LEGATO-HD: A Clinical Study in Participants With Huntington's Disease (HD) to Assess Efficacy and Safety of Three Oral Doses of Laquinimod

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02215616
• Collaborator: (none)
• Enrollment: 352
• Locations: 53
• Arms: 4
• Actual Duration (Months): 43.7
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Huntington's Disease	Drug: Laquinimod; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 352 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Oct 28, 2014
• Actual Primary Completion Date: Jun 19, 2018
• Actual Study Completion Date: Jun 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants will receive 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.	Drug: Placebo; Matching laquinimod placebo will be administered as per the schedule specified in the respective arms.
Experimental: Laquinimod 0.5 mg Participants will receive 1 capsule of laquinimod 0.5 milligrams (mg) and 2 capsules of matching placebo, orally once daily for 52 weeks.	Drug: Laquinimod; Laquinimod capsules will be administered as per the dose and schedule specified in the respective arms.; Drug: Placebo; Matching laquinimod placebo will be administered as per the schedule specified in the respective arms.
Experimental: Laquinimod 1.0 mg 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.	Drug: Laquinimod; Laquinimod capsules will be administered as per the dose and schedule specified in the respective arms.; Drug: Placebo; Matching laquinimod placebo will be administered as per the schedule specified in the respective arms.
Experimental: Laquinimod 1.5 mg 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.	Drug: Laquinimod; Laquinimod capsules will be administered as per the dose and schedule specified in the respective arms.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in UHDRS-TMS at Week 52 [Baseline, Week 52]

   UHDRS is a research tool developed by Huntington Disease (HD) Study Group to provide a uniform assessment of the clinical features and course of HD. Components of the full UHDRS assess motor function, cognition, behaviour, functional abilities, independence scale and total functional capacities. Motor function assessment includes TMS and Total Functional Capacity (TFC) score. The UHDRS TMS assesses all the motor features of HD and includes maximal chorea, maximal dystonia, ocular pursuit, saccade initiation and velocity, dysarthria, tongue protrusion, finger tapping, hand pronation and supination, luria, rigidity, bradykinesia, gait, tandem walking, and retropulsion pull test. Each of these was rated on a scale of 0 (normal motor function) to 4 (severely impaired motor function). TMS score is a sum of individual scores ranging from 0 (normal motor function) to 124 (severely impaired motor function). Lower TMS scores indicate better motor function.

Secondary Outcome Measures

1. Percent Change From Baseline in Caudate Volume (Brain Atrophy) at Week 52 [Baseline, Week 52]

   Brain atrophy was assessed using magnetic resonance imaging (MRI) measures of caudate volume. Caudate volume atrophy is a sensitive biomarker in very early HD and correlates with disease progression. Brain atrophy in the caudate refers to the shrinkage in volume, so that a decrease in volume is a positive value, while an increase in volume is a negative value. Percent change in caudate volume at Week 52 was calculated as the change in caudate volume since the baseline visit, divided by the baseline caudate volume and multiplied by 100.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documentation of prior positive genetic testing for HD, or a clinical diagnosis of symptomatic HD.

• Presence of 36-49 cytosine-adenosine-guanine (CAG) repeats, inclusive, in the huntingtin gene based on centralized CAG testing during screening.

• Male or female between 21-55 years of age, inclusive, with an onset of HD at or after 18 years of age.

• Women of child-bearing potential (women who are not post menopausal or who have 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.

• A sum of greater than (>) 5 points on the UHDRS-TMS at the screening visit.

• Able and willing to provide written informed consent prior to any study related procedure being performed at the screening visit. Participants with a legal guardian should be consented according to local requirements.

• Willing to provide a blood sample for genomic CAG analysis at the screening visit.

• Willing and able to take oral medication and able to comply with the study specific procedures.

• Ambulatory, being able to travel to the study center, and judged by the investigator as likely to be able to continue to travel for the duration of the study.

• Availability and willingness of a caregiver, informant, or family member to provide input at study visits assessing Clinician's Interview-Based Impression of Change (CIBIC)-Plus, Clinical Dementia Rating - Sum of Boxes (CDR-SB), Problem Behaviors Assessment-Short form (PBA-s) and Huntington's Disease Quality of Life (HD-QoL). A caregiver is recommended to be someone who attends to the participant 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.

• For participants 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.

• Additional criteria may apply, please contact the investigator for more information.

Exclusion Criteria:

• Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azatioprine within 12 months prior to screening.

• Previous use of laquinimod.

• Use of moderate/strong inhibitors of cytochrome P450 (CYP)3A4 within 2 weeks prior to randomization.

• Use of inducers of CYP3A4 within 2 weeks prior to randomization.

• Pregnant or breastfeeding.

• Participants with a clinically significant or unstable medical or surgical condition that may put the participant at risk when participating in the study or may influence the results of the study or affect the participant's ability to take part in the study, as determined by medical history, physical examinations, electrocardiogram (ECG), or laboratory tests. Such conditions may include:

• A major cardiovascular event (for example; myocardial infarction, acute coronary syndrome, de-compensated congestive heart failure, pulmonary embolism, coronary revascularization) that occurred prior to randomization.

• Any acute pulmonary disorder.

• A central nervous system (CNS) disorder other than HD that may jeopardize the participant's participation in the study, including such disorders that are demonstrated on the baseline MRI (based on local read).

• A gastrointestinal disorder that may affect the absorption of study medication.

• Acute or chronic renal disease including acute kidney injury (AKI).

• Any form of acute or chronic liver disease.

• Known human immunodeficiency virus (HIV) positive status. Participants will undergo an HIV test at screening per local requirements, if applicable.

• Any malignancies, excluding basal cell carcinoma, in the 5 years prior to randomization.

• Any clinically significant, abnormal, screening laboratory result which in the opinion of the investigator, affects the participant' suitability for the study or puts the participant at risk if he/she enters the study.

• Unsuitable for MRI (for example; claustrophobia, metal implants).

• 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.

• Participants 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 participants 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 participants who, in the opinion of the investigator, present a serious risk of suicide.

• Participants with known intracranial neoplasms, vascular malformations, or intracranial hemorrhage.

• Known drug hypersensitivity that would preclude administration of laquinimod or placebo, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.

• Swallowing difficulties that would preclude administration of laquinimod or placebo capsules.

• Treatment with any investigational product within 30 days of screening or participants planning to participate in another clinical study assessing any investigational product during the study. Participants in non-interventional and/or observational studies will not be excluded from participating in this study.

• Treatment with tetrabenazine within 30 days of the study baseline visit.

• Treatment with antipsychotic medication within 30 days of the study baseline visit.

• Additional criteria may apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 12566	La Jolla	California	United States	92037
2	Teva Investigational Site 12565	Los Angeles	California	United States	90095
3	Teva Investigational Site 12567	San Francisco	California	United States	94143
4	Teva Investigational Site 12575	Englewood	Colorado	United States	80113
5	Teva Investigational Site 13490	Tampa	Florida	United States	33612
6	Teva Investigational Site 13326	Iowa City	Iowa	United States	52242
7	Teva Investigational Site 12568	Wichita	Kansas	United States	67226
8	Teva Investigational Site 12574	Baltimore	Maryland	United States	21287-0005
9	Teva Investigational Site 12571	Golden Valley	Minnesota	United States	55427
10	Teva Investigational Site 12572	Saint Louis	Missouri	United States	63110
11	Teva Investigational Site 12570	New York	New York	United States	10032
12	Teva Investigational Site 12569	Rochester	New York	United States	14618
13	Teva Investigational Site 13489	Memphis	Tennessee	United States	38163
14	Teva Investigational Site 13325	Nashville	Tennessee	United States	37232
15	Teva Investigational Site 12815	Houston	Texas	United States	77030
16	Teva Investigational Site 12576	Kirkland	Washington	United States	98034
17	Teva Investigational Site 11080	Vancouver	British Columbia	Canada	V6T 2B5
18	Teva Investigational Site 11118	Ottawa	Ontario	Canada	K1G 4G3
19	Teva Investigational Site 11079	Toronto	Ontario	Canada	M3B 2S7
20	Teva Investigational Site 11124	Edmonton		Canada	T6G 2G3
21	Teva Investigational Site 54108	Prague		Czechia	12800
22	Teva Investigational Site 32480	Berlin		Germany	10117
23	Teva Investigational Site 32482	Bochum		Germany	44791
24	Teva Investigational Site 32618	Erlangen		Germany	91054
25	Teva Investigational Site 32483	Munchen		Germany	81675
26	Teva Investigational Site 32481	Munster		Germany	48149
27	Teva Investigational Site 32479	Ulm		Germany	89081
28	Teva Investigational Site 30168	Bologna		Italy	40139
29	Teva Investigational Site 30098	Milano		Italy	20133
30	Teva Investigational Site 30100	Milano		Italy	20133
31	Teva Investigational Site 30097	Napoli		Italy	80131
32	Teva Investigational Site 30099	San Giovanni Rotondo		Italy	71013
33	Teva Investigational Site 38066	Leiden		Netherlands	2333 ZA
34	Teva Investigational Site 36026	Lisboa		Portugal	1649-035
35	Teva Investigational Site 50379	Kazan		Russian Federation	420101
36	Teva Investigational Site 50380	Moscow		Russian Federation	125367
37	Teva Investigational Site 50381	Nyznij Novgorod		Russian Federation	603126
38	Teva Investigational Site 31185	Barakaldo		Spain	48903
39	Teva Investigational Site 31097	Barcelona		Spain	8036
40	Teva Investigational Site 31110	Barcelona		Spain	8041
41	Teva Investigational Site 31186	Burgos		Spain	09006
42	Teva Investigational Site 31131	Madrid		Spain	28034
43	Teva Investigational Site 31187	Sevilla		Spain	41009
44	Teva Investigational Site 34176	Aberdeen		United Kingdom	AB25 2ZN
45	Teva Investigational Site 34177	Birmingham		United Kingdom	B15 2SG
46	Teva Investigational Site 34194	Liverpool		United Kingdom	L9 7LJ
47	Teva Investigational Site 34179	London		United Kingdom	NW1 2PG
48	Teva Investigational Site 34209	London		United Kingdom	SE1 9RT
49	Teva Investigational Site 34204	London		United Kingdom	SW17 0QT
50	Teva Investigational Site 34203	London		United Kingdom	W12 0NN
51	Teva Investigational Site 34175	Manchester		United Kingdom	M13 9WL
52	Teva Investigational Site 34215	Newcastle-Upon-Tyne		United Kingdom	NE6 4QD
53	Teva Investigational Site 34216	Sheffield		United Kingdom	S5 7AU

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 16, 2016
• Statistical Analysis Plan - Jun 19, 2018

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02215616
• Other Study ID Numbers: TV5600-CNS-20007; 2014-000418-75
• First Posted: Aug 13, 2014
• Last Update Posted: May 4, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Huntington Disease

Study Results

Participant Flow

Recruitment Details	A total of 468 participants were screened, of whom 116 participants were screen failures and 352 participants were enrolled. Of 352 enrolled participants, 123 participants were randomized in 1:1:1:1 ratio to receive laquinimod 0.5, 1.0, 1.5 milligrams/day (mg/day), or matching placebo prior to 10 January 2016.
Pre-assignment Detail	As of 10 January 2016; following recommendation of Data Safety Monitoring Board (DSMB), treatment of laquinimod 1.5 mg dose arm was discontinued as a proactive safety measure. After 10 January 2016; additional eligible participants, who were enrolled, were randomized in 1:1:1 ratio to receive laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo.

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1.0 mg	Laquinimod 1.5 mg
Arm/Group Description	Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.	Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.	Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.	Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
Period Title: Overall Study
STARTED	108	107	107	30
Received at Least 1 Dose of Study Drug	108	107	106	29
COMPLETED	97	90	93	17
NOT COMPLETED	11	17	14	13

Baseline Characteristics

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1.0 mg	Laquinimod 1.5 mg	Total
Arm/Group Description	Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.	Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.	Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.	Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.	Total of all reporting groups
Overall Participants	108	107	107	30	352
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.8 (7.76)	43.3 (7.75)	44.0 (7.83)	45.5 (6.03)	43.9 (7.64)
Sex: Female, Male (Count of Participants)
Female	56 51.9%	52 48.6%	54 50.5%	11 36.7%	173 49.1%
Male	52 48.1%	55 51.4%	53 49.5%	19 63.3%	179 50.9%
Race/Ethnicity, Customized (Count of Participants)
White	104 96.3%	103 96.3%	105 98.1%	28 93.3%	340 96.6%
Black	0 0%	1 0.9%	1 0.9%	0 0%	2 0.6%
Asian	2 1.9%	0 0%	0 0%	1 3.3%	3 0.9%
Other	0 0%	1 0.9%	0 0%	0 0%	1 0.3%
Missing	2 1.9%	2 1.9%	1 0.9%	1 3.3%	6 1.7%
Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-TMS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	26.4 (14.63)	24.0 (13.23)	22.1 (10.74)	26.8 (13.75)	24.4 (13.12)
Normalized Caudate Volume (milliliters (mL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliliters (mL)]	6.06 (1.857)	5.78 (1.818)	6.02 (1.781)	5.39 (1.218)	5.90 (1.781)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in UHDRS-TMS at Week 52
Description	UHDRS is a research tool developed by Huntington Disease (HD) Study Group to provide a uniform assessment of the clinical features and course of HD. Components of the full UHDRS assess motor function, cognition, behaviour, functional abilities, independence scale and total functional capacities. Motor function assessment includes TMS and Total Functional Capacity (TFC) score. The UHDRS TMS assesses all the motor features of HD and includes maximal chorea, maximal dystonia, ocular pursuit, saccade initiation and velocity, dysarthria, tongue protrusion, finger tapping, hand pronation and supination, luria, rigidity, bradykinesia, gait, tandem walking, and retropulsion pull test. Each of these was rated on a scale of 0 (normal motor function) to 4 (severely impaired motor function). TMS score is a sum of individual scores ranging from 0 (normal motor function) to 124 (severely impaired motor function). Lower TMS scores indicate better motor function.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all participants in the ITT population (all randomized participants) who received at least 1 dose of study drug and had at least 1 post-baseline TMS assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1.0 mg	Laquinimod 1.5 mg
Arm/Group Description	Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.	Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.	Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.	Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
Measure Participants	98	92	95	4
Mean (Standard Deviation) [units on a scale]	1.3 (8.00)	1.4 (8.34)	2.0 (7.27)	11.0 (7.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod 1.0 mg
	Comments	Analysis was performed using Mixed Model Repeated Measures model (MMRM) with treatment group (3 levels: placebo, laquinimod 0.5 mg and laquinimod 1 mg), categorical week (4 levels: Weeks 4, 13, 26, and 52), treatment by week interaction, country, TMS baseline value and TMS baseline by week interaction as fixed effects. Unstructured variance-covariance structure was used in the initial model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4853
	Comments	Threshold for significance at 0.045 level.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; -1.42 to 2.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent Change From Baseline in Caudate Volume (Brain Atrophy) at Week 52
Description	Brain atrophy was assessed using magnetic resonance imaging (MRI) measures of caudate volume. Caudate volume atrophy is a sensitive biomarker in very early HD and correlates with disease progression. Brain atrophy in the caudate refers to the shrinkage in volume, so that a decrease in volume is a positive value, while an increase in volume is a negative value. Percent change in caudate volume at Week 52 was calculated as the change in caudate volume since the baseline visit, divided by the baseline caudate volume and multiplied by 100.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS included all participants in the ITT population (all randomized participants) who received at least 1 dose of study drug and had at least 1 post-baseline TMS assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1.0 mg	Laquinimod 1.5 mg
Arm/Group Description	Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.	Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.	Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.	Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
Measure Participants	87	87	85	2
Mean (Standard Deviation) [percent change]	5.13 (3.265)	4.03 (3.275)	3.14 (3.360)	4.11 (0.598)

Adverse Events

Time Frame	Baseline up to Week 56
Adverse Event Reporting Description	Safety analysis set included all participants who had received at least 1 dose of study drug.
Arm/Group Title	Placebo		Laquinimod 0.5 mg		Laquinimod 1.0 mg		Laquinimod 1.5 mg
Arm/Group Description	Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.		Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.		Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.		Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
All Cause Mortality
	Placebo		Laquinimod 0.5 mg		Laquinimod 1.0 mg		Laquinimod 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/108 (0.9%)		0/107 (0%)		0/106 (0%)		0/29 (0%)
Serious Adverse Events
	Placebo		Laquinimod 0.5 mg		Laquinimod 1.0 mg		Laquinimod 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/108 (7.4%)		7/107 (6.5%)		5/106 (4.7%)		1/29 (3.4%)
Cardiac disorders
Defect conduction intraventricular	0/108 (0%)	0	0/107 (0%)	0	0/106 (0%)	0	1/29 (3.4%)	1
Gastrointestinal disorders
Gastrooesophageal reflux disease	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Small intestinal obstruction	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Infections and infestations
Burn infection	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Diverticulitis	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Gastroenteritis	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Gastrointestinal viral infection	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Osteomyelitis chronic	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Injury, poisoning and procedural complications
Fall	1/108 (0.9%)	1	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Femur fracture	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Multiple injuries	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Rib fracture	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Road traffic accident	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Skin abrasion	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Traumatic liver injury	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Gastric cancer	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Nervous system disorders
Cluster headache	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Product Issues
Device dislocation	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Psychiatric disorders
Depression	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Psychiatric decompensation	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Psychotic disorder	1/108 (0.9%)	1	0/107 (0%)	0	0/106 (0%)	0	0/29 (0%)	0
Suicide attempt	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/108 (0%)	0	0/107 (0%)	0	1/106 (0.9%)	1	0/29 (0%)	0
Mediastinal haematoma	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Skin and subcutaneous tissue disorders
Cutaneous lupus erythematosus	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Laquinimod 0.5 mg		Laquinimod 1.0 mg		Laquinimod 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/108 (57.4%)		69/107 (64.5%)		58/106 (54.7%)		19/29 (65.5%)
Gastrointestinal disorders
Abdominal pain	1/108 (0.9%)	1	7/107 (6.5%)	10	2/106 (1.9%)	2	1/29 (3.4%)	1
Constipation	3/108 (2.8%)	3	3/107 (2.8%)	3	3/106 (2.8%)	3	2/29 (6.9%)	2
Diarrhoea	9/108 (8.3%)	9	12/107 (11.2%)	14	9/106 (8.5%)	11	3/29 (10.3%)	6
Nausea	4/108 (3.7%)	4	5/107 (4.7%)	10	5/106 (4.7%)	5	4/29 (13.8%)	4
Vomiting	3/108 (2.8%)	3	7/107 (6.5%)	10	4/106 (3.8%)	7	2/29 (6.9%)	2
Infections and infestations
Influenza	7/108 (6.5%)	9	8/107 (7.5%)	8	7/106 (6.6%)	7	0/29 (0%)	0
Nasopharyngitis	19/108 (17.6%)	33	10/107 (9.3%)	12	10/106 (9.4%)	13	0/29 (0%)	0
Upper respiratory tract infection	7/108 (6.5%)	7	3/107 (2.8%)	5	2/106 (1.9%)	2	1/29 (3.4%)	1
Urinary tract infection	5/108 (4.6%)	5	1/107 (0.9%)	1	2/106 (1.9%)	2	2/29 (6.9%)	2
Injury, poisoning and procedural complications
Contusion	6/108 (5.6%)	8	0/107 (0%)	0	1/106 (0.9%)	1	1/29 (3.4%)	3
Fall	9/108 (8.3%)	15	10/107 (9.3%)	12	5/106 (4.7%)	7	2/29 (6.9%)	6
Ligament sprain	2/108 (1.9%)	2	1/107 (0.9%)	1	1/106 (0.9%)	1	2/29 (6.9%)	4
Investigations
Alanine aminotransferase increased	0/108 (0%)	0	2/107 (1.9%)	2	4/106 (3.8%)	5	2/29 (6.9%)	2
Amylase increased	0/108 (0%)	0	8/107 (7.5%)	10	6/106 (5.7%)	10	1/29 (3.4%)	1
Blood folate decreased	0/108 (0%)	0	1/107 (0.9%)	1	6/106 (5.7%)	6	1/29 (3.4%)	1
Haemoglobin decreased	0/108 (0%)	0	1/107 (0.9%)	1	3/106 (2.8%)	3	3/29 (10.3%)	3
Pancreatic enzymes increased	0/108 (0%)	0	2/107 (1.9%)	2	2/106 (1.9%)	2	2/29 (6.9%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	5/108 (4.6%)	5	5/107 (4.7%)	7	4/106 (3.8%)	4	2/29 (6.9%)	2
Back pain	7/108 (6.5%)	8	7/107 (6.5%)	7	8/106 (7.5%)	12	2/29 (6.9%)	2
Nervous system disorders
Balance disorder	0/108 (0%)	0	1/107 (0.9%)	1	0/106 (0%)	0	2/29 (6.9%)	2
Chorea	3/108 (2.8%)	4	3/107 (2.8%)	3	0/106 (0%)	0	2/29 (6.9%)	2
Headache	7/108 (6.5%)	7	19/107 (17.8%)	22	14/106 (13.2%)	31	5/29 (17.2%)	5
Psychiatric disorders
Anxiety	4/108 (3.7%)	4	3/107 (2.8%)	3	1/106 (0.9%)	1	2/29 (6.9%)	2
Depression	5/108 (4.6%)	7	0/107 (0%)	0	2/106 (1.9%)	2	2/29 (6.9%)	2
Insomnia	4/108 (3.7%)	4	4/107 (3.7%)	4	2/106 (1.9%)	2	2/29 (6.9%)	2
Irritability	4/108 (3.7%)	5	6/107 (5.6%)	7	3/106 (2.8%)	3	1/29 (3.4%)	2
Respiratory, thoracic and mediastinal disorders
Cough	4/108 (3.7%)	5	3/107 (2.8%)	4	6/106 (5.7%)	7	0/29 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.