Primary Progressive Multiple Sclerosis
Conditions
Keywords
multiple sclerosis, primary progressive multiple sclerosis, oral immunomodulator
Brief summary
This Phase 2 study is intended to serve as a proof of concept for potential treatment with laquinimod in patients with PPMS. The study is also aimed at evaluating 2 doses of laquinimod in this population.
Detailed description
Due to serious cardiovascular adverse events, Data Monitoring Committee (DMC) made a recommendation to stop all laquinimod treatment arms above 0.6 mg in the multiple sclerosis (MS) trials; therefore the 1.5 mg treatment arm in the ARPEGGIO study was discontinued as of 01 January 2016. The DMC did not identify any definite cardiovascular risk in the 0.6 mg treatment arm, but felt that long term monitoring for emergence of any potential signal was necessary. Therefore, the 0.6 mg treatment arm was continued while the sponsor closely monitored cardiovascular events in all laquinimod studies. Prior to 01 January 2016, eligible patients were randomized in a 1:1:1 ratio into 1 of the following treatment arms (a total of 286 patients were randomized 1:1:1 prior to 01 January 2016): * Laquinimod 0.6 mg daily * Laquinimod 1.5 mg daily * Daily placebo As of 01 January 2016, following the decision to discontinue the laquinimod 1.5 mg dose arm, additional eligible patients (87 patients) who were enrolled were randomized in a 1:1 ratio into one of the following treatment arms: * Laquinimod 0.6 mg daily * Daily placebo
Interventions
DRUGPlacebo
Placebo
DRUGLaquinimod
Laquinimod capsules in 0.5 mg and 0.6 mg strengths
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria 2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord 3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits 4. Documented evidence of clinical disability progression in the 2 years prior to screening. 5. Functional System Score (FSS) of \> or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction 6. Patients must be between 25 to 55 years of age, inclusive 7. Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered. 8. Patients must sign and date a written informed consent prior to entering the study. 9. Patients must be willing and able to comply with the protocol requirements for the duration of the study.
Exclusion criteria
1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis. 2. Progressive neurological disorder other than PPMS. 3. Any MRI record showing presence of cervical cord compression. 4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms. 5. Relevant history of vitamin B12 deficiency. 6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology. 7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model | Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits | Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. BA was analyzed using baseline-adjusted repeated measures analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast was constructed in order to compare between laquinimod 0.6 mg and placebo. The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects. Only on-treatment observations (include all the assessments done up to one month after the last dose of the study drug) were included. Values are adjusted means. The cancelled laquinimod 1.5 mg treatment arm was not included in the repeated measures ANCOVA model analysis. However PBVC by visit data are offered in outcome #2. |
| Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 | Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. Early termination scans of participants who discontinued the study after week 36 are considered scans at week 48. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Baseline (Week 0), Weeks 12, 24, 36, 48 | The T25FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. In cases when a patient could not complete a T25FW trial due to the physical limitations, a value of 180 seconds was assigned for that trial (this is the maximal possible value for the T25FW test). Increasing time scores indicate increasing impairment. Baseline values are summaries of observed values. Week values are change from baseline values. |
| Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 | Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks) | CDP was defined as increase in EDSS of \>=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of \>=0.5 point, if EDSS at entry is \>=5.5. This increase should be confirmed after at least 12 weeks. Progression cannot be confirmed during a protocol defined relapse. EDSS is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments with 0=no disability and 10=death due to MS. Only an Examining Neurologist administered the EDSS. The Examining Neurologist did not have access to the patient's medical records or source documents, including previous EDSS forms or adverse events. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death. |
| Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 up to Week 130 (longest duration of treatment) | An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. |
| Number of New T2 Brain Lesions at Week 48 | Baseline (Week 0), 48 weeks | Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new T2 lesions at week 48 as compared to baseline. Scans of patients who discontinued the study after week 36 are considered scans at week 48, and are included in week 48. |
| Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48 | Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks) | CDP was defined as increase in EDSS of \>=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of \>=0.5 point, if EDSS at entry is \>=5.5 confirmed after at least 12 weeks, OR increase of \>= 20% from baseline in the T25FW test, confirmed after at least 12 weeks. EDSS quantifies disability in MS and monitors changes in the level of disability over time. The EDSS scale is 0-10 in 0.5 unit increments with 0=no disability and 10=death due to MS. The T25-FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. Increasing time scores indicate increasing impairment. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death. |
Countries
Canada, Germany, Italy, Netherlands, Poland, Russia, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 447 patients were screened for enrollment into this study. Of the patients screened, 374 patients met entry criteria and were enrolled into the study. One participant withdrew before taking any study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 3 capsules containing placebo were administered orally once daily for at least 48 weeks. | 140 |
| Laquinimod 0.6 mg 1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks. | 139 |
| Laquinimod 1.5 mg 3 capsules containing 0.5 mg laquinimod were administered orally once daily for at least 48 weeks. However this arm was discontinued as of 01 January 2016 and no participants reached the 48 week timeframe. | 95 |
| Total | 374 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 9 | 4 |
| Overall Study | Lack of Efficacy | 4 | 7 | 0 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 |
| Overall Study | Noncompliance | 1 | 0 | 0 |
| Overall Study | Noncompliance with study drug admin | 1 | 2 | 0 |
| Overall Study | Other | 1 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Sponsor requested patient stop treatment | 0 | 0 | 90 |
| Overall Study | Withdrawal by Subject | 22 | 21 | 1 |
| Overall Study | Withdrew before taking study drug | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Laquinimod 1.5 mg | Laquinimod 0.6 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 46.6 years STANDARD_DEVIATION 7.18 | 46.1 years STANDARD_DEVIATION 7.21 | 46.1 years STANDARD_DEVIATION 6.68 | 46.3 years STANDARD_DEVIATION 6.99 |
| Body Mass Index | 25.136 kg/m^2 STANDARD_DEVIATION 5.0283 | 25.026 kg/m^2 STANDARD_DEVIATION 4.1002 | 25.373 kg/m^2 STANDARD_DEVIATION 4.5539 | 25.196 kg/m^2 STANDARD_DEVIATION 4.6208 |
| Expanded Disability Status Scale (EDSS) EDSS score 3 | 10 Participants | 10 Participants | 12 Participants | 32 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 3.5 | 27 Participants | 20 Participants | 25 Participants | 72 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 4 | 24 Participants | 18 Participants | 30 Participants | 72 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 4.5 | 26 Participants | 17 Participants | 19 Participants | 62 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 5 | 17 Participants | 6 Participants | 15 Participants | 38 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 5.5 | 24 Participants | 16 Participants | 23 Participants | 63 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 6 | 9 Participants | 4 Participants | 12 Participants | 25 Participants |
| Expanded Disability Status Scale (EDSS) EDSS score 6.5 | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Height | 171.25 cm STANDARD_DEVIATION 9.818 | 171.03 cm STANDARD_DEVIATION 9.677 | 172.61 cm STANDARD_DEVIATION 9.246 | 171.70 cm STANDARD_DEVIATION 9.573 |
| Normalized Brain Volume | 1457.9 mL STANDARD_DEVIATION 109.78 | 1455.2 mL STANDARD_DEVIATION 101.44 | 1461.3 mL STANDARD_DEVIATION 96.63 | 1458.5 mL STANDARD_DEVIATION 102.69 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized Not HIspanic or Latino | 135 Participants | 91 Participants | 134 Participants | 360 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 138 Participants | 92 Participants | 132 Participants | 362 Participants |
| Sex: Female, Male Female | 67 Participants | 45 Participants | 57 Participants | 169 Participants |
| Sex: Female, Male Male | 73 Participants | 50 Participants | 82 Participants | 205 Participants |
| Time Since First MS Symptom | 7.4 years STANDARD_DEVIATION 5.22 | 8.5 years STANDARD_DEVIATION 5.61 | 8.3 years STANDARD_DEVIATION 6.33 | 8.0 years STANDARD_DEVIATION 5.76 |
| Time Since First PPMS Diagnosis | 3.1 years STANDARD_DEVIATION 2.98 | 4.1 years STANDARD_DEVIATION 4.04 | 4.0 years STANDARD_DEVIATION 4.05 | 3.7 years STANDARD_DEVIATION 3.7 |
| Weight | 73.97 kg STANDARD_DEVIATION 16.809 | 73.47 kg STANDARD_DEVIATION 14.831 | 75.91 kg STANDARD_DEVIATION 16.668 | 74.57 kg STANDARD_DEVIATION 16.275 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 140 | 0 / 138 | 1 / 95 |
| other Total, other adverse events | 77 / 140 | 74 / 138 | 40 / 95 |
| serious Total, serious adverse events | 6 / 140 | 10 / 138 | 3 / 95 |
Outcome results
Primary
Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model
Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. BA was analyzed using baseline-adjusted repeated measures analysis of covariance (ANCOVA- SAS® PROC MIXED) in which 1 contrast was constructed in order to compare between laquinimod 0.6 mg and placebo. The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects. Only on-treatment observations (include all the assessments done up to one month after the last dose of the study drug) were included. Values are adjusted means. The cancelled laquinimod 1.5 mg treatment arm was not included in the repeated measures ANCOVA model analysis. However PBVC by visit data are offered in outcome #2.
Time frame: Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits
Population: Modified Intent to Treat 1 (mITT1) population with at least 1 post-baseline PBVC value and will include assessments taken up to/including early termination/study completion visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model | -0.454 percentage change from baseline | Standard Error 0.0897 |
| Laquinimod 0.6 mg | Percent Brain Volume Change (PBVC) From Baseline to Week 48 Using a Repeated Measures ANCOVA Model | -0.438 percentage change from baseline | Standard Error 0.0945 |
Comparison: The statistical model was a repeated measures analysis of covariance with treatment group, week, treatment group by week interaction, normalized brain volume at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects.p-value: 0.90395% CI: [-0.239, 0.2705]Repeated Measures ANCOVA
Primary
Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48
Brain atrophy (BA) was measured using magnetic resonance imaging (MRI) scans of the brain. Early termination scans of participants who discontinued the study after week 36 are considered scans at week 48.
Time frame: Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48
Population: Modified Intent to Treat 1 (mITT1) population with at least 1 post-baseline PBVC value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Week 24 | -0.241 percentage change from baseline | Standard Deviation 0.8978 |
| Placebo | Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Week 48 | -0.455 percentage change from baseline | Standard Deviation 0.977 |
| Laquinimod 0.6 mg | Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Week 24 | -0.042 percentage change from baseline | Standard Deviation 0.7537 |
| Laquinimod 0.6 mg | Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Week 48 | -0.418 percentage change from baseline | Standard Deviation 0.9806 |
| Laquinimod 1.5 mg | Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Week 24 | -0.820 percentage change from baseline | Standard Deviation 1.2693 |
| Laquinimod 1.5 mg | Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 | Week 48 | 0.550 percentage change from baseline | — |
Secondary
Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48
The T25FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. In cases when a patient could not complete a T25FW trial due to the physical limitations, a value of 180 seconds was assigned for that trial (this is the maximal possible value for the T25FW test). Increasing time scores indicate increasing impairment. Baseline values are summaries of observed values. Week values are change from baseline values.
Time frame: Baseline (Week 0), Weeks 12, 24, 36, 48
Population: Modified Intent to Treat #2 (mITT2) population is a subset of the ITT population. It includes all participants in the ITT population with at least 1 post baseline efficacy assessment other than PBVC.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 48 | 0.300 seconds |
| Placebo | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 24 | 0.100 seconds |
| Placebo | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 12 | 0.100 seconds |
| Placebo | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 36 | 0.200 seconds |
| Placebo | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Baseline | 7.750 seconds |
| Laquinimod 0.6 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 48 | 0.050 seconds |
| Laquinimod 0.6 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Baseline | 7.600 seconds |
| Laquinimod 0.6 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 12 | 0.050 seconds |
| Laquinimod 0.6 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 24 | 0.350 seconds |
| Laquinimod 0.6 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 36 | 0.450 seconds |
| Laquinimod 1.5 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Baseline | 6.850 seconds |
| Laquinimod 1.5 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 36 | 12.550 seconds |
| Laquinimod 1.5 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 12 | 0.100 seconds |
| Laquinimod 1.5 mg | Change From Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48 | Week 24 | 0.150 seconds |
Comparison: placebo n=121 Laquinimod 0.6 mg n=108 The estimate of parameter, standard error, and 95% confidence intervals for change from baseline was from a Mann-Whitney-Wilcoxon Test using Hodges-Lehmann estimates.p-value: 0.24895% CI: [-0.85, 0.2]Repeated Measures ANCOVA
Secondary
Number of New T2 Brain Lesions at Week 48
Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new T2 lesions at week 48 as compared to baseline. Scans of patients who discontinued the study after week 36 are considered scans at week 48, and are included in week 48.
Time frame: Baseline (Week 0), 48 weeks
Population: Modified intent to treat 1 (mITT1) population includes participants with at least 1 post-baseline PBVC value. Participants from the mITT1 with MRI data at week 48 are reported .
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Number of New T2 Brain Lesions at Week 48 | 3.5 lesions | Standard Deviation 10.82 |
| Laquinimod 0.6 mg | Number of New T2 Brain Lesions at Week 48 | 1.3 lesions | Standard Deviation 3.01 |
| Laquinimod 1.5 mg | Number of New T2 Brain Lesions at Week 48 | 1.0 lesions | — |
Comparison: This analysis was performed using baseline adjusted negative binomial regression model (SAS® PROC GENMOD) in which 1 contrast for comparing laquinimod 0.6 mg to placebo was constructed. In addition to the treatment group, the natural logarithm of T2 lesion volume at baseline, age at baseline and country/geographical region (CGR) were used as covariates.p-value: 0.00195% CI: [0.26, 0.69]negative binomial regression model
Secondary
Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time frame: Day 1 up to Week 130 (longest duration of treatment)
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 109 Participants |
| Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 6 Participants |
| Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAE | 27 Participants |
| Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 6 Participants |
| Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Withdrawn from treatment due to TEAE | 2 Participants |
| Laquinimod 0.6 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Withdrawn from treatment due to TEAE | 8 Participants |
| Laquinimod 0.6 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 115 Participants |
| Laquinimod 0.6 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Laquinimod 0.6 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 10 Participants |
| Laquinimod 0.6 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 6 Participants |
| Laquinimod 0.6 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAE | 41 Participants |
| Laquinimod 1.5 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 3 Participants |
| Laquinimod 1.5 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAE | 29 Participants |
| Laquinimod 1.5 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Withdrawn from treatment due to TEAE | 4 Participants |
| Laquinimod 1.5 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 1 Participants |
| Laquinimod 1.5 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 63 Participants |
| Laquinimod 1.5 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 3 Participants |
Secondary
Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48
CDP was defined as increase in EDSS of \>=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of \>=0.5 point, if EDSS at entry is \>=5.5 confirmed after at least 12 weeks, OR increase of \>= 20% from baseline in the T25FW test, confirmed after at least 12 weeks. EDSS quantifies disability in MS and monitors changes in the level of disability over time. The EDSS scale is 0-10 in 0.5 unit increments with 0=no disability and 10=death due to MS. The T25-FW is a quantitative mobility and leg function performance test based on the average time of two trials in which participants walk 25 feet as quickly as possible. Increasing time scores indicate increasing impairment. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death.
Time frame: Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48 | 34 percentage of participants |
| Laquinimod 0.6 mg | Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48 | 32 percentage of participants |
| Laquinimod 1.5 mg | Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) or the Timed 25-foot Walk (T25FW) Test up to Week 48 | 2 percentage of participants |
Comparison: The statistical model was a Cox proportional hazards regression model with treatment group, categorical EDSS at baseline (≤4.5 or \>4.5), age at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects.p-value: 0.86795% CI: [0.68, 1.59]Regression, Cox
Secondary
Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48
CDP was defined as increase in EDSS of \>=1 point from baseline EDSS, if EDSS at entry is ≤5.0 or increase of \>=0.5 point, if EDSS at entry is \>=5.5. This increase should be confirmed after at least 12 weeks. Progression cannot be confirmed during a protocol defined relapse. EDSS is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments with 0=no disability and 10=death due to MS. Only an Examining Neurologist administered the EDSS. The Examining Neurologist did not have access to the patient's medical records or source documents, including previous EDSS forms or adverse events. If a patient died due to MS disease progression, the patient was analyzed as having CDP with the time to CDP as the onset date of progression. If a patient died due to MS before having progression, then the time to disability progression was censored using the date of death.
Time frame: Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 | 23 percentage of participants |
| Laquinimod 0.6 mg | Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 | 17 percentage of participants |
| Laquinimod 1.5 mg | Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48 | 1 percentage of participants |
Comparison: The statistical model was a Cox proportional hazards regression model with treatment group, categorical EDSS at baseline (≤4.5 or \>4.5), age at baseline, natural logarithm of T2 lesion volume at baseline, and country as fixed effects.p-value: 0.42695% CI: [0.48, 1.37]Log Rank