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    Clinical Trial Results:
    A Multinational, Multicenter, Open-Label, Single-Assignment Extension of the MS-LAQ-301 (ALLEGRO) Study, to Evaluate the Long-Term Safety, Tolerability and Effect on Disease Course of Daily Oral Laquinimod 0.6 mg in Subjects with Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    2009-012989-30
    Trial protocol
    GB   NL   EE   ES   HU   DE   CZ   IT   FR   LT   AT   SE   BG  
    Global end of trial date
    01 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jan 2019
    First version publication date
    23 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MS-LAQ-301E
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00988052
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries, Ltd
    Sponsor organisation address
    5 Bael Street, Petach-Tikva, Israel, 49131
    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
    14 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objectives of the study were as follows: - to make treatment with oral laquinimod 0.6 mg available to all subjects who participated in the double-blind, placebo-controlled MS-LAQ-301 study and who completed the termination visit of this study according to the MS-LAQ-301 protocol, as long as the Sponsor continued the development of laquinimod 0.6 mg for RRMS - to assess the long-term safety and tolerability of laquinimod 0.6 mg once daily in patients with RRMS to assess the long-term effects of laquinimod 0.6 mg on the disease course, as measured by clinical efficacy outcomes, which were evaluated in the double-blind treatment phase in this subject population
    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. 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. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each Investigator kept the original consent forms, and copies were given to the patient. This study included the following separate informed consent forms: - a single informed consent form at the baseline visit - an informed consent for patients who were permitted by the Sponsor to re-enroll in the study after study discontinuation due to a planned pregnancy (introduced by Global Protocol Amendment 2) - additional informed consent forms for ancillary studies at the baseline visit (in selected countries/sites) - magnetic resonance imaging (MRI) ancillary study - magnetization transfer (MT) ancillary study - magnetic resonance spectroscopy (MRS) ancillary study - As of 25 February 2016, a separate reconsent form that described the cardiovascular risk findings at higher doses of laquinimod (1.2 and 1.5 mg/day) was required to be signed by all patients, as introduced by Global Protocol Amendment 3.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Nov 2009
    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
    Austria: 5
    Country: Number of subjects enrolled
    Bulgaria: 81
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 99
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Estonia: 15
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Georgia: 22
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Lithuania: 12
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 100
    Country: Number of subjects enrolled
    Romania: 23
    Country: Number of subjects enrolled
    Russian Federation: 86
    Country: Number of subjects enrolled
    Serbia: 20
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 62
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    839
    EEA total number of subjects
    508
    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)
    839
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    In the preceding double-blind, placebo-controlled ALLEGRO study (study MS-LAQ-301), 1106 subjects with RRMS were randomized to treatment, and 864 subjects completed the study according to the protocol (ie, by completing the ALLEGRO study termination visit procedures).

    Pre-assignment
    Screening details
    In this open-label extension study, 839 subjects with RRMS were enrolled to receive laquinimod 0.6 mg at 135 study sites in 22 countries by 135 investigators.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Early laquinimod
    Arm description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Early laquinimod subgroup included participants in MS-LAQ-301 double-blind study who were administered laquinimod 0.6 mg daily for 24 months.
    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
    One capsule containing laquinimod 0.6 mg was taken orally at the same hour every day.

    Arm title
    Switch from placebo
    Arm description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Switch from placebo subgroup included participants in MS-LAQ-301 double-blind study who were administered placebo daily for 24 months.
    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
    One capsule containing laquinimod 0.6 mg was taken orally at the same hour every day.

    Number of subjects in period 1
    Early laquinimod Switch from placebo
    Started
    423
    416
    Completed
    0
    0
    Not completed
    423
    416
         Protocol deviation
    6
    5
         Missing
    1
    -
         Physician decision
    27
    28
         Lack of efficacy
    8
    7
         Teva requested subject withdrawal
    3
    1
         Pregnancy
    6
    6
         Adverse event, serious fatal
    1
    3
         Study terminated by sponsor
    240
    236
         Adverse event, non-fatal
    35
    28
         Consent withdrawn by subject
    90
    91
         Lost to follow-up
    6
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Early laquinimod
    Reporting group description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Early laquinimod subgroup included participants in MS-LAQ-301 double-blind study who were administered laquinimod 0.6 mg daily for 24 months.

    Reporting group title
    Switch from placebo
    Reporting group description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Switch from placebo subgroup included participants in MS-LAQ-301 double-blind study who were administered placebo daily for 24 months.

    Reporting group values
    Early laquinimod Switch from placebo Total
    Number of subjects
    423 416 839
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    423 416 839
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.1 ± 9.10 40.5 ± 9.14 -
    Sex: Female, Male
    Units: Subjects
        Female
    298 271 569
        Male
    125 145 270
    Race/Ethnicity, Customized
    Units: Subjects
        Asian / Oriental
    2 0 2
        Black / African American
    1 5 6
        Caucasian
    414 401 815
        Unknown
    3 6 9
        Other
    2 2 4
        Missing
    1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Early laquinimod
    Reporting group description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Early laquinimod subgroup included participants in MS-LAQ-301 double-blind study who were administered laquinimod 0.6 mg daily for 24 months.

    Reporting group title
    Switch from placebo
    Reporting group description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Switch from placebo subgroup included participants in MS-LAQ-301 double-blind study who were administered placebo daily for 24 months.

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

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    End point title
    Participants with Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    A treatment-emergent adverse event was defined as any untoward medical occurrence that develops or worsens in severity following start of treatment 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 normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs (SAE) 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. TEAEs associated with cancer, ischemic heart disease, cerebrovascular events, and arthritis were considered to be of special interest.
    End point type
    Primary
    End point timeframe
    Day 1 up to 7.64 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No intention to make inference based on stat analysis; the intent is to support clinical judgment.
    End point values
    Early laquinimod Switch from placebo
    Number of subjects analysed
    423
    416
    Units: participants
        =>1 TEAE|
    375
    374
        =>1 Severe TEAE|
    76
    69
        =>1 TEAE of special interest|
    109
    105
        =>1 treatment-related TEAE|
    139
    153
        =>1 TEAE leading to death|
    3
    3
        =>1 Serious TEAE|
    108
    92
        =>1 TEAE causing discontinuation|
    35
    32
    No statistical analyses for this end point

    Secondary: Participants with Potentially Clinically Significant Abnormal Vital Signs

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    End point title
    Participants with Potentially Clinically Significant Abnormal Vital Signs
    End point description
    Vital signs with potentially clinically significant abnormal results were evaluated using the following significance criteria: - Pulse rate low: <=45 and decrease >=30 beats/minute - Pulse rate high: >=120 and increase >=30 beats/minute - Systolic blood pressure low: <=90 and decrease >=30 mmHg - Systolic blood pressure high: >=180 and increase >=30 mmHg - Diastolic blood pressure low: <=50 and decrease >=20 mmHg - Diastolic blood pressure high: >=100 and increase >=20 mmHg
    End point type
    Secondary
    End point timeframe
    Day 1 up to 7.64 years
    End point values
    Early laquinimod Switch from placebo
    Number of subjects analysed
    423
    416
    Units: participants
        Participants with at least one abnormality|
    36
    34
        Pulse rate - low|
    1
    1
        Pulse rate - high|
    2
    1
        Systolic blood pressure - low|
    20
    10
        Systolic blood pressure - high|
    1
    2
        Diastolic blood pressure - low|
    7
    7
        Diastolic blood pressure - high|
    8
    14
    No statistical analyses for this end point

    Secondary: Participants with Serum Chemistry Laboratory Tests That Were Potentially Clinically Significant (PCS) Abnormal Comparing Baseline to Any Time During the Study

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    End point title
    Participants with Serum Chemistry Laboratory Tests That Were Potentially Clinically Significant (PCS) Abnormal Comparing Baseline to Any Time During the Study
    End point description
    Counts include two conditions: - a change from High / Non-PCS at baseline to Low PCS at any point during the study - a change from Low / Non-PCS at baseline to High PCS at any point during the study Participants whose condition was not changed from baseline or was changed to a non- PCS value are included in the population count. ALT=alanine aminotransferase ALP=alkaline phosphatase P-amylase=amylase, pancreatic AST=aspartate aminotransferase CRP=C reactive protein CK=creatine kinase CTN=creatinine FIB=fibrinogen GGT=gamma glutamyl transferase K=potassium
    End point type
    Secondary
    End point timeframe
    Day 1 up to 7.64 years
    End point values
    Early laquinimod Switch from placebo
    Number of subjects analysed
    422
    415
    Units: participants
        ALT - change from Low / Non- PCS to High PCS|
    8
    14
        Albumen - change from High / Non-PCS to Low PCS|
    1
    0
        ALP - change from Low / Non- PCS to High PCS|
    3
    0
        p-Amylase - change from Low / Non-PCS to High PCS|
    2
    6
        AST - change from Low / Non- PCS to High PCS|
    4
    5
        CRP - change from Low / Non- PCS to High PCS|
    41
    51
        Calcium - change from High / Non-PCS to Low PCS|
    1
    4
        Calcium - change from Low / Non-PCS to High PCS|
    1
    2
        CK - change from Low / Non- PCS to High PCS|
    16
    17
        CTN - change from Low / Non- PCS to High PCS|
    2
    2
        FIB - change from Low / Non- PCS to High PCS|
    37
    38
        GGT - change from Low / Non- PCS to High PCS|
    33
    24
        Glucose - change from High / Non-PCS to Low PCS|
    23
    27
        Glucose - change from Low / Non-PCS to High PCS|
    9
    5
        Phosphate-change from High / Non-PCS to Low PCS|
    14
    15
        Phosphate-change from Low / Non-PCS to High PCS|
    19
    16
        K - change from High / Non- PCS to Low PCS|
    4
    3
        K - change from Low / Non- PCS to High PCS|
    46
    55
        Sodium - change from High / Non-PCS to Low PCS|
    8
    3
        Sodium - change from Low / Non-PCS to High PCS|
    13
    17
        Urea - change from Low / Non- PCS to High PCS|
    3
    4
    No statistical analyses for this end point

    Secondary: Participants with Serum Hematology Laboratory Tests That Were Potentially Clinically Significant (PCS) Abnormal Comparing Baseline to Any Time During the Study

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    End point title
    Participants with Serum Hematology Laboratory Tests That Were Potentially Clinically Significant (PCS) Abnormal Comparing Baseline to Any Time During the Study
    End point description
    Counts include two conditions: - a change from High / Non-PCS at baseline to Low PCS at any point during the study - a change from Low / Non-PCS at baseline to High PCS at any point during the study Participants whose condition was not changed from baseline or was changed to a non- PCS value are included in the population count.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 7.64 years
    End point values
    Early laquinimod Switch from placebo
    Number of subjects analysed
    422
    415
    Units: participants
        Hematocrit-change from High/Non-PCS to Low PCS|
    36
    29
        Hemoglobin-change from High/Non-PCS to Low PCS|
    27
    22
        Hemoglobin-change from Low/Non-PCS to High PCS|
    0
    1
        Leukocytes- change from High/Non-PCS to Low PCS|
    1
    1
        Leukocytes- change from Low/Non-PCS to High PCS|
    4
    3
        Neutrophils-change from High/Non-PCS to Low PCS|
    15
    12
        Platelets-change from High/Non-PCS to Low PCS|
    4
    7
        Platelets-change from Low/Non-PCS to High PCS|
    2
    6
    No statistical analyses for this end point

    Secondary: Participants with Electrocardiogram (ECG) Fiindings That Shifted from Baseline to Any Time During the Study

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    End point title
    Participants with Electrocardiogram (ECG) Fiindings That Shifted from Baseline to Any Time During the Study
    End point description
    Shifts are presented as Baseline finding / Worse finding at anytime during the study. Categories for findings are: - normal - abnormal, not clinically significant (Not CS) - abnormal, clinically significant (CS)
    End point type
    Secondary
    End point timeframe
    Day 1 up to 7.64 years
    End point values
    Early laquinimod Switch from placebo
    Number of subjects analysed
    420
    412
    Units: participants
        Normal / Normal|
    189
    198
        Normal / Abnormal, Not CS|
    145
    126
        Normal / Abnormal, CS|
    2
    3
        Abnormal, Not CS / Normal|
    12
    14
        Abnormal, Not CS / Abnormal, Not CS|
    70
    67
        Abnormal, Not CS / Abnormal, CS|
    2
    4
        Abnormal, CS / Normal|
    0
    0
        Abnormal, CS / Abnormal, Not CS|
    0
    0
        Abnormal, CS / Abnormal, CS|
    0
    0
    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 7.64 years
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Switch from Placebo to Laquinimod 0.6 mg
    Reporting group description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Switch from placebo subgroup included participants in MS-LAQ-301 double-blind study who were administered placebo daily for 24 months.

    Reporting group title
    Early Laquinimod 0.6 mg
    Reporting group description
    All participants in MS-LAQ-301E were administered 1 capsule containing laquinimod 0.6 mg taken orally at the same hour every day until the product was commercially available or development stopped. The Early laquinimod subgroup included participants in MS-LAQ-301 double-blind study who were administered laquinimod 0.6 mg daily for 24 months.

    Serious adverse events
    Switch from Placebo to Laquinimod 0.6 mg Early Laquinimod 0.6 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 416 (22.12%)
    108 / 423 (25.53%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc operation
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrectomy
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fusion surgery
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign ovarian tumour
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 416 (0.24%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer stage II
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia stage 1
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Langerhans' cell histiocytosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lung
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncocytoma
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubular breast carcinoma
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    4 / 416 (0.96%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cancer
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    3 / 416 (0.72%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device pain
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agoraphobia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Depression
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic disorder
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    2 / 416 (0.48%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrocystic breast disease
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrosalpinx
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 416 (0.00%)
    6 / 423 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 416 (0.24%)
    4 / 423 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 416 (0.48%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 416 (0.48%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silent myocardial infarction
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal polyp
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow oedema
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral artery occlusion
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 416 (0.00%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 416 (0.48%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 416 (0.24%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Omental infarction
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder dysfunction
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketonuria
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 416 (0.24%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral meatus stenosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 416 (0.24%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hidradenitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 416 (0.72%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc space narrowing
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint hyperextension
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee impingement syndrome
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon calcification
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperparathyroidism primary
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parathyroid gland enlargement
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 416 (0.72%)
    4 / 423 (0.95%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 416 (0.24%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholin's abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic echinococciasis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Latent syphilis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycotoxicosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 416 (0.00%)
    4 / 423 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periumbilical abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 416 (0.72%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 416 (0.24%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Switch from Placebo to Laquinimod 0.6 mg Early Laquinimod 0.6 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    300 / 416 (72.12%)
    299 / 423 (70.69%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 416 (6.25%)
    32 / 423 (7.57%)
         occurrences all number
    26
    32
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    23 / 416 (5.53%)
    20 / 423 (4.73%)
         occurrences all number
    30
    30
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 416 (5.29%)
    13 / 423 (3.07%)
         occurrences all number
    27
    16
    C-reactive protein increased
         subjects affected / exposed
    31 / 416 (7.45%)
    26 / 423 (6.15%)
         occurrences all number
    37
    31
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    16 / 416 (3.85%)
    22 / 423 (5.20%)
         occurrences all number
    23
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    35 / 416 (8.41%)
    24 / 423 (5.67%)
         occurrences all number
    40
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 416 (3.85%)
    22 / 423 (5.20%)
         occurrences all number
    17
    25
    Nervous system disorders
    Headache
         subjects affected / exposed
    86 / 416 (20.67%)
    57 / 423 (13.48%)
         occurrences all number
    160
    132
    Multiple sclerosis relapse
         subjects affected / exposed
    29 / 416 (6.97%)
    17 / 423 (4.02%)
         occurrences all number
    36
    35
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    31 / 416 (7.45%)
    25 / 423 (5.91%)
         occurrences all number
    38
    30
    Psychiatric disorders
    Depression
         subjects affected / exposed
    28 / 416 (6.73%)
    35 / 423 (8.27%)
         occurrences all number
    35
    41
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    31 / 416 (7.45%)
    19 / 423 (4.49%)
         occurrences all number
    39
    23
    Diarrhoea
         subjects affected / exposed
    21 / 416 (5.05%)
    24 / 423 (5.67%)
         occurrences all number
    23
    31
    Nausea
         subjects affected / exposed
    26 / 416 (6.25%)
    24 / 423 (5.67%)
         occurrences all number
    37
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    47 / 416 (11.30%)
    41 / 423 (9.69%)
         occurrences all number
    59
    57
    Back pain
         subjects affected / exposed
    77 / 416 (18.51%)
    78 / 423 (18.44%)
         occurrences all number
    124
    127
    Musculoskeletal pain
         subjects affected / exposed
    25 / 416 (6.01%)
    11 / 423 (2.60%)
         occurrences all number
    29
    15
    Pain in extremity
         subjects affected / exposed
    33 / 416 (7.93%)
    28 / 423 (6.62%)
         occurrences all number
    45
    35
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    33 / 416 (7.93%)
    33 / 423 (7.80%)
         occurrences all number
    46
    44
    Influenza
         subjects affected / exposed
    34 / 416 (8.17%)
    28 / 423 (6.62%)
         occurrences all number
    46
    41
    Nasopharyngitis
         subjects affected / exposed
    112 / 416 (26.92%)
    106 / 423 (25.06%)
         occurrences all number
    210
    169
    Sinusitis
         subjects affected / exposed
    28 / 416 (6.73%)
    27 / 423 (6.38%)
         occurrences all number
    47
    36
    Upper respiratory tract infection
         subjects affected / exposed
    41 / 416 (9.86%)
    43 / 423 (10.17%)
         occurrences all number
    65
    69
    Urinary tract infection
         subjects affected / exposed
    39 / 416 (9.38%)
    55 / 423 (13.00%)
         occurrences all number
    76
    110

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Nov 2009
    Amendment 1 (dated 01 November 2009) to the protocol was issued before any subjects were enrolled into the study. The amendment was aimed to modify the protocol according to the Food and Drug Administration (FDA) Guidance for Industry on the issue of Drug-Induced Liver Injury: Premarketing Clinical Evaluation. The following major procedural changes (not all-inclusive) were made to the protocol: - Modification of the “Guidance for Safety Monitoring” (Appendix 6) adopting the principles of the FDA Guideline titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” (July, 2009) - Clarification of the sequence of administration of questionnaires and the Multiple Sclerosis Functional Composite assessment at each visit - Modification of the MRI outcome of brain volume change in light of technical capabilities of the equipment
    17 Jul 2014
    Amendment 2 (dated 17 July 2014) to the protocol was issued when 639 subjects were ongoing in this study. Changes to the protocol were considered to have no negative impact on the safety of subjects ongoing in this study. These changes did not alter the study population, study design, or endpoints. The following major procedural changes (not all-inclusive) were made to the protocol: - Updates were made to the introduction and safety sections based on accumulating data with laquinimod and more stringent pregnancy prevention measures. - In addition to the major revisions, this amended protocol included updates, modifications, and clarifications in sections related to stopping rules, disallowed medication, and study duration.
    25 Feb 2016
    Amendment 3 (dated 25 February 2016) to the protocol was issued when 542 subjects were ongoing in this study. The primary purpose of this amendment was to introduce additional safety measures due to cardiovascular (CV) findings in other MS studies where higher doses of laquinimod (1.2 and 1.5 mg) were administered. The DMC recommended that study subjects continuing on laquinimod 0.6 mg be reconsented with information about the CV risk seen in higher doses. The following major procedural changes (not all-inclusive) were made to the protocol: - All ongoing subjects were asked to re-consent to a revised form that includes information on the CV risk findings at higher doses of laquinimod (1.2 mg and 1.5 mg). - Stopping rules were added for renal and hepatic impairment. - Glomerular filtration rate and weight were to be performed at all visits to assess renal function. - Extra emphasis was placed on moderate/strong inhibitors of cytochrome p450 (CYP)3A4 being disallowed. - Unscheduled urgent safety laboratory samples, pharmacokinetic blood samples, and/or samples for potential biomarker analyses may have been collected at the discretion of the Investigator at any time to assist with further investigations of CV events or other clinical event of interest. - A CV risk assessment and management procedure were added. - Ischemic cardiac events and cerebrovascular events were classed as protocol-defined adverse events for expedited reporting and were to be reported to the Sponsor within 48 hours. - Subjects who were discontinued from study drug were encouraged to continue all scheduled visits and procedures until completion of the study.

    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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