Relapsing Remitting Multiple Sclerosis
Conditions
Brief summary
This is a multinational, multicenter, randomized, double-blind, parallel-group active extension of LAQ/5062 study (NCT00349193), assessing the tolerability, safety and efficacy of two doses (0.3 mg and 0.6 mg) of laquinimod, orally administered in participants with relapsing remitting multiple sclerosis (RRMS), followed by an open-label phase of laquinimod 0.6 mg daily. This study is LAQ/5063 (i.e., double-blind extension) and LAQ/5063 OL (i.e., subsequent open-label extension). - The first period of the extension study is an active, double-blind period. Participants from the active treatment arms in LAQ/5062 continue their assigned treatment in blinded fashion. Participants who were assigned to placebo treatment in LAQ/5062 are equally randomized in blinded-fashion to laquinimod 0.6 mg or laquinimod 0.3 mg. - Once termination visit of LAQ/5063 active double-blind phase (completion of the full 36 weeks or as requested by the Sponsor) is performed, all participants continue on laquinimod 0.6 mg daily as an open-label intervention. The open-label period continues as long as the Sponsor continues the development of laquinimod 0.6 mg for RRMS or early discontinuation.
Interventions
DRUGLaquinimod
Laquinimod tablets/capsules will be administered as per the dose and schedule specified in the respective arms.
DRUGPlacebo
Placebo matching to laquinimod will be administered as per the dose and schedule specified in the respective arms.
Sponsors
Teva Pharmaceutical Industries, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Blinding performed by interactive voice response system (IVRS) and relevant only to the first period of the extension. General medical evaluations will be assessed separately from neurological assessment evaluations by two different neurologists/ physicians. Magnetic resonance imaging (MRI) scan evaluation will be performed at a central reading center by staff that does not have access to the clinical data.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
- Participants must have completed the 36 weeks of treatment (completion of the full 36 weeks or as requested by the Sponsor) of the active double-blind phase. - Women of childbearing potential (for example, women who were not postmenopausal or surgically sterilized) must have practiced 2 acceptable methods of birth control for the duration of the study and until 30 days after the last dose of study medication (acceptable methods of birth control in this open-label extension phase included intrauterine devices, barrier methods \[condom or diaphragm with spermicide\], and hormonal methods of birth control \[for example, oral contraceptive, contraceptive patch, and long-acting injectable contraceptive\]). - Participants must have been willing and able to comply with the protocol requirements for the duration of LAQ/5063 OL. - Participants must have given signed, written informed consent prior to entering LAQ/5063 OL. - For the 36 months further extension: Participants must have completed the 24 months of treatment of the first period of the open label phase.
Exclusion criteria
- For the 36 month further extension: Premature discontinuation from LAQ/5063 OL phase prior to completion of 24 months of treatment period. - Pregnancy or breastfeeding. - Participants with clinically significant or unstable medical or surgical condition, detected or worsened during the active double-blind phase of LAQ/5063, which would have precluded safe and complete study participation. - Use of experimental drugs, immunosuppressive drugs, and/or participation in clinical studies within the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Previous treatment with immunomodulators with the exception of laquinimod (including interferon \[IFN\] 1a and 1b, glatiramer acetate, and intravenous \[IV\] immunoglobulin) within 2 months prior to entering the open-label phase for those subjects who had a time gap between termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of corticosteroids within 30 days prior to entering the open-label phase, except for IV methylprednisolone 1 grams/day for a maximum of 3 days, in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of potent inhibitors of cytochrome P3A4 (CYP3A4) within 2 weeks prior to LAQ/5063 OL and/or use of fluoxetine 1 month prior to entering LAQ/5063 OL, in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of the following substrates of cytochrome P1A2 (CYP1A2): theophylline and/or warfarin within 2 weeks prior to entering LAQ/5063 OL, in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Use of amiodarone in the period from termination of LAQ/5063 active double-blind phase to LAQ/5063 OL. - Following the switch to new formulation (capsules), hypersensitivity to mannitol, meglumine, or sodium stearyl fumarate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind Extension Period: Number of Participants With Adverse Events (AEs) | Baseline (Week 0) to Week 36 | 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'. |
| Open-label Extension Period: Number of Participants With AEs | 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) | 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'. |
| Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Baseline (Week 0) to Week 36 | 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. |
| Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind Period: Volume of T2 Lesions | At the end of active double-blind phase or termination/early termination visit (up to Week 36) | Volume of T2 lesion was assessed by magnetic MRI. |
| Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses | Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36) | Relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in the absence of fever or any infection) 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 the participant's symptoms were accompanied by observed objective neurological changes, consistent with an increase of at least 0.5 in the Expanded disability status scale (EDSS); or one grade in the score of 2 or more of the 7 Functional Systems (FS) (excluding changes in bowel or bladder function or cognition); or 2 grades in the score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]). |
| Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score | At the end of active double-blind phase or termination/early termination visit (up to Week 36) | 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. |
| Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans | At the end of active double-blind phase or termination/early termination visit (up to Week 36) | Inflammatory disease activity was assessed by MRI measurement of the number of new hypointense T1 lesions. |
| Double-Blind Period: Percentage of Relapse-Free Participants | Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36) | Relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in the absence of fever or any infection) 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 the 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 the score of 2 or more of the 7 FS (excluding changes in bowel or bladder function or cognition); or 2 grades in the score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). |
| Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images | At the end of active double-blind phase or termination/early termination visit (up to Week 36) | 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). |
| Double-Blind Period: Number of New T2 Lesions | At the end of active double-blind phase or termination/early termination visit (up to Week 36) | Inflammatory disease activity was assessed by MRI measurement of the number of new T2 lesions. |
Countries
Czechia, Germany, Hungary, Israel, Italy, Poland, Russia, Spain, United Kingdom
Participant flow
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.
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind: Laquinimod 0.3 mg Participants who were receiving laquinimod 0.3 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. | 80 |
| Double-Blind: Laquinimod 0.6 mg 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. | 94 |
| Double-Blind: Placebo/Laquinimod 0.3 mg 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. | 39 |
| Double-Blind: Placebo/Laquinimod 0.6 mg 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. | 44 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double-Blind Extension (36 Weeks) | Adverse Event | 2 | 3 | 1 | 1 | 0 | 0 |
| Double-Blind Extension (36 Weeks) | Other Than Specified | 0 | 1 | 0 | 0 | 0 | 0 |
| Double-Blind Extension (36 Weeks) | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 |
| Double-Blind Extension (36 Weeks) | Pregnancy | 0 | 1 | 0 | 0 | 0 | 0 |
| Double-Blind Extension (36 Weeks) | Withdrawal by Subject | 3 | 1 | 0 | 4 | 0 | 0 |
| Open-Label (up to Approx 10.5 Years) | Adverse Event | 0 | 0 | 0 | 0 | 2 | 8 |
| Open-Label (up to Approx 10.5 Years) | Death | 0 | 0 | 0 | 0 | 0 | 1 |
| Open-Label (up to Approx 10.5 Years) | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 1 |
| Open-Label (up to Approx 10.5 Years) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 3 |
| Open-Label (up to Approx 10.5 Years) | Other Than Specified | 0 | 0 | 0 | 0 | 8 | 10 |
| Open-Label (up to Approx 10.5 Years) | Physician Decision | 0 | 0 | 0 | 0 | 9 | 11 |
| Open-Label (up to Approx 10.5 Years) | Pregnancy | 0 | 0 | 0 | 0 | 2 | 5 |
| Open-Label (up to Approx 10.5 Years) | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 50 | 50 |
| Open-Label (up to Approx 10.5 Years) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 19 | 19 |
Baseline characteristics
| Characteristic | Double-Blind: Laquinimod 0.3 mg | Total | Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind: Laquinimod 0.6 mg |
|---|---|---|---|---|---|
| Age, Continuous | 34.4 years STANDARD_DEVIATION 8.3 | 33.5 years STANDARD_DEVIATION 8.3 | 31.0 years STANDARD_DEVIATION 6.6 | 34.5 years STANDARD_DEVIATION 8.8 | 33.4 years STANDARD_DEVIATION 8.7 |
| Race/Ethnicity, Customized Asian/Oriental | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black of African Heritage | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 79 Participants | 255 Participants | 44 Participants | 39 Participants | 93 Participants |
| Region of Enrollment Czech Republic | 8 Participants | 21 Participants | 3 Participants | 3 Participants | 7 Participants |
| Region of Enrollment Germany | 7 Participants | 22 Participants | 3 Participants | 5 Participants | 7 Participants |
| Region of Enrollment Hungary | 7 Participants | 20 Participants | 3 Participants | 3 Participants | 7 Participants |
| Region of Enrollment Israel | 3 Participants | 11 Participants | 2 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Italy | 8 Participants | 23 Participants | 4 Participants | 2 Participants | 9 Participants |
| Region of Enrollment Poland | 19 Participants | 60 Participants | 9 Participants | 11 Participants | 21 Participants |
| Region of Enrollment Russia | 18 Participants | 69 Participants | 14 Participants | 9 Participants | 28 Participants |
| Region of Enrollment Spain | 7 Participants | 23 Participants | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 8 Participants | 1 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Female | 51 Participants | 154 Participants | 27 Participants | 23 Participants | 53 Participants |
| Sex: Female, Male Male | 29 Participants | 103 Participants | 17 Participants | 16 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 119 | 0 / 138 | 2 / 113 | 0 / 96 |
| other Total, other adverse events | 68 / 119 | 74 / 138 | 95 / 113 | 82 / 96 |
| serious Total, serious adverse events | 6 / 119 | 6 / 138 | 30 / 113 | 19 / 96 |
Outcome results
Primary
Double-Blind Extension Period: Number of Participants With Adverse Events (AEs)
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'.
Time frame: Baseline (Week 0) to Week 36
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Extension Period: Number of Participants With Adverse Events (AEs) | 57 Participants |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Extension Period: Number of Participants With Adverse Events (AEs) | 66 Participants |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Extension Period: Number of Participants With Adverse Events (AEs) | 23 Participants |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Extension Period: Number of Participants With Adverse Events (AEs) | 32 Participants |
Primary
Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs
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.
Time frame: Baseline (Week 0) to Week 36
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to any reason | 5 Participants |
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to AEs | 2 Participants |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to AEs | 3 Participants |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to any reason | 7 Participants |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to any reason | 1 Participants |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to AEs | 1 Participants |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to any reason | 5 Participants |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to AEs | 1 Participants |
Primary
Open-label Extension Period: Number of Participants With AEs
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'.
Time frame: 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)
Population: Safety analysis set included all participants who had received at least 1 dose of study drug during the open-label extension period LAQ/5063OL.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Open-label Extension Period: Number of Participants With AEs | 86 Participants |
| Double-Blind: Laquinimod 0.6 mg | Open-label Extension Period: Number of Participants With AEs | 100 Participants |
Primary
Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs
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.
Time frame: 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)
Population: Safety analysis set included all participants who had received at least 1 dose of study drug during the open-label extension period LAQ/5063OL.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to any reason | 91 Participants |
| Double-Blind: Laquinimod 0.3 mg | Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to AEs | 1 Participants |
| Double-Blind: Laquinimod 0.6 mg | Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to any reason | 108 Participants |
| Double-Blind: Laquinimod 0.6 mg | Open-Label Period: Number of Participants Who Prematurely Discontinued From the Study Due to Any Reason and Due to AEs | Due to AEs | 9 Participants |
Secondary
Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score
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.
Time frame: At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score | 2.53 units on a scale | Standard Deviation 1.6 |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score | 2.44 units on a scale | Standard Deviation 1.21 |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score | 2.51 units on a scale | Standard Deviation 1.4 |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Kurtzke's Expanded Disability Status Scale (EDSS) Score | 2.27 units on a scale | Standard Deviation 1.35 |
Secondary
Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images
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).
Time frame: At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images | 2.50 lesions | Standard Deviation 4.77 |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images | 2.18 lesions | Standard Deviation 5.67 |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images | 2.64 lesions | Standard Deviation 4.32 |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Number of Enhancing Lesions on T1-Weighted Images | 1.63 lesions | Standard Deviation 3.04 |
Secondary
Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans
Inflammatory disease activity was assessed by MRI measurement of the number of new hypointense T1 lesions.
Time frame: At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans | 1.23 lesions | Standard Deviation 2.69 |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans | 0.70 lesions | Standard Deviation 2.01 |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans | 1.11 lesions | Standard Deviation 2.11 |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Number of New Hypointense T1 Lesion on Enhanced T1 Scans | 1.24 lesions | Standard Deviation 2.67 |
Secondary
Double-Blind Period: Number of New T2 Lesions
Inflammatory disease activity was assessed by MRI measurement of the number of new T2 lesions.
Time frame: At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Number of New T2 Lesions | 4.58 lesions | Standard Deviation 8.36 |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Number of New T2 Lesions | 3.55 lesions | Standard Deviation 6.76 |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Number of New T2 Lesions | 4.47 lesions | Standard Deviation 6.23 |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Number of New T2 Lesions | 2.42 lesions | Standard Deviation 3.45 |
Secondary
Double-Blind Period: Percentage of Relapse-Free Participants
Relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in the absence of fever or any infection) 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 the 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 the score of 2 or more of the 7 FS (excluding changes in bowel or bladder function or cognition); or 2 grades in the score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS).
Time frame: Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Percentage of Relapse-Free Participants | 70.0 percentage of participants |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Percentage of Relapse-Free Participants | 68.1 percentage of participants |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Percentage of Relapse-Free Participants | 64.1 percentage of participants |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Percentage of Relapse-Free Participants | 72.7 percentage of participants |
Secondary
Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses
Relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in the absence of fever or any infection) 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 the participant's symptoms were accompanied by observed objective neurological changes, consistent with an increase of at least 0.5 in the Expanded disability status scale (EDSS); or one grade in the score of 2 or more of the 7 Functional Systems (FS) (excluding changes in bowel or bladder function or cognition); or 2 grades in the score of one of the FS as compared to the previous evaluation. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]).
Time frame: Baseline (Week 0) up to end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses | 0.39 relapses | Standard Deviation 0.68 |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses | 0.36 relapses | Standard Deviation 0.58 |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses | 0.38 relapses | Standard Deviation 0.54 |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Relapse Rate: Total Number of Confirmed Relapses | 0.39 relapses | Standard Deviation 0.72 |
Secondary
Double-Blind Period: Volume of T2 Lesions
Volume of T2 lesion was assessed by magnetic MRI.
Time frame: At the end of active double-blind phase or termination/early termination visit (up to Week 36)
Population: 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, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: Laquinimod 0.3 mg | Double-Blind Period: Volume of T2 Lesions | 16930 cubic millimeters (mm^3) | Standard Deviation 12816 |
| Double-Blind: Laquinimod 0.6 mg | Double-Blind Period: Volume of T2 Lesions | 17015 cubic millimeters (mm^3) | Standard Deviation 15298 |
| Double-Blind: Placebo/Laquinimod 0.3 mg | Double-Blind Period: Volume of T2 Lesions | 17436 cubic millimeters (mm^3) | Standard Deviation 16808 |
| Double-Blind: Placebo/Laquinimod 0.6 mg | Double-Blind Period: Volume of T2 Lesions | 15816 cubic millimeters (mm^3) | Standard Deviation 14274 |