with laquinimod. 
5.3.2 Allowed Medications/Therapies During Study Other 
Concomitant Medications  
Clinical studies have shown laquinimod 0.6 mg/day to be a potent 
inducer of CYP1A2. Subjects taking drugs that are metabolized by 
CYP1A2 (examples listed in Appendix C) should be advised that 
plasma levels of these drugs may need dose adjustment and more 
frequent clinical monitoring when treatment with laquinimod is 
initiated or stopped. 
 
Drug Drug interaction studies have been performed with the 
laquinimod doses of 0.6 mg/day and 1.2 mg/day dose. These studies 
show that laquinimod at both doses is a weak inhibitor of CYP3A4. 
Subjects taking drugs that are metabolized by CYP3A4 (specifically 
those with a Narrow Therapeutic Index (listed in Appendix C) 
should be advised that plasma levels of these drugs could increase 
when combined with laquinimod. 
 
Studies have shown that laquinimod is a strong inducer of 
CYP1A2 and a weak inhibitor of CYP3A4. Therefore, co-
administration of laquinimod may affect the systemic exposure of 
drugs metabolized by CYP450 1A2 or CYP3A4. 
5.3.2.1 CYP1A2 
Laquinimod 0.6 mg/day reduces the systemic exposure of caffeine 
(a compound mainly metabolized by CYP1A2) 5-fold. Laquinimod 
doses higher than 0.6 mg/day may further increase CYP1A2 
induction and decrease exposure of CYP1A2 substrates.  
Plasma levels of drugs that are CYP1A2 substrates may decrease 
when combined with laquinimod. Also, during a period of 30 days 
following the last laquinimod dose these CYP1A2 substrates are 
potentially less effective due to decreased plasma levels.  
Revised subsection 
regarding laquinimod 
possible effect on CYP1A2 
and CYP3A4 substrates and 
partial lists of such drugs. 
 
This change was made In 
response to the FDA request 
to avoid the use of CYP1A2 
substrates in th study. 


 
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Reason/justification for 
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Table 7, appendix C presents a partial list of drugs that are mainly 
metabolized by CYP1A2, i.e. CYP1A2 plays a major role in their 
biotransformation. The systemic exposure of these drugs is 
expected to be significantly reduced by laquinimod co-
administration. Drugs that are mainly metabolized by CYP1A2 and 
have a narrow therapeutic index are of special concern and appear 
in bolded text.  
In general, as a precautionary measure, it is recommended to 
avoid the use of CYP1A2 substrates in clinical trials of 
laquinimod. Therapeutic alternatives may be considered in the 
appropriate clinical context. 
 
5.3.2.2. CYP3A4 
Laquinimod 0.6 mg/day increases the systemic exposure of 
midazolam (a sensitive CYP3A4 substrate) 1.5-fold and for the 1.2 
mg/day dose 1.7 fold. Therefore, plasma levels of drugs that are 
CYP3A4 substrates may increase when combined with laquinimod. 
Patients taking drugs that are metabolized by CYP3A4, specifically 
those with a Narrow Therapeutic Index (Appendix C) should be 
advised that plasma levels of these drugs could increase when 
combined with laquinimod.  
6 ASSESSMENT OF EFFICACY 
Section 6.2.1 (Other sections affected by this change: 17)  
Participants will undergo MRI at baseline and Month 12.  
Change in whole-brain, caudate and ventricular volume 
over the scanning interval will be calculated using the 
Boundary Shift Integral (BSI) technique (Freeborough and 
Fox, 1997, Leung et al, 2010). This is an intensity-driven 
technique within the MIDAS software (Freeborough et al, 
1997) which measures change over time in the brain 
directly from within-subject registered (aligned) MR scan 
pairs. This technique has been optimised to provide robust 
measures of brain-volume change from multi-site data 
(Freeborough and Fox, 1997) and has been shown to be 
sensitive to HD-related pathology over a 12-month interval 
in the multi-site TRACK-HD study (Tabrizi et al, 2011). 
Imaging methods will follow those described within the 
Participants will undergo 3T MRI at baseline and Month 12 
following unaccelerated volumetric T1-weighted acquisition 
protocols developed during the ADNI study (www.adni-info.org).  
Change in whole brain, caudate and ventricular volume over the 
scanning interval will be calculated using the Boundary Shift 
Integral (BSI) technique (Hobbs et al, 2009, Freeborough and Fox, 
1997 Leung et al, 2010). Change in whole brain and ventricular 
volume will also be calculated using this approach (see section 
6.3.1). This The BSI is an intensity-driven technique within the 
MIDAS software (Freeborough et al, 1997) which measures change 
over time in the brain directly from within-subject registered 
(aligned) MR scan pairs. This technique has been optimised to 
provide robust measures of brain-volume change from multi-site 
data (Freeborough and Fox, 1997Leung et al, 2010) and has been 
Updated text to reflect use of 
ADNI parameters instead of 
the TRACK-HD parameters. 


 
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Reason/justification for 
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TRACK-HD study (Tabrizi et al, 2011, Tabrizi et al, 2012) 
and will be described in detail in a separate imaging 
manual. In brief, all images will undergo intensity 
normalisation using the N3 software (Sled et al, 1998, 
Boyes et al, 2008). The brain will be delineated at baseline 
and follow-up using MIDAS software (Freeborough et al, 
1997). Within-subject scan pairs will be registered with 12 
degrees-of-freedom and change in whole-brain volume 
estimated using the Brain BSI (BBSI). Change in caudate 
volume will be estimated using the caudate BSI (CBSI) 
(Hobbs et al, 2009) which involves delineation of the 
baseline caudates and an additional local rigid registration 
of the baseline and follow-up scans to achieve more 
accurate alignment of the caudates, prior to application of 
the BSI algorithm. The ventricles will be delineated at 
baseline and follow-up, after which the Ventricular BSI 
(VBSI) will be applied to estimate change in ventricular 
volume (Freeborough and Fox, 1997). 
White-matter volume change will be computed using 
methods described within the TRACK-HD study (Tabrizi 
et al, 2011 Tabrizi et al, 2012) and will be described in 
detail in a separate imaging manual. In brief, voxel-level 
volume change will be estimated using a fluid registration 
approach, which generates voxel-compression maps for 
each participant. These maps will be convolved with the 
native-space baseline white-matter segmentation generated 
using unified segmentation within SPM8 
(www fil.ion.ucl.ac.uk/spm), to provide an estimate of 
white-matter volume change.  
All segmentations and registrations will be visually 
checked by trained analysts to ensure accuracy. 
Longitudinal change in caudate, whole-brain and white-
matter volume will be expressed as a percentage of their 
baseline value. Longitudinal change in ventricular volume 
will be expressed in absolute terms (ml). 
MRI scans may be evaluated locally for any incidental 
pathology (ie, pathology unrelated to, or inconsistent with, 
the subject’s known HD) according to locally determined 
shown to be sensitive to HD-related pathology over a 12-month 
interval in the multi-site TRACK-HD study (Tabrizi et al, 2011). 
Details of how the BSI has been implemented for this study are 
described in the Imaging Review Charter.  
Imaging methods will follow those described within the TRACK
HD study (Tabrizi et al, 2011, Tabrizi et al, 2012) and will be 
described in detail in a separate imaging manual. In brief, all images 
will undergo intensity normalisation using the N3 software (Sled et 
al, 1998, Boyes et al, 2008). The brain will be delineated at baseline 
and follow up using MIDAS software (Freeborough et al, 1997). 
Within subject scan pairs will be registered with 12 degrees of
freedom and change in whole brain volume estimated using the 
Brain BSI (BBSI). Change in caudate volume will be estimated 
using the caudate BSI (CBSI) (Hobbs et al, 2009) which involves 
delineation of the baseline caudates and an additional local rigid 
registration of the baseline and follow up scans to achieve more 
accurate alignment of the caudates, prior to application of the BSI 
algorithm. The ventricles will be delineated at baseline and follow
up, after which the Ventricular BSI (VBSI) will be applied to 
estimate change in ventricular volume (Freeborough and Fox, 1997). 
White-matter volume change (see Section 6.3.1) will be computed 
estimated using a non-linear registration approach methods 
described within the TRACK HD study (Tabrizi et al, 2011, Tabrizi 
et al, 2012) and will be described in detail in a separate imaging 
manual. In brief, vVoxel-level volume change will be estimated 
using a fluid registration approach, which generates voxel
compression maps for each participant. These maps will be 
convolved with the native space baseline white matter segmentation 
generated 
using 
unified 
segmentation 
within 
SPM8 
(www.fil.ion.ucl.ac.uk/spm), to provide an estimate of white matter 
volume change derived from within-subject non-linear registration 
will be summed over an automated baseline white-matter mask, to 
estimate within-subject volume change over the interval. This 
analysis is detailed in the Imaging Review Charter. 
All segmentations and registrations will be visually checked by 
trained analysts to ensure accuracy. End-point quality control will 
be performed by trained analysts to ensure accuracy.  
Longitudinal change in caudate, whole-brain and white-matter 


 
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procedures. If such pathology is found, the Treating 
Neurologist/ Physician should be notified. The MRI 
reading center will evaluate the scans only for the purpose 
of performing quantitative measurements. In order not to 
compromise blinding of the study, the MRI Reading Center 
will not report MRI findings back to clinical site. 
Patients who develop unsuitability for MRI measures after 
baseline visit, will be allowed to continue in the study 
without performing the MRI assessment. 
volume will be expressed as measured in mls and converted to a 
percentage of their baseline value for subsequent analysis. 
Longitudinal change in ventricular volume will be expressed 
measured and analysed in absolute terms (ml). 
MRI scans may be evaluated locally for any incidental pathology (ie, 
pathology unrelated to, or inconsistent with, the subject’s known 
HD) according to locally determined procedures. If such pathology 
is found, the Treating Neurologist/ Physician should be notified. The 
MRI reading center will evaluate the scans only for the purpose of 
performing quantitative measurements. In order not to compromise 
blinding of the study, the MRI Reading Center will not report 
quantitative MRI findings back to the clinical site. 
Patients who develop unsuitability for MRI measures after baseline 
visit, will be allowed to continue in the study without performing the 
MRI assessment. 
7 ASSESSMENT OF SAFETY 
Section 7.1.5.3.1  
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. 
On the basis of this assessment, a decision will be made 
concerning the need for further medical intervention. 
…  
The blinding will be maintained for the people who are 
involved directly in the study. Therefore, in case of a 
suspected unexpected serious adverse reaction (SUSAR), 
only the LSO/CRO will receive the unblinded report for 
regulatory submission.  
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. On the basis of this 
assessment, a decision will be made concerning the need for further 
medical intervention.  
… 
The blinding will be maintained for the people who are involved 
directly in the study. Therefore, in case of a suspected unexpected 
serious adverse reaction (SUSAR), only the LSO/CRO will receive 
the unblinded report for regulatory submission; the others will 
receive a blinded report.  
Language updated by PhV. 
Section 7.1.5.3.2 
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.  
In addition to notifying the investigators and regulatory 
authorities, other measures may be required, including the 
following:  
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 (and 
IEC/IRB, if appropriate).  
In addition to notifying the investigators and regulatory authorities 
(and IEC/IRB, if appropriate), other measures may be required, 
including the following:  
Language updated by PhV. 


 
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change 
• 
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 
• 
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 
Section 7.4 (Other changes affected by this section: 3.11) 
Vital signs will be measured at all in-clinic visits (Visits 1-
4 and 6-9). Vital signs include the following: 
• 
pulse 
• 
blood pressure (including postural BP 
changes) 
• 
body temperature 
Before pulse and blood pressure are measured, the patient 
must be in a supine position and resting for at least 
5 minutes. The same position and arm should be used each 
time vital signs are measured for a given patient. For any 
abnormal vital sign finding, the measurement should be 
repeated as soon as possible. Any vital sign value that is 
judged by the investigator as a clinically significant change 
(worsening) from a baseline value will be considered an 
adverse event, recorded on the source documentation and 
transcribed onto the CRF, and monitored as described in 
Section 7.1.2  
During the visits, vital sign measurements, physical 
examinations (see Section 7.6) and ECG (see Section 7.5) 
should be performed prior to the blood draw for clinical 
laboratory tests and pharmacokinetic sampling. 
Vital signs will be measured at all in-clinic visits (Visits 1-4 and 6-
9). Vital signs include the following: 
• 
pulse 
• 
blood pressure (including postural BP changes) 
• 
body temperature 
Before pulse and blood pressure are measured, the patient must be in 
a supine position and resting for at least 5 minutes. The same 
position and arm should be used each time vital signs are measured 
for a given patient. For any abnormal vital sign finding, the 
measurement should be repeated as soon as possible. Any vital sign 
value that is judged by the investigator as a clinically significant 
change (worsening) from a baseline value will be considered an 
adverse event, recorded on the source documentation and transcribed 
onto the CRF, and monitored as described in Section 7.1.2.  
 
During the visits, vital sign measurements, physical examinations 
(see Section 7.6 ) and ECG (see Section 7.5 ) should be performed 
prior to the blood draw for clinical laboratory tests and 
pharmacokinetic sampling. 
All references to postural 
blood pressure changes were 
removed. Only supine 
measurements will be 
captured. 
 
The prescribed order of 
laboratory tests, ECGs and 
vital signs has been deleted 
to simplify conduct of study 
procedures. 
Section 7.7.3 
(Not applicable) 
7.7.3 Abdominal Computed Tomography Scan 
In case of pancreatitis or suspected pancreatitis, an abdominal 
computed tomography (CT) scan should be performed as soon as 
New section added per 
LAQ-MS-305 DMC request. 


 
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possible in order to clarify the diagnosis and enable assessment of 
severity of this condition.  
For complete guidance on monitoring subjects with elevated 
pancreatic amylase levels, see Appendix A, Section 5.  
8 ASSESSMENT OF PHARMACOKINETICS/PHARMACOGENOMICS/OTHER ANCILLARY STUDIES  
Section 8.2.1 (Other sections affected by this change: Table 2; 3.11.2; 3.11.3.1.5 ) 
... 
• 
50 mL whole blood samples for monocyte 
isolation will be collected at baseline and Month 
12 only at selected sites in a subgroup of patients. 
The sample collection has to be done in the 
morning, at 12:00 at the latest.  
... 
... 
• 
50 mL whole blood samples for monocyte isolation will be 
collected at baseline and Month 12 only at selected sites in 
a subgroup of patients (aiming at 25 per treatment arm). 
The sample collection has to be done in the morning, at 
12:00 at the latest. accordance with the laboratory manual. 
For UK patients, the sample can be drawn prior to the 
baseline or Month 12 visit, as it coincides with the PET 
scan visits. 
... 
Reference to specific time 
points for monocyte analysis 
was omitted; updated 
number of patients for 
substudy; clarification 
regarding analysis for 
patients participating in the 
PET study. 
 
Section 8.2.4 (Other sections affected by this change: Table 2; 3.11.2; 3.11.3.1.5 ) 
(Not applicable) 
Not all benzodiazepines have been tested for TSPO binding. Patients 
taking benzodiazepines should be instructed to stop taking them for 
3 days prior to having the PET scan. 
New text to disallow 
benzodiazepines 3 days prior 
to the PET scan. 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
Section 11.4 
(Not applicable) 
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 
New subsection added per 
regulatory authority request 
and change in Sponsor 
template. 


 
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Reason/justification for 
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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, 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 


 
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Amended or new wording 
Reason/justification for 
change 
• 
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 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. 


 
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APPENDIX A 
2. Use of Moderate/Strong CYP3A4 Inhibitors  
Laquinimod PK is affected by moderate and strong 
CYP3A4 inhibitors; therefore, moderate/strong CYP3A4 
inhibitors are disallowed during study and 30 days after the 
last dose has been administered. A partial list of commonly 
used CYP3A4 inhibitors is presented in Appendix B.  
... 
 
2. Use of Moderate/Strong CYP3A4 Inhibitors  
Laquinimod PK is affected by moderate and strong CYP3A4 
inhibitors; therefore, moderate/strong CYP3A4 inhibitors are 
disallowed during study and 30 days after the last dose has been 
administered. A partial list of commonly used CYP3A4 inhibitors is 
presented in Appendix B. 
3.Use of CYP3A4 Substrates with Narrow Therapeutic Index 
Plasma levels of drugs that are CYP3A4 substrates may increase 
when combined with laquinimod. Patients taking drugs that are 
metabolized by CYP3A4, specifically those with a Narrow 
Therapeutic Index (Table 6 in Appendix C) should be advised that 
plasma levels of these drugs could increase when combined with 
laquinimod.  
4. Use of CYP1A2 Substrates 
Plasma levels of drugs that are CYP1A2 substrates may decrease 
when combined with laquinimod and within 30 days after the last 
laquinimod dose, rendering these drugs less effective.  
In general, it is recommended to avoid the use of CYP1A2 
substrates in clinical trials of laquinimod. Therapeutic alternatives 
may be considered in context. 
For additional information on concomitant use of laquinimod with 
CYP1A2 substrates, please refer to Section 5.3.2. 
...  
Addition of text regarding 
use of CYP3A4 substrates 
with a narrow therapeutic 
index and CYP1A2 
substrates in combination 
with laquinimod. 
  
This change was made In 
response to the FDA request 
to avoid the use of CYP1A2 
substrates in th study. 
 
As a result, the numbering of 
the subsequent subsections 
has changed. 
(Not applicable) 
5. Guidance on monitoring subjects with elevated pancreatic 
amylase levels 
Amylase and pancreatic amylase will be measured at each study 
visit.  
 
In any case of abnormal pancreatic amylase results to a level 
exceeding of ≥1×ULN the subject will be invited to an unscheduled 
visit to test lipase levels. Lipase will be tested on all follow up visits 
until normalization of pancreatic amylase levels.  
 
In case of suspected pancreatitis, the subject should undergo a 
thorough clinical evaluation including an abdominal computed 
tomography (CT) scan as soon as possible in order to clarify the 
diagnosis and enable assessment of severity of this condition.  
Addition of guidance on 
monitoring patients with 
elevated pancreatic amylase 
levels following 
CONCERTO DMC request.  
 
 


 
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APPENDIX B (Other sections affected by this change: Section 5.3.1.1; Appendix A)  
A partial list of moderate/strong CYP3A4 inhibitors: 
 
Medication class 
Drug name 
Protease inhibitors 
Indinavir, saquinavir, lopinavir, nelfinavir, 
amprenavir, atazanavir, darunavir, 
ritonavir 
Antivirals: 
Boceprevir, telaprevir 
Antifungals: 
Ketoconazole, itraconazole, voriconazole, 
posaconazole, fluconazole 
Antibiotics 
Troleandomycin, clarithromycin, 
telithromycin, ciprofloxacin, erythromycin 
Antidepressant 
Nefazodone 
Calcium channel 
blocker 
Diltazem, verapamil, mibefradil 
Antiemetics 
Aprepitant, casopitant, netupitant 
Diuretics 
Conivaptan 
Antineoplastic agents 
Imatinib 
... 
A partial list of CYP3A4 inducers: 
• Carbamazepine 
• Phenobarbital 
• Phenytoin 
• Rifabutin 
• Rifampin 
• St. John's Wort 
Table 4: A partial list of moderate/strong CYP3A4 inhibitors; 
These drugs may increase the level of laquinimod and therefore 
are disallowed 2 weeks prior to study, during study and 30 days 
after last study dose: 
 
Medication class 
Drug name 
Protease inhibitors 
Indinavir, saquinavir, lopinavir, nelfinavir, 
amprenavir, atazanavir, darunavir, ritonavir 
Antivirals: 
Boceprevir, telaprevir, danoprevir, ledipasvir 
Antifungals: 
Ketoconazole, itraconazole, voriconazole, 
posaconazole, fluconazole 
Antibiotics 
Troleandomycin, clarithromycin, telithromycin, 
ciprofloxacin, erythromycin 
Antidepressant 
Nefazodone 
Calcium channel 
blocker 
DiltazemDiltiazem, verapamil, mibefradil 
Antiemetics 
Aprepitant, casopitant, netupitant 
Diuretics 
Conivaptan 
Antineoplastic agents 
Imatinib 
Antiarrhythmics 
dronedarone 
 ... 
A partial list of CYP3A4 inducers: 
• Carbamazepine 
• Phenobarbital 
• Phenytoin 
• Rifabutin 
• Rifampin 
• St. John's Wort 
 
Table 5: A partial list of CYP3A4 inducers. These drugs may 
decrease the level of laquinimod and are therefore disallowed 2 
weeks prior to study and during study:  
Medication class 
Drug name 
Antibiotics  
Rifampin, Rifabutin, Nafcillin 
Anticonvulsants 
Phenytoin, Carbamazepine, Phenobarbital 
Antineoplastic agents  
Mitotane 
Anti retroviral 
Efavirenz, Talviraline, Etravirine, Lersivirine 
Protease inhibitors 
Lopinavir, Tipranavir, Ritonavir 
Antilipemics agents 
Avasimibe 
Antiandrogens 
Enzalutamide 
The lists of disallowed and 
allowed medications in 
Appendix B and Appendix C 
are now arranged according 
to medication classes, and 
are presented in a tabular 
format to facilitate usage.  
 
Several additional 
medications were added to 
the groups. 
 


 
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Alzheimer's Treatments 
Semagacestat 
Endothelin Receptor 
Antagonists 
Bosentan 
Psychostimulants 
Modafinil 
Herbal Medications 
St. John's Wort 
APPENDIX C 
APPENDIX C: LIST OF ALLOWED 
MEDICATION/THERAPIES DURING STUDY 
A partial list of CYP3A4 substrates with a narrow 
therapeutic index: 
• 
Alfentanil 
• 
Cyclosporine 
• 
Diergotamine 
• 
Ergotamine 
• 
Fentanyl 
• 
Pimozide 
• 
Quinidine 
• 
Sirolimus 
• 
Tacrolimus 
A partial list of drugs known to be metabolized by 
CYP1A2: 
• 
Clozapine 
• 
Duloxetine 
• 
Theophylline 
• 
Tizanidine 
• 
Alosetron 
• 
Ramelteon 
• 
Tacrine 
 
APPENDIX C: LIST OF ALLOWED 
MEDICATION/THERAPIES DURING STUDYOTHER 
CONCOMITANT MEDICATIONS/THERAPIES 
A partial list of CYP3A4 substrates with a narrow therapeutic index: 
• 
Alfentanil 
• 
Cyclosporine 
• 
Diergotamine 
• 
Ergotamine 
• 
Fentanyl 
• 
Pimozide 
• 
Quinidine 
• 
Sirolimus 
• 
Tacrolimus 
Table 6: A partial list of drugs with a narrow therapeutic index 
that are metabolized by CYP3A4 (plasma levels of these drugs 
could increase when combined with laquinimod): 
Note: The medications list is considered partial. All medication 
that fall under prohibited medication classes should be excluded. 
Please contact the sponsor if you have questions about prohibited 
medication. 
 
Medication class 
Drug name 
Opioids 
Fentanyl, alfentanil 
Migraine treatment 
Ergotamine, diergotamine 
Antiarrhythmic 
Quinidine 
 
A partial list of drugs known to be metabolized by CYP1A2: 
• 
Clozapine 
• 
Duloxetine 
The lists of disallowed and 
allowed medications 
mentioned in Appendix B 
and Appendix C are now 
arranged according to 
medication classes, and are 
presented in a tabular format 
to facilitate usage.  
 
Several additional 
medications were added to 
the groups. 
 
A list of CYP1A2 substrates 
is included. 
 


 
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Reason/justification for 
change 
• 
Theophylline 
• 
Tizanidine 
• 
Alosetron 
• 
Ramelteon 
• 
Tacrine 
Table 7: A partial list of drugs that are mainly metabolized by 
CYP1A2. Drugs with a narrow therapeutic index appear in bolded 
text. 
Note: The medications list is considered partial. All medication 
that fall under prohibited medication classes should be excluded. 
Please contact the sponsor if you have questions about prohibited 
medication. 
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 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for 
change 
Alpha adrenergic 
agonist 
Guanabenz 
Beta blockers 
Propranolol 
Parkinson's 
treatment 
Rasagiline, ropinirole 
Alzheimer's 
Treatments 
Tacrine 
Diuretics 
Triamterene 
Miscellaneous 
agents 
Alosetron (IBS treatment), Riluzole (ALS 
treatment), methadone 
APPENDIX D 
(Not applicable) 
Appendix D. Magnetic Resonance Imaging 
The patients will undergo MRI scans at Baseline and Month 12 or 
Early Termination. The scans will be obtained according to a 
standard protocol that will be provided by the Imaging CRO 
(iCRO). The scans will be sent to the iCRO for approval and 
processing.  
MRI scan will be performed using the following schedule: 
• 
Month 0/Baseline: as soon as possible after eligibility has 
been confirmed but not less than 7 days prior to baseline. 
• 
Month 12: up to 7 days prior to the Month 12 visit. 
• 
Early Termination: as soon as possible, but not more than 
7 days after discontinuation of study drug.  
Note that the first MRI scan will be performed at least 7 days prior 
to the baseline visit to enable image approval and to set the 
reference for comparison to subsequent MRIs. 
If a patient terminates within 3 months of the baseline visit, they 
will not undergo an Early Termination scan.  
MRI facilities will undergo a qualification procedure, which will 
include the acquisition 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 ethics 
committee-approved informed consent. The scans will be reviewed 
by the MRI facility and a report will be given to the healthy 
volunteer. Qualification of sites will be formally indicated by an 
Addition of appendix 
detailing MRI procedures. 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for 
change 
approval certification. Sites must be qualified prior to the first 
patient inclusion.  
Detailed instructions are provided in the Site Operations Guide.  
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 iCRO in electronic format, or when not possible, by courier. 
The procedure for sending electronic data and accompanying 
documentations is specified in the Site Operations Guide. 
The iCRO will perform quality control checks of all images 
received. If both scans from one visit fail QC, the scan will need to 
be repeated. If the baseline scan fails QC, rescanning of the 
patient should be performed as soon as possible, prior to 
randomization. In cases of a failed QC at all other visits, the 
window for rescanning will be no longer than 2 weeks. Images 
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 to be evaluated locally for any incidental pathology 
(ie, pathology unrelated to, or inconsistent with, the patient’s 
known HD) according to locally determined procedures. If such 
pathology is found, the Treating Neurologist should be notified. 
The iCRO will evaluate the scans for the purposes of performing 
quantitative analyses. In order not to compromise the blinding of 
the study, the iCRO will not report results from the quantitative 
analyses back to the clinical site.  
17 REFERENCES 
Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-
Tourenne C, Zuccato C, et al. Mutant Huntingtin promotes 
autonomous microglia activation via myeloid lineage-
determining factors. Nat Neurosci. 2014 Mar 2. [Epub 
ahead of print] 
Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, 
Zuccato C, et al. Mutant Huntingtin promotes autonomous microglia 
activation via myeloid lineage-determining factors. Nat Neurosci. 
2014 Mar 2. [Epub ahead of print]17(4):513-21. 
Corrected from "Epub ahead 
of print" to actual journal 
reference. 
Tabrizi SJ, Reilmann R, Roos RA et al. Potential endpoints 
for clinical trials in premanifest and early Huntington's 
disease in the TRACK-HD study: analysis of 24 month 
observational data. Lancet Neurol 2012;11:42-53. 
Reference deleted from protocol. 
This reference is no longer 
relevant following the 
revision of the text in 
Section 6.2.1. 
Sled JG, Zijdenbos AP, Evans AC. A nonparametric 
method for automatic correction of intensity nonuniformity 
Reference deleted from protocol. 
This reference is no longer 
relevant following the 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for 
change 
in MRI data. IEEE Trans Med Imaging 1998;17:87-97. 
revision of the text in 
Section 6.2.1. 
Boyes RG, Gunter JL, Frost C, Janke AL, Yeatman T, Hill 
DLG et al. Intensity non-uniformity correction using N3 on 
3T scanners with multichannel phased array receiver coils. 
NeuroImage 2008; 39:1752-62. 
Reference deleted from protocol. 
This reference is no longer 
relevant following the 
revision of the text in 
Section 6.2.1. 
 


 
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16.9. 
SUMMARY OF CHANGES FOR LOCAL PROTOCOL 
AMENDMENT 02 FOR ETHICS COMMITTEE SUBMISSION IN 
THE UNITED KINGDOM DATED 25 JANUARY 2015 
 
The revisions listed below have been made to the protocol, and synopsis as appropriate, and are 
considered non-substantial by the sponsor’s Authorized Representative. 
The primary reason for this amendment is to comply with the UK Ethics Committee's request to  
(i) exclude from the study patients who lack the capacity to provide their own consent, and  
(ii), for women of child bearing potential, to perform a home pregnancy test prior to traveling to 
London for the PET scan. 
Substantive changes from the EC UK Local Amendment 01 to the EC UK Local Amendment 02 
are provided below. 
New text is shown in bold italics; deleted text is marked by strikethrough. 


 
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16.10. 
ADMINISTRATIVE LETTER 02 DATED 14 NOVEMBER 2014 
 


 
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16.11. 
SUMMARY OF CHANGES FOR LOCAL PROTOCOL 
AMENDMENT 01 FOR ETHICS COMMITTEE SUBMISSION IN 
THE UNITED KINGDOM  
Dated: 30 September 2014 
 
The revisions listed below have been made to the protocol, as appropriate, and are considered 
non-substantial by the sponsor’s Authorized Representative.  
The primary reason for this amendment is to introduce exclusion criteria specific to patients 
randomized to participate in the PET ancillary study investigating the microglial activation 
marker TSPO, as well as pregnancy testing for women of child bearing potential on the same 
day, prior to the scan. 
Substantive changes from the Amendment 01 to the Local Amendment are provided below. 
New text is shown in bold italics; deleted text is marked by strikethrough. 
All changes will be implemented in the next global protocol amendment. 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for change 
COVER PAGE, INVESTIGATOR AGREEMENT, COORDINATING INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 01 
Clinical Study Protocol with Amendment 01 and Local 
Amendment for Ethics Committee Submission in the United 
Kingdom 01  
Updated to reflect amendment. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
(Not applicable) 
HAB - High affinity binding 
Newly-added abbreviation. 
(Not applicable) 
LAB – low affinity binding 
Newly-added abbreviation. 
(Not applicable) 
MAB – mixed affinity binding 
Newly-added abbreviation. 
SYNOPSIS 
Other ancillary studies: 
• 
Microglial activation state will be investigated 
at selected sites and patients (N=aiming at 20 
per treatment arm). Positron emission 
tomography (PET) scans and imaging analysis 
of microglial activation marker translocator 
protein (TSPO) will be performed at baseline 
and Month 12. 
... 
Other ancillary studies: 
• 
Microglial activation state will be investigated at 
selected sites and patients (N=aiming at 20 10 per 
treatment arm). Positron emission tomography (PET) 
scans and imaging analysis of microglial activation 
marker translocator protein (TSPO) will be performed at 
baseline and Month 12. 
... 
Updated number of patients to be 
recruited for this ancillary study. 
2 PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
Section 2.2.5 
 
 
(Not applicable) 
… 
o 
To assess the correlation between microglial 
activation state at baseline and the clinical 
characteristics of HD patients (age, gender, 
number of triplets, disease onset, disease duration, 
motor and behavioural scores). 
… 
New ancillary objective added. 
3 STUDY DESIGN 
Section 3.11 – Table 2 
(Not applicable) 
l. An additional urine β-HCG test will be performed at the PET 
facilities at Imperial College in London at the Baseline visit and 
at Visit 8. This is a requirement for women of child-bearing 
potential participating in the PET substudy. Its result will be 
available on site prior to any procedures involving ionizing 
radiation and will be considered accordingly. 
New footnote describing 
pregnancy testing in women of 
child bearing potential 
randomized to the PET ancillary 
study at baseline and Month 12.  
 
Consequently, the numbering of 
the subsequent footnotes has 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for change 
changed. 
(Not applicable) 
New row added titled "Blood sample for TSPO genotype 
analysis"; the procedure will be performed at screening. 
Procedure added to correspond 
with Section 8.2.4.1. 
Section 3.11.1 (Other sections affected by this change: Table 2) 
… 
• 
serum β-HCG in women of childbearing 
potential within the 7 days prior to 
initiation of treatment 
• 
C-SSRS (baseline screening version) 
… 
 
… 
• 
serum β-HCG in women of childbearing potential 
within the 7 days prior to initiation of treatment 
• 
blood sample for TSPO genotype analysis (Only at 
selected sites in a subgroup of patients) 
• 
C-SSRS (baseline screening version) 
… 
Procedure added to correspond 
with Section 8.2.4.1. 
Section 3.11.2 (Other sections affected by this change: Table 2; 3.11.3.1.5; 8.2.4.2) 
… 
• 
serum β-HCG in women of childbearing 
potential 
• 
urine β-HCG in women of childbearing 
potential 
• 
Ascertaining use of effective contraception 
… 
… 
• 
serum β-HCG in women of childbearing potential 
• 
urine β-HCG in women of childbearing potential 
• 
additional urine β-HCG in women of childbearing 
potential at PET facilities (Only in a subgroup of 
patients) 
• 
Ascertaining use of effective contraception 
… 
New bullet in baseline procedures 
describing pregnancy testing in 
women of child bearing potential 
randomized to the PET ancillary 
study. 
Section 3.11.3.1.5 (Other sections affected by this change: Table 2; 3.11.2; 8.2.4.2) 
… 
• 
serum β-HCG in women of childbearing 
potential 
• 
urine β-HCG in women of childbearing 
potential 
• 
Ascertaining use of effective contraception 
… 
… 
• 
serum β-HCG in women of childbearing potential 
• 
urine β-HCG in women of childbearing potential 
• 
additional urine β-HCG in women of childbearing 
potential at PET facilities (Only in a subgroup of 
patients) 
• 
Ascertaining use of effective contraception 
… 
New bullet in Month 12 
procedures describing pregnancy 
testing in women of child bearing 
potential randomized to the PET 
ancillary study. 
8 ASSESSMENT OF PHARMACOKINETICS/PHARMACOGENOMICS/OTHER ANCILLARY STUDIES 
Section 8.2.4 
At selected sites, patients will be referred to a PET scan 
at baseline and end of treatment (Month 12). Each 
participant in the ancillary study will undergo a TSPO 
tracer PET scan at baseline and at the end of treatment 
(Month 12).  
At selected sites, patients will be referred to a PET scan at 
baseline and end of treatment (Month 12). Each participant in the 
ancillary study will undergo a TSPO tracer PET scan at baseline 
and at the end of treatment (Month 12).  
 
Clarification regarding the PET 
imaging location. 
 
New text excluding patients, who 
will exceed exposure to ionizing 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for change 
 
The 18-kDa TSPO is expressed within microglia and 
macrophages and has been used as a target for PET 
ligands to study neurodegenerative disease processes 
that involve microglial activation, such as HD, 
Parkinson’s disease (PD) and Alzheimer's disease (AD) 
(Politis et al, 2012)41 The PET radioligand 11C-PK11195 
has been used most frequently for this purpose, but 
signal quantification is limited by poor specific signal-
to-background ratio.  
At selected sites, patients will be referred to the Imperial College 
in London, where PET Imaging will be performed at the 
Imanova Imaging Centre on the Hammersmith Hospital site. 
The PET imaging will be performed at baseline and after 
treatment with laquinimod over a 12–month period of time. 
 
All patients participating in the PET arm of the study will be 
exposed to additional ionizing radiation due to the PET/CT 
scans. There are no alternatives methods available to explore 
neuroinflammtion in vivo. While any ionizing radiation 
exposure increases the risk of future malignancy, for the 
radiation exposure in this study such exposure is small and the 
increased risk is minimal. Patients who recently took part in 
clinical studies or underwent medical procedures involving 
ionizing radiation, such that participation in this study would 
lead to an exposure of >10mSv in the last 12 months, will be 
excluded from participation in this ancillary study. This will not 
affect the patient's participation in the main study. 
 
The 18-kDa TSPO is expressed within microglia and 
macrophages and has been used as a target for PET ligands to 
study neurodegenerative disease processes that involve microglial 
activation, such as HD, Parkinson’s disease (PD) and Alzheimer's 
disease (AD) (Politis et al, 2012) 41 The PET radioligand 11C-
PK11195 has been used most frequently for this purpose, but 
signal quantification is limited by poor specific signal-to-
background ratio.  
radiation of >10mSv in the last 12 
months, from participation in the 
PET ancillary study. 
Section 8.2.4.1 
Genomic DNA will be collected at the screening visit as 
described in Section 8.3.1 and used to genotype the 
rs6971 polymorphism within the TSPO gene on 
chromosome 22q13.2 (Owen et al, 201146, Kreisl et al, 
201345). 
Genomic DNA will be collected at the screening visit as 
described in Section 8.3.1 and used to genotype the rs6971 
polymorphism within the TSPO gene on chromosome 22q13.2 
(Owen et al, 201146, Kreisl et al, 201345). 
 
Patients who have A/A genotype for rs6971 polymorphism on 
the TSPO gene, which has been shown to result in low affinity 
binding (LAB) of the 11C-PBR28 radioligand, will be excluded 
from the PET ancillary study. Patients with LAB for TSPO can 
participate in the main study even if they are excluded from the 
PET ancillary study. Patients with G/G and A/G rs6971 
New text regarding inclusion and 
exclusion of patients with the 
various genotypes for the rs6971 
polymorphism from participation 
in the PET ancillary study. 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for change 
genotype have been shown to have high (HAB) and mixed 
(MAB) affinity binding, respectively, and will be included in the 
PET ancillary study. 
Section 8.2.4.2 
 
 
 
 
Specific activity, chemical purity, and radiochemical 
purity of 11C-PBR28 will be determined by radio high 
performance liquid chromatography (HPLC) coupled 
with a gamma detector. Specific activity will be 
determined by counting an aliquot in a dose calibrator 
and determining the mass by HPLC against a calibration 
curve of the cold standard. Identity will be confirmed by 
co-injecting the standard.  
 
Approximately 600 MBq of 11C-PBR28 as intravenous 
bolus will be injected, and a two-hour emission scan will 
be acquired on a Siemens HiRez 6 PET/CTI scanner 
(Siemens Healthcare, Erlanger, Germany). A low dose 
CTI scan will be performed immediately before each 
PET study for subsequent attenuation and scatter 
correction. Imaging data will be reconstructed with filter 
backprojection (direct inversion Fourier transform) with 
a 128 matrix, a zoom of 2.6, a transaxial Gaussian filter 
of 5 mm, scatter correction and attenuation correction. 
All subjects will have a volumetric T1-weighted MR 
sequence for co-registration purpose with PET images. 
For women of child bearing potential, a urine pregnancy test 
will be performed on the same day, and prior to, the PET scan 
at Imperial College in London. If the result of this test is 
positive, the PET procedure will not be performed and the 
patient will be monitored as outlined in Section 7.2. 
 
Specific activity, chemical purity, and radiochemical purity of 
11C-PBR28 will be determined by radio high performance liquid 
chromatography (HPLC) coupled with a gamma detector. 
Specific activity will be determined by counting an aliquot in a 
dose calibrator and determining the mass by HPLC against a 
calibration curve of the cold standard. Identity will be confirmed 
by co-injecting the standard.  
 
Approximately 600 400 MBq of 11C-PBR28 as intravenous bolus 
will be injected, and a two hour an approximately 90 minutes 
emission PET-CT scan will be acquired on a Siemens HiRez 6 
PET/CTI scanner (Siemens Healthcare, Erlanger, Germany). A 
low dose CTI scan of the head will be performed immediately 
before each PET study for subsequent attenuation and scatter 
correction of PET signal. Imaging data will be reconstructed with 
filter backprojection (direct inversion Fourier transform) with a 
128 matrix, a zoom of 2.6, a transaxial Gaussian filter of 5 mm, 
scatter correction and attenuation correction. All subjects will 
have a volumetric T1-weighted MR sequence for co-registration 
purpose with PET images. 
 
Patients will be advised that they should not participate in 
further research studies involving ionizing radiation for a year 
following the last performed scan.  
New text describing pregnancy 
testing in women of child bearing 
potential randomized to the PET 
ancillary study. 
 
Updated information regarding 
the PET procedure. 
 
Advice to patients to refrain from 
participation in studies involving 
ionizing radiation for a year 
following the last scan has been 
added. 
 


 
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16.12. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01 
DATED 10 SEPTEMBER 2014 
The revisions listed below have been made to the protocol, and synopsis as appropriate, and are 
considered substantial by the Teva Authorized Representative. 
The primary reasons for this amendment are to ascertain that patients with ongoing alcohol 
and/or drug abuse are excluded from the study, to clarify the unblinding procedure that can be 
performed by the investigator in a medical emergency situation, and to further clarify that HIV 
screening will be done per local requirements at screening. 
A comparison table showing substantive changes from the original protocol to Amendment 01 is 
provided below. Previous text is presented in the column titled “Previous approved wording,” 
revised or new text is presented in bold italics and deletions are struck through in the column 
titled “Amended or new wording,” and the reason or justification for the change is presented in 
the column titled “Reason/justification for change.”  
Changes to the synopsis are not detailed in the table but have been made according to the 
corresponding changes in the body of the protocol. 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for change 
COVER PAGE, INVESTIGATOR AGREEMENT, COORDINATING INVESTIGATOR AGREEMENT 
Clinical Study Protocol 
Clinical Study Protocol with Amendment 01 
Updated to reflect amendment. 
Protocol Approval Date:  
27 May 2014 
Protocol Approval Date: 27 May 2014 
10 September 2014  
Date changed to that of amended 
document. 
PROTOCOL AMENDMENTS PAGE 
(Not applicable) 
Page 2, describing the document history, has been added. 
Page added per sponsor template. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
(Not applicable) 
CDT - Carbohydrate deficient transferrin 
New abbreviation added to list 
following request for CDT testing, 
where applicable. 
3 STUDY DESIGN 
Section 3.8  
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.  
 
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.  
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) or pharmacist(s) at the 
study center via the IRT, both via telephone and 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. 
Text has been revised to properly 
describe the mechanism for 
unblinding. 
Section 3.11 Table 3 (Other sections affected by this change: 3.11.1; 4.2) 
(Not applicable) 
New row to indicate drug testing and/or CDT testing at screening.  
These tests will be performed, 
when applicable, to confirm 
abstinence in former alcohol and/or 
drug abusers. 
(Not applicable) 
b. When applicable, patients will be screened for drug substances in 
urine and/or CDT level in blood at screening to confirm abstinence in 
former (more than 12 months from screening) alcohol and/or drug 
abusers.  
New footnote to accompany added 
procedure. 
(Not applicable)  
d. When applicable per local requirements, patients will undergo an 
HIV test at screening. 
Footnote added to specify serology 
for HIV at screening per exclusion 
criteria. 


 
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Previous approved wording 
Amended or new wording 
Reason/justification for change 
Section 3.11.1 (Other sections affected by this change: Table 3; 4.2) 
… 
• 
HD history  
• 
review prior medication history 
• 
blood sample for genomic analysis 
including CAG analysis  
• 
perform clinical laboratory tests 
• 
clinical hematology 
• 
perform urinalysis 
perform vital signs measurements (including 
postural BP changes) 
… 
… 
• 
HD history  
• 
review prior medication history 
• 
blood sample for genomic analysis including CAG analysis  
• 
when applicable, patients will be screened for drug 
substances in urine and/or CDT level in blood to confirm 
abstinence in former (more than 12 months from 
screening) alcohol and/or drug abusers 
• 
perform clinical laboratory tests 
• 
when applicable per local requirements, patients will 
undergo an HIV test  
• 
clinical hematology 
• 
perform urinalysis 
• 
perform vital signs measurements (including postural BP 
changes) 
… 
Drug testing and/or CDT testing 
(when applicable) added to 
screening procedures. 
 
Serology for HIV specified per 
exclusion criteria, and to 
correspond with Table of Study 
Procedures and Assessments.  
4 SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.2 (Other sections affected by this change: Table 3; 3.11.1) 
Exclusion criterion l: 
Alcohol and/or drug abuse within the 6 months 
prior to screening, as defined by Diagnostic and 
Statistical Manual of Mental Disorders – Fourth 
Edition Text Revision (DSM-IV TR) criteria for 
substance abuse.  
Exclusion criterion l: 
Alcohol and/or drug abuse within the 6 12 months prior to screening, as 
defined by Diagnostic and Statistical Manual of Mental Disorders – 
Fourth Edition Text Revision (DSM-IV TR) criteria for substance abuse. 
For former alcohol and/or drug abusers, the abstinence should be 
confirmed by laboratory tests (drug testing and/or carbohydrate 
deficient transferrin (CDT) level in blood). 
History of drug and alcohol abuse 
updated to 12 months prior to 
screening. 
 
Abstinence should be confirmed by 
laboratory tests (drug testing and 
CDT level in blood). 
7 ASSESSMENT OF SAFETY 
Section 7.3 
Clinical laboratory tests (serum chemistry and 
hematology) will be performed at Visits 1-4 and 
6-9. Urinalysis will be performed at screening.  
Specific laboratory tests to be performed are 
listed below.  
Clinical laboratory tests (serum chemistry and hematology) will be 
performed at Visits 1-4 and 6-9. Urinalysis will be performed at 
screening. When applicable per local requirements, patients will 
undergo an HIV test at screening. Also when applicable, patients will 
be screened for drug substances in urine and/or CDT level in blood at 
screening to confirm abstinence in former alcohol and/or drug abusers.  
Specific laboratory tests to be performed are listed below.  
Language regarding serology for 
HIV and drug/CDT testing added 
to this section. 
 
 


 
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16.13. 
ADMINISTRATIVE LETTER 01 DATED 18 JULY 2014 
 


 
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APPENDIX A. GUIDANCE ON SAFETY MONITORING 
1. Guidance on Monitoring Subjects with Elevated Liver Function Tests 
Liver enzymes (ALT, AST, GGT, ALP), as well as total bilirubin4 will be measured at each 
study visit.  
In any case of elevated ALT or AST to a level exceeding of ≥2xULN (including subjects whose 
baseline ALT or AST levels are ≥2x and ≤3x the ULN, who may be enrolled in the study), a 
thorough medical history and physical examination with a focus on liver disease should be 
undertaken5. In addition, the subject should be instructed to refrain from alcoholic beverages.  
In case of symptoms compatible with drug-induced liver injury, the subject should be invited for 
an unscheduled visit to measure liver enzymes as soon as possible. 
Solitary elevations of total bilirubin, not accompanied by elevations of ALT or AST should be 
managed according to the discretion of the Treating Physician. 
1.1. Elevation of Either ALT or AST to ≥3 x ULN: 
Confirmation of the abnormality (in case the abnormality is of ALT or AST ≥ 8 times the ULN, 
no confirmation is required prior to study drug discontinuation, but the assessments below should 
be performed): 
• The day in which the abnormal value is received from the laboratory will be 
considered as Day 0. 
• The Investigator should repeat the test before Day 2, for confirmation purposes (this 
may be performed in a local laboratory along with CBC and differential to assess for 
eosinophilia. In general, in case a blood sample is sent to a local laboratory, the 
following assessments [and reference ranges] are mandatory: ALT [serum glutamic 
pyruvic transaminase; SGPT], AST [serum glutamic oxaloacetic transaminase; 
SGOT], ALP, total bilirubin, CBC [with differential for eosinophil count, separate 
tube], and INR [separate tube; not to be sent in a confirmatory test]). The investigator 
should also question the subject regarding symptoms. 
The abnormality will be regarded as confirmed in each of the following scenarios: 
1. In case baseline value was within normal range and ALT or AST is still ≥3xULN 
2. In case baseline value was above ULN and ALT or AST is ≥2 times the baseline 
value. 
Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the eCRF. 
 
                                                 
4 In case total bilirubin is >ULN, then direct bilirubin will be checked. 
5 Thorough medical history with a focus on liver disease: Personal or family history of liver disease; personal history 
of a systemic disease with potential liver involvement; exposure to alcohol, medications (prescription or OTC), 
herbal preparations, dietary supplements, recreational drugs, special diets or environmental chemical agents; 
potential exposure to infectious agents (eg, travel to developing countries, history of potential exposure to blood or 
blood products, high-risk sexual relations) and any additional information deemed relevant by the investigator. 
Physical examination – including signs of chronic liver disease. 


 
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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), ASMA (Anti 
Smooth Muscle Antibodies), anti-LKM (Liver Kidney Microsomal) 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 e.g. 
serology for hepatitis E virus in case of travel to endemic geography)  
Observation and Follow-Up (to be performed after the abnormality was confirmed as above) 
1.1.1. ALT or AST ≥3x (>3.5x ULN if baseline value is >2.5xULN) but less than 
5xULN  
In addition to the above procedures required for any elevation to levels >3xULN: 
• ALT, AST, GGT, ALP, total and direct bilirubin, CBC and differential (to assess for 
eosinophilia) and INR should be monitored on days 5 (±2), 8 (±2), 14 (±3), and 28 
(±3). On at least 1 of these days, the test should be performed centrally. (INR should 
be sent to a local laboratory only.) 
• In cases where a local laboratory is used, the results should be recorded in the eCRF, 
accompanied by the reference range of the relevant measurements. 
• Should the abnormality (≥3xULN in case baseline within normal range or ≥2xULN in 
case the baseline value was above ULN, but still <5xULN) persist further, the subject 
will be followed according to the investigator's discretion, but at least once a month a 
blood sample for ALT, AST, GGT, ALP, and total and direct bilirubin should be sent 
to the central laboratory. 
1.1.2. ALT or AST ≥5x but less than 8xULN 
In addition to the above procedures required for any elevation to levels >3xULN: 
• ALT, AST, GGT, ALP, total and direct bilirubin, CBC and differential count (to 
assess for eosinophilia), and INR should be monitored twice a week. 
• At least for every other measurement, the tests should be sent to the central 
laboratory. The rest of the tests may be sent to a local laboratory. INR should always 
be sent to a local laboratory. 
1.1.3. ALT or AST ≥8xULN 
In addition to the above procedures required for any elevation to levels >3xULN: 
• The study drug should be discontinued immediately and the ETD visit should be 
performed. 
• For follow-up guidance, please see below section "Follow-Up of Liver Enzymes 
After Stopping-Rules Are Met". 


 
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1.2. Stopping Rules: 
In the following circumstances, the study drug will be discontinued immediately: 
• Any increase in ALT or AST to ≥3xULN, combined with INR >1.5 or total bilirubin 
>2xULN 
• Any increase in ALT or AST to ≥3xULN, which is accompanied by nausea, 
vomiting, fever, rash, or eosinophilia 
• Any increase in ALT or AST to levels ≥5x but <8xULN, which is persistent for 
≥2 weeks of repeated measurements 
• Any increase in ALT or AST to levels ≥8xULN 
• In any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance 
1.2.1. Follow-Up of Liver Enzymes After Stopping-Rules Are Met: 
• A subject who meets the above criteria for discontinuation of the study drug should 
be invited to the site to return the study drug. ETD 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 ETD, the minimal follow-up period will be 30 days and will 
include measurement of liver enzymes at least once weekly (may be performed in a 
local laboratory, with at least 1 test being sent to the central laboratory). 
• Every effort should be made to complete the additional tests/ evaluations, as 
described above. 
2. Use of Moderate/Strong CYP3A4 Inhibitors  
Laquinimod PK is affected by moderate and strong CYP3A4 inhibitors; therefore, 
moderate/strong CYP3A4 inhibitors are disallowed during study and 30 days after the last dose 
has been administered. A partial list of commonly used CYP3A4 inhibitors is presented in 
Appendix B.  
3. Use of CYP3A4 Substrates with Narrow Therapeutic Index 
Plasma levels of drugs that are CYP3A4 substrates may increase when combined with 
laquinimod. Patients taking drugs that are metabolized by CYP3A4, specifically those with a 
Narrow Therapeutic Index (Table 6 in Appendix C)should be advised that plasma levels of these 
drugs could increase when combined with laquinimod.  
4. Use of CYP1A2 Substrates 
Plasma levels of drugs that are CYP1A2 substrates may decrease when combined with 
laquinimod and within 30 days after the last laquinimod dose, rendering these drugs less 
effective.  
In general, it is recommended to avoid the use of CYP1A2 substrates in clinical trials of 
laquinimod. Therapeutic alternatives may be considered in context. 
For additional information on concomitant use of laquinimod with CYP1A2 substrates, please 
refer to Section 5.3.2.  


 
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5. Management of Pregnancy and Pregnancy Testing During the Study 
Exposure to laquinimod during pregnancy should be avoided.  
Women of child-bearing potential (women who are not post menopausal or who have not 
undergone surgical sterilization) must practice an acceptable method of birth control for 30 days 
before taking the study treatment, and 2 acceptable methods of birth control during all study 
duration and until 30 days after the last dose of treatment was administered.  
Acceptable methods of birth control in this study include: Intrauterine device, barrier method 
(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. 
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 occurs despite all recommended measures, the following measures 
will be taken: 
1. Female subjects of child-bearing potential (women who are not post menopausal or 
who have not undergone surgical sterilization) will be reminded at each study visit 
about: 
a. The importance of using acceptable contraception. 
The importance of immediately stopping the study drug and informing the site 
in any case of suspected pregnancy (following a positive urine test, absence of 
menstruation or any other reason suggesting pregnancy). 
2. At each scheduled visit, female subjects of childbearing potential (women who are 
not post menopausal or who have not undergone surgical sterilization) will undergo a 
urine β-hCG test. In addition, a serum pregnancy β-hCG test will be performed at 
each visit. 
a. In case the the urine test is negative, study drugs will be dispensed according 
to planned visit tasks (see Table 3). 
i.  If the blood test is positive the subject will be contacted immediately 
and instructed to stop taking the study drug. The subject should be 
invited to attend an ETD visit. 
ii. If the blood test is negative – study procedures will be undertaken as 
planned. 
b. In case the urine test is positive – the study drug will not be dispensed (if this 
occurs at baseline visit, the subject will not be eligible to participate in the 
study and will be considered as a screening failure) 
iii. If the blood test is positive, the subject will be invited to the site for an 
ETD visit  
iv. If the blood test is negative, the subject will be contacted and informed 
about the test result and the study drugs will be sent to her by courier 
as soon as possible. 


 
Placebo-Controlled Study – Huntington's Disease 
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Study TV5600-CNS-20007 
240 
In case of an established diagnosis of pregnancy, the Treating Physician/Neurologist should 
discuss with the subject the possible risk to the fetus, including the possibility of termination of 
the pregnancy. Subjects who become pregnant will be monitored for the outcome of the 
pregnancy (including spontaneous or voluntary termination). If the pregnancy continues to term, 
the outcome (health of the infant up to 8 weeks of age), details of birth, and presence or absence 
of any birth defect, congenital abnormalities, or maternal and newborn complications, will be 
reported to the sponsor. Any complication of pregnancy during the study and any complication 
of pregnancy that the investigator becomes aware of after termination from the study will be 
reported as an adverse event or serious adverse event, as appropriate.  
1. Starting from Visit 3 (Month 1), the following actions will be taken: 
a. The subject will be provided with home pregnancy urine β-hCG test kits and will be 
guided how to perform the test.  
b. The subject will be instructed to perform the test in monthly intervals (every 28 (±2) 
days) from the visit date. These dates should be recorded by the study coordinator and 
a telephone call, will be scheduled to be performed within 72 hours of the urine test 
date.  
c. A mandatory phone call will be performed by the Treating Neurologist/ Physician or 
by the site’s nurse/ study coordinator every month in order to verify whether the test 
has been performed and to record the result of the test in the subject’s file. In case of 
a suspected pregnancy, the subject will be instructed to stop taking the study drug and 
arrive to the site as soon as possible for an unscheduled visit, with the remaining 
study medications. In the site, a quantitative urine β-hCG pregnancy test should be 
performed and the rest of the activities will be as in 2b. 
6. Cancer 
Patients who are diagnosed with malignant solid or liquid tumor while participating in the study 
should be discontinued from the study. 
7. Guidance on monitoring subjects with elevated pancreatic amylase levels  
Amylase and pancreatic amylase will be measured at each study visit.  
In any case of abnormal pancreatic amylase results to a level exceeding of ≥1×ULN the subject 
will be invited to an unscheduled visit to test lipase levels. Lipase will be tested on all follow up 
visits until normalization of pancreatic amylase levels.  
In case of suspected pancreatitis, the subject should undergo a thorough clinical evaluation 
including an abdominal computed tomography (CT) scan as soon as possible in order to clarify 
the diagnosis and enable assessment of severity of this condition. 
Necessary medical procedures including repeat labs will be performed based on clinical needs 
determined by the treating physician’s judgement. 
8. Guidance on monitoring subjects with hemoglobin decrease 
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. 


 
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Study TV5600-CNS-20007 
241 
• At baseline: B12, 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 
Necessary medical procedures including repeat labs will be performed based on clinical needs 
determined by the treating physician’s judgement. 
9. Guidance on monitoring subjects with CPK increase  
• In case of CPK results >ULN, troponin and creatine kinase MB isoenzyme (CK-MB) 
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. 
10. Acute Coronary Syndrome, Myocardial Infarction or Any Major Cardiovascular Event 
Patients who experience acute coronary syndrome, myocardial infarction or any major 
cardiovascular event will permanently discontinue treatment with study medication. Patients will 
be asked to continue all scheduled visits for safety assessment. 
11. Liver Impairment 
Patients who develop liver disease associated with liver functional impairment while 
participating in the study should stop study medication.  
12. Renal Impairment 
Patients who develop chronic renal disease associated with moderate-severe functional 
impairment, defined as estimated CrCl <60 mL/min/1.73 m2, while participating in the study 
should stop study medication temporarily until normalization of renal function or confirmation of 
renal impairment diagnosis. In case moderate-severe renal impairment is diagnosed, the patient 
will permanently discontinue treatment with study medication. 


 
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Study TV5600-CNS-20007 
242 
APPENDIX B. LIST OF DISALLOWED MEDICATIONS PRIOR TO AND 
DURING STUDY 
Laquinimod pharmacokinetics are affected by moderate and strong CYP3A4 inhibitors; 
moderate/strong CYP3A4 inhibitors are disallowed within 2 weeks of baseline until 30 days after 
the last dose has been administered. 
Moderate and strong CYP3A4 inhibitors are prohibited because concomitant administration is 
predicted to increase laquinimod exposure and may increase the likelihood of adverse events. 
 
Table 4: 
A Partial List of Moderate/Strong CYP3A4 Inhibitors Disallowed 2 Weeks 
Prior to Study, During Study and 30 Days After Last Study Dose. 
Medication class 
Drug name 
Protease inhibitors 
Indinavir, saquinavir, lopinavir, nelfinavir, amprenavir, atazanavir, 
darunavir, ritonavir 
Antivirals: 
Boceprevir, telaprevir, danoprevir, ledipasvir, elvitegravir 
Antifungals: 
Ketoconazole, itraconazole, voriconazole, posaconazole, fluconazole 
Antibiotics 
Troleandomycin, clarithromycin, telithromycin, ciprofloxacin, 
erythromycin 
Antidepressant 
Nefazodone 
Calcium channel blocker 
Diltiazem, 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 expected with 
laquinimod. 
 


 
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243 
Table 5: 
A Partial List of CYP3A4 Inducers  
Medication class 
Drug name 
Antibiotics  
Rifampin, Rifabutin, Nafcillin 
Anticonvulsants 
Phenytoin, Carbamazepine, Phenobarbital, Oxcarbazepine 
Antineoplastic agents  
Mitotane 
Anti retroviral 
Efavirenz, Talviraline, Etravirine, Lersivirine 
Protease inhibitors 
Lopinavir, Tipranavir, Ritonavir 
Antilipemics agents 
Avasimibe 
Antiandrogens 
Enzalutamide 
Endothelin Receptor Antagonists 
Bosentan 
Antipsychotics 
Thioridazine 
Psychostimulants 
Modafinil, Armodafinil 
Herbal Medications 
St. John's Wort 


 
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244 
APPENDIX C. LIST OF OTHER CONCOMITANT 
MEDICATION/THERAPIES  
Table 6: 
A Partial List of Cytochrome P450 3A4 Substrates with a Narrow 
Therapeutic Index 
Note: The medications list is considered partial. All medication that fall under prohibited 
medication classes should be excluded. Please contact the sponsor if you have questions about 
prohibited medication. 
alfentanil 
cyclosporine 
diergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine 
sirolimus 
tacrolimus 
Table 7: 
A Partial List of Drugs That Are Mainly Metabolized by CYP1A2.  
Note: The medications list is considered partial. All medication that fall under prohibited 
medication classes should be excluded. Please contact the sponsor if you have questions about 
prohibited medication. 
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 (IBS treatment), Riluzole (ALS treatment), Methadone 
Drugs with a narrow therapeutic index appear in bolded text. 


 
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Study TV5600-CNS-20007 
245 
For additional information on concomitant use of laquinimod with CYP1A2 and CYP3A4 
substrates, please refer to the IB. 
 


 
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246 
APPENDIX D. MAGNETIC RESONANCE IMAGING 
The patients will undergo MRI scans at Baseline and Month 12 or Early Termination. The scans 
will be obtained according to a standard protocol that will be provided by the Imaging CRO 
(iCRO). The scans will be sent to the iCRO for approval and processing.  
MRI scan will be performed using the following schedule: 
• Month 0/Baseline: as soon as possible after eligibility has been confirmed but not less 
than 7 days prior to baseline. 
• Month 12: up to 7 days prior to the Month 12 visit. 
• Early Termination: as soon as possible, but not more than 7 days after discontinuation of 
study drug.  
Note that the first MRI scan will be performed at least 7 days prior to the baseline visit to enable 
image approval and to set the reference for comparison to subsequent MRIs. 
If a patient terminates within 3 months of the baseline visit, they will not undergo an Early 
Termination scan.  
MRI facilities will undergo a qualification procedure, which will include the acquisition 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 ethics committee-approved informed consent. The scans will 
be reviewed by the MRI facility and a report will be given to the healthy volunteer. Qualification 
of sites will be formally indicated by an approval certification. Sites must be qualified prior to 
the first patient inclusion.  
Detailed instructions are provided in the Site Operations Guide.  
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 iCRO in electronic format, or when not possible, by courier. The procedure for sending 
electronic data and accompanying documentations is specified in the Site Operations Guide. 
The iCRO will perform quality control checks of all images received. If both scans from one 
visit fail QC, the scan will need to be repeated. If the baseline scan fails QC, rescanning of the 
patient should be performed as soon as possible prior to randomization . In cases of failed QC at 
all other visits, the window for rescanning will be no longer than 2 weeks. Images 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 to be evaluated locally for any incidental pathology (ie, pathology unrelated to, or 
inconsistent with, the patient’s known HD) according to locally determined procedures. If such 
pathology is found, the Treating Neurologist should be notified. The iCRO will evaluate the 
scans for the purposes of performing quantitative analyses. In order not to compromise the 
blinding of the study, the iCRO will not report results from the quantitative analyses back to the 
clinical site.  


 
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247 
17. 
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Imaizumi M, Briard E, Zoghbi SS, Gourley JP, Hong J, Fujimura Y et al. Brain and whole-body 
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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 1.0 and 1.5 mg/day) 
as Treatment in Patients with Huntington's Disease 
 
 
Study Number TV5600-CNS-20007 
 
NCT02215616 
 
Statistical Analysis Plan Approval Date: 19 June 2018  
 


 
Placebo-Controlled Study Huntington’s Disease 
Statistical Analysis Plan 
Study TV5600-CNS-20007 
1 
 
 
 
 
 
Statistical Analysis Plan 
 
Study TV5600-CNS-20007 
 
A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 1.0 and 1.5 mg/day) 
as Treatment in Patients with Huntington's Disease 
(LEGATO-HD - Laquinimod Efficacy and Safety in a GlobAl Trial Of HD) 
Phase 2 
 
 
 
IND number: 120331;  NDA number: not applicable; EudraCT number: 2014-000418-75 
 
 
Approval Date: 19 June 2018 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
 
 
 
 
Prepared by: 
 
 


 
Placebo-Controlled Study Huntington’s Disease 
Statistical Analysis Plan 
Study TV5600-CNS-20007 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
 
 
 


 
Placebo-Controlled Study Huntington’s Disease 
Statistical Analysis Plan 
Study TV5600-CNS-20007 
3 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
INTRODUCTION .........................................................................................................................11 
1. 
STUDY OBJECTIVES ..............................................................................................12 
2. 
STUDY DESIGN .......................................................................................................13 
2.1. 
General Design ...........................................................................................................13 
2.2. 
Randomization and Blinding ......................................................................................20 
2.3. 
Data Monitoring Committee .......................................................................................20 
2.4. 
Primary, Secondary and other Efficacy Variables and Safety Variables ...................20 
2.4.1. 
Primary Efficacy Variable ..........................................................................................20 
2.4.2. 
Secondary Efficacy Variable ......................................................................................20 
2.4.3. 
Other Efficacy Variables ............................................................................................21 
2.5. 
Sample Size and Power Considerations .....................................................................22 
2.6. 
Sequence of Planned Analyses ...................................................................................22 
2.6.1. 
Planned Interim Analyses ...........................................................................................22 
2.6.2. 
Final Analyses and Reporting .....................................................................................22 
3. 
ANALYSIS SETS ......................................................................................................23 
3.1. 
Intent-to-Treat Population ..........................................................................................23 
3.2. 
Safety Population ........................................................................................................23 
3.3. 
Full Analysis Set .........................................................................................................23 
3.4. 
Pharmacokinetic Analysis Set ....................................................................................23 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................24 
4.1. 
General ........................................................................................................................24 
4.2. 
Specification of Baseline Values ................................................................................24 
4.3. 
Handling Withdrawals and Missing Data ...................................................................24 
4.4. 
Study Days and Visits .................................................................................................25 
5. 
STUDY POPULATION .............................................................................................27 
5.1. 
General ........................................................................................................................27 
5.2. 
Patient Disposition ......................................................................................................27 
5.3. 
Demographics and Baseline Characteristics ...............................................................27 


 
Placebo-Controlled Study Huntington’s Disease 
Statistical Analysis Plan 
Study TV5600-CNS-20007 
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5.3.1. 
Baseline MRI Parameters ...........................................................................................28 
5.4. 
Medical History ..........................................................................................................28 
5.5. 
Prior Therapy and Medication ....................................................................................28 
5.6. 
Electrocardiography ....................................................................................................29 
5.7. 
Childbearing Potential and Methods of Contraception ..............................................29 
5.8. 
Subject Characteristics ................................................................................................29 
5.9. 
Study Protocol Violations ...........................................................................................29 
6. 
EFFICACY ANALYSIS ............................................................................................30 
6.1. 
General ........................................................................................................................30 
6.2. 
Primary Efficacy Endpoint and Analysis ...................................................................30 
6.2.1. 
Definition ....................................................................................................................30 
6.2.2. 
Primary Efficacy Analysis ..........................................................................................30 
6.2.3. 
Sub-Group Analysis ....................................................................................................31 
6.3. 
Secondary Efficacy Endpoint and Analysis ...............................................................32 
6.3.1. 
Definition ....................................................................................................................32 
6.3.2. 
Analysis ......................................................................................................................33 
6.3.3. 
Sub-Group Analysis ....................................................................................................33 
6.4. 
Exploratory Efficacy Endpoints Analysis ..................................................................34 
6.4.1. 
Change From Baseline in Total Motor Score (laquinimod 0.5 mg arm vs 
placebo) at Week 52 ...................................................................................................35 
6.4.1.1. 
Definition ....................................................................................................................35 
6.4.1.2. 
Analysis ......................................................................................................................35 
6.4.2. 
Percent Change from Baseline in Caudate Volume at Week 52 (laquinimod 
0.5 mg arm vs placebo) ...............................................................................................35 
6.4.2.1. 
Definition ....................................................................................................................35 
6.4.2.2. 
Analysis ......................................................................................................................35 
6.4.3. 
Change from Baseline in the Total Functional Capacity at Week 52 .........................35 
6.4.3.1. 
Definition ....................................................................................................................35 
6.4.3.2. 
Analysis ......................................................................................................................35 
6.4.4. 
Change from Baseline in the Functional Assessment at Week 52 .............................36 
6.4.5. 
Brain Atrophy Evaluated at Week 52/ET Versus Baseline ........................................36 
6.4.5.1. 
Definition ....................................................................................................................36 
6.4.5.2. 
Analysis ......................................................................................................................36 


 
Placebo-Controlled Study Huntington’s Disease 
Statistical Analysis Plan 
Study TV5600-CNS-20007 
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6.4.6. 
Quantitative Motor Assessments (Q-Motor) ..............................................................37 
6.4.6.1. 
Digitomotography (Speeded Index Finger Tapping) ..................................................37 
6.4.6.2. 
Dysdiadochomotography (Pronation/Supination Hand Tapping) ..............................37 
6.4.6.3. 
Manumotography and Choreomotography (Grip Force and Chorea Analysis) .........38 
6.4.6.4. 
Pedomotography (Speeded Foot Tapping) .................................................................38 
6.4.6.5. 
Analysis ......................................................................................................................38 
6.4.7. 
Change from Baseline in the Huntington’s Disease Cognitive Assessment 
Battery Composite Score at Week 52 (laquinimod 1mg arm vs placebo) ..................38 
6.4.7.1. 
Definition ....................................................................................................................38 
6.4.7.2. 
Analysis ......................................................................................................................41 
6.4.8. 
Clinician’s Interview-Based Impression of Change (CIBIC) - PLUS Global 
Score at Week 52 ........................................................................................................41 
6.4.8.1. 
Definition ....................................................................................................................41 
6.4.8.2. 
Analysis ......................................................................................................................42 
6.4.9. 
Modified Physcial Performance Test (mPPT) ............................................................42 
6.4.9.1. 
Definition ....................................................................................................................42 
6.4.9.2. 
Analysis ......................................................................................................................45 
6.4.10. 
Huntington’s Disease Quality of Life (HD-QoL) and 5-Level EuroQol Five 
Dimensions Questionnaire (EQ-5D-5L) .....................................................................45 
6.4.10.1. 
HD-QoL Definition ....................................................................................................45 
6.4.10.2. 
EQ-5D-5L Definition ..................................................................................................45 
6.4.10.3. 
Analysis ......................................................................................................................46 
6.4.11. 
Work Limitations Questionnaire (WLQ) ....................................................................46 
6.4.12. 
CDR-SB ......................................................................................................................47 
6.4.12.1. 
Definition ....................................................................................................................47 
6.4.12.2. 
Analysis ......................................................................................................................48 
6.4.13. 
Hospital Anxiety and Depression Scale (HADS) .......................................................48 
6.4.13.1. 
Definition ....................................................................................................................48 
6.4.13.2. 
Analysis ......................................................................................................................48 
6.4.14. 
Problem Behaviors Assessment-Short Form (PBA-s) ................................................48 
6.4.14.1. 
Definition ....................................................................................................................48 
6.4.14.2. 
Analysis ......................................................................................................................49 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................50 


 
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8. 
SAFETY ANALYSIS ................................................................................................52 
8.1. 
General ........................................................................................................................52 
8.2. 
Duration of Exposure to Study Drug ..........................................................................52 
8.3. 
Duration of Exposure to Study ...................................................................................52 
8.4. 
Adverse Events ...........................................................................................................52 
8.5. 
Deaths .........................................................................................................................53 
8.6. 
Clinical Laboratory Tests ...........................................................................................53 
8.6.1. 
Anemia Panel ..............................................................................................................54 
8.6.2. 
Estimated Creatinine Clearance Calculation ..............................................................54 
8.7. 
Physical Examinations ................................................................................................55 
8.8. 
Vital Signs ..................................................................................................................55 
8.9. 
Electrocardiography ....................................................................................................55 
8.10. 
Concomitant Medications or Therapies ......................................................................56 
8.11. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................56 
9. 
PHARMACOKINETIC ANALYSIS .........................................................................58 
10. 
PHARMACODYNAMIC ANALYSIS ......................................................................59 
11. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ..............................60 
12. 
BIOMARKER ANALYSIS........................................................................................61 
13. 
ANCILLARY STUDIES ANALYSIS .......................................................................62 
14. 
ANCILLARY PK ANALYSIS ..................................................................................63 
15. 
STATISTICAL SOFTWARE ....................................................................................64 
16. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............65 
16.1. 
Definition of Primary, Secondary and Exploratory Endpoints ...................................65 
16.2. 
Patient Disposition of Laquinimod 1.5 mg/Day Treatment Group ............................66 
16.3. 
Type 1 Error Control ..................................................................................................66 
16.4. 
Country Replaces Site in the Efficacy Analyses ........................................................66 
16.5. 
No Application of Last Observation Carried Forward (LOCF) for Early 
Terminating Patients ...................................................................................................66 
16.6. 
Ancillary Studies Beyond the Scope of This SAP ......................................................66 
16.7. 
Estimated Creatinine Clearance Calculation Units .....................................................66 
REFERENCES ..............................................................................................................................66 
 


 
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LIST OF TABLES 
Table 1: 
TV5600-CNS-20007 (LEGATO-HD) - Study Procedures and Assessments ............15 
Table 2: 
Visit Windows in days for Early Termination and Unscheduled Visits .....................26 
Table 3: 
HD-CAB Test Details and Calculation Methods ........................................................40 
Table 4: 
Modified - Physical Performance Test – Scoring Method .........................................43 
Table 5: 
Criteria for Potentially Clinically Significant Laboratory Values ..............................53 
Table 6: 
CTCAE v4.0 Severity Criteria for Hemoglobin .........................................................54 
Table 7: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................55 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Schema (from to 10 January 2016) .....................................................14 
Figure 2: 
Fallback with Loopback – Hypotheses Test Flow ......................................................51 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Term 
βHCG 
beta human chorionic gonadotropin  
ANCOVA 
analysis of covariance 
CAB 
Cognitive Assessment Battery  
CAG 
cytosine-adenosine-guanine repeat 
CDR-SB 
Clinical Dementia Rating - Sum of Boxes 
CDT 
Carbohydrate deficient transferrin 
CIBIC 
Clinician’s Interview-Based Impression of Change 
CIBIS 
Clinician's Interview-Based Impression of Severity 
CNS 
Central nervous system 
CrCl 
Creatinine Clearance 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CSC 
Clinical Supply Chain  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computed tomography 
CTCAE 
Common Terminology for Adverse Events 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DSM–IV 
Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition Text Revision 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiography, electrocardiogram 
ET 
Early Termination 
EU 
European Union 
FAS 
full analysis set  
FDA 
US Food and Drug Administration 
HADS 
Hospital Anxiety and Depression Scale 
HCG 
human chorionic gonadotropin 
HD 
Huntington's Disease 
HD- CAB 
Huntington’s Disease Cognitive Assessment Battery 
HD-QoL 
Huntington’s Disease Quality of Life 
HIV 
Human Immunodeficiency Virus 
HVLT-R 
Hopkins Verbal Learning Test, revised 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonisation 


 
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Abbreviation 
Term 
IL 
Interleukin 
IOI 
Inter onset intervals 
IPI 
Inter peak intervals 
IRT 
interactive response technology 
ISCED 
International Standard Classification of Education 
ITI 
Inter tap intervals 
ITT 
intent-to-treat  
LOCF 
Last Observation Carried Forward 
Max 
maximum 
mPPT 
Modified Physical Performance Test 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Myo-inositol 
ML 
Maximum Likelihood 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
MS 
Multiple Sclerosis 
OTS 
One Touch Stockings of Cambridge 
PBA-s 
Problem Behaviors Assessment-Short form 
PET  
Positron Emission Tomography 
PGx 
pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PPK 
Population Pharmacokinetics 
PT 
Preferred Term 
QC 
Quality Control 
Qd 
once daily 
Q-Motor 
Quantitative Motor Assessments 
QoL 
Quality of Life 
REML 
Restricted Maximum-Likelihood 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDMT 
Symbol Digit Modalities Test 
SOC 
system organ class 
SOP 
standard operating procedure 
tmax  
time to maximal plasma drug concentration 


 
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Abbreviation 
Term 
TD 
Tap duration 
TE 
Echo Time 
TF 
Tapping forces 
TR 
Repetition Time 
TSH 
thyroid stimulating hormone 
TSPO 
Translocator Protein 
(UHDRS-)FA 
(Unified Huntington’s Disease Rating Scale) Functional Assessment 
(UHDRS-)TFC 
(Unified Huntington’s Disease Rating Scale) Total Functional Capacity 
(UHDRS-)TMS 
(Unified Huntington’s Disease Rating Scale) Total Motor Score 
ULN 
upper limit of the normal range 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO Drug 
World Health Organization (WHO) drug dictionary 
WLQ 
Work Limitations Questionnaire 
 


 
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INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. study TV5600-CNS-20007, (A Multicenter, 
Multinational, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of Laquinimod [0.5, 1.0 and 1.5 mg/day] as Treatment in 
Patients with Huntington’s Disease), and was written in accordance with SOP GBP_RD_702 
(Statistical Analysis Plan). 
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.  
The following documents were reviewed in preparation of this SAP: 
• Clinical Study Protocol TV5600-CNS-20007 issued on 27MAY2014, amendment 1 
issued on 10SEP2014, amendment 2 issued on 16FEB2015, amendment 3 issued on 
24SEP2015, amendment 4 issued on 16Feb2016  
• Case report form (CRF) for TV5600-CNS-20007 
• ICH E9 Guidance on Statistical Principles for Clinical Trials 
• ICH E3 Structure and Content of Clinical Study Reports (CSRs) 
• Multiple Endpoints in Clinical Trials Guidance for Industry by FDA 
• E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials 
Any other references indicated throughout the SAP are cited from the study protocol, and the 
reader is requested to search there for the details. 
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details or changes regarding these particular points of interest, or other types of analyses (eg 
other endpoints). When differences exist in descriptions or explanations provided in the study 
protocol and this SAP, the SAP prevails; the differences will be explained in the Clinical Study 
Report. 
 


 
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1. 
STUDY OBJECTIVES  
The primary objective of this study is to assess the efficacy of laquinimod as treatment in 
patients with Huntington’s Disease (HD) after 52 weeks using the Unified Huntington’s Disease 
Rating Scale Total Motor Score (UHDRS-TMS or TMS). 
The secondary objective of this study is to assess the effect of laquinimod in patients with HD 
after 52 weeks of treatment on change in brain volume (i.e. atrophy) using magnetic resonance 
imaging (MRI) measures of caudate volume. 
Other efficacy endpoints will also be analyzed in an exploratory manner; these are detailed in 
Section 2.4.3. 
The additional objectives are as follows: 
• To evaluate the safety and tolerability of laquinimod (0.5, 1.0 and 1.5 mg/day) doses 
in patients with HD during 52 weeks of treatment 
• To evaluate the pharmacokinetics of laquinimod and its metabolites in patients with 
HD 
Some additional ancillary studies defined in the Protocol are beyond the scope of this SAP and 
will be reported separately if applicable (see Section 16).  


 
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2. 
STUDY DESIGN 
2.1. 
General Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of laquinimod treatment at dosages of 0.5, 1.0, and 1.5 mg/day in 
adults with HD. 
The study will consist of a screening period (2 weeks up to 5 weeks), followed by a 52-week 
double-blind treatment period and a follow-up visit (one month after end of treatment). Prior to 
10 January 2016, a total of 400 patients were planned to be equally randomized in a 1:1:1:1 ratio 
(100 patients within each treatment arm) to receive laquinimod 0.5, 1.0, 1.5 mg/day, or matching 
placebo for 52 weeks. A total of 123 patients were randomized prior to 10 January 2016. 
As of 10 January 2016, following the decision to endorse the DMC recommendation to 
discontinue treatment of the laquinimod 1.5 mg dose arm as a proactive safety measure, 
additional eligible patients who are enrolled will be randomized in a 1:1:1 ratio to receive 
laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo for 52 weeks. Thus, approximately 300 
patients (100 patients within each study arm), plus the 30 patients who were already randomized 
to the laquinimod 1.5 mg treatment arm, were planned to be enrolled in the study. See the study 
schema from 10 January 2016 on Figure 1 for reference. 
As of recruitment completion in May 2017, 352 patients, including the 30 patients who were 
randomized  to the laquinimod 1.5 mg treatment arm, were enrolled in the study. After signing 
the informed consent, including consent to provide a blood sample for genetic analyses including 
CAG repeat length analysis, patients will be screened for a period of 2 weeks up to 5 weeks in 
order to determine whether they are eligible to participate in the study. Patients with a legal 
guardian should be consented according to local requirements. 
Study procedures and assessments with their timing are summarized in Table 1.  
During the visits, vital sign measurements, physical examinations and ECG will be performed 
prior to the blood draw for clinical laboratory tests and pharmacokinetic sampling. Further, the 
efficacy assessments (UHDRS-TMS, Huntington’s Disease Cognitive Assessment Battery (HD-
CAB), Clinician’s Interview-Based Impression of Change (CIBIC)-Plus and Total Functional 
Capacity (UHDRS-TFC)) will be done prior to the other assessments. 
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the final visit (Visit 8, Month 12). Patients who withdraw from the study before completing 
the 52-week evaluation period will have Visit 8 procedures and assessments performed at their 
last visit. 
A single blood sample will be collected from all patients at Months 1, 3, 6 and 12 for evaluation 
of laquinimod and its metabolites. 
For PK ancillary study, PK samples were collected from approximately 4 patients per each of the 
three continuing treatment groups (at selected sites at Month 1), for a total of 13 patients at pre-
dose, 15, 30 min and 1, 2, 3, 6 and 24 hours post dose. Additionally, PK samples were collected 
from 2 patients in the laquinimod 1.5 mg/day treatment group at the time this treatment group 
was discontinued; no further PK samples will be collected from the laquinimod 1.5 mg/day 
treatment group. 


 
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Figure 1: 
Overall Study Schema (from to 10 January 2016) 
 
 
 


 
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Table 1: 
TV5600-CNS-20007 (LEGATO-HD) - Study Procedures and Assessments 
  


 
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2.2. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Prior to 10 January 2016, eligible 
patients were randomly assigned to receive treatment with laquinimod at a dosage of 0.5, 1.0 or 
1.5 mg qd or a matching placebo in a 1:1:1:1 ratio. 
As of 10 January 2016, following a decision to discontinue treatment of the laquinimod 1.5 mg 
dose arm, future eligible patients were to be randomized in a 1:1:1 ratio to receive laquinimod 
0.5 mg/day or 1.0 mg/day or matching placebo for 52 weeks. No change was performed to the 
original randomization list except that the patient numbers assigned to laquinimod 1.5 mg/day 
were removed from the list by the interactive response technology (IRT) vendor. 
All patients who discontinued the 1.5 mg/day dose have been unblinded. No attempts were made 
to re-randomize patients whose 1.5 mg treatment was stopped to a lower dose of laquinimod. 
The remaining ongoing patients retained their originally randomized treatment assignments. 
Patients and investigators will remain blinded to treatment assignment during the study. 
Patients were randomly assigned to treatment through a qualified randomization service provider 
(eg, IRT). This system is used to ensure a balance across treatment groups.  
The randomization code were  generated by the Clinical Supply Chain (CSC) department 
following specifications from the Biostatistics Department. 
In addition, the sponsor’s clinical personnel involved in the study are blinded to the study drug 
identity until the database is locked for analysis and the treatment assignment revealed. 
However, in case a prioritized sample analysis is needed, bioanalytical personnel may not be 
blinded .  
A statistician not assigned to the study will be responsible for reviewing the randomization code, 
and the final randomization code will be maintained by the CSC department. 
2.3. 
Data Monitoring Committee 
An independent Data Safety Monitoring Board (DSMB) will oversee the study. The DSMB will 
review unblinded accumulating safety data on a regular basis to ensure the continuing safety of 
the study patients and study conduct issues. An external unblinded statistician will provide the 
unblinded data to DSMB.  
2.4. 
Primary, Secondary and other Efficacy Variables and Safety 
Variables 
2.4.1. 
Primary Efficacy Variable 
The primary objective of this study is to assess the efficacy of laquinimod 1.0 mg in patients with 
HD after 12 months of treatment using the UHDRS-TMS. 
2.4.2. 
Secondary Efficacy Variable 
The secondary objective of this study is to assess the effect of laquinimod 1.0 mg in patients with 
HD after 12 months of treatment on brain atrophy using MRI measures of caudate volume. 


 
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2.4.3. 
Other Efficacy Variables 
Analyses of the primary and secondary endpoints on the 0.5 mg laquinimod arm vs. placebo arm: 
• Change from baseline in UHDRS-TMS at week 52; 
• Percent change from baseline in caudate volume at week 52. 
Additional analyses of each dose, 0.5 mg and 1.0 mg laquinimod, in comparison with placebo:  
• Change from baseline in UHDRS-TFC at week 52;  
• Change from baseline in HD-CAB composite score at week 52;  
• CIBIC-Plus global score at week 52 as compared to baseline (rated by an independent 
rater);  
• Change in brain volume (i.e. atrophy) evaluated at week 52/Early Termination (ET) 
versus baseline as defined by 
− Percent change from baseline in whole brain volume at week 52/ET; 
− Percent change from baseline in white-matter volume at week 52/ET; 
− Absolute change in ventricular volume at week 52/ET; 
• Change from baseline in UHDRS Functional Assessment (FA) at week 52/ET 
(evaluated at baseline,week 26 and 52)  
• Change from baseline in Quantitative-Motor (Q-Motor) assessments at week 52/ET 
(evaluated at baseline and week 4, 13, 26 and 52) 
• Change from baseline in the modified physical performance test (mPPT) at week 
52/ET (evaluated at baseline and week 26 and 52) 
• Change from baseline in the Huntington’s Disease Quality of Life (HD QoL) and 
5-Level EuroQol Five Dimensions Questionnaire (EQ-5D-5L) at week 52/ET 
(evaluated at baseline and week 52) 
• Change from baseline in the Work Limitations Questionnaire (WLQ) at week 52/ET 
(evaluated at baseline and week 52) 
• Change from baseline in HD-CAB sub-components at week 52/ET (evaluated at 
baseline and week 26 and 52) - Symbol Digit Modalities Test (SDMT), Emotion 
Recognition, Trail Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), 
Paced Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 
trial version) 
• Change from baseline in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) at 
week 52/ET (evaluated at baseline and week 52)  
• Change from baseline in the Hospital Anxiety and Depression Scale (HADS) at week 
52/ET (evaluated at baseline and week 52) 
• Change from baseline in the Problem Behaviors Assessment-Short form (PBA-s) at 
week 52/ET (evaluated at baseline and week 52) 


 
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Pharmacokinetics (PK) analysis 
• To potentially evaluate the plasma concentrations of laquinimod in patients with HD 
2.5. 
Sample Size and Power Considerations 
The study aims to detect potential beneficial effects in deteriorating clinical signs and symptoms. 
Based on previous studies in patients with HD, the UHDRS-TMS has been shown to be one of 
the more sensitive clinical measures to detect decline in symptoms of HD. It is estimated that 
approximately 100 patients per arm will provide a power of 80% to detect a significant effect of 
an active laquinimod arm compared to placebo, assuming a true mean difference of 2.5 points or 
more in the change from baseline in UHDRS-TMS, standard deviation (SD) of 6.2 and type I 
error of 5%.  
As the intention is to investigate laquinimod as a treatment with the potential to slow disease 
progression and prohibit neuronal death in the CNS, the study should also be sized to be able to 
detect changes in brain atrophy rate after treatment with laquinimod. One of the most sensitive 
measures to detect brain atrophy over time in patients with HD is change in the caudate volume.  
It is estimated that approximately 100 patients per arm will enable a power of 80% to detect a 
beneficial effect of 0.95 (30% of the estimated decline in placebo) or more in the percent change 
from baseline in caudate brain atrophy of an active laquinimod arm compared to placebo, 
assuming SD of 2.36 and type I error of 5%. 
2.6. 
Sequence of Planned Analyses 
2.6.1. 
Planned Interim Analyses 
No interim analysis is planned for this study. 
2.6.2. 
Final Analyses and Reporting 
All analyses identified in this Statistical Analysis Plan will be performed after the end of study as 
defined in the study protocol. 
This Statistical Analysis Plan and any corresponding amendments will be approved before 
database lock, in accordance to SOP GBP_RD_702 (Statistical Analysis Plan). 
The randomization codes will not be unblinded until this Statistical Analysis Plan has been 
approved and issued and the database has been locked. 
Any results of ancillary studies  or exploratory analyses completed to support study analyses, 
which were not identified in this SAP, will be documented and reported separately as addendums 
to the CSR.  
 
 


 
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3. 
ANALYSIS SETS 
3.1. 
Intent-to-Treat 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. 
3.2. 
Safety Population 
The safety 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. 
3.3. 
 Full Analysis Set 
The full analysis set (FAS) will include all patients in the ITT population who receive at least 
1 dose of study drug and have at least 1 post-baseline TMS assessment. In analyses and 
summaries based on the FAS analysis set, patients will be included in the treatment group to 
which they were randomized, regardless of the treatment that was actually received. 
3.4. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic analysis set (PAS) will include all patients from the safety analysis set who 
also have ≥1 plasma concentration measured. 
 


 
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4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include n, mean, SD, standard error (SE), median, 
minimum, and maximum. Descriptive statistics for categorical variables include patient counts 
and percentages, missing category will be displayed as appropriate. 
4.2. 
Specification of Baseline Values 
Baseline is defined as the last observed data before the first dose of study drug, unless otherwise 
noted. 
4.3. 
Handling Withdrawals and Missing Data 
For all variables, only the observed data from the patients will be used in the by visit summary. 
For the TMS component of the UHDRS, if responses of up to 25% of items are missing, the 
missing responses will be replaced by the average of the remaining responses within the TMS 
component. If eight or more of the items are missing, the missing items will not be replaced and 
the TMS will be set to missing.  
For the TFC component of the UHDRS, if responses of up to 25% of items are missing, the 
missing responses will be replaced by the average of the remaining responses within the TFC 
scale. If responses to more than 25% of the items are missing, the missing responses will not be 
replaced and the TFC will be set to missing. 
For the FA component of the UHDRS, if responses to 1 assessment up to 25% of assessments are 
missing, the missing responses will be replaced by the average of the remaining responses within 
the FA component. If more than 25% of the assessments are missing, the missing responses will 
not be replaced and the UHDRS-FA will be set to missing. 
For mPPT, item 1 (balance tasks), item 4 (put on and remove a jacket), and item 6 (turn 360 
degrees) have to be calculated before calculating the total score. For all 3 items, if any 
assessment is missing then the missing responses will not be replaced and the item will be set to 
missing. After calculating items 1, 4, and 6, if responses of up to two items (25% of 9) are 
missing, the missing responses will be replaced by the average of the remaining responses. If 
responses to more than two items are missing, the missing responses will not be replaced and the 
total score will be set to missing.  
For PBA-s, the (severity times frequency)  scores per item need to be calculated before 
calculating the total score. If either the severity or frequency value is missing then the item will 
be equal to the nonmissing value. After calculating the items, if responses of at least one and up 
to 25% of items are missing, the missing responses will be replaced by the average of the 
remaining responses. If responses to more than 25% of the items are missing, the missing 
responses will not be replaced and the total score will be set to missing. 
For tests from the Q-Motor assessments, if either the left or right value is missing, then the 
average value will be equal to the nonmissing value. 


 
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If more than 1 out 6 HD-CAB tests is missing, the HD-CAB composite score will be set to 
missing. 
For the four WLQ scales, if one of the item responses is missing (either left blank or includes a 
“does not apply to my job” response), then the half-scale imputation rule is applied by assigning 
the valid item score to the missing item. If both of the items within a scale are missing, the WLQ 
scale score will be left missing. 
The possible impact of missing values on the analysis will not be evaluated. 
4.4. 
Study Days and Visits 
Study days are numbered relative to the first day of study drug administration. The start of 
treatment (Day 1) is defined as the date on which a patient takes the first dose of study drug, as 
recorded on the Case report form (CRF). Days will be numbered relative to treatment start (ie, ..., 
–2, –1, 1, 2, ...; with day 1 being the first day of study drug administration and day –1 being the 
day before the first day of study drug administration). 
The actual visit day will be verified against  the allowed visit window according to Table 1. 
For by-visit summaries, if there are multiple assessments at a postbaseline visit day, then the last 
non-missing assessment at that visit day will be used for the summary, for both scheduled and 
unscheduled assessments.  
For by-visit efficacy summaries and/or statistical models, early termination or unscheduled visit 
for a specific measure will be assigned to the closest non-missing planned scheduled visit of this 
measure. See Table 2 for the rules of the assignment.  
For safety summaries, unscheduled, ET and Follow Up visits will be mapped using visit 
windows according to Table 1.  
For both safety and efficacy summaries, if there is a scheduled visit assessment in the visit 
window, it will be preferably used in the analysis. Among the unscheduled and ET visit (and also 
Follow Up for safety data), the visit with closest date to the planned scheduled visit will be used. 
For last safety assessment, the last available non-missing value will be used. Unscheduled, ET 
and Follow Up visits that could not be mapped will not be displayed in the safety by visit 
summaries except they will be considered for the endpoint/last assessment visit. 
All assessments will be listed.  


 
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Table 2: 
Visit Windows in days for Early Termination and Unscheduled Visits 
Assessments 
Time Points 
Visit 3  
(Month 1/ 
Week 4) 
Visit 4  
(Month 3/ 
Week 13) 
Visit 6  
(Month 6/ 
Week 26) 
Visit 8  
(Month 12/ 
Week 52) 
UHDRS-TMS 
Q-Motor Assessments 
HD-CABa 
2-60 
61-135 
136-270 
≥271 
UHDRS-TFC 
UHDRS-FA 
mPPT 
CIBIC-plus 
HD-CABb 
2-270 
≥271 
PBA-s 
HD-QoL 
EQ-5D-5L 
HADS 
WLQ 
CDR-SB 
MRIc 
>180 
a SDMT and Trail Making Test 
b Other than SDMT and Trail Making Test 
c The MRI measurement after 6 months (180 days) on study and out of the window ±7 days from the day 365 will 
be annualized assuming linear change with time. The annualized value will be presented on the descriptive tables 
and used in the analysis. See details in Section 6.3.1  


 
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5. 
STUDY POPULATION 
5.1. 
General 
The ITT population will be used for all study population summaries unless otherwise noted. 
Summaries will be presented by treatment group and for all patients unless otherwise noted. 
Due to the decision from 10 January 2016 to discontinue treatment of the laquinimod 1.5 mg 
dose arm, and the low number of enrolled patients compared to the target at that time, data from 
the laquinimod 1.5 mg treatment arm will be presented descriptively only, and will not be 
included in any inferential analyses for efficacy or safety. 
5.2. 
Patient Disposition 
Data from patients screened, patients screened but not randomized, patients in the ITT 
population (ie, randomized patients), patients who were randomized but not treated, patients in 
the safety, FAS population, patients who complete the study and patients who withdraw from the 
study, as well as patients who complete the treatment and patients who withdraw from the 
treatment, will be summarized using descriptive statistics. Data from patients who withdraw 
from the study as well as patients who withdraw from the treatment will also be summarized by 
reason for withdrawal using descriptive statistics. 
Patients in the high dose group (1.5mg/day), who were requested to discontinue study drug 
before week 52 but continued to attend scheduled study visits for safety assessments, will be 
considered to have completed the study, but not treatment (see Section 16.2). 
5.3. 
Demographics and Baseline Characteristics 
Patient demographic and baseline characteristics will be examined regarding the comparability 
of the treatment groups and will be summarized using descriptive statistics using both ITT and 
FAS analysis sets. For continuous variables, descriptive statistics (number, mean, SD, SE, 
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. 
P-values for the simultaneous testing (for detecting the difference between at least two treatment 
groups) of the placebo, laquinimod 0.5 mg and laquinimod 1.0 mg treatment groups will be 
presented.  
For demographics, the continuous variables of patient age, weight, height, and body mass index 
(BMI) will be summarized using descriptive statistics. The categorical variables of patient sex, 
race, and ethnicity will be summarized using descriptive statistics for each category. 
For baseline characteristics, the number of Cytosine-Adenosine-Guanine (CAG) repeats, efficacy 
and safety scales scores will be summarized using descriptive statistics. 
Months from HD diagnosis and months from onset of first HD symptoms at the study consent 
day will be presented. In case the reported dates are partial, with a missing day of the month or 
missing month,  full dates will be imputed. If the day is missing, the first day of the month will 
be imputed. If  the month is missing, it will be imputed as January of that year. 
Smoker status will be summarized using descriptive statistics.  


 
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5.3.1. 
Baseline MRI Parameters  
The baseline MRI parameters will be presented using descriptive statistics using both ITT and 
FAS analysis sets: caudate volume, total intracranial volume, ventricular volume, whole brain 
volume and white-matter volume.  
The baseline normalized volume will be calculated by dividing the volume for each region by 
total intracranial volume, and will be presented using descriptive statistics using both ITT and 
FAS analysis sets. The total intracranial volume is also called pseudo total intracranial volume, 
since it is unitless. 
The baseline volumes for caudate, whole brain and  lateral ventricles are outlined by a trained 
analyst (semi-automatically) and subsequentially do not have associated endpoint Quality 
Control (QC) grades. However, total intracranial volume and baseline white-matter volume 
volume are generated completely automatically and do have endpoint QC grades, due to the 
importance of testing the reliability of the automated pipeline at this stage.   
The baseline white-matter volume endpoint QC is different from the longitudinal white-matter 
volume change endpoint QC, as these are different processes/pipelines. Baseline white-matter 
volume endpoint QC represents the reliability of the white matter volume numerical result at 
baseline.  The longitudinal change in white-matter volume endpoint QC grade represents the 
reliability of the volume change measurement over the scanning interval. 
Where there is an endpoint QC fail, the data point will not be shown and will be further removed 
from the statistical analysis.   
5.4. 
Medical History 
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 
once in each preferred term and SOC category. Summaries will be presented by treatment group 
and for all patients. 
5.5. 
Prior Therapy and Medication 
Any prior therapy, medication, or procedure a patient has had within 3 months before study drug 
administration will be recorded on the CRF. Trade name or International Nonproprietary Name 
(INN), indication, and dosage will be recorded. The sponsor will encode all therapy and 
medication according to the World Health Organization drug dictionary (WHO Drug). 
The incidence of prior therapies and medications will be summarized using descriptive statistics 
by therapeutic class and preferred term. Patients are counted only once in each therapeutic class 
category, and only once in each preferred term category. Prior therapies and medications will 
include all medications taken and therapies administered before the first day of study drug 
administration. 


 
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5.6. 
Electrocardiography 
Electrocardiogram (ECG) findings (normal and abnormal) at baseline will be summarized using 
descriptive statistics. The worst result of up to three last measurements during the last visit prior 
to first dose administration will be used for the interpretation. 
5.7. 
Childbearing Potential and Methods of Contraception 
For female patients, information related to childbearing potential, and menopause will be 
collected at all visits including Week 19 telephone visit. The data will be listed. 
5.8. 
Subject Characteristics 
An evaluation of cardiovascular risk factors should take place as soon as possible for patients 
already in the study, following approval of Global Amendment 04. Assessment of changes in 
cardiovascular risk and appropriate cardiovascular risk management with appropriate medical 
follow-up, if clinically indicated, should be performed during the scheduled and unscheduled 
visits.  
Liver disease risk factor evaluation will be performed for the patients who develop any chronic 
liver disease associated with hepatic function impairment. 
Data will be listed. 
5.9. 
Study Protocol Violations 
Data from patients with any protocol violations (as recorded in protocol violation CRF) during 
the study will be summarized overall and for each category using descriptive statistics. Of note, 
medication errors, overdose, misuse, abuse, off-label use, and occupational exposure will be 
summarized in category ”Non-Compliance to study medication” as per study protocol.  


 
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6. 
EFFICACY ANALYSIS 
6.1. 
General 
The FAS will be used for efficacy analyses. Summaries will be presented by treatment unless 
otherwise noted. As noted in Section 5.1, the data from the laquinimod 1.5 mg treatment arm will 
be presented descriptively only, and will not be included in any inferential analyses for efficacy. 
6.2. 
Primary Efficacy Endpoint and Analysis 
6.2.1. 
Definition 
The UHDRS comprises a broad assessment of features associated with HD. It is a research tool 
which has been developed to provide a uniform assessment of the clinical features and course of 
HD. The TMS component of UHDRS comprises 31 assessments from the 15 items of the 
UHDRS. The TMS is calculated as the sum of the 31 motor assessments. 
The primary efficacy variable and endpoint for this study is the change from baseline to week 52/ 
ET (evaluated at baseline and week 4, 13, 26 and 52) in the TMS. Specifically, the change from 
baseline to week 52/ET in the TMS comparison between laquinimod 1 mg and placebo is 
prioritized to serve as the primary efficacy endpoint, while the change from baseline to week 
52/ET in the TMS comparison between laquinimod 0.5 mg and placebo will be an exploratory 
endpoint.  
A detailed description for all rating scales can be found in the protocol and below. 
6.2.2. 
Primary Efficacy Analysis 
The primary analysis of efficacy will be performed using the FAS analysis set. The change from 
baseline to week 52/ET in the TMS will be compared between laquinimod 1.0 mg and placebo 
using a Mixed Model Repeated Measures model (MMRM) using SAS® MIXED procedure with 
REPEATED sub-command. The model will include the following fixed effects: treatment group  
with 3 levels: placebo, laquinimod 0.5 mg and laquinimod 1 mg; categorical week in trial with 4 
levels: week 4, 13, 26 and 52; treatment by week interaction, country, TMS at baseline and week 
by TMS at baseline interaction.  Categorical week in study by baseline TMS interaction term was 
added to the primary analysis model since it was found statistically significant in the previous 
HD studies. Subject will be a random effect. 
The unstructured covariance matrix for repeated observations within patients will be used. In 
case that the model does not converge, the Maximum-Likelihood (ML) estimation method will 
be used instead of the default Restricted ML (REML). If the model still does not converge then a 
simpler covariance structures with less parameters will be used, according to the following order: 
Heterogeneous Autoregressive(1) [ARH(1)], Heterogeneous Compound Symmetry (CSH), 
Autoregressive(1) [AR(1)], and Compound Symmetry (CS). The Kenward-Rodger (KR) method 
will be used to calculate the denominator degrees of freedom. 
The least square (LS) mean and standard error for the laquinimod 0.5 mg , laquinimod 1.0 mg 
and placebo groups, and the LS mean difference, 95% confidence interval (CI), and p-value for 
each laquinimod dose versus placebo comparison (laquinimod 0.5 mg vs placebo and laquinimod 
1.0 mg vs placebo) will be presented at all visits.  


 
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The inferential p-value for the primary endpoint is for the comparison of laquinimod 1.0 mg vs 
placebo at week 52.  
The comparison between laquinimod 0.5 mg and placebo change from baseline to week 52/ET in 
the TMS will serve as an exploratory endpoint. See Section 6.4.1  for details. 
The SAS code for the repeated measures model is as follows: 
Ods Output LSMeans=LSM Diffs=Diff; 
Proc Mixed Method=REML;  
Class USUBJID Arm Week country ; 
Model TMSChange = Arm | Week  country TMSBaseline Week*TMSBaseline /DDFM=KR; 
Repeated Week /Type=Un Subject= USUBJID R Rcorr; 
LSMeans  Arm*Week / PDiff CL;  
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’ , ‘laquinimod 1mg’); 
Run; 
 
The hypotheses for testing the primary analysis are: 
Ho: μa ≡ μp vs. Ha: μa ≠ μp 
where μa is the mean change from baseline to week 52/ET in the TMS for the laquinimod 1.0 mg 
arm and μp is the mean change from baseline to week 52/ET in the TMS for placebo arm. This 
two-sided test will be performed at the alpha level of 0.9*0.05=0.045, as supported by the 
Fallback with Loop-back approach for the familywise Type I error control for the primary and 
secondary endpoints. Details are provided in Section 7. 
The TMS score values and changes from baseline to week 4, 13, 26 and 52 will be summarized 
using descriptive statistics for all treatment groups.  
 
6.2.3. 
Sub-Group Analysis 
Subgroup analysis will be performed for the primary efficacy endpoint by gender, median 
baseline TMS / TFC / caudate volume / CAG repeat length and USA vs outside of  USA. Data 
will be analyzed in a manner analogous to the method described in the Section 6.2.2. Subgroup 
analysis will be performed on the FAS analysis set with fixed effects for subgroup, treatment, week 
and their interaction.  


 
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Ods Output LSMeans=LSM Diffs=Diff; 
Proc Mixed Method=REML;  
Class USUBJID Arm Week country Subgroup; 
Model TMSChange = Arm | Week | Subgroup  country TMSBaseline Week*TMSBaseline 
/DDFM=KR; 
Repeated Week /Type=Un Subject= USUBJID R Rcorr; 
LSMeans  Arm*Week*Subgroup /PDiff CL;   
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’ , ‘laquinimod 1mg’); 
Run; 
6.3. 
Secondary Efficacy Endpoint and Analysis 
6.3.1. 
Definition 
The percent change from baseline in caudate volume at week 52 / percent caudate atrophy from 
baseline at week 52 was chosen as the secondary objective for the study. 
The  percent change in caudate volume at week 52 or percent caudate atrophy at week 52 is 
calculated as the change in caudate volume since baseline visit divided by the baseline caudate 
volume and multiplied by 100. 
In this study, brain MRI is used to assess the change in volume of certain regions, including the 
caudate, whole brain, white-matter, and ventricles, over the time period from baseline to the end 
of study. Participants will undergo 3 Tesla MRI at baseline and week 52 following unaccelerated 
volumetric T1-weighted acquisition protocols developed during the ADNI study (www.adni-
info.org). Change in caudate volume over the scanning interval was shown to provide robust 
measures of brain-volume change from multi-site data and has been shown to be sensitive to 
HD-related pathology over a 12-month interval in the multi-site TRACK-HD study.  
A more detailed description of the MRI assessments can be found in the protocol. 
Brain atrophy in the caudate and whole brain refers to the shrinkage in volume of these 
structures, so that a decrease in volume will be a positive value, while an increase in volume will 
be a negative value. In contrast, for white matter and ventricles a decrease in volume will be a 
negative value and an increase in volume will be a positive value. Since ventricles are fluid filled 
spaces, an increase in the volume of the ventricles (i.e., ventricle expansion) reflects a loss of 
volume of the surrounding brain tissues. The SAP uses the terms “atrophy” and “change in 
volume” interchangeably, referring to the sign convention explained hitherto. 
The caudate atrophy since baseline measurement after 6 months (180 days) on study and out of 
the scanning window ±7 days from the day 365, will be annualized assuming linear change with 
time. The annualization calculation formula will be as follows: denoting the distance between the 
baseline and postbaseline MRI scans in days as X, the caudate atrophy will be multiplied by the 
factor of 365/X. The annualized value will be presented in the descriptive tables and will be used 
in the analysis. 


 
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Each caudate atrophy result, as well as the other MRI measurements, is accompanied by a 
specific QC result with a response value “Pass” or “Fail”. If the QC results in “Fail”, the 
corresponding caudate atrophy result should not be used in the statistical analysis. All the results 
will be listed. 
6.3.2. 
Analysis 
The Percent caudate atrophy from baseline to week 52/ET will be compared between laquinimod 
1.0 mg and placebo using an Analysis Of Covariance (ANCOVA) model (SAS® MIXED 
procedure). The model will include the following fixed effects: treatment group (Arm, 3 levels: 
placebo, laquinimod 0.5 mg and laquinimod 1 mg), country, and caudate volume at baseline 
(CVBaseline).  
The estimated means at week 52 will be compared between the laquinimod 1.0 mg and the 
placebo arm, presented with the least square (LS) mean and SE for the laquinimod 1.0 mg and 
placebo groups, and the LS mean difference, 95% CI, and inferential p-value for the comparison 
(laquinimod 1.0 mg vs placebo).  
Sample SAS code is as follows: 
Proc Mixed;  
Class Arm country; 
Model Change=Arm country CVBaseline; 
LSMeans Arm /PDiff CL; 
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’ , ‘laquinimod 1mg’); 
Run;  
The analysis will be based on the FAS analysis set. A Fallback with Loop-back approach for the 
Type I error control will be applied. If the primary endpoint is significant at a 2-sided alpha of 
0.045 then the secondary endpoint will be tested at the 2-sided alpha level of 0.05. If the primary 
endpoint fails to reach significance, then the secondary endpoint will be tested at the 2-sided 
alpha level of 0.005. Details are described in Section 7. 
Percent of change in caudate volume (i.e. atrophy) from baseline to week 52/ET will be 
summarized using descriptive statistics for all treatment groups.  
The percent change in caudate volume from baseline to week 52/ET compared between 
laquinimod 0.5 mg and placebo will serve as an exploratory endpoint. See Section 6.4.2 for 
details. 
6.3.3. 
Sub-Group Analysis 
Subgroup analysis will be performed for the secondary efficacy endpoint by gender, median 
baseline TMS / TFC / caudate volume / CAG repeat length and USA vs outside of USA. Data 
will be analyzed in a manner analogous to the method described in the Section 6.3.2. Subgroup 
analysis will be performed on the FAS analysis set with fixed effects for gender, treatment and 
their interaction.  


 
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Proc Mixed;  
Class Arm country Subgroup; 
Model Change=Arm | Subgroup country CVBaseline; 
LSMeans Arm*Subgroup /PDiff CL; 
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’, ‘laquinimod 1mg’); 
Run;  
6.4. 
Exploratory Efficacy Endpoints Analysis 
Exploratory efficacy endpoints will include the analyses of the primary and secondary endpoints 
applied on the 0.5 mg laquinimod arm vs. placebo arm, as well as additional endpoints, either 
based on rating scales or using MRI measures. See the list of the exploratory endpoints below. 
Analyses of the primary and secondary endpoints on the 0.5 mg laquinimod arm vs placebo arm: 
• Change from baseline in TMS at week 52; 
• Percent change in caudate volume (i.e. atrophy) from baseline at week 52. 
Additional analyses end-points to be compared between each dose of laquinimod, and placebo:  
• Change from baseline in TFC at week 52;  
• Change from baseline in HD-CAB composite score at week 52;  
• CIBIC-Plus global score at week 52 as compared to baseline (rated by an independent 
rater);  
• Brain atrophy evaluated at week 52/ET versus baseline as defined by 
− Percent whole brain volume change (i.e. atrophy) from baseline at week 52/ET; 
− Percent white-matter volume change from baseline at week 52/ET; 
− Absolute ventricular volume change at week 52/ET; 
• Change from baseline in FA at week 52/ET (evaluated at baseline,week 26 and 52)  
• Change from baseline in Q-Motor assessments at week 52/ET (evaluated at baseline 
and week 4, 13, 26 and 52) 
• Change from baseline in mPPT at week 52/ET (evaluated at baseline and week 26 
and 52) 
• Change from baseline in HD QoL and EQ-5D-5L at week 52/ET (evaluated at 
baseline and week 52) 
• Change from baseline in WLQ at week 52/ET (evaluated at baseline and week 52) 
• Change from baseline in HD-CAB sub-components at week 52/ET (evaluated at 
baseline and week 26 and 52) - SDMT, Emotion Recognition, Trail Making Test, 
HVLT-R, Paced Tapping at 3 Hz, OTS (abbreviated 10 trial version) 


 
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• Change from baseline in CDR-SB at week 52/ET (evaluated at baseline and week 52)  
• Change from baseline in HADS at week 52/ET (evaluated at baseline and week 52) 
• Change from baseline in PBA-s at week 52/ET (evaluated at baseline and week 52) 
6.4.1. 
Change From Baseline in Total Motor Score (laquinimod 0.5 mg arm vs 
placebo) at Week 52 
6.4.1.1. 
Definition 
See Section 6.2.1.  
6.4.1.2. 
Analysis 
Analysis of change from baseline to Week 52 in UHDRS-TMS for the laquinimod 0.5 mg arm vs 
placebo will be analysed as described in Section 6.2.2. The hypothesis testing will be done on the 
mean change difference between the laquinimod 0.5 mg arm and the placebo arm. 
6.4.2. 
Percent Change from Baseline in Caudate Volume at Week 52 (laquinimod 
0.5 mg arm vs placebo) 
6.4.2.1. 
Definition 
See Section 6.3.1. 
6.4.2.2. 
Analysis 
The analysis will be performed as described in Section 6.3.2
 
with
  
the hypothesis testing done on 
the mean change difference between the laquinimod 0.5 mg arm and the placebo arm. 
6.4.3. 
Change from Baseline in the Total Functional Capacity at Week 52 
6.4.3.1. 
Definition 
The TFC scale of the UHDRS assesses 5 functional domains associated with disability 
(occupation, finances, domestic chores, activities of daily living, and care level) and is rated from 
0-13 (maximum functionality). The TFC is the sum of the 5 functional capacity domains. TFC is 
evaluated at baseline, week 26 and 52. 
6.4.3.2. 
Analysis 
Analysis of change from baseline in the UHDRS-TFC at week 52 will be analyzed in a manner 
analogous to that described in Section 6.2.2 except that baseline TFC will be included in the 
model instead of baseline TMS (including the interaction term). Comparisons will be performed 
between laquinimod 1.0 mg arm and the placebo arm, as well as between laquinimod 0.5 mg arm 
and the placebo arm. 
The SAS code for the repeated measures model is as follows: 


 
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Ods Output LSMeans=LSM Diffs=Diff; 
Proc Mixed Method=REML;  
Class USUBJID Arm Week country ; 
Model  TFCChange = Arm | Week  country TFCBaseline Week*TFCBaseline /DDFM=KR; 
Repeated Week /Type=Un Subject= USUBJID R Rcorr; 
LSMeans  Arm*Week /PDiff CL;   
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’ , ‘laquinimod 1mg’); 
Run; 
6.4.4. 
Change from Baseline in the Functional Assessment at Week 52 
The FA scale of the UHDRS assesses functionality in 25 tasks of daily living (eg, “Could patient 
engage in gainful employment in his/her accustomed work?”). Each question is answered with 
‘yes=1’ or ‘no=0’. The FA component of the UHDRS is calculated as the sum of the 25 items. 
The FA, similarly to TFC assessment, was collected at baseline, weeks 26 and 52. Analysis of 
change from baseline in the FA at week 52 will be analyzed using the same model as for TFC 
with the baseline FA replacing baseline TFC, see Section 6.4.3.2 for details. The comparisons 
will be the same. 
6.4.5. 
Brain Atrophy Evaluated at Week 52/ET Versus Baseline  
6.4.5.1. 
Definition 
Brain atrophy will be evaluated at week 52/ET versus baseline as defined by 
a. Percent change in whole brain volume (i.e. atrophy) from baseline at week 52/ET; 
b. Percent change in white-matter volume from baseline at week 52/ET; 
c. Absolute change in ventricular volume from baseline at week 52/ET; 
See Section 6.3.1 for the details about the MRI assessments. In particular, the annualization will 
be performed on the postbaseline MRI measurement after 6 months (180 days) on study, by 
multiplying the change or the atrophy by the factor of 365/X, where X is the interval between the 
baseline and postbaseline MRI scans in days. The annualized value will be presented on the 
descriptive tables and will be used in the analysis. 
Each change or the atrophy result is accompanied by a specific QC result with a response value 
“Pass” or “Fail”. If the QC results in “Fail”, the corresponding change or the atrophy result 
should not be used in the statistical analysis and will not be presented in the descriptive analysis. 
6.4.5.2. 
Analysis 
Analysis of percent whole brain atrophy, percent white-matter volume change and absolute 
ventricular volume change from baseline at week 52 will be analogous to that described in 
Section 6.3.2 with the corresponding baseline MRI measurement (MRIBaseline) as baseline 
covariate instead of caudate volume. Comparisons will be performed between laquinimod 1.0 mg 
arm and the placebo arm, as well as between laquinimod 0.5 mg arm and the placebo arm. 


 
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The SAS code for the ANCOVA model is as follows: 
Proc Mixed;  
Class Arm country; 
Model Change=Arm country MRIBaseline; 
LSMeans Arm /PDiff CL; 
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’ , ‘laquinimod 1mg’); 
Run;  
6.4.6. 
Quantitative Motor Assessments (Q-Motor) 
Q-Motor assessments will be performed only in those sites that have access to the devices 
needed to perform the assessments and, where this is the case, only in those patients who are 
capable of performing the assessments. 
Motor deficits can be objectively assessed using different Q-Motor assessments. All Q-Motor 
assessments are based on the application of pre-calibrated and temperature controlled force 
transducers and 3-dimensional position sensors with very high sensitivity and test-retest 
reliability across sessions and sites in a multicenter clinical study. Q-Motor measures thus aim to 
reduce the limited sensitivity of categorical clinical rating scales, the intra- and inter-rater 
variability, and placebo effects observed in scales such as TMS. In addition, Q-Motor 
assessments allow for the objective monitoring of unintended motor side-effects in clinical 
studies. 
Tasks detailed in the sections below have been selected for use in the current study. Data transfer 
will be performed using a secure web based platform, allowing continuous centralized data 
monitoring and quality control. Data analysis will be performed blinded and automated. 
The Q-Motor assessments are collected at screening, baseline, week 4, 13, 26 and 52. 
6.4.6.1. 
Digitomotography (Speeded Index Finger Tapping) 
The patient will place their hand on a hand rest with their index finger positioned above a force-
transducer. Recordings will start after practice runs. The patient will be instructed to finger tap as 
fast as possible between 2 auditory cues. The beginning of a tap is defined as a rise of the force 
by 0.05 N above maximal baseline level. The tap ends when it drops to 0.05 N before the 
maximal baseline level is reached again. The duration and variability of tap durations (TD), 
inter-onset intervals (IOI), inter peak intervals (IPI), and inter tap intervals (ITI) are the 
exploratory outcome measures for speeded tapping. In addition, variability of peak tapping 
forces (TF) will be calculated, and the tapping frequency (Freq), ie, the number of taps between 
the onsets of the first and the last tap divided by the time in between, will be determined. Five 
trials of 10 seconds duration are performed with each hand.  
6.4.6.2. 
Dysdiadochomotography (Pronation/Supination Hand Tapping) 
This task assesses the regularity of hand taps performed when alternating between the palm and 
dorsal surface of the hand performing a repetitive pronation/supination movement. The force and 
duration of the hand tapsare recorded and analyzed similarly to the speeded tapping task. A tone 


 
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cues the start and end of an assessment. Five trials of 10 seconds duration are performed with 
each hand. 
6.4.6.3. 
Manumotography and Choreomotography (Grip Force and Chorea Analysis) 
This task assesses the coordination of isometric grip forces in the precision grip between the 
thumb and index finger. Grip forces are assessed during grip initiation, object transport, and in a 
static holding phase. Patients are instructed to grasp and lift a device equipped with a force 
transducer and 3-dimensional position sensor in the precision grip between thumb and index 
finger and hold it stable adjacent to a marker 10-cm high. Grip forces and 3-dimensional position 
and orientation of the object are recorded. Mean isometric grip forces and grip force variability 
in the static phase (expressed as coefficient of variation = SD/mean × 100) (GFV-C) are 
calculated during a 15-second period prior to the second cueing tone. 
Five trials of 20 seconds duration are performed with each hand. Chorea is assessed calculating a 
“position-index” and “orientation-index”. Start and end of assessment are signaled by a cueing 
tone. 
6.4.6.4. 
Pedomotography (Speeded Foot Tapping) 
The patient will place a foot on the foot device such that the ball of the foot is positioned above a 
force-transducer. Recordings will start after practice runs. The patient will be instructed to tap 
with the foot as fast as possible between 2 auditory cues. The beginning of a tap is defined as a 
rise of the force by 0.05 N above maximal baseline level. The tap ends when it dropped to 0.05 N 
before the maximal baseline level is reached again. The duration and variability of TD, IOI, IPI, 
and ITI are the exploratory outcome measures for speeded foot tapping. In addition, variability of 
peak TF will be calculated, and the tapping Freq, ie, the number of taps between the onsets of the 
first and the last tap divided by the time in between, will be determined. Five trials of 10 seconds 
duration are performed with each foot. 
6.4.6.5. 
Analysis 
The Q-Motor assessments will be analyzed in the same way as described in Section 6.4.3.2 
except that the matching baseline assessment will be included in the model as the efficacy 
measure at baseline. 
The summary will be done by the left, right and the average of the two extremeties.  
6.4.7. 
Change from Baseline in the Huntington’s Disease Cognitive Assessment Battery 
Composite Score at Week 52 (laquinimod 1mg arm vs placebo) 
6.4.7.1. 
Definition 
The following sections describe the tests that will be included in the HD-CAB. 
The CAB assessments will be performed only in those sites that have access to the devices 
needed to perform the assessments and, where this is the case, only in those patients who are 
capable of performing the assessments. 
To avoid variability due to different operating systems, hardware and computer accessories (i.e. 
mouse), sites will be provided with standardized equipment (tablets) to perform the 
computerized cognitive assessments. 


 
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6.4.7.1.1. Symbol Digit Modalities Test (SDMT) 
The SDMT is a paper-and-pencil test of attention, psychomotor speed and working memory. 
Participants view a ‘key’ at the top of the page containing symbols paired with numbers. The 
remainder of the page displays rows of symbols, and the participant has 90 seconds to write in 
the corresponding number that matches each symbol. 
6.4.7.1.2. Emotion Recognition 
Recognition of facial expressions of emotions is examined using computerized images of faces 
depicting 6 basic emotions or a neutral expression. Participants are asked to indicate the emotion 
expressed in each photograph by selecting from the words fear, disgust, happy, sad, surprise, 
angry, and neutral (a total of 36 items). The score used is correct identification of negative 
emotions (out of 24 possible). 
6.4.7.1.3. Trail Making Test 
Visual attention and task switching are assessed using the Trail Making test, which consists of 
25 circles on a standard sheet of paper. For Trails A, participants are required to connect, as 
quickly as possible, circles containing numbers in ascending numerical order. For Trails B, 
participants are to connect, as quickly as possible, circles containing numbers and letters, 
alternating between numbers and letters in ascending order (eg, 1, A, 2, B, 3, C, etc.). Trail A is 
administered first (to ensure preparedness for Trail B), followed by Trail B. Only the Trail B 
score is used as an outcome measure in the HD-CAB. 
6.4.7.1.4. Hopkins Verbal Learning Test, Revised (HVLT-R) 
The HVLT-R is a paper-based instrument that offers a brief assessment of verbal learning and 
memory (recall). It is easy to administer and score and is well tolerated even by significantly 
impaired individuals. 
Its use has been validated with brain-disordered populations (eg, Alzheimer's disease, HD, 
amnestic disorders) as a measure of verbal learning and memory. There are six alternate forms 
available, but 3 of the 6 forms, which have relatively greater equivalence with each other (Forms 
4, 5, and 6) will be used, in randomized order. Each form consists of a list of 12 nouns (targets) 
with 4 words drawn from each of 3 semantic categories. The semantic categories differ across 
the 6 forms, but the forms are very similar in their psychometric properties. Only the three 
learning trials (Trials 1-3) and the delayed recall trial (Trial 4) will be administered as part of the 
HD-CAB. The primary scores that will be examined as part of the HD-CAB is the sum of Trials 
1-4; however, the sum of Trials 1-3 and separately Trial 4 will also be examined in exploratory 
analyses. The HVLT-R has high test-retest reliability, and its construct, concurrent, and 
discriminant validity have been well established. 
6.4.7.1.5. Paced Tapping at 3 Hz 
Psychomotor function is assessed in a computerized Paced Tapping test. Participants tap on left 
and right mouse buttons, alternating between thumbs, at 3.0 Hz. They first listen to a tone 
presented at the 3.0 Hz rate, and then begin tapping in time with the tone. After 11 taps with the 
tone, the repetition tone is discontinued, and participants attempt to continue tapping at the same 
rate until the end of the trial (31 taps later). Four trials are administered. 


 
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6.4.7.1.6. One Touch Stocking of Cambridge (OTS) 
OTS is a computerized spatial planning task which gives a measure of frontal lobe function. OTS 
is a variant of the Stockings of Cambridge task, and places greater demands on working memory 
as the participant has to visualize the solution. As with Stockings of Cambridge, the participant is 
shown 2 displays containing 3 colored balls. The displays are presented in such a way that they 
can easily be perceived as stacks of colored balls held in stockings or socks suspended from a 
beam.  
Along the bottom of the screen, there is a row of numbered boxes. The test administrator first 
demonstrates to the participant how to use the balls in the lower display to copy the pattern in the 
upper display, and completes 1 demonstration problem, where the solution requires 1 move. The 
participant must then complete 3 further problems, 1 each of 2 moves, 3 moves, and 4 moves. 
Next, the participant is shown further problems, and must work out in their head how many 
moves the solutions to these problems require, then select the appropriate box at the bottom of 
the screen to indicate their response. 
6.4.7.1.7. HD-CAB Test Details and Calculation Mehthods 
HD-CAB is evaluated at baseline, week 26 and 52. The HD-CAB consists of sub-components 
described in Table 3. 
Table 3: 
HD-CAB Test Details and Calculation Methods 
Test 
Variable 
Score Range Interpretation of 
scores 
Recode Method 
Min. 
value 
Max. 
value 
Hopkins Verbal 
Learning Test-
Revised 
Total correct items summed across 
the 3 learning and 1 delayed recall 
trials 
0 
48 
High scores =  
Better performance 
No Recode 
Symbol Digit 
Modalities Test 
Number of correctly coded items 
0 
110 
High scores =  
Better performance 
No Recode 
Trail Making Test: 
Part B 
Time (seconds) to complete the task 
0 
240 
High scores =  
Worse performance 
No Recode  
Emotion 
Recognition Test 
Number of negative emotions 
correctly identified 
0 
24 
High scores =  
Better performance 
No Recode 
Paced tapping test (3 
Hz) 
The reciprocal of the standard 
deviation of the inter-tap intervals 
that occurred following cessation of 
the pacing tones over all trials taken 
(msec). This must be computed 
from standard deviation, which is 
provided in the summary files.  
0 
Infinite High scores =  
Better performance 
Mutiply the 
reciprocal of the 
raw score (rs), 
which is the 
standard 
deviation, eg 1/rs 
by 1000 
One Touch 
Stockings of 
Cambridge test 
Mean time to reach a correct 
response (sec), averaged across all 
10 trials 
0 
Infinite High scores =  
Worse performance 
No recode  
 


 
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The computation of the standardized HD-CAB composite score is described below. 
1. Convert the recoded or raw scores of the 6 HD-CAB modules to standardized Z scores: 
Standardized Z score = (Raw/Recoded score - Total Baseline population 
mean)/Total Baseline population SD 
Total population should include all randomized patients. Note that the 
standardized scores are to be calculated on a per visit basis, using the raw/recoded 
score from that visit. 
To make Trail Making Test: Part B and One Touch Stockings of Cambridge 
consistent with other 4 HD-CAB tests, the Standardized Z score for Trail Making 
Test: Part B and One Touch Stockings of Cambridge will be multiplied by -1 for 
calculation of HD-CAB composite score. 
2. For each patient and visit, calculate the average of the Z scores across the 6 HD-CAB 
tests as the HD-CAB composite score. This creates an equal weighting composite score. 
6.4.7.2. 
Analysis 
Change from baseline in the HD-CAB components and the composite score at week 52 will be 
analyzed in a manner analogous to that described in Section 6.4.3.2 except that appropriate 
baseline measurement will be included in the model instead of baseline TFC. The comparisons 
are the same. 
6.4.8. 
Clinician’s Interview-Based Impression of Change (CIBIC) - PLUS Global Score 
at Week 52  
6.4.8.1. 
Definition 
Global change in HD will be measured using the CIBIS scale at baseline and the CIBIC-Plus 
scale at subsequent time points. The CIBIC-Plus (version ADCS-CGIC) was developed, 
validated, and is commonly used in studies of anti-dementia drugs in Alzheimer’s disease. 
An independent rater whose only role in the study is to conduct these global assessments will 
evaluate the patient’s overall disease severity during the baseline visit (Visit 2) prior to the 
administration of study drug. This assessment, known as the CIBIS, rates severity of the patient’s 
HD on a 7-point Likert scale (1 = normal, not at all ill to 7 = among the most extremely ill 
patients).  
At each subsequent visit in which the evaluation is performed (Months 6 and 12; Visits 6 and 8), 
the CIBIC-Plus will be preferentially administered by the same independent rater, but without 
knowledge of other endpoint assessments or the Adverse Events (AE) experienced by the patient 
during the study (so as not to confound the rating of CIBIC-Plus as an efficacy measure or to 
unblind the study). The independent rater is not permitted to discuss the medical condition of the 
patient with the treating physician. Instead, the independent rater exclusively will consider 
observations of the patient’s cognitive, functional, and behavioral performance obtained through 
interviewing the patient and the caregiver. The rater then compares those findings to the baseline 
assessment. The overall impression of change from baseline (CIBIC-Plus) is rated on a 7-point 
scale: 1 = marked improvement; 2 = moderate improvement; 3 = minimal improvement; 4 = no 


 
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change; 5 = minimal worsening; 6 = moderate worsening; 7 = marked worsening; all 
assessments were relative to baseline. A higher score indicates a worsening of global function. 
6.4.8.2. 
Analysis 
The CIBIC-Plus will be analyzed in the same way as described in Section 6.4.3.2 except that the 
baseline CIBIS (Clinician’s Interview-Based Impression of Severity) will be included in the 
model as the efficacy measure at baseline. 
6.4.9. 
Modified Physcial Performance Test (mPPT) 
6.4.9.1. 
Definition 
The mPPT quantifies the patient’s performance in physical tasks. It is a standardized 9-item test 
that measures the patient’s performance on functional tasks. Both the speed and accuracy at 
which the patients complete the items are taken into account during scoring.  
The mPPT total score is the sum of the mPPT items scores,  
The maximum score of the test is 36, with higher scores indicating better performance. 
The mPPT is collected at baseline, weeks 26 and 52/Early Termination. 
The following is the testing protocol and scoring method:  
Administer the test as outlined below. Patients are given up to two chances to complete each 
item. Assistive devices are permitted for tasks 6 – 9. 
1. Standing Static Balance 
• 
Feet together: “Stand still with your feet together as demonstrated for 10 seconds.” 
• 
Semi Tandem: “Stand with the heel of one foot placed to the side of the 1st toe of  the opposite 
foot for 10 seconds.” Subject chooses which foot goes forward. 
• 
Tandem: “Stand with the heel of one foot directly in front of the other foot, for 10 seconds. 
Patient chooses which foot goes forward. 
2. Chair Rise: Use a straight back chair with a solid seat that is 16” high. Ask participant to sit on the 
chair with arms folded across their chest. “Stand up and sit down as quickly as possible 5 times, keeping 
your arms folded across your chest.” Stop timing when the participant stands the 5th time. 
3. Book Lift: Place a Physician’s Desk Reference Book (1988 PDR: 5.5 lbs) or other heavy book on a table 
in front of the patient. Ask the patient, when given the command “go” to place the book, as quickly as 
they can, on a shelf above shoulder level. Time from the command “go” until when the book is resting 
on the shelf. Starting position is with their hands at their side. 
4. Put on and remove a jacket: If the patient has a jacket or cardigan sweater, ask them to remove it. If 
not, give the patient a lab coat. Ask the patient, on the command “go” to quickly put the coat on 
completely such that it is straight on their shoulders and then remove the garment completely. Time 
from the command “go” until the garment has been completely removed. Hint: it is more accurate to 
time putting on the garment, then pause (pause the stopwatch), then time taking off the garment. 
5. Pick up a penny from floor: Place a penny approximately 12 inches from the patient’s foot on the 
dominant side. Ask the patient, on the command “go” to pick up the penny from the floor and stand up. 


 
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This is to be done as quickly as they can; yet allowing for safety and comfort. Time from the command 
“go” until the patient is standing erect with a penny in hand. If dexterity is a problem, a pen or similar 
lightweight object can be used. 
6. Turn 360 degrees: Ask the patient to turn 360 degrees “as quickly as you can, as you feel comfortable 
and safe”. Evaluate using the scale on PPT scoring sheet. Additional data: count the number of steps 
required. 
7. 50-foot walk test: Bring patient to start on a 50 foot walk test course (25 feet out and 25 feet back) 
and ask the patient, on the command “go” to walk as quickly as they can to the 25-foot mark and back. 
Time from the command “go” until the starting line is crossed on the way back. 
8-9. Stairs: Take vital signs. Bring patient to foot of stairs (nine to 12 steps) and ask patient, on 
the command ”go” to begin climbing up to a total of 4 flights stairs (as quickly as they can, as 
they feel comfortable and safe) or until they feel tired and wish to stop. Before beginning this 
task, alert the patient to the possibility of developing chest pain or shortness of breath and inform 
the patient to tell you if any of these symptoms occur. You will walk with the patient. Time from 
the command “go” until the patients’ first foot reaches the top of the first flight of stairs. Go on 
to record the number of flights (maximum is four) completed (up and down is one flight). 
Provide a chair for resting when completed, so vital signs can be taken immediately post. 
Table 4: 
Modified - Physical Performance Test – Scoring Method 
No. 
Task 
Items Score Values 
1. 
Balance Tasks 
Standing Balance Feet Together 
• ≥ 10 sec                       = 1 
• 0 - <10 sec or Unable  = 0 
Standing Balance Semi Tandem 
• ≥ 10 sec                      = 1 
• 0 - <10 sec or Unable = 0 
Standing Balance Tandem 
• ≥ 10 sec                     = 2 
• 3 – <10 sec                = 1 
• 0 - <3 sec or Unable  = 0 
2. 
Chair rise 
• >0  - 11 sec      = 4 
• >11 - 14 sec     = 3 
• >14 - 17 sec     = 2 
• >17 sec             = 1 
• 0, Unable          = 0 


 
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No. 
Task 
Items Score Values 
3. 
Lift a book and put it on a shelf 
• >0 - 2 sec      = 4 
• >2 - 4 sec      = 3 
• >4 - 6 sec      = 2 
• >6 sec            = 1 
• 0, Unable       = 0 
4. 
Put on and remove a jacket (sum of time to put and 
to remove the jacket) 
 
• >0 - 10 sec     = 4 
• >10 - 15 sec   = 3 
• >15 – 20 sec   = 2 
• >20 sec           = 1 
• 0, Unable        = 0 
5. 
Pick up a penny from floor 
• >0 - 2 sec        = 4 
• >2 - 4 sec        = 3 
• >4 - 6 sec        = 2 
• > 6 sec             = 1 
• 0, Unable         = 0 
6. 
Turn 360 degrees 
Steps 
• Continuous      = 2 
• Discontinuous = 0 
Steadiness 
• Steady                                 = 2 
• Unsteady (grabs, staggers) = 0 
7. 
50-foot walk test 
• >0  - 15 sec     = 4 
• >15 - 20 sec    = 3 
• >20 - 25 sec    = 2 
• >25 sec            = 1 
• 0, Unable         = 0 


 
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No. 
Task 
Items Score Values 
8. 
Climb one flight of stairs 
• >0 - 5 sec        = 4 
• >5 - 10 sec      = 3 
• >10 – 15 sec    = 2 
• >15 sec            = 1 
• 0, Unable         = 0 
9. 
Climb 4 flights of stairs (Number of flights climbed 
up and down) 
• 4 flights           = 4  
• 3 flights           = 3 
• 2 flights           = 2 
• 1 flights           = 1 
• Unable             = 0 
 
Total mPPT Score 
Sum of all Item score values [0-36] 
6.4.9.2. 
Analysis 
The mPPT will be analyzed in the same way as described in Section 6.4.3.2 except that the 
baseline mPPT will be included in the model as the efficacy measure at baseline. 
6.4.10. 
Huntington’s Disease Quality of Life (HD-QoL) and 5-Level EuroQol Five 
Dimensions Questionnaire (EQ-5D-5L) 
6.4.10.1. HD-QoL Definition 
The HD-QoL questionnaire includes 40 items (ranged 0='Never' to 6='All the Time') and is 
collected at baseline and Week 52. 
The HD-QoL total score is defined as the sum of the 40 items. 
The HD-QoL total score range is from 0 to 240. 
6.4.10.2. EQ-5D-5L Definition 
The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale. The 
EQ-5D descriptive system includes 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. The values for each of the dimensions are: 1=no 
problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=unable 
to/extreme problems.  
The EQ visual analogue scale records the respondent’s self-rated health on a vertical, visual 
analogue scale where the endpoints are labeled ‘100=Best imaginable health state’ and ‘0=Worst 
imaginable health state’. 


 
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6.4.10.3. Analysis 
The change from baseline in HD-QoL and in EQ-5D-5L domains at endpoint, will be analyzed 
using an Analysis of Covariance (ANCOVA) Model. The model will include the following fixed 
effects: treatment, country and baseline HD-QoL or EQ-5D-5L domains scores.  
The least square mean and standard error of the least square mean for each treatment group, and 
the 95% CI for the comparisons (laquinimod dose vs placebo) will be presented. 
The SAS code for the ANCOVA model is as follows: 
Ods Output LSMeans=LSM Diffs=Diff; 
Proc Mixed;  
Class Arm Country; 
Model Change=Arm Country Baseline; 
LSMeans Arm /PDiff CL; 
Where Arm in (‘Placebo’, ‘laquinimod 0.5mg’ , ‘laquinimod 1mg’); 
Run;  
6.4.11. 
Work Limitations Questionnaire (WLQ) 
HD imposes a substantial burden on patients in the form of impaired ability to perform 
productive activity such as paid employment, domestic household activity, or schooling. The 
WLQ captures a multidimensional look at work productivity. It is designed to measure 
productivity among workers who are employed, but may be performing at less than full capacity. 
It measures the degree to which health problems interfere with specific aspects of job 
performance and the productivity impact of these work limitations. The eight-item version 
(Lerner, et al. revised 2009, unpublished, email communication) will be used to reduce 
respondent burden, though it is potentially less precise than the full 25-item version (Lerner, et 
al, 2001). 
This version captures the most important subset of the original 25 questions, choosing two items 
from each of the four full scale dimensions: 
• Time Management Scale addresses the difficulty of performing a job easily at the 
beginning of the workday and starting the job soon after arriving at work (Question 1 
– a and b).  
• The Physical Tasks Scale covers a person’s ability to perform job tasks that involve 
sitting and standing in one position and performing the same motion repeatedly 
(Question 2 – a and b).  
•  The Mental-Interpersonal Tasks Scale assesses the difficulty concentrating on work 
and a person’s ability to interact with people on-the-job (Questions 3 and 4).   
•  The Output Tasks Scale concerns the person’s ability to complete work (Question 5 – 
a and b). 


 
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The responses to each of the WLQ’s 8 items describe the amount of time in the prior 2 weeks an 
employee was limited with regard to performing a specific type of job task. The values of the 
response for each WLQ item represent, by design, the item labels (to lessen the responder bias) 
rather than the severity score itself. A severity score for each WLQ item will be defined such that 
the highest score, 5, corresponds to the highest degree of work limitation, whereas the lowest 
score, 1, corresponds to no limitation in performing the job tasks. 
Thus, for the Time Management Scale, Mental-Interpersonal Tasks Scale and the Output Tasks 
Scale, the severity score will be defined such that the highest severity score, 5, will correspond to 
“Difficult all of the time (100%)”, while the lowest severity score, 1, will correspond to 
“Difficult none of the time (0%)”.  
For the Physical Tasks Scale, the response of “Able all of the time (100%)”, will correspond to 
the severity score of 1, while the response of “Able none of the time (0%)” will correspond to the 
severity score of 5. 
The “Does not apply to my job” category will be set as a missing severity score (Lerner et al, 
2009) 
For each of the four scales, the average item score will be calculated, after imputing the missing 
values as specified in Section 4.3, where possible. The average item score is then converted to 
the scale score by the following formula: WLQ scale score=25*(average item score -1). 
The work productivity will be assessed in all employed patients, regardless of their disease 
severity.  
The WLQ could be completed by the patients with caregiver assistance if needed.  
The WLQ questionnaire is collected at baseline and Week 52. The endpoint, change from 
baseline in the WLQ scale, will be analysed as described in Section 6.4.10 for each WLQ scale, 
except that baseline WLQ scale will be used instead of baseline HD QoL.  
6.4.12. 
CDR-SB 
6.4.12.1. Definition 
The Clinical Dementia Rating – Sum of Boxes (CDR-SB) is a widely used scale that has 
demonstrated validity and reliability in the longitudinal assessment of patients with cognitive and 
functional deficits that do not rise to the level of a diagnosis of overt dementia. 
The utilization of CDR-SB scores for staging dementia severity offers several advantages over 
the global score because the optimal characteristics of both scores can be combined into a single 
score. First, CDR-SB scores are much simpler to calculate than the global score and they do not 
require an algorithm for computation, which will ultimately result in fewer calculation errors for 
those not using the online system. Second, CDR-SB scores can be treated as interval data in 
statistical analyses, whereas global CDR scores are ordinal by the nature of the algorithm 
approach to condensing the data. Finally, the most significant advantage to using CDR-SB scores 
for staging of dementia severity is the increased precision afforded for tracking changes across 
time. 
The CDR is obtained through semistructured interviews of patients and informants, and 
cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and 


 
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problem solving, community affairs, home and hobbies, and personal care. Each domain is rated 
on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, 
mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on 
a 4-point scale without a 0.5 rating available). The global CDR score is computed via an 
algorithm. The CDR-SB score is obtained by summing each of the domain box scores, with 
scores ranging from 0 to 18. 
Where possible, the same person should act as a patient’s caregiver/informant throughout the 
study. If this is not possible, a patient should have no more than 2 caregivers throughout the 
study. All possible attempts should be made to assure that caregiver/informant will attend the 
clinical visits in person together with the patient. If the caregiver/informant is not available to 
attend the clinic visit, the interview can be done over phone. 
6.4.12.2. Analysis 
The CDR-SB is assessed at baseline and Week 52. The change from baseline in CDR-SB will be 
analysed as described in Section 6.4.10, except that baseline CDR-SB will be used instead of 
baseline HD QoL. 
6.4.13. 
Hospital Anxiety and Depression Scale (HADS) 
6.4.13.1. Definition 
The Hospital Anxiety and Depression Scale, HADS (Zigmond and Snaith, 1983), is a 14 item 
(each item scored 0-3), self-administered rating scale that consists of two subscales assessing the 
presence and severity of depression (0–21) and anxiety (0–21), with a global score of 0–42. It 
was designed to diminish the influence of somatic symptoms and consequently does not include 
items relating to the physical symptoms of depression and has a medium overall cognitive 
complexity.  
6.4.13.2. Analysis 
The HADS scale is assessed at baseline and Week 52. The endpoint, change from baseline, will 
be analysed as described in Section 6.4.10, except that baseline HADS will be used instead of 
baseline HD QoL. 
6.4.14. 
Problem Behaviors Assessment-Short Form (PBA-s) 
6.4.14.1. Definition 
The PBA-s is a brief semi-structured interview covering the most common behavioral and 
psychiatric manifestations of HD. The interview is not restricted to a single construct, but rather 
covers several broad symptom domains relevant to HD, comprising 11 items: low mood, suicidal 
ideation, anxiety, irritability, anger/aggressive behavior, loss of motivation, perseverative 
thinking or behavior, obsessive-compulsive behaviors, paranoid thinking, hallucinations, 
behavior suggestive of disorientation. Each symptom is rated for severity on a 5-point scale 
according to detailed scoring criteria which roughly correspond to the following: 0 = “not at all”; 
1 = trivial; 2 = mild; 3 = moderate (disrupting everyday activities) and 4 = severe or intolerable. 
Each symptom is also scored for frequency on a 5-point scale as follows: 0 = symptom absent; 


 
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1 = less than once weekly; 2 = at least once a week; 3 = most days (up to and including some 
part of every day); and 4 = all day, every day.  
Severity and frequency scores are multiplied (after setting all values outside the range of 0-4 to 
missing) to produce an overall ‘PBA-s score’ for each symptom domain. 
The total PBA-s score is calculated by the sum of all PBA-s scores across symptom domains.  
6.4.14.2. Analysis 
The PBA-s assessments are collected at baseline and Week 52. The endpoint, change from 
baseline, will be analysed as described in Section 6.4.10.3, except that baseline PBA-s will be used 
instead of baseline HD-QoL. 


 
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7. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
In order to to maintain the experiment-wise type I error rate of 5% , the Fallback method with the 
loop-back feature will be used to test the primary and secondary endpoints. The methodology has 
been recommended in the recent Guidance for Industry on the Multiple Endpoints in Clinical 
Trials1 to increase the study power. 
The fallback method permits interpretation of an endpoint with a robust treatment effect using 
modest amount of alpha retained as a fallback, even if the preceding endpoint is unsuccessful, 
without inflating the Type I error rate. In this method, the alpha is split between the endpoints of 
interest using weights reflecting the endpoint clinical importance; sum of weights always equals 
1. In our setting, we suggest using weights of 0.9 and 0.1 for the TMS and caudate volume (CV) 
respectively, yielding alpha of 0.9*0.05=0.045 for TMS, and alpha of 0.1*0.05=0.005 for CV. 
The hypothesis testing starts with the TMS tested at an alpha of 0.045 and if successful, the CV 
hypothesis will be tested at the alpha level of 0.05 (“full alpha”). In case the TMS is not 
successful, the CV hypothesis has the chance of being successful when tested at the alpha of 
0.005. 
The loop-back feature has been proposed to increase the power of the fallback method giving a 
“second chance” to an endpoint that was not statistically significant at the initially assigned 
endpoint-specific alpha, by receiving pass-along or “looped back” alpha from a different endpoint 
that was successful. Thus, in our previously discussed setting, if the TMS hypothesis fails at the 
alpha level of 0.045, and the CV hypothesis is successful at the alpha of 0.005, the TMS hypothesis 
can be retested at the alpha level of 0.05 (“full alpha”). See Figure 2 for the graphical depiction of 
the hypotheses testing, where the green and the yellow boxes represent the fallback and the “looped 
back” alpha paths. 
This procedure can be viewed as a modification of the Holm procedure for multiple testing, 
where instead of splitting the alpha equally between the tested hypotheses, it is divided using the 
prespecified weights. 
                                                          
1 US Department of Health and Human Services, Center for Drug Evaluation and Research (CDER), Food and Drug 
Administration. Draft guidance: Multiple endpoints in clinical trials: Guidance for Industry. January 2017. 


 
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Figure 2: 
Fallback with Loopback – Hypotheses Test Flow  
 
Abbreviations: TMS = Total Motor Score; CV = Caudate Volume. 
Note:Traditional gate keeping on the left side of the chart, with the the green and the yellow boxes representing the 
fallback and the “looped back” alpha paths. The TMS endpoint is assigned α=0.045 (w1=0.9) and the CV is assigned 
α=0.005 (w2=0.1). 
 
TMS<0.045
CV<0.05
Success
TMS&CV
Success
TMS 
CV<0.005
TMS<0.05
Success
TMS&CV
Success
CV
Failure 
Yes  
No 
Yes  
Yes  
Yes  
 
No 
No 


 
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8. 
SAFETY ANALYSIS 
8.1. 
General 
The safety population will be used for all safety analyses, unless otherwise noted. Summaries 
will be presented by treatment group, unless otherwise stated. 
8.2. 
Duration of Exposure to Study Drug  
Duration of treatment (days treated) is the number of days on treatment based on the first and last 
days of treatment with the study drug (last day of study drug – first day of study drug + 1).  
Weeks on treatment using the categories ≤2 week, >2 to ≤4 weeks, >4 to ≤6 weeks, 
>6 to ≤8 weeks, >8 to ≤12 weeks, >12 to ≤16 weeks, >16 to ≤20 weeks, >20 to ≤26 weeks, >26 
to ≤39 weeks, >39 to ≤52 weeks or more than 52 weeks will be summarized using descriptive 
statistics.  Duration of treatment (days) will also be summarized using descriptive statistics. 
In case of missing end of treatment date, last study drug return date or last date of study drug 
administration on the Study Drug Administration exposure forms will be used per study team 
decision. 
8.3. 
Duration of Exposure to Study  
Duration of study (days) is the number of days on study based on the difference between the 
randomization date and study completion date (study completion date – randomization date + 1).  
Weeks on study using the categories ≤2 week, >2 to ≤4 weeks, >4 to ≤6 weeks, >6 to ≤8 weeks, 
>8 to ≤12 weeks, >12 to ≤16 weeks, >16 to ≤20 weeks, >20 to ≤26 weeks, >26 to ≤39 weeks, 
>39 to ≤52 weeks or more than 52 weeks will be summarized using descriptive statistics.  
Duration of study (days) will also be summarized using descriptive statistics. 
In case of missing end of study date or a lost to follow up subject, last date of subject 
assessments will be used.  
8.4. 
Adverse Events 
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 treatment 
emergent adverse events (overall and by severity), adverse events determined by the investigator 
to be related to study treatment (ie, reasonable possibility) (defined as related or with missing 
relationship) (overall and by severity), serious adverse events, and adverse events causing 
withdrawal from the treatment. Summaries will be presented by treatment group. 
Multiple records with the same Preferred Term (PT) and AE onset date for the same patient, or 
with overlapping or consecutive dates, are counted only once selecting the AE with the highest 
severity and seriousness. If onset date of AEs with the same PT is partially unknown or duration 
is < 24 hours, then these AEs will be counted as separate AEs, except for the cases where an AE 
with duration of < 24 hours has the same onset date as another AE with longer duration, then the 
longer duration AE will be counted.The event rate per 100 years (PY) of patient treatment 
exposure is calculated as 100*(Number of cases/PY). 


 
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Patient listings of all adverse events, serious adverse events, adverse events leading to 
withdrawal and adverse events leading to death will be presented. 
8.5. 
Deaths 
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. 
8.6. 
Clinical Laboratory Tests 
Summary statistics for chemistry and hematology laboratory tests will be presented at baseline, 
Weeks 4, 13, 26, 39, 52, 56, and last assesment. Laboratory values and changes from baseline to 
each visit endpoint will be summarized using descriptive statistics.  
Shifts (below, within, and above the normal range) from baseline to each visit and endpoint will 
be summarized using patient counts for chemistry and hematology laboratories. 
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 
clinically significant abnormal values will be summarized for laboratory variables using 
descriptive statistics with the criteria specified in Table 5. 
Table 5: 
Criteria for Potentially Clinically Significant Laboratory Values 
Test 
Criterion value 
Serum chemistry 
 
  Alanine aminotransferase (ALT) 
≥3x ULN 
  Aspartate aminotransferase (AST) 
≥3x ULN 
  Alkaline phosphatase 
≥3x ULN 
  Gamma-glutamyl transpeptidase (GGT) 
≥3x ULN 
  Lactate dehydrogenase (LDH) 
≥3x ULN 
  Blood urea nitrogen (BUN) 
≥10.71 mmol/L 
  Creatinine 
≥177 µmol/L 
  Uric acid 
Men 
≥625 µmol/L 
 
Women 
≥506 µmol/L 
  Bilirubin (total) 
≥34.2 µmol/L 
Hematology 
 
  Hematocrit 
Men 
<0.37 L/L 
 
Women 
<0.32 L/L 
  Hemoglobin 
Men 
≤115 g/L 
 
Women 
≤95 g/L 
  White blood cell (WBC) counts 
≤3 x 109/L  
≥20 x 109/L 


 
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Test 
Criterion value 
  Eosinophils 
≥10% 
  Absolute neutrophil counts (ANC) 
≤1 x 109/L 
  Platelet counts 
≤75 x 109/L  
≥700 x 109/L 
In addition, Common Terminology Criteria for Adverse Events grade values for the hemoglobin 
will be summarized using patient counts of the worst post baseline shift, using the grades shown 
in Table 6. 
Table 6: 
CTCAE v4.0 Severity Criteria for Hemoglobin  
Hematology 
Grade 1 
Grade 2 
Grade 3 
Hemoglobin 
10.0 g/dL-<LLN 
8.0-<10.0 g/dL 
<8.0 g/dL 
Note: LLN refers to lower limit of normal as provided by the laboratory. 
Shifts of liver enzymes (ALT, AST, GGT) from normal levels at baseline to the following 
abnormal levels any time post-baseline (including unscheduled visits and withdrawal visits) will 
be presented: >1 and ≤ 3x upper limit of normal range (ULN), >3 and ≤ 5x ULN, >5 and ≤ 8x 
ULN and > 8x ULN. Similarly, shifts of bilirubin from normal levels at baseline to the following 
abnormal level>=2xULN will be presented. Patients will be categorized for their highest post-
baseline shift at any time during study. 
All the laboratory results will be presented in listings. 
8.6.1. 
Anemia Panel 
The anemia panel is assessed at baseline and also at one 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 the following measurements will be taken: B12, blood smear, serum iron, ferritin, 
total iron binding capacity, folic acid, haptoglobin, IL-1, IL-6, interferon IFN-γ, TNF-α, and 
hepcidin. They will be summarized using descriptive statistics, and also presented in the listing. 
In case of hemoglobin decrease of >1g/dL from the patient's hemoglobin level at baseline, 
subject will be re-tested to ascertain true decrease, and if confirmed, the actions taken are 
detailed in the corresponding section in the protocol. Among others, the same  anemia panel 
measurements as at baseline will be performed and will be presented in the listing. 
8.6.2. 
Estimated Creatinine Clearance Calculation 
Estimated Creatinine Clearance (CrCl) will be calculated at all visits to monitor renal function in 
the study in order to identify patients with a potential renal impairment. The Cockcroft-Gault 
equation is used for the calculation, and the reported units of measure are mL/min. 
Each CrCl result is checked whether <60 mL/min. If yes, CrCl assessment should be repeated 
and the patient should stop study medication. If the renal impairment is confirmed (estimated 
CrCl <60 mL/min/1.73 m2), the patient should stop study medication permanently. 


 
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The estimated CrCl values and changes from baseline will be presented by visit using descriptive 
statistics. The individual CrCl measurements will also be presented in the listing. 
There will be a separate listing with all the CrCl values for subjects that have at least 1 CrCl 
result below 60 mL/min. 
8.7. 
Physical Examinations 
Physical examinations, including height (to be measured at the screening visit only) and weight, 
will be performed at weeks 4, 13, 26, 39, 52 and 56. Any physical examination finding that is 
judged by the investigator as a clinically significant change (worsening) compared with a 
baseline value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2 of the study protocol. 
8.8. 
Vital Signs 
Summary statistics for vital signs blood pressure, pulse, temperature and weight will be 
presented at weeks 4, 13, 26, 39, 52, 56, and at last assesment. Vital signs values and changes 
from baseline to each visit will be summarized using descriptive statistics. 
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 
clinically significant abnormal values will be summarized using descriptive statistics with the 
criteria specified in Table 7.  
Table 7 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. 
Table 7: 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Criterion value 
Pulse 
≥120 bpm 
 
≤50 bpm 
Systolic blood pressure 
≥180 mm Hg 
 
≤90 mm Hg 
Diastolic blood pressure 
≥105 mm Hg 
 
≤50 mm Hg 
Body temperature 
≥38.3°C 
Only supine measurements will be presented in the summaries. All the data will be listed. 
8.9. 
Electrocardiography 
Shifts (normal and abnormal) from baseline to overall result interpretation and each visit and 
endpoint, meaning at weeks 4, 13, 26, 39, 52, 56, and last assessment, will be summarized using 
patient counts. For overall result interpretation the worst postbaseline finding for the patient (the 
abnormal finding if there are both normal and abnormal findings) will be used in the summaries. 
Summary statistics for ECG variables values will be presented. Actual values and changes from 


 
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baseline at weeks 4, 13, 26, 39, 52, 56, and last assesment will be summarized using descriptive 
statistics. 
In general, 3 ECG assessments are performed per baseline visit, and their average will be 
calculated. If the number of measurement is different, up to three last measurements during the 
last visit prior to first dose administration will be used both for the average calculation and for 
choosing the worst result for the interpretation. 
The incidence of potentially clinically significant abnormal values for ECG variables will be 
summarized using descriptive statistics with the criteria specified below. 
• QTcF values >450 ms or >480 ms or >500 ms. 
• QTcF change from baseline values >30 or >60. 
• PR change from baseline ≥25% and value >200. 
• QRS change from baseline ≥25% and value >110. 
• Heart rate value <60 bpm or >100 bpm. 
8.10. 
Concomitant Medications or Therapies  
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Details of prohibited 
medications may be found in Section 5.3 of the study protocol. All concomitant medications will 
be coded using the WHO Drug. 
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and preferred term. Patients are counted only once in each 
therapeutic class, and only once in each preferred term category. Concomitant therapies and 
medications will include all medications up to the end of study as defined in the study protocol. 
8.11. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale Screening/Baseline Version (C-SSRS-BL) is 
assessed at screening. The Columbia-Suicide Severity Rating Scale Since Last Visit (C-SSRS-
SLV) is assessed at baseline, weeks 4, 13, 26, 39, 52, 52, and 56.  
Any positive answer to the behavior subcomponents at screening or baseline identifies a patient 
as with “Suicidal Behavior at Baseline”. Similarly, any positive answer to the ideation 
subcomponents at any of these two visits identified a patient as with “Suicidal Ideation at 
Baseline”. A patient identified with either “Suicidal Behavior at Baseline” or with “Suicidal 
Ideation at Baseline” is also classified as with “Suicidal Behavior or Ideation at Baseline”. 
Similarly, any positive answer to the behavior subcomponents in any of the post-dosing visits 
identifies a patient as with “Suicidal Behavior Post Dosing”. Also, any positive answer to the 
ideation subcomponents in any of the post-randomization visits identified a patient as with 
“Suicidal Ideation Post Dosing”. A patient identified with either “Suicidal Behavior Post 
Dosing” or with “Suicidal Ideation Post Dosing” is also classified as with “Suicidal Behavior or 
Ideation Post Dosing” 
Frequency counts and percentages of the C-SSRS outcomes: Suicidal Behavior at Baseline, 
Suicidal Ideation at Baseline, Suicidal Behavior or Ideation at Baseline, Suicidal Behavior Post 


 
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Dosing, Suicidal Ideation Post Dosing, Suicidal Behavior or Ideation Post Dosing, and shifts 
from baseline will be summarized. 
 


 
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9. 
PHARMACOKINETIC ANALYSIS 
A single blood sample will be collected from all patients at Months 1, 3, 6 and 12 for evaluation 
of laquinimod, see Table 1. 
Individual plasma concentrations of laquinimod will be listed by dose and visit. Descriptive 
statistics summary tables for plasma concentrations by dose and visit will be presented. The 
pharmacokinetic analysis set (PAS) will be used for the descriptive statistics summary. 
Pharmacokinetics of laquinimod and its metabolites, and potentially the effect of various 
covariates (e.g., demographics and clinical parameters) on laquinimod's pharmacokinetics, may 
be evaluated in this study using a population pharmacokinetics approach. This analysis will be 
reported in a separate population pharmacokinetic report. 


 
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10. 
PHARMACODYNAMIC ANALYSIS 
The pharmacodynamic analysis will be performed as described in the study protocol and 
reported separately, if applicable. 
 


 
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11. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
The exploratory pharmacokinetic/pharmacodynamic analysis described in the study protocol is 
beyond the scope of this SAP and may be reported separately, if applicable. 
 
 
 


 
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12. 
BIOMARKER ANALYSIS 
The biomarker analysis will be performed as described in the study protocol and will be reported 
separately if applicable. 
Any collected data will be presented descriptively only and listed as part of the laboratory data. 


 
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13. 
ANCILLARY STUDIES ANALYSIS 
The ancillary study objectives (substudies) (see Section 2.2.5. in the protocol) are beyond the 
scope of this SAP and might be reported separately if applicable. 


 
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14. 
ANCILLARY PK ANALYSIS 
PK samples of laquinimod and its metabolites will be collected from approximately 4 patients 
per each of the 3 continuing treatment groups (at selected sites at Month 1), for a total of 
approximately 12 patients. Additionally, PK samples were collected from 2 patients in the 
laquinimod 1.5 mg/day treatment group when the treatment was stopped; no further PK samples 
will be collected from the laquinimod 1.5 mg/day treatment group. 
Samples will be collected at pre-dose, 15, 30 min and 1, 2, 3, 6 and 24 hours post dose. Individual 
concentrations by treatment and timepoint will be listed. 


 
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15. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.3 or 
later. 
 


 
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16. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL 
16.1. 
Definition of Primary, Secondary and Exploratory Endpoints  
The SAP defines that the primary objective of this study is to assess the efficacy of laquinimod 
1.0 mg in patients with HD using the UHDRS-TMS after 12 months of treatment. Previously, in 
the protocol, the treatment groups were not distinguished with regard to analysis of the primary 
or secondary endpoints. 
The SAP defines the secondary objective of this study as determining the effect of laquinimod 
1.0 mg in patients with HD after 12 months of treatment on brain atrophy using MRI measures of 
caudate volume.  
In the protocol, several additional secondary endopoints were defined to evaluate the effect of 
laquinimod in patients with HD after 12 months of treatment, as follows: 
• Functional capacity using the TFC scale;  
• Change from baseline in HD-CAB total score (sum of the standardized sub-
components) at Month 12/ET (evaluated at baseline and Months 6 and 12)  
• Clinical global impression using the CIBIC-Plus. 
As per the SAP, these endpoints are now considered exploratory.  
Note that the HD-CAB total score has been revised to HD-CAB composite score (Stout et al 
2014), calculated as the average of the Z scores across the 6 HD-CAB tests. The reason for the 
change is that the HD-CAB composite score, rather than HD-CAB total score, is described in the 
literature and is also used as an exploratory endpoint in other HD studies. The change is rather 
technical in nature, being just a division of the sum by the number of the tests. 
In addition, in the definition of the HD-CAB component “Emotion Recognition”, the wording 
about the number of items was changed from “10 stimuli per emotion” to “the total of 36”. The 
change reflects the modification of the original test (Stout et al 2014), as well as the data 
collected in the study. It was also clarified that only identification of negative emotions (out of 
24 possible) was used in the composite score. 
In  addition, exploratory efficacy endpoints now also include the analyses of the primary and 
secondary endpoints on the 0.5 mg laquinimod arm vs. placebo arm.  
The following exploratory study objective is outside of the scope of the SAP: 
• To investigate the relationship between exposure to laquinimod and its metabolites 
and outcome measures (eg, clinical effect and toxicity parameters). 
The following exploratory study objective has been changed as follows: 
• Protocol: To evaluate the pharmacokinetics of laquinimod and its metabolites in 
patients with HD 
• SAP: To potentially evaluate the plasma concentrations of laquinimod in patients 
with HD 


 
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16.2. 
Patient Disposition of Laquinimod 1.5 mg/Day Treatment Group 
Patients in the high dose group (1.5mg/day) who were requested to discontinue study drug before 
week 52, but continued to attend scheduled study visits for safety assessments, will be considered 
to have completed the study, contrary to the text in Protocol Section 3.11.3.1.5. 
16.3. 
Type 1 Error Control 
The Fallback method with the Loop-back feature (see Section 7) will be used to test the primary 
and secondary endpoints instead of the initially-described hierarchical method to control 
inflation in type I error rate. 
16.4. 
Country Replaces Site in the Efficacy Analyses 
The country, instead of site, will serve as a covariate in the primary efficacy analysis, as well as 
in the other statistical models that include site as a covariate. The change was done due to the 
small numbers of patients in each site. 
16.5. 
No Application of Last Observation Carried Forward (LOCF) for 
Early Terminating Patients 
The Last Observation Carried Forward (LOCF) method will not be applied for observations of 
patients who terminated the study early. Visit Windows for Early Termination and Unscheduled 
Visits will be implied instead (see Section 4.4 for reference).  
16.6. 
Ancillary Studies Beyond the Scope of This SAP 
The ancillary studies in the protocol are beyond the scope of this SAP and might be reported 
separately if applicable. 
16.7. 
Estimated Creatinine Clearance Calculation Units 
The estimated creatinine clearance (CrCl) threshold is 60 mL/min, and not 60 mL/min/1.73 m2. 
The difference in the units reflects the method of estimation, and the values in mL/min can be 
compared with those in mL/min/1.73 m2 without the need of a conversion factor. The units 
mL/min appear in the Protocol Section 4.2 in a description of the relevant patient exclusion 
criteria. In Protocol Section 7.7, CrCl <60 mL/min/1.73 m2 is defined as the renal impairment 
criterion. 
REFERENCES 
Stout JC, Queller S, Baker KN, Cowlishaw S, Sampaio C, Fitzer-Attas C, Borowsky B, and the 
HD-CAB Investigators. HD-CAB: A Cognitive Assessment Battery for Clinical Trials in 
Huntington’s Disease. Movement Disorders 2014; 29(10):1281-1288. 
Walker T, Tullar J, Diamond P, Kohl H, Amick B. Validity and Reliability of the 8-Item Work 
Limitations Questionnaire. Journal of Occupational Rehabilitation. 2017; 27(4):576-583. 
 


 
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Lerner D, Amick BC, Rogers WH, Malspeis S, Bungay K, Cynn D.  The Work Limitations 
Questionnaire. Medcial Care. 2001;39(1):72–85.