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    Clinical Trial Results:
    A Multinational, Multicenter, Randomized, Double Blind, Parallel Group, Placebo Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients With Primary Progressive Multiple Sclerosis (PPMS)

    Summary
    EudraCT number
    2014-001579-30
    Trial protocol
    GB   IT   ES   DE   NL  
    Global end of trial date
    01 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Oct 2018
    First version publication date
    24 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV5600-CNS-20006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02284568
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries Ltd
    Sponsor organisation address
    5 Basel St, Petach-Tikva, Israel, 4951033
    Public contact
    Director, Clinical Research, Teva Pharmaceutical Industries Ltd, 001 888-483-8279, info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Pharmaceutical Industries Ltd, 001 888-483-8279, info.era-clinical@teva.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were to assess the efficacy, safety, and tolerability of a once daily oral dose of laquinimod (0.6 or 1.5 mg) compared to placebo in primary progressive multiple sclerosis (PPMS) patients.
    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 (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Overall, this study included: (I) an informed consent for the clinical study (main study), (II) informed consent forms for the ancillary studies (cerebrospinal fluid [CSF] and optical coherence tomography [OCT]), and (III) informed consent forms for dummy run scans (magnetic resonance imaging [MRI] and OCT) required prior to initiation of the study and ancillary study respectively. Genetic testing for DNA analysis was mandatory, and by signing the main informed consent form patients were consenting to have pharmacogenomic samples collected and analyzed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 35
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Spain: 60
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Ukraine: 52
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    374
    EEA total number of subjects
    221
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    374
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening 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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    3 capsules containing placebo were administered orally once daily for at least 48 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules taken once daily oral dose for at least 48 weeks

    Arm title
    Laquinimod 0.6 mg
    Arm description
    1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    Other name
    TV-5600
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod capsules in 0.6 mg strengths

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 capsules taken once daily for at least 48 weeks

    Arm title
    Laquinimod 1.5 mg
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    Other name
    TV-5600
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules in 0.5 mg strengths taken once daily

    Number of subjects in period 1
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Started
    140
    139
    95
    Safety population
    140
    138
    95
    Completed Week 48 MRI - on treatment
    113
    107
    0
    Completed
    109
    93
    0
    Not completed
    31
    46
    95
         Protocol deviation
    -
    1
    -
         Withdrew before taking study drug
    -
    1
    -
         Noncompliance
    1
    -
    -
         Lack of efficacy
    4
    7
    -
         Not specified
    1
    2
    -
         Sponsor requested patient stop treatment
    -
    -
    90
         Adverse event, non-fatal
    2
    9
    4
         Consent withdrawn by subject
    22
    21
    1
         Noncompliance with study drug admin
    1
    2
    -
         Lost to follow-up
    -
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    3 capsules containing placebo were administered orally once daily for at least 48 weeks.

    Reporting group title
    Laquinimod 0.6 mg
    Reporting group description
    1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.

    Reporting group title
    Laquinimod 1.5 mg
    Reporting group description
    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.

    Reporting group values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg Total
    Number of subjects
    140 139 95 374
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    140 139 95 374
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    46.6 ± 7.18 46.1 ± 6.68 46.1 ± 7.21 -
    Sex: Female, Male
    Units: Subjects
        Female
    67 57 45 169
        Male
    73 82 50 205
    Race/Ethnicity, Customized
    Units: Subjects
        White
    138 132 92 362
        Black
    0 2 2 4
        Asian
    0 2 0 2
        Other
    2 3 1 6
    Race/Ethnicity, Customized
    Units: Subjects
        Not HIspanic or Latino
    135 134 91 360
        Hispanic or Latino
    4 5 1 10
        Unknown
    1 0 3 4
    Expanded Disability Status Scale (EDSS)
    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.
    Units: Subjects
        EDSS score 3
    10 12 10 32
        EDSS score 3.5
    27 25 20 72
        EDSS score 4
    24 30 18 72
        EDSS score 4.5
    26 19 17 62
        EDSS score 5
    17 15 6 38
        EDSS score 5.5
    24 23 16 63
        EDSS score 6
    9 12 4 25
        EDSS score 6.5
    3 3 4 10
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    73.97 ± 16.809 75.91 ± 16.668 73.47 ± 14.831 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    171.25 ± 9.818 172.61 ± 9.246 171.03 ± 9.677 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    25.136 ± 5.0283 25.373 ± 4.5539 25.026 ± 4.1002 -
    Time Since First MS Symptom
    Multiple sclerosis (MS)
    Units: years
        arithmetic mean (standard deviation)
    7.4 ± 5.22 8.3 ± 6.33 8.5 ± 5.61 -
    Time Since First PPMS Diagnosis
    Primary progressive multiple sclerosis (PPMS)
    Units: years
        arithmetic mean (standard deviation)
    3.1 ± 2.98 4.0 ± 4.05 4.1 ± 4.04 -
    Normalized Brain Volume
    Obtained from magnetic resonance imaging (MRI) scans
    Units: mL
        arithmetic mean (standard deviation)
    1457.9 ± 109.78 1461.3 ± 96.63 1455.2 ± 101.44 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    3 capsules containing placebo were administered orally once daily for at least 48 weeks.

    Reporting group title
    Laquinimod 0.6 mg
    Reporting group description
    1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.

    Reporting group title
    Laquinimod 1.5 mg
    Reporting group description
    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.

    Primary: Percent Brain Volume Change (PBVC) from Baseline to Week 48 Using a Repeated Measures ANCOVA Model

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    End point title
    Percent Brain Volume Change (PBVC) from Baseline to Week 48 Using a Repeated Measures ANCOVA Model
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48 and including early termination visits
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    128 [1]
    124 [2]
    0 [3]
    Units: percentage change from baseline
        arithmetic mean (standard error)
    -0.454 ± 0.0897
    -0.438 ± 0.0945
    ±
    Notes
    [1] - Modified ITT population with >=1 post-baseline PBVC value
    [2] - Modified ITT population with >=1 post-baseline PBVC value
    [3] - No participants reached the 48 Week timeframe.
    Statistical analysis title
    PBVC - Repeated Measures ANCOVA
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Laquinimod 0.6 mg
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.903 [4]
    Method
    Repeated Measures ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.239
         upper limit
    0.2705
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1293
    Notes
    [4] - significance at 0.05.

    Primary: Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48

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    End point title
    Percent Brain Volume Change (PBVC) From Baseline to Weeks 24 and 48 [5]
    End point description
    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. 9999=not applicable
    End point type
    Primary
    End point timeframe
    Baseline (at least 14 days but not more than 6 weeks prior to Day 1), Weeks 24, 48
    Notes
    [5] - 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: Data was not offered for the Laquinimod 1.5 mg treatment arm in the primary outcome due to early termination of the arm (see the previous outcome). PBVC data for all three treatment arms are shared here in a format different than the previous outcome. No statistical analysis was pre-specified for this data format.
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    131 [6]
    128 [7]
    47 [8]
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Week 24|
    -0.241 ± 0.8978
    -0.042 ± 0.7537
    -0.820 ± 1.2693
        Week 48|
    -0.455 ± 0.9770
    -0.418 ± 0.9806
    0.550 ± 9999
    Notes
    [6] - Week 24: n=124 Week 48: n=114
    [7] - Week 24: n=121 Week 48: n=110
    [8] - Week 24: n=20 Week 48: n=1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48

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    End point title
    Percentage of Participants With 12-Week Confirmed Disability Progression (CDP) As Measured by Expanded Disability Status Scale (EDSS) up to Week 48
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    140
    139
    95
    Units: percentage of participants
    23
    17
    1
    Statistical analysis title
    CDP by EDSS #1
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Laquinimod 0.6 mg
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.426 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.37
    Notes
    [9] - significance at 0.05. p-value was from a log-rank test, and estimate and confidence limits were from a Cox model with treatment group as fixed effect, due to the violation of the proportionality assumption.

    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

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    End point title
    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
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 12, 24, 36, 48 (end if treatment if < 48 weeks)
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    140
    139
    95
    Units: percentage of participants
    34
    32
    2
    Statistical analysis title
    CDP by EDSS or T25FW
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Laquinimod 0.6 mg
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.867 [10]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.59
    Notes
    [10] - significance at 0.05.

    Secondary: Change from Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48

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    End point title
    Change from Baseline for the Timed 25-foot Walk (T25FW) Score at Weeks 12, 24, 36 and 48
    End point description
    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. 9999=no data
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 12, 24, 36, 48
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    139
    137
    89
    Units: seconds
    median (full range (min-max))
        Baseline (n=139, 137, 89)
    7.750 (3.15 to 46.00)
    7.600 (4.20 to 88.40)
    6.850 (4.25 to 62.00)
        Week 12 (n=135, 130, 55)
    0.100 (-8.85 to 16.00)
    0.050 (-56.90 to 113.05)
    0.100 (-6.15 to 172.00)
        Week 24 (n=133, 127, 25)
    0.100 (-20.50 to 16.85)
    0.350 (-58.50 to 113.05)
    0.150 (-4.00 to 172.15)
        Week 36 (n=123, 118, 4)
    0.200 (-18.15 to 21.80)
    0.450 (-64.60 to 113.05)
    12.550 (1.65 to 27.60)
        Week 48 (n=121, 108, 0)
    0.300 (-22.65 to 134.00)
    0.050 (-63.50 to 68.35)
    9999 (9999 to 9999)
    Statistical analysis title
    T25FW
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Laquinimod 0.6 mg
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.248 [11]
    Method
    Repeated Measures ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.325
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.85
         upper limit
    0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2679
    Notes
    [11] - significance at 0.05. The p-value for ranked change from baseline values was from a repeated measures analysis of covariance with trt group, week, treatment group by week interaction, rank of T25FW score at baseline, and country as fixed effects.

    Secondary: Number of New T2 Brain Lesions at Week 48

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    End point title
    Number of New T2 Brain Lesions at Week 48
    End point description
    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. 9999=not applicable
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), 48 weeks
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    119 [12]
    112 [13]
    1 [14]
    Units: lesions
        arithmetic mean (standard deviation)
    3.5 ± 10.82
    1.3 ± 3.01
    1.0 ± 9999
    Notes
    [12] - mITT including participants with MRI data at week 48
    [13] - mITT including participants with MRI data at week 48
    [14] - mITT including participants with MRI data at week 48
    Statistical analysis title
    New T2 brain lesions
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Laquinimod 0.6 mg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [15]
    Method
    negative binomial regression model
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    0.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [15] - significance at 0.05

    Secondary: Participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Participants with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 130 (longest duration of treatment)
    End point values
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Number of subjects analysed
    140 [16]
    138 [17]
    95 [18]
    Units: participants
        Any TEAE|
    109
    115
    63
        Severe TEAE|
    6
    6
    3
        Treatment-related TEAE|
    27
    41
    29
        Deaths|
    0
    0
    1
        Serious TEAE|
    6
    10
    3
        Withdrawn from treatment due to TEAE|
    2
    8
    4
    Notes
    [16] - Safety population
    [17] - Safety population
    [18] - Safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 130 (longest duration of treatment)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    3 capsules containing placebo were administered orally once daily for at least 48 weeks.

    Reporting group title
    Laquinimod 0.6 mg
    Reporting group description
    1 capsule containing 0.6 mg laquinimod and 2 capsules containing placebo were administered orally once daily for at least 48 weeks.

    Reporting group title
    Laquinimod 1.5 mg
    Reporting group description
    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.

    Serious adverse events
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 140 (4.29%)
    10 / 138 (7.25%)
    3 / 95 (3.16%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 138 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    HIV test positive
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 138 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 140 (0.00%)
    0 / 138 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral plexopathy
         subjects affected / exposed
    0 / 140 (0.00%)
    0 / 138 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuromyelitis optica spectrum disorder
         subjects affected / exposed
    0 / 140 (0.00%)
    0 / 138 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 138 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 138 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 138 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 138 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular abscess
         subjects affected / exposed
    0 / 140 (0.00%)
    0 / 138 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 140 (1.43%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 138 (0.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Laquinimod 0.6 mg Laquinimod 1.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 140 (55.00%)
    74 / 138 (53.62%)
    40 / 95 (42.11%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    9 / 140 (6.43%)
    9 / 138 (6.52%)
    4 / 95 (4.21%)
         occurrences all number
    13
    15
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 140 (11.43%)
    14 / 138 (10.14%)
    15 / 95 (15.79%)
         occurrences all number
    28
    16
    18
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 140 (3.57%)
    7 / 138 (5.07%)
    3 / 95 (3.16%)
         occurrences all number
    5
    7
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 140 (2.14%)
    5 / 138 (3.62%)
    5 / 95 (5.26%)
         occurrences all number
    4
    5
    5
    Constipation
         subjects affected / exposed
    6 / 140 (4.29%)
    7 / 138 (5.07%)
    3 / 95 (3.16%)
         occurrences all number
    8
    7
    3
    Diarrhoea
         subjects affected / exposed
    6 / 140 (4.29%)
    9 / 138 (6.52%)
    1 / 95 (1.05%)
         occurrences all number
    7
    12
    1
    Nausea
         subjects affected / exposed
    3 / 140 (2.14%)
    4 / 138 (2.90%)
    6 / 95 (6.32%)
         occurrences all number
    3
    4
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 140 (4.29%)
    8 / 138 (5.80%)
    6 / 95 (6.32%)
         occurrences all number
    6
    10
    8
    Back pain
         subjects affected / exposed
    15 / 140 (10.71%)
    12 / 138 (8.70%)
    5 / 95 (5.26%)
         occurrences all number
    17
    15
    5
    Pain in extremity
         subjects affected / exposed
    8 / 140 (5.71%)
    6 / 138 (4.35%)
    1 / 95 (1.05%)
         occurrences all number
    8
    6
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    13 / 140 (9.29%)
    7 / 138 (5.07%)
    2 / 95 (2.11%)
         occurrences all number
    15
    7
    2
    Nasopharyngitis
         subjects affected / exposed
    24 / 140 (17.14%)
    24 / 138 (17.39%)
    4 / 95 (4.21%)
         occurrences all number
    31
    34
    4
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 140 (4.29%)
    12 / 138 (8.70%)
    2 / 95 (2.11%)
         occurrences all number
    7
    16
    2
    Urinary tract infection
         subjects affected / exposed
    11 / 140 (7.86%)
    9 / 138 (6.52%)
    4 / 95 (4.21%)
         occurrences all number
    16
    13
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2015
    Amendment 01 (dated 01 July 2015) to the protocol was issued after 49 patients were enrolled in the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The primary reasons for this global amendment were to introduce an additional secondary efficacy endpoint (change from baseline to week 48 in the T25FW score) and an additional exploratory efficacy measure (mRS). The T25FW endpoint was added due to its established role in quantifying clinically meaningful benefit in MS, and due to the beneficial effects seen on this measure in previous RRMS trials of laquinimod. Other important changes include: - Omission of the interim analysis (this was intended to provide actionable information with respect to an ongoing planned Phase 3 trial; however, the rationale no longer applies, since that trial will not be initiated in parallel with ARPEGGIO). - Omission of baseline CSF sampling (omitted in order to maximize participation in the week 48 sampling, which is more important scientifically; the decision was taken based feedback from an expert who noted that previous trials were not successful in consistently collecting 2 CSF samples, whereas the yield was better with a single CSF collection). - Creation of 2 separate modified intent-to-treat (mITT) populations: mITT1 and mITT2 (mITT1 introduced specifically for the primary endpoint; mITT2 is what was previously defined as the mITT population).
    01 Feb 2016
    Amendment 02 (dated 01 February 2016) to the protocol was issued after 301 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The primary reason for this global amendment was to discontinue treatment for patients receiving 1.5 mg laquinimod, and to implement additional safety measures to help ensure the safety of subjects (both ongoing subjects and those who were still to be enrolled) receiving 0.6 mg laquinimod. To avoid increased exposure to laquinimod at the 0.6 mg dose, stopping rules were introduced for renal impairment and hepatic impairment, with additional assessments of glomerular filtration rate introduced for increased monitoring of renal function.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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