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Clinical Trial Results:
An Active Extension of LAQ/5062 Study. A Multinational, Multisite, Randomized, Double-Blind, Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of Two Doses (0.3 mg and 0.6 mg) of Laquinimod, Orally Administered in Relapsing Remitting (R-R) Multiple Sclerosis (MS) Subjects (Study LAQ/5063 Active Double-Blind Phase) Followed by an Open-Label Phase of Laquinimod 0.6 mg Daily (LAQ/5063 OL)

Summary
EudraCT number	2005-004334-41
Trial protocol	GB HU ES DE CZ IT
Global end of trial date	23 Jul 2017

Results information
Results version number	v1(current)
This version publication date	20 Mar 2019
First version publication date	20 Mar 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

LAQ/5063OL

ISRCTN number

US NCT number

NCT00745615

WHO universal trial number (UTN)

Sponsor organisation name

Teva Pharmaceutical Industries, Ltd

Sponsor organisation address

5 Basel Street, Petach, Tikva, Israel, 49131

Public contact

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, info.eraclinical@teva.de

Scientific contact

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, info.eraclinical@teva.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Jul 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

To make treatment with laquinimod available to all participants who previously participated in LAQ/5062 study and those who completed the termination visit of LAQ/5063 active double-blind (DB) phase (completion of the full 36 weeks or as requested by the Sponsor); To assess the long-term safety and tolerability in the group that received active treatment in LAQ/5062 protocol and additional short-term safety and tolerability in the group who received placebo treatment (LAQ/5063 open-label [OL] phase assessed long-term safety and tolerability of laquinimod 0.6 milligrams [mg] once daily).

Protection of trial subjects

This study was 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 (for example, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical studies on medicinal products for human use).

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Dec 2005

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 21

Country: Number of subjects enrolled

Germany: 22

Country: Number of subjects enrolled

Spain: 23

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

Hungary: 20

Country: Number of subjects enrolled

Israel: 11

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Poland: 60

Country: Number of subjects enrolled

Russian Federation: 69

Worldwide total number of subjects

257

EEA total number of subjects

177

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

257

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study is LAQ/5063 (i.e., double-blind extension) and LAQ/5063OL (i.e., subsequent open-label extension). Participants who completed double-blind core study LAQ/5062 (NCT00349193) and agreed to continue in active extension study were enrolled in this study.

Screening details

Double-blind extension: Participants treated with placebo in LAQ/5062 study were equally randomized to one of 2 groups: Laquinimod 0.6 mg or Laquinimod 0.3 mg. Participants previously treated with laquinimod 0.6 mg or laquinimod 0.3 mg continued on their original treatment. Open-label extension: All participants received laquinimod 0.6 mg.

Period 1 title

Double-Blind Extension (36 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Double-Blind: Laquinimod 0.3 mg

Arm description

Participants who were receiving laquinimod 0.3 milligram (mg) tablet once daily orally in double-blind core study, were continued to receive laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36.

Arm type

Experimental

Investigational medicinal product name

Laquinimod

Investigational medicinal product code

TV-5600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Laquinimod tablets were administered as per the dose and schedule specified in the respective arms.

Double-Blind: Laquinimod 0.6 mg

Arm description

Participants who were receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) once daily orally in double-blind core study, were continued to receive laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36.

Arm type

Experimental

Investigational medicinal product name

Laquinimod

Investigational medicinal product code

TV-5600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Laquinimod tablets were administered as per the dose and schedule specified in the respective arms.

Double-Blind: Placebo/Laquinimod 0.3 mg

Arm description

Participants who were receiving placebo matched to laquinimod 0.3 mg tablet once daily orally in double-blind core study, received laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36.

Arm type

Experimental

Investigational medicinal product name

Laquinimod

Investigational medicinal product code

TV-5600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Laquinimod tablets were administered as per the dose and schedule specified in the respective arms.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matched to laquinimod was administered as per the dose and schedule specified in the respective arms.

Double-Blind: Placebo/Laquinimod 0.6 mg

Arm description

Participants who were receiving placebo matched to laquinimod 0.6 mg (2 tablets of placebo) once daily orally in double-blind core study, received laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36.

Arm type

Experimental

Investigational medicinal product name

Laquinimod

Investigational medicinal product code

TV-5600

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Laquinimod tablets were administered as per the dose and schedule specified in the respective arms.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matched to laquinimod was administered as per the dose and schedule specified in the respective arms.

Number of subjects in period 1	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Started	80	94	39	44
Completed	75	87	38	39
Not completed	5	7	1	5
Consent withdrawn by subject	3	1	-	4
Physician decision	-	1	-	-
Other Than Specified	-	1	-	-
Pregnancy	-	1	-	-
Adverse event	2	3	1	1

Period 2 title

Open-Label (up to approx 10.5 years)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg

Arm description

Participants who were receiving laquinimod 0.3 mg tablet once daily orally either in double-blind core study or double-blind extension period, received laquinimod 0.6 mg capsule once daily orally in open-label extension period of this study until termination (as long as the Sponsor continued the development of laquinimod 0.6 mg for relapsing-remitting multiple sclerosis [RRMS]) or early discontinuation (up to approximately 10.5 years).

Arm type

Experimental

Investigational medicinal product name

Laquinimod

Investigational medicinal product code

TV-5600

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Laquinimod capsule was administered as per the dose and schedule specified in the respective arms.

Open Label: Laquinimod 0.6 mg

Arm description

Participants who were receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) once daily orally either in double-blind core study or double-blind extension period, received laquinimod 0.6 mg capsule once daily orally in open-label extension period of this study until termination (as long as the Sponsor continued the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years).

Arm type

Experimental

Investigational medicinal product name

Laquinimod

Investigational medicinal product code

TV-5600

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Laquinimod capsule was administered as per the dose and schedule specified in the respective arms.

Number of subjects in period 2 ^[1]	Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg	Open Label: Laquinimod 0.6 mg
Started	96	113
Completed	5	5
Not completed	91	108
Consent withdrawn by subject	19	19
Physician decision	9	11
Other Than Specified	8	10
Death	-	1
Pregnancy	2	5
Adverse event	2	8
Study Terminated by Sponsor	50	50
Lost to follow-up	1	3
Lack of efficacy	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: All participants who completed Period 1, did not continue to Period 2.

Baseline characteristics

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Reporting group title

Double-Blind: Laquinimod 0.3 mg

Reporting group description

Reporting group title

Double-Blind: Laquinimod 0.6 mg

Reporting group description

Reporting group title

Double-Blind: Placebo/Laquinimod 0.3 mg

Reporting group description

Reporting group title

Double-Blind: Placebo/Laquinimod 0.6 mg

Reporting group description

Reporting group values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg	Total
Number of subjects	80	94	39	44	257
Age categorical
Units: Subjects
Adults (18-64 years)	80	94	39	44	257
Age Continuous
Units: years
arithmetic mean (standard deviation)	34.4 ( 8.3 )	33.4 ( 8.7 )	34.5 ( 8.8 )	31.0 ( 6.6 )	-
Sex: Female, Male
Units: Subjects
Female	51	53	23	27	154
Male	29	41	16	17	103
Race/Ethnicity, Customized
Units: Subjects
Asian/Oriental	1	0	0	0	1
Black of African Heritage	0	1	0	0	1
Caucasian	79	93	39	44	255
Region of Enrollment
Units: Subjects
Czech Republic	8	7	3	3	21
Germany	7	7	5	3	22
Hungary	7	7	3	3	20
Israel	3	3	3	2	11
Italy	8	9	2	4	23
Poland	19	21	11	9	60
Russia	18	28	9	14	69
Spain	7	8	3	5	23
United Kingdom	3	4	0	1	8

End points

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Reporting group title

Double-Blind: Laquinimod 0.3 mg

Reporting group description

Reporting group title

Double-Blind: Laquinimod 0.6 mg

Reporting group description

Reporting group title

Double-Blind: Placebo/Laquinimod 0.3 mg

Reporting group description

Reporting group title

Double-Blind: Placebo/Laquinimod 0.6 mg

Reporting group description

Reporting group title

Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg

Reporting group description

Reporting group title

Open Label: Laquinimod 0.6 mg

Reporting group description

Primary: Double-Blind Extension Period: Number of Participants With Adverse Events (AEs)

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End point title

Double-Blind Extension Period: Number of Participants With Adverse Events (AEs) ^[1]

End point description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least one dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase.

End point type

Primary

End point timeframe

Baseline (Week 0) to Week 36

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is reporting statistics for open-label extension period only. Safety analyses were descriptive in nature.

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	80	94	39	44
Units: participants	57	66	23	32

No statistical analyses for this end point

Primary: Open-label Extension Period: Number of Participants With AEs

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End point title

Open-label Extension Period: Number of Participants With AEs ^[2]

End point description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. Safety analysis set included all participants who had received at least 1 dose of study drug during the open-label extension period LAQ/5063OL.

End point type

Primary

End point timeframe

Baseline (Month 0/termination visit of double-blind extension phase [completion of full 36 weeks] until termination (as long as the Sponsor continued the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is reporting statistics for open-label extension period only. Safety analyses were descriptive in nature.

End point values	Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg	Open Label: Laquinimod 0.6 mg
Number of subjects analysed	96	113
Units: participants	86	100

No statistical analyses for this end point

Primary: Double-Blind Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

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End point title

Double-Blind Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs ^[3]

End point description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least one dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase.

End point type

Primary

End point timeframe

Baseline (Week 0) to Week 36

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is reporting statistics for open-label extension period only. Safety analyses were descriptive in nature.

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	80	94	39	44
Units: participants
Due to any reason	5	7	1	5
Due to AEs	2	3	1	1

No statistical analyses for this end point

Primary: Open-Label Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

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End point title

Open-Label Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs ^[4]

End point description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Safety analysis set included all participants who had received at least 1 dose of study drug during the open-label extension period LAQ/5063OL.

End point type

Primary

End point timeframe

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is reporting statistics for open-label extension period only. Safety analyses were descriptive in nature.

End point values	Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg	Open Label: Laquinimod 0.6 mg
Number of subjects analysed	96	113
Units: participants
Due to any reason	91	108
Due to AEs	1	9

No statistical analyses for this end point

Secondary: Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses

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End point title

Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses

End point description

Relapse: Appearance of 1 or more new neurological abnormalities or reappearance of 1 or more previously observed neurological abnormalities, lasting for at least 48 hours and immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. An event was counted as a relapse only when participant’s symptoms were accompanied by observed objective neurological changes, consistent with increase of at least 0.5 in Expanded disability status scale (EDSS); or 1 grade in score of 2 or more of 7 Functional Systems (FS) (excluding changes in bowel/bladder function or cognition); or 2 grades in score of 1 of FS as compared to previous evaluation. EDSS assesses disability in 8 FS with an overall score ranging from 0 (normal) to 10 (death due to MS). ITT analysis set:all participants who entered in extension study LAQ/5063 (after completion of entire treatment period in LAQ/5062) and received at least 1 dose of laquinimod during active double-blind phase.

End point type

Secondary

End point timeframe

Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	80	94	39	44
Units: relapses
arithmetic mean (standard deviation)	0.39 ( 0.68 )	0.36 ( 0.58 )	0.38 ( 0.54 )	0.39 ( 0.72 )

No statistical analyses for this end point

Secondary: Double-Blind Period: Percentage of Relapse-Free Participants

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End point title

Double-Blind Period: Percentage of Relapse-Free Participants

End point description

Relapse: Appearance of 1 or more new neurological abnormalities or reappearance of 1 or more previously observed neurological abnormalities, lasting for at least 48 hours and immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. An event was counted as a relapse only when participant’s symptoms were accompanied by observed objective neurological changes, consistent with an increase of at least 0.5 in the EDSS; or one grade in score of 2 or more of 7 FS (excluding changes in bowel or bladder function or cognition); or 2 grades in score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 FS with an overall score ranging from 0 (normal) to 10 (death due to MS). ITT analysis set: all participants who entered in extension study LAQ/5063 (after completion of entire treatment period in LAQ/5062) and received at least 1 dose of laquinimod (either 0.3 mg or 0.6 mg) during active double-blind phase.

End point type

Secondary

End point timeframe

Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	80	94	39	44
Units: percentage of participants
number (not applicable)	70.0	68.1	64.1	72.7

No statistical analyses for this end point

Secondary: Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images

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End point title

Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images

End point description

Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of gadolinium-enhanced T1 lesions. T1-weighted scan was taken after administration of gadolinium-gadopentetic acid (Gd-DTPA). ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least one dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase. Here, ‘Number of participants analyzed’=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

At the end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	66	82	36	38
Units: lesions
arithmetic mean (standard deviation)	2.50 ( 4.77 )	2.18 ( 5.67 )	2.64 ( 4.32 )	1.63 ( 3.04 )

No statistical analyses for this end point

Secondary: Double-Blind Period: Number of New T2 Lesions

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End point title

Double-Blind Period: Number of New T2 Lesions

End point description

Inflammatory disease activity was assessed by MRI measurement of the number of new T2 lesions. ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least one dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase. Here, ‘Number of participants analyzed’=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

At the end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	66	82	36	38
Units: lesions
arithmetic mean (standard deviation)	4.58 ( 8.36 )	3.55 ( 6.76 )	4.47 ( 6.23 )	2.42 ( 3.45 )

No statistical analyses for this end point

Secondary: Double-Blind Period: Volume of T2 Lesions

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End point title

Double-Blind Period: Volume of T2 Lesions

End point description

Volume of T2 lesion was assessed by magnetic MRI. ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least one dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase. Here, ‘Number of participants analyzed’=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

At the end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	66	82	36	38
Units: cubic millimeters (mm^3)
arithmetic mean (standard deviation)	16930 ( 12816 )	17015 ( 15298 )	17436 ( 16808 )	15816 ( 14274 )

No statistical analyses for this end point

Secondary: Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans

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End point title

Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans

End point description

Inflammatory disease activity was assessed by MRI measurement of the number of new hypointense T1 lesions. ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least one dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase. Here, ‘Number of participants analyzed’=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

At the end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	66	82	36	38
Units: lesions
arithmetic mean (standard deviation)	1.23 ( 2.69 )	0.70 ( 2.01 )	1.11 ( 2.11 )	1.24 ( 2.67 )

No statistical analyses for this end point

Secondary: Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score

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End point title

Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score

End point description

EDSS (developed by John F. Kurtzke) is a scale for assessing disability in 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and other functions). Each functional system score and an overall score ranges from 0 to 10, where 0 = Normal; 1-1.5 = No disability, but some abnormal neurological signs; 2-2.5 = Minimal disability; 3-4.5 = Moderate disability, affecting daily activities, but can still walk; 5-8 = More severe disability, impairing daily activities and requiring assistance with walking; 8.5-9.5=Very severe disability, restricting to bed; 10=Death due to MS. A lower score indicated less disability. ITT analysis set included all participants who entered in extension study LAQ/5063 (after completion of the entire treatment period in LAQ/5062) and received at least 1 dose of laquinimod (either 0.3 mg or 0.6 mg) during the active double-blind phase. Here, ‘Number of participants analyzed’=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

At the end of active double-blind phase or termination/early termination visit (up to Week 36)

End point values	Double-Blind: Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg	Double-Blind: Placebo/Laquinimod 0.3 mg	Double-Blind: Placebo/Laquinimod 0.6 mg
Number of subjects analysed	78	92	39	43
Units: units on a scale
arithmetic mean (standard deviation)	2.53 ( 1.60 )	2.44 ( 1.21 )	2.51 ( 1.40 )	2.27 ( 1.35 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

DB Extension Period(Week 0 to Week 36) and OL Extension Period(Month 0/termination of DB extension until termination or early discontinuation[up to approximately 10.5 years]):defined for DB treatment and OL treatment both as start and end dates of events.

Adverse event reporting additional description

AEs occurred after the DB end date and OL start date are reported only once in the DB phase. AEs occurred after the DB end date for participants who did not switch to the OL treatment are reported only once in the DB phase.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Double-Blind: Laquinimod 0.3 mg/Placebo to Laquinimod 0.3 mg

Reporting group description

Participants who were receiving either laquinimod 0.3 mg or placebo matched to laquinimod 0.3 mg tablet once daily orally in double-blind core study, received laquinimod 0.3 mg tablet once daily orally in double-blind extension period of this study for up to Week 36.

Reporting group title

Double-Blind: Laquinimod 0.6 mg/Placebo to Laquinimod 0.6 mg

Reporting group description

Participants who were receiving laquinimod 0.6 mg (2 tablets of 0.3 mg each) or placebo matched to laquinimod 0.6 mg (2 tablets of placebo) once daily orally in double-blind core study, received laquinimod 0.6 mg once daily orally in double-blind extension period of this study for up to Week 36.

Reporting group title

Open Label: Laquinimod 0.6 mg

Reporting group description

Reporting group title

Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg

Reporting group description

Participants who were receiving laquinimod 0.3 mg tablet once daily orally either in double-blind core study or double-blind extension period, received laquinimod 0.3 mg tablet once daily orally in open-label extension period of this study until termination (as long as the Sponsor continued the development of laquinimod 0.6 mg for RRMS) or early discontinuation (up to approximately 10.5 years).

Serious adverse events	Double-Blind: Laquinimod 0.3 mg/Placebo to Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg/Placebo to Laquinimod 0.6 mg	Open Label: Laquinimod 0.6 mg	Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 119 (5.04%)	6 / 138 (4.35%)	30 / 113 (26.55%)	19 / 96 (19.79%)
number of deaths (all causes)	0	0	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pituitary tumour benign
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Cervical conisation
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Knee operation
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus operation
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillectomy
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tricuspid valve repair
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine dilation and curettage
subjects affected / exposed	1 / 119 (0.84%)	1 / 138 (0.72%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Paranasal cyst
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Borrelia test positive
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiovascular evaluation
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
HIV test positive
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal haematoma
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Tibia fracture
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia supraventricular
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial fibrosis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tricuspid valve incompetence
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar ischaemia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Demyelination
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertebrobasilar insufficiency
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vestibular disorder
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal degeneration
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	2 / 113 (1.77%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	2 / 113 (1.77%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back disorder
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	0 / 113 (0.00%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Groin pain
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Borrelia infection
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic tonsillitis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	2 / 96 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometritis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salpingo-oophoritis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Subacute endocarditis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	0 / 96 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Metabolism and nutrition disorders
Malnutrition
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	0 / 113 (0.00%)	1 / 96 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Double-Blind: Laquinimod 0.3 mg/Placebo to Laquinimod 0.3 mg	Double-Blind: Laquinimod 0.6 mg/Placebo to Laquinimod 0.6 mg	Open Label: Laquinimod 0.6 mg	Open-Label: Laquinimod 0.3 mg/Laquinimod 0.6 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	68 / 119 (57.14%)	74 / 138 (53.62%)	95 / 113 (84.07%)	82 / 96 (85.42%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 119 (0.84%)	1 / 138 (0.72%)	5 / 113 (4.42%)	7 / 96 (7.29%)
occurrences all number	1	1	5	9
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 119 (0.84%)	2 / 138 (1.45%)	5 / 113 (4.42%)	6 / 96 (6.25%)
occurrences all number	1	2	8	8
Fatigue
subjects affected / exposed	3 / 119 (2.52%)	4 / 138 (2.90%)	12 / 113 (10.62%)	2 / 96 (2.08%)
occurrences all number	3	5	15	2
Pyrexia
subjects affected / exposed	1 / 119 (0.84%)	4 / 138 (2.90%)	6 / 113 (5.31%)	5 / 96 (5.21%)
occurrences all number	6	4	15	5
Immune system disorders
Seasonal allergy
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	1 / 113 (0.88%)	5 / 96 (5.21%)
occurrences all number	1	0	1	6
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	3 / 113 (2.65%)	5 / 96 (5.21%)
occurrences all number	0	0	4	5
Respiratory, thoracic and mediastinal disorders
Catarrh
subjects affected / exposed	1 / 119 (0.84%)	2 / 138 (1.45%)	5 / 113 (4.42%)	5 / 96 (5.21%)
occurrences all number	1	2	6	5
Cough
subjects affected / exposed	2 / 119 (1.68%)	6 / 138 (4.35%)	4 / 113 (3.54%)	5 / 96 (5.21%)
occurrences all number	2	7	6	5
Psychiatric disorders
Depression
subjects affected / exposed	2 / 119 (1.68%)	1 / 138 (0.72%)	11 / 113 (9.73%)	9 / 96 (9.38%)
occurrences all number	2	2	16	10
Sleep disorder
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	5 / 96 (5.21%)
occurrences all number	0	0	1	7
Insomnia
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	5 / 113 (4.42%)	5 / 96 (5.21%)
occurrences all number	1	0	5	5
Investigations
Blood cholesterol increased
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	6 / 113 (5.31%)	1 / 96 (1.04%)
occurrences all number	0	0	8	1
Blood fibrinogen increased
subjects affected / exposed	3 / 119 (2.52%)	6 / 138 (4.35%)	7 / 113 (6.19%)	5 / 96 (5.21%)
occurrences all number	3	7	7	5
C-reactive protein increased
subjects affected / exposed	3 / 119 (2.52%)	2 / 138 (1.45%)	8 / 113 (7.08%)	5 / 96 (5.21%)
occurrences all number	3	2	10	6
Haematocrit decreased
subjects affected / exposed	2 / 119 (1.68%)	0 / 138 (0.00%)	3 / 113 (2.65%)	5 / 96 (5.21%)
occurrences all number	2	0	3	7
Neutrophil count increased
subjects affected / exposed	3 / 119 (2.52%)	1 / 138 (0.72%)	6 / 113 (5.31%)	2 / 96 (2.08%)
occurrences all number	3	1	6	2
White blood cell count increased
subjects affected / exposed	3 / 119 (2.52%)	3 / 138 (2.17%)	6 / 113 (5.31%)	3 / 96 (3.13%)
occurrences all number	3	3	6	3
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 119 (0.00%)	2 / 138 (1.45%)	9 / 113 (7.96%)	5 / 96 (5.21%)
occurrences all number	0	2	9	6
Fall
subjects affected / exposed	0 / 119 (0.00%)	2 / 138 (1.45%)	6 / 113 (5.31%)	1 / 96 (1.04%)
occurrences all number	0	2	8	1
Cardiac disorders
Tachycardia
subjects affected / exposed	3 / 119 (2.52%)	6 / 138 (4.35%)	4 / 113 (3.54%)	5 / 96 (5.21%)
occurrences all number	3	6	6	5
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 119 (5.04%)	5 / 138 (3.62%)	1 / 113 (0.88%)	4 / 96 (4.17%)
occurrences all number	6	6	1	4
Headache
subjects affected / exposed	16 / 119 (13.45%)	16 / 138 (11.59%)	17 / 113 (15.04%)	21 / 96 (21.88%)
occurrences all number	19	20	23	29
Multiple sclerosis relapse
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	1 / 113 (0.88%)	5 / 96 (5.21%)
occurrences all number	1	0	1	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	7 / 113 (6.19%)	8 / 96 (8.33%)
occurrences all number	0	1	8	13
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	11 / 113 (9.73%)	1 / 96 (1.04%)
occurrences all number	0	1	13	1
Abdominal pain upper
subjects affected / exposed	0 / 119 (0.00%)	5 / 138 (3.62%)	7 / 113 (6.19%)	2 / 96 (2.08%)
occurrences all number	0	6	9	2
Diarrhoea
subjects affected / exposed	2 / 119 (1.68%)	2 / 138 (1.45%)	6 / 113 (5.31%)	4 / 96 (4.17%)
occurrences all number	3	3	6	7
Dyspepsia
subjects affected / exposed	2 / 119 (1.68%)	3 / 138 (2.17%)	4 / 113 (3.54%)	8 / 96 (8.33%)
occurrences all number	4	5	5	10
Nausea
subjects affected / exposed	2 / 119 (1.68%)	2 / 138 (1.45%)	2 / 113 (1.77%)	5 / 96 (5.21%)
occurrences all number	5	2	2	6
Toothache
subjects affected / exposed	2 / 119 (1.68%)	2 / 138 (1.45%)	6 / 113 (5.31%)	2 / 96 (2.08%)
occurrences all number	2	2	6	2
Vomiting
subjects affected / exposed	2 / 119 (1.68%)	2 / 138 (1.45%)	3 / 113 (2.65%)	5 / 96 (5.21%)
occurrences all number	3	3	4	5
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	2 / 113 (1.77%)	5 / 96 (5.21%)
occurrences all number	0	0	2	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 119 (4.20%)	3 / 138 (2.17%)	17 / 113 (15.04%)	10 / 96 (10.42%)
occurrences all number	6	3	22	18
Back pain
subjects affected / exposed	4 / 119 (3.36%)	12 / 138 (8.70%)	31 / 113 (27.43%)	22 / 96 (22.92%)
occurrences all number	5	15	54	32
Intervertebral disc protrusion
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	7 / 113 (6.19%)	2 / 96 (2.08%)
occurrences all number	0	0	7	2
Musculoskeletal pain
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	7 / 113 (6.19%)	2 / 96 (2.08%)
occurrences all number	1	0	9	3
Neck pain
subjects affected / exposed	4 / 119 (3.36%)	2 / 138 (1.45%)	4 / 113 (3.54%)	5 / 96 (5.21%)
occurrences all number	6	2	4	5
Pain in extremity
subjects affected / exposed	1 / 119 (0.84%)	2 / 138 (1.45%)	3 / 113 (2.65%)	6 / 96 (6.25%)
occurrences all number	1	2	3	6
Spinal osteoarthritis
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	6 / 113 (5.31%)	1 / 96 (1.04%)
occurrences all number	1	0	6	1
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 119 (2.52%)	2 / 138 (1.45%)	10 / 113 (8.85%)	11 / 96 (11.46%)
occurrences all number	3	2	13	14
Cystitis
subjects affected / exposed	1 / 119 (0.84%)	0 / 138 (0.00%)	8 / 113 (7.08%)	6 / 96 (6.25%)
occurrences all number	1	0	21	6
Gastroenteritis
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	1 / 113 (0.88%)	5 / 96 (5.21%)
occurrences all number	0	0	1	6
Influenza
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	8 / 113 (7.08%)	8 / 96 (8.33%)
occurrences all number	0	0	9	9
Nasopharyngitis
subjects affected / exposed	18 / 119 (15.13%)	23 / 138 (16.67%)	38 / 113 (33.63%)	39 / 96 (40.63%)
occurrences all number	25	30	96	80
Oral herpes
subjects affected / exposed	3 / 119 (2.52%)	2 / 138 (1.45%)	7 / 113 (6.19%)	7 / 96 (7.29%)
occurrences all number	3	2	15	9
Pharyngitis
subjects affected / exposed	5 / 119 (4.20%)	3 / 138 (2.17%)	12 / 113 (10.62%)	10 / 96 (10.42%)
occurrences all number	8	3	18	21
Respiratory tract infection viral
subjects affected / exposed	1 / 119 (0.84%)	1 / 138 (0.72%)	10 / 113 (8.85%)	10 / 96 (10.42%)
occurrences all number	1	1	15	15
Rhinitis
subjects affected / exposed	2 / 119 (1.68%)	4 / 138 (2.90%)	7 / 113 (6.19%)	11 / 96 (11.46%)
occurrences all number	2	4	8	14
Tonsillitis
subjects affected / exposed	1 / 119 (0.84%)	1 / 138 (0.72%)	6 / 113 (5.31%)	8 / 96 (8.33%)
occurrences all number	1	1	6	15
Upper respiratory tract infection
subjects affected / exposed	5 / 119 (4.20%)	3 / 138 (2.17%)	12 / 113 (10.62%)	14 / 96 (14.58%)
occurrences all number	6	3	22	33
Urinary tract infection
subjects affected / exposed	6 / 119 (5.04%)	3 / 138 (2.17%)	9 / 113 (7.96%)	8 / 96 (8.33%)
occurrences all number	8	6	11	15
Viral infection
subjects affected / exposed	0 / 119 (0.00%)	1 / 138 (0.72%)	2 / 113 (1.77%)	5 / 96 (5.21%)
occurrences all number	0	1	3	6
Furuncle
subjects affected / exposed	0 / 119 (0.00%)	0 / 138 (0.00%)	6 / 113 (5.31%)	2 / 96 (2.08%)
occurrences all number	0	0	9	2
Sinusitis
subjects affected / exposed	0 / 119 (0.00%)	2 / 138 (1.45%)	7 / 113 (6.19%)	4 / 96 (4.17%)
occurrences all number	0	2	9	5
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	0 / 119 (0.00%)	2 / 138 (1.45%)	5 / 113 (4.42%)	6 / 96 (6.25%)
occurrences all number	0	2	5	6

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Were there any global substantial amendments to the protocol? Yes

24 Nov 2005

It included the following major procedural changes (not all-inclusive): - Guidelines of assessment and follow-up in cases of abnormal liver function tests and inflammatory markers were implemented. - Additional safety assessments to the study procedures and 2 additional visits, Week 8 and Week 16, were added in order to increase monitoring frequency of safety parameters. - Clinical laboratory testing was added to be performed at all study visits instead of solely 4 visits.

23 Oct 2006

It included the following major procedural changes (not all-inclusive): - The study design was modified from an active double-blind phase to an open-label phase (LAQ/5063OL), switching all participants to 1 arm of 0.6 mg for a period of an additional 24 months.

19 Jun 2007

It included the following major procedural changes (not all-inclusive): - The existing guidance of assessment and follow-up cases of abnormal liver function tests was upgraded with a new version. - Guidance on monitoring inflammatory conditions was added. - Guidance on monitoring the potential of developing thrombosis was added. - Factor V Leiden Mutation testing (as part of risk management plan of potential developing thrombosis) was added. - New safety stopping rules were added.

22 Nov 2007

It included the following major procedural changes (not all-inclusive): - This global amendment addressed the switch of clinical study material in the open-label phase of study number LAQ/5063 (LAQ/5063 OL) from laquinimod tablets 0.3 mg, administered as 2 tablets once daily, to laquinimod capsules 0.6 mg. The clinical dosage remained unchanged at 0.6 mg of laquinimod, administered orally once a day. - The use of CYP3A4 inhibitors following early termination from the study was clarified due to an adverse event.

30 Jul 2008

It included the following major procedural changes (not all-inclusive): - An unscheduled visit to inform all enrolled women of childbearing potential about the new findings and signature of the appendix to the Informed Consent Form (ICF) was introduced. - The performance of rapid urine beta-human chorionic gonadotropin (β-hCG) tests for women of childbearing potential was introduced at each of the scheduled study visits except at screening. - The performance of rapid urine β-hCG tests every 28 (+/-2) days was introduced starting after visit month 3. - The procedures involved in cases where the diagnosis of pregnancy was suspected or established were described.

28 Aug 2008

It included the following major procedural changes (not all-inclusive): - The activities to be performed in the additional period of open-label phase of LAQ/5063 were presented, following the completion of visit number 10 (Month 24) of the LAQ/5063 OL. - The disallowed medication list was updated.

09 Nov 2009

It included the following major procedural changes (not all-inclusive): - The “Guidance for Safety Monitoring” adopting the principles of the Food and Drug Administration Guideline titled "Drug-Induced Liver Injury: Premarketing Clinical Evaluation" (July, 2009) was modified, and it was matched to the Guidance appearing in the MS-LAQ-301, MS-LAQ-301E, MS-LAQ-302, and MS-LAQ-302E study protocols.

15 Sep 2011

It included the following major procedural changes (not all-inclusive): - The LAQ/5063 OL study duration was extended until laquinimod was commercially available for the treatment of MS or until the development of laquinimod 0.6 mg for MS was stopped by the Sponsor. - Based on all safety information gathered for laquinimod until now: Collection of inflammatory markers (eg, C-reactive protein [CRP], fibrinogen) and amylase from Month 60 (Visit 16) and onwards was omitted; Testing for Factor V Leiden Mutation was clarified that it would not be performed during the extension open-label phase of the study; Any stopping rule related to inflammatory/thromboembolic events and pancreatitis was deleted. - The partial list of commonly used CYP3A4 inhibitors during the study was updated.

17 Jul 2014

This amendment was issued after 117 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of participants already enrolled into the study. These changes did not alter the study population, study design, or endpoints. The following major procedural changes (not all-inclusive) were made to the protocol: - Introduction and safety sections were updated based on accumulating data with laquinimod; and more stringent pregnancy prevention measures. - Modifications and clarifications in sections related to stopping rules, disallowed medication, and study duration were added.

25 Feb 2016

This amendment was issued after 110 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of participants already enrolled into the study. These changes did not alter the study population or endpoints. The following major procedural changes (not all-inclusive) were made to the protocol: - All ongoing participants were asked to re-consent to a revised form that included information on the cardiovascular risk findings at higher doses of laquinimod (1.2 and 1.5 mg). - Stopping rules were added for renal and hepatic impairment. - Glomerular filtration rate (GFR) monitoring (including measurement of weight) was implemented at all visits. - Emphasis on disallowed moderate/strong inhibitors of CYP3A4 that could lead to increased laquinimod exposure was made. - A cardiovascular risk assessment and management procedure was added. - Ischemic cardiac events and cerebrovascular events were now classed as protocol-defined AEs for expedited reporting and should have been reported to the Sponsor within 48 hours, including completion of the corresponding dedicated Case Report Form (CRF). - Participants who were discontinued from study drug were encouraged to continue all scheduled visits and procedures until completion of the study (with the exception of procedures associated with drug dispensing and accountability, pregnancy testing, and GFR estimation [including body weight measurement]).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Sponsor terminated RRMS studies as sufficient long term clinical data was collected for the study drug in the relevant dose.

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Primary: Double-Blind Extension Period: Number of Participants With Adverse Events (AEs)

Primary: Double-Blind Extension Period: Number of Participants With Adverse Events (AEs)

Primary: Open-label Extension Period: Number of Participants With AEs

Primary: Open-label Extension Period: Number of Participants With AEs

Primary: Double-Blind Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Primary: Double-Blind Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Primary: Open-Label Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Primary: Open-Label Period: Number of Participants who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs

Secondary: Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses

Secondary: Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses

Secondary: Double-Blind Period: Percentage of Relapse-Free Participants

Secondary: Double-Blind Period: Percentage of Relapse-Free Participants

Secondary: Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images

Secondary: Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images

Secondary: Double-Blind Period: Number of New T2 Lesions

Secondary: Double-Blind Period: Number of New T2 Lesions

Secondary: Double-Blind Period: Volume of T2 Lesions

Secondary: Double-Blind Period: Volume of T2 Lesions

Secondary: Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans

Secondary: Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans

Secondary: Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score

Secondary: Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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