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    Clinical Trial Results:
    A Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Laquinimod (0.5, 1.0 and 1.5 mg/day) as Treatment in Patients with Huntington's Disease

    Summary
    EudraCT number
    2014-000418-75
    Trial protocol
    IT   GB   CZ   DE   PT   NL   ES  
    Global end of trial date
    19 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jul 2019
    First version publication date
    05 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV5600-CNS-20007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02215616
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@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
    19 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of laquinimod as treatment in participants with Huntington’s Disease (HD) after 52 weeks using the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS or TMS).
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (for example, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Oct 2014
    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: 16
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Spain: 69
    Country: Number of subjects enrolled
    United Kingdom: 39
    Country: Number of subjects enrolled
    Italy: 61
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    352
    EEA total number of subjects
    234
    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)
    352
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 468 participants were screened, of whom 116 participants were screen failures and 352 participants were enrolled. Of 352 enrolled participants, 123 participants were randomized in 1:1:1:1 ratio to receive laquinimod 0.5, 1.0, 1.5 milligrams/day (mg/day), or matching placebo prior to 10 January 2016.

    Pre-assignment
    Screening details
    As of 10 January 2016; following recommendation of Data Safety Monitoring Board (DSMB), treatment of laquinimod 1.5 mg dose arm was discontinued as a proactive safety measure. After 10 January 2016; additional eligible participants, who were enrolled, were randomized in 1:1:1 ratio to receive laquinimod 0.5 mg/day, 1.0 mg/day, or matching placebo.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 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
    Placebo matching to laquinimod was administered as per the schedule specified in the respective arms.

    Arm title
    Laquinimod 0.5 mg
    Arm description
    Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod was administered as per the dose and schedule specified in the respective arms.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching to laquinimod was administered as per the schedule specified in the respective arms.

    Arm title
    Laquinimod 1.0 mg
    Arm description
    Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod was administered as per the dose and schedule specified in the respective arms.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching to laquinimod was administered as per the schedule specified in the respective arms.

    Arm title
    Laquinimod 1.5 mg
    Arm description
    Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.
    Arm type
    Experimental

    Investigational medicinal product name
    Laquinimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Laquinimod was administered as per the dose and schedule specified in the respective arms.

    Number of subjects in period 1
    Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
    Started
    108
    107
    107
    30
    Received at least 1 dose of study drug
    108
    107
    106
    29
    Completed
    97
    90
    93
    17
    Not completed
    11
    17
    14
    13
         Adverse event, serious fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    8
    2
    5
         Adverse event, non-fatal
    7
    4
    9
    2
         Non-compliance
    -
    2
    1
    -
         Other than specified
    1
    -
    1
    1
         Lost to follow-up
    1
    1
    -
    1
         Protocol deviation
    -
    2
    -
    -
         Sponsor requested to stop study drug
    -
    -
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 0.5 mg
    Reporting group description
    Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 1.0 mg
    Reporting group description
    Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 1.5 mg
    Reporting group description
    Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.

    Reporting group values
    Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg Total
    Number of subjects
    108 107 107 30 352
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    108 107 107 30 352
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    43.8 ± 7.76 43.3 ± 7.75 44.0 ± 7.83 45.5 ± 6.03 -
    Sex: Female, Male
    Units: Subjects
        Female
    56 52 54 11 173
        Male
    52 55 53 19 179
    Race/Ethnicity, Customized
    Units: Subjects
        White
    104 103 105 28 340
        Black
    0 1 1 0 2
        Asian
    2 0 0 1 3
        Other
    0 1 0 0 1
        Missing
    2 2 1 1 6
    Unified Huntington’s Disease Rating Scale - Total Motor Score (UHDRS-TMS)
    'Number of participants analysed' for this parameter: 108, 107, 106, and 30 for placebo, Laquinimod 0.5 mg, Laquinimod 1.0 mg, and Laquinimod 1.5 mg arms respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    26.4 ± 14.63 24.0 ± 13.23 22.1 ± 10.74 26.8 ± 13.75 -
    Normalized Caudate Volume
    'Number of participants analysed' for this parameter: 106, 103, 102, and 28 for placebo, Laquinimod 0.5 mg, Laquinimod 1.0 mg, and Laquinimod 1.5 mg arms respectively.
    Units: milliliters (mL)
        arithmetic mean (standard deviation)
    6.06 ± 1.857 5.78 ± 1.818 6.02 ± 1.781 5.39 ± 1.218 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 0.5 mg
    Reporting group description
    Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 1.0 mg
    Reporting group description
    Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 1.5 mg
    Reporting group description
    Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.

    Primary: Change From Baseline in UHDRS-TMS at Week 52

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    End point title
    Change From Baseline in UHDRS-TMS at Week 52
    End point description
    UHDRS assess motor function, cognition, behaviour, functional abilities, independence scale and total functional capacities (TFC). Motor function assessment includes TMS and TFC score. UHDRS TMS assesses all motor features of HD and includes maximal chorea, maximal dystonia, ocular pursuit, saccade initiation and velocity, dysarthria, tongue protrusion, finger tapping, hand pronation and supination, luria, rigidity, bradykinesia, gait, tandem walking, and retropulsion pull test. Each of these was rated on a scale of 0(normal motor function) to 4 (severely impaired motor function). TMS score: sum of individual scores ranging from 0 (normal motor function) to 124 (severely impaired motor function). Lower TMS scores=better motor function. Full analysis set (FAS):all participants in ITT population (randomized participants) who received at least 1 dose of study drug and had at least 1 post-baseline TMS assessment. ‘Number of participants analysed'=participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
    Number of subjects analysed
    98
    92
    95
    4
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.3 ± 8.00
    1.4 ± 8.34
    2.0 ± 7.27
    11.0 ± 7.12
    Statistical analysis title
    Placebo versus Laquinimod 1.0 mg
    Statistical analysis description
    Analysis was performed using Mixed Model Repeated Measures model (MMRM) with treatment group (3 levels: placebo, laquinimod 0.5 mg and laquinimod 1 mg), categorical week (4 levels: Weeks 4, 13, 26, and 52), treatment by week interaction, country, TMS baseline value and TMS baseline by week interaction as fixed effects. Unstructured variance-covariance structure was used in the initial model.
    Comparison groups
    Placebo v Laquinimod 1.0 mg
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4853 [1]
    Method
    Mixed models analysis
    Parameter type
    Least square (LS) mean difference
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.42
         upper limit
    2.98
    Notes
    [1] - Threshold for significance at 0.045 level.

    Secondary: Percent Change From Baseline in Caudate Volume (Brain Atrophy) at Week 52

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    End point title
    Percent Change From Baseline in Caudate Volume (Brain Atrophy) at Week 52
    End point description
    Brain atrophy was assessed using magnetic resonance imaging (MRI) measures of caudate volume. Caudate volume atrophy is a sensitive biomarker in very early HD and correlates with disease progression. Brain atrophy in the caudate refers to the shrinkage in volume, so that a decrease in volume is a positive value, while an increase in volume is a negative value. Percent change in caudate volume at Week 52 was calculated as the change in caudate volume since the baseline visit, divided by the baseline caudate volume and multiplied by 100. FAS included all participants in the ITT population (all randomized participants) who received at least 1 dose of study drug and had at least 1 post-baseline TMS assessment. 'Number of participants analysed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg
    Number of subjects analysed
    87
    87
    85
    2
    Units: percent change
        arithmetic mean (standard deviation)
    5.13 ± 3.265
    4.03 ± 3.275
    3.14 ± 3.360
    4.11 ± 0.598
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 56
    Adverse event reporting additional description
    Safety analysis set included all participants who had received at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Laquinimod 0.5 mg
    Reporting group description
    Participants received 1 capsule of laquinimod 0.5 mg and 2 capsules of matching placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 1.0 mg
    Reporting group description
    Participants received 2 capsules of laquinimod 0.5 mg (total 1.0 mg laquinimod) and 1 capsule of matching placebo, orally once daily for 52 weeks.

    Reporting group title
    Laquinimod 1.5 mg
    Reporting group description
    Participants received 3 capsules of laquinimod 0.5 mg (total 1.5 mg laquinimod), orally once daily. The treatment of this high dose arm was discontinued as of 10 January 2016.

    Reporting group title
    Placebo
    Reporting group description
    Participants received 3 capsules of matching laquinimod placebo, orally once daily for 52 weeks.

    Serious adverse events
    Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 107 (6.54%)
    5 / 106 (4.72%)
    1 / 29 (3.45%)
    8 / 108 (7.41%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mediastinal haematoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Rib fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Skin abrasion
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic liver injury
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    1 / 29 (3.45%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cluster headache
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Burn infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 29 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 29 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Laquinimod 0.5 mg Laquinimod 1.0 mg Laquinimod 1.5 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 107 (64.49%)
    58 / 106 (54.72%)
    19 / 29 (65.52%)
    62 / 108 (57.41%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 107 (1.87%)
    4 / 106 (3.77%)
    2 / 29 (6.90%)
    0 / 108 (0.00%)
         occurrences all number
    2
    5
    2
    0
    Amylase increased
         subjects affected / exposed
    8 / 107 (7.48%)
    6 / 106 (5.66%)
    1 / 29 (3.45%)
    0 / 108 (0.00%)
         occurrences all number
    10
    10
    1
    0
    Blood folate decreased
         subjects affected / exposed
    1 / 107 (0.93%)
    6 / 106 (5.66%)
    1 / 29 (3.45%)
    0 / 108 (0.00%)
         occurrences all number
    1
    6
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 107 (0.93%)
    3 / 106 (2.83%)
    3 / 29 (10.34%)
    0 / 108 (0.00%)
         occurrences all number
    1
    3
    3
    0
    Pancreatic enzymes increased
         subjects affected / exposed
    2 / 107 (1.87%)
    2 / 106 (1.89%)
    2 / 29 (6.90%)
    0 / 108 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    1 / 29 (3.45%)
    6 / 108 (5.56%)
         occurrences all number
    0
    1
    3
    8
    Fall
         subjects affected / exposed
    10 / 107 (9.35%)
    5 / 106 (4.72%)
    2 / 29 (6.90%)
    9 / 108 (8.33%)
         occurrences all number
    12
    7
    6
    15
    Ligament sprain
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 106 (0.94%)
    2 / 29 (6.90%)
    2 / 108 (1.85%)
         occurrences all number
    1
    1
    4
    2
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    2 / 29 (6.90%)
    0 / 108 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Chorea
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 106 (0.00%)
    2 / 29 (6.90%)
    3 / 108 (2.78%)
         occurrences all number
    3
    0
    2
    4
    Headache
         subjects affected / exposed
    19 / 107 (17.76%)
    14 / 106 (13.21%)
    5 / 29 (17.24%)
    7 / 108 (6.48%)
         occurrences all number
    22
    31
    5
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 107 (6.54%)
    2 / 106 (1.89%)
    1 / 29 (3.45%)
    1 / 108 (0.93%)
         occurrences all number
    10
    2
    1
    1
    Constipation
         subjects affected / exposed
    3 / 107 (2.80%)
    3 / 106 (2.83%)
    2 / 29 (6.90%)
    3 / 108 (2.78%)
         occurrences all number
    3
    3
    2
    3
    Diarrhoea
         subjects affected / exposed
    12 / 107 (11.21%)
    9 / 106 (8.49%)
    3 / 29 (10.34%)
    9 / 108 (8.33%)
         occurrences all number
    14
    11
    6
    9
    Nausea
         subjects affected / exposed
    5 / 107 (4.67%)
    5 / 106 (4.72%)
    4 / 29 (13.79%)
    4 / 108 (3.70%)
         occurrences all number
    10
    5
    4
    4
    Vomiting
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 106 (3.77%)
    2 / 29 (6.90%)
    3 / 108 (2.78%)
         occurrences all number
    10
    7
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 107 (2.80%)
    6 / 106 (5.66%)
    0 / 29 (0.00%)
    4 / 108 (3.70%)
         occurrences all number
    4
    7
    0
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 107 (2.80%)
    1 / 106 (0.94%)
    2 / 29 (6.90%)
    4 / 108 (3.70%)
         occurrences all number
    3
    1
    2
    4
    Depression
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 106 (1.89%)
    2 / 29 (6.90%)
    5 / 108 (4.63%)
         occurrences all number
    0
    2
    2
    7
    Insomnia
         subjects affected / exposed
    4 / 107 (3.74%)
    2 / 106 (1.89%)
    2 / 29 (6.90%)
    4 / 108 (3.70%)
         occurrences all number
    4
    2
    2
    4
    Irritability
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 106 (2.83%)
    1 / 29 (3.45%)
    4 / 108 (3.70%)
         occurrences all number
    7
    3
    2
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 107 (4.67%)
    4 / 106 (3.77%)
    2 / 29 (6.90%)
    5 / 108 (4.63%)
         occurrences all number
    7
    4
    2
    5
    Back pain
         subjects affected / exposed
    7 / 107 (6.54%)
    8 / 106 (7.55%)
    2 / 29 (6.90%)
    7 / 108 (6.48%)
         occurrences all number
    7
    12
    2
    8
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 107 (7.48%)
    7 / 106 (6.60%)
    0 / 29 (0.00%)
    7 / 108 (6.48%)
         occurrences all number
    8
    7
    0
    9
    Nasopharyngitis
         subjects affected / exposed
    10 / 107 (9.35%)
    10 / 106 (9.43%)
    0 / 29 (0.00%)
    19 / 108 (17.59%)
         occurrences all number
    12
    13
    0
    33
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 107 (2.80%)
    2 / 106 (1.89%)
    1 / 29 (3.45%)
    7 / 108 (6.48%)
         occurrences all number
    5
    2
    1
    7
    Urinary tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 106 (1.89%)
    2 / 29 (6.90%)
    5 / 108 (4.63%)
         occurrences all number
    1
    2
    2
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2015
    There were 3 global amendments after start of recruitment. The following major procedural changes (not all-inclusive) were made to the protocol via this amendment: - During the Investigational New Drug (IND) process of laquinimod for HD trial, the Food and Drug Administration (FDA) commented that given that laquinimod 0.6 mg/day leads to a 5- fold reduction in the systemic concentration of caffeine, a cytochrome P450 (CYP) 1A2 probe substrate, an even larger effect on CYP1A2 may be observed when the higher doses of 1.0 mg and 1.5 mg planned in the HD trial are administered. The FDA recommended that in view of this potential increased effect of laquinimod on the pharmacokinetics of CYP1A2 substrates, use of drugs metabolized by CYP1A2 should be avoided during the trial. Based on this recommendation, Sponsor decided to modify all laquinimod protocols in which higher doses of laquinimod than 0.6 mg/day are administered and updated the guidance regarding the co-administration of laquinimod and drugs that are mainly metabolized by CYP1A2. - In addition, following the LAQ-MS-305 (CONCERTO) Data Monitoring Committee (DMC) recommendation, this amendment included a requirement to perform abdominal computed tomography (CT) as soon as possible when pancreatitis was suspected. Evaluation of pancreatitis was important in order to enable adequate or better medical treatment/care. The complete guidance for monitoring participants with elevated pancreatic amylase levels were added. - Clarifications regarding other study procedures, including (but not limited to): a) References to "postural blood pressure changes" were removed; only supine measurements were to be captured. b) Clarification regarding timing of Magnetic Resonance Imaging (MRI) scan in case of anxiolysis. c) New text to disallow benzodiazepines 3 days prior to the Positron Emission Tomography (PET) scan, as benzodiazepines could interfere with Translocator Protein (TSPO) binding.
    24 Sep 2015
    The following major procedural changes (not all-inclusive) were made to the protocol: - Contraception language updated for consistency with other laquinimod protocols; - To reduce participant burden, the Clinical Dementia Rating - Sum of Boxes (CDR-SB), Hospital Anxiety and Depression Scale (HADS) and Problem Behaviors Assessment-Short form (PBA-s) scales will only be assessed at baseline and at Month 12/early termination (ET); - The option to perform the MRI scan at screening has been introduced to reduce participant burden; - Newly added anaemia panel assessment for consistency with other laquinimod protocols; - Clarification that both urine and pregnancy tests were to be performed at baseline, and the randomization will be based on the results of urine pregnancy test; - Washout time from previous investigational product shortened; - New text added for clarification regarding medication errors and special situations; - List of concomitant medications/therapies was updated for consistency with other laquinimod protocols and Investigator's Brochure (IB). - Newly added section to appendix to clarify monitoring of participants with haemoglobin decrease and participants with creatinine phosphokinase (CPK) increase.
    16 Feb 2016
    The following major procedural changes (not all-inclusive) were made to the protocol: - Clarification of the study randomization following the discontinuation of the laquinimod 1.5 mg/day treatment arm; - More stringent criterion for exclusion of participants with significant cardiac events or conditions in their medical history, and for hepatic parameters. - To avoid increased exposure to laquinimod, stopping rules were introduced for renal impairment and hepatic impairment, with additional assessments of estimated creatinine clearance (CrCl) introduced for increased monitoring of renal function; - The risks and benefits sections of the protocol were updated to reflect the new findings observed in the Multiple Sclerosis (MS) trials; - Additional clarifications related to study conduct were implemented. These include (not all inclusive): a) clarifications regarding determination of eligibility of participants with exclusionary variance from historical cytosine-adenosine-guanine (CAG) repeat results, b) testing of both troponin and creatine kinase-muscle/brain (CK-MB) in case of creatine phosphokinase levels above the upper limit of normal (ULN) to provide additional cardiovascular assessment, c) and adjustment of blood volume collected to allow for unscheduled visits. - Assessment of laquinimod metabolites was added to the overall exploratory pharmacokinetic assessment for better characterization of laquinimod disposition; - As an enhanced monitoring and safety precaution, data on participant’s smoking habits were to be collected and an evaluation of cardiac risk factors was to be performed.

    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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