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    Clinical Trial Results:
    A Multinational, Multicenter, Open-Label, Single-Assignment Extension of the MS-LAQ-302 (BRAVO) 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
    2009-015815-42
    Trial protocol
    EE   IT   ES   CZ   SK   PL   BG   LT   DE  
    Global end of trial date
    30 Jun 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    MS-LAQ-302E
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01047319
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries, Ltd
    Sponsor organisation address
    5 Basel 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
    30 Jun 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 MS-LAQ-302 study (regardless of their treatment assignment, whether oral or injectable) and who completed the termination visit of this study according to the MS-LAQ-302 protocol as long as the Sponsor continued the development of laquinimod 0.6 mg for relapsing-remitting multiple sclerosis (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 MS-LAQ-302 study in this subject population.
    Protection of trial subjects
    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 patients. This study includes the following separate informed consent forms: - an informed consent form at the baseline visit - an informed consent for patients who were permitted by the Sponsor to re-enroll in the study following study discontinuation due to a planned pregnancy (introduced by Global Protocol Amendment 1) 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 2 .
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 May 2010
    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
    Bulgaria: 134
    Country: Number of subjects enrolled
    Czech Republic: 28
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Estonia: 14
    Country: Number of subjects enrolled
    Georgia: 36
    Country: Number of subjects enrolled
    Croatia: 39
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Lithuania: 20
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 18
    Country: Number of subjects enrolled
    Poland: 187
    Country: Number of subjects enrolled
    Romania: 67
    Country: Number of subjects enrolled
    Russian Federation: 99
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Ukraine: 234
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    South Africa: 26
    Worldwide total number of subjects
    1047
    EEA total number of subjects
    557
    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)
    1047
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All participants who completed the full duration of the double-blind BRAVO study (study MS-LAQ-302) were eligible to enter into Study MS-LAQ-302E. Of the 1090 participants who completed MS-LAQ-302, 1047 opted to continue into the open-label extension study.

    Pre-assignment
    Screening details
    1047 subjects with RRMS were enrolled to receive laquinimod 0.6 mg daily at 144 study sites in 18 countries by 144 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-302E 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-302 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 of 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-302E 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-302 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 of laquinimod 0.6 mg was taken orally at the same hour every day.

    Arm title
    Switch from Avonex
    Arm description
    All participants in MS-LAQ-302E 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 Avonex subgroup included participants in MS-LAQ-302 rater-blind study who were administered Avonex 30 mcg IM once weekly 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 of laquinimod 0.6 mg was taken orally at the same hour every day.

    Number of subjects in period 1
    Early laquinimod Switch from placebo Switch from Avonex
    Started
    345
    350
    352
    Completed
    0
    0
    0
    Not completed
    345
    350
    352
         Protocol deviation
    3
    2
    4
         Physician decision
    12
    9
    10
         Lack of efficacy
    4
    3
    3
         Pregnancy
    13
    8
    8
         Adverse event, serious fatal
    5
    1
    5
         Adverse event, non-fatal
    16
    27
    21
         Study terminated by Sponsor
    198
    215
    203
         Consent withdrawn by subject
    77
    75
    87
         Teva requested participant withdrawal
    3
    -
    1
         Lost to follow-up
    14
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Early laquinimod
    Reporting group description
    All participants in MS-LAQ-302E 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-302 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-302E 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-302 double-blind study who were administered placebo daily for 24 months.

    Reporting group title
    Switch from Avonex
    Reporting group description
    All participants in MS-LAQ-302E 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 Avonex subgroup included participants in MS-LAQ-302 rater-blind study who were administered Avonex 30 mcg IM once weekly for 24 months.

    Reporting group values
    Early laquinimod Switch from placebo Switch from Avonex Total
    Number of subjects
    345 350 352 1047
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    345 350 352 1047
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.2 ± 9.16 40.1 ± 9.23 40.1 ± 9.34 -
    Sex: Female, Male
    Units: Subjects
        Female
    228 245 234 707
        Male
    117 105 118 340
    Race/Ethnicity, Customized
    Units: Subjects
        Asian/Oriental
    1 0 1 2
        Black/African American
    2 2 2 6
        White
    338 346 348 1032
        Unknown
    2 2 0 4
        Other
    2 0 1 3

    End points

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    End points reporting groups
    Reporting group title
    Early laquinimod
    Reporting group description
    All participants in MS-LAQ-302E 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-302 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-302E 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-302 double-blind study who were administered placebo daily for 24 months.

    Reporting group title
    Switch from Avonex
    Reporting group description
    All participants in MS-LAQ-302E 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 Avonex subgroup included participants in MS-LAQ-302 rater-blind study who were administered Avonex 30 mcg IM once weekly 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 7.13 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 Switch from Avonex
    Number of subjects analysed
    345
    350
    352
    Units: participants
        =>1 TEAE|
    290
    303
    279
        =>1 Serious TEAE|
    54
    65
    51
        =>1 Severe TEAE|
    36
    54
    44
        =>1 TEAE causing discontinuation|
    20
    28
    23
        =>1 TEAE of special interest|
    66
    64
    73
        =>1 treatment-related TEAE|
    66
    76
    96
        =>1 TEAE leading to death|
    5
    3
    5
    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: >=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 Note that the change is compared to baseline,
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0 for extension), Day 1 up to 7.13 years
    End point values
    Early laquinimod Switch from placebo Switch from Avonex
    Number of subjects analysed
    345
    350
    352
    Units: participants
        Participants with at least one abnormality|
    19
    23
    19
        Pulse rate - high|
    2
    0
    0
        Systolic blood pressure - low|
    4
    7
    9
        Systolic blood pressure - high|
    0
    2
    0
        Diastolic blood pressure - low|
    4
    5
    4
        Diastolic blood pressure - high|
    9
    10
    7
    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
    Baseline (Day 0), Day 1 to 7.13 years
    End point values
    Early laquinimod Switch from placebo Switch from Avonex
    Number of subjects analysed
    344
    349
    347
    Units: participants
        ALT - change from Low / Non-PCS to High PCS|
    5
    8
    10
        Albumen - change from High / Non-PCS to Low PCS|
    0
    1
    0
        ALP - change from Low / Non-PCS to High PCS|
    0
    2
    0
        p-Amylase - change from Low / Non-PCS to High PCS|
    5
    1
    2
        AST - change from Low / Non-PCS to High PCS|
    3
    2
    5
        Bilirubin - change from Low / Non-PCS to High PCS|
    2
    3
    2
        CRP - change from Low / Non-PCS to High PCS|
    36
    32
    31
        Calcium - change from High / Non-PCS to Low PCS|
    1
    1
    1
        Calcium - change from Low / Non-PCS to High PCS|
    1
    1
    2
        CK - change from Low / Non-PCS to High PCS|
    11
    12
    10
        CTN - change from Low / Non-PCS to High PCS|
    1
    1
    0
        FIB - change from Low / Non-PCS to High PCS|
    22
    24
    25
        GGT - change from Low / Non-PCS to High PCS|
    16
    22
    18
        Glucose - change from High / Non-PCS to Low PCS|
    12
    16
    11
        Glucose - change from Low / Non-PCS to High PCS|
    4
    5
    2
        Phosphate-change from High / Non-PCS to Low PCS|
    12
    12
    6
        Phosphate-change from Low / Non-PCS to High PCS|
    17
    18
    16
        K - change from High / Non-PCS to Low PCS|
    2
    4
    2
        K - change from Low / Non-PCS to High PCS|
    46
    39
    38
        Sodium - change from High / Non-PCS to Low PCS|
    4
    2
    3
        Sodium - change from Low / Non-PCS to High PCS|
    21
    16
    17
        Urea - change from Low / Non-PCS to High PCS|
    4
    4
    3
    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
    Baseline (Day 0), Day 1 to 7.13 years
    End point values
    Early laquinimod Switch from placebo Switch from Avonex
    Number of subjects analysed
    344
    349
    347
    Units: participants
        Hematocrit-change from High/Non-PCS to Low PCS
    30
    25
    21
        Hemoglobin-change from High/Non-PCS to Low PCS
    21
    24
    15
        Leukocytes-change from High/Non-PCS to Low PCS
    2
    4
    2
        Leukocytes-change from Low/Non-PCS to High PCS
    4
    1
    5
        Neutrophils-change from High/Non-PCS to Low PCS
    25
    12
    14
        Platelets-change from High/Non-PCS to Low PCS
    5
    3
    2
        Platelets-change from Low/Non-PCS to High PCS
    4
    4
    4
    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
    Baseline (Day 0), Day 1 to 7.13 years
    End point values
    Early laquinimod Switch from placebo Switch from Avonex
    Number of subjects analysed
    340
    346
    345
    Units: participants
        Normal / Normal
    150
    148
    134
        Normal / Abnormal, Not CS
    109
    125
    119
        Normal / Abnormal, CS
    5
    3
    5
        Abnormal, Not CS / Normal
    5
    7
    20
        Abnormal, Not CS / Abnormal, Not CS
    67
    62
    64
        Abnormal, Not CS / Abnormal, CS
    4
    0
    2
        Abnormal, CS / Normal
    0
    0
    0
        Abnormal, CS / Abnormal, Not CS
    0
    0
    1
        Abnormal, CS / Abnormal, CS
    0
    1
    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 7.13 years
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Early laquinimod
    Reporting group description
    All participants in MS-LAQ- 302E 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-302 double-blind study who were administered laquinimod 0.6 mg daily for 24 months.

    Reporting group title
    Switch from Avonex
    Reporting group description
    All participants in MS-LAQ- 302E 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 Avonex subgroup included participants in MS-LAQ-302 rater-blind study who were administered Avonex 30 mcg IM once weekly for 24 months.

    Reporting group title
    Switch from Placebo
    Reporting group description
    All participants in MS-LAQ- 302E 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-302 double-blind study who were administered placebo daily for 24 months.

    Serious adverse events
    Early laquinimod Switch from Avonex Switch from Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 345 (15.65%)
    51 / 352 (14.49%)
    65 / 350 (18.57%)
         number of deaths (all causes)
    5
    5
    3
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiphyseal fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Skeletal injury
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric injury
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 345 (0.58%)
    2 / 352 (0.57%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Coronary artery dissection
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 345 (0.00%)
    3 / 352 (0.85%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    3 / 350 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract nuclear
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ocular hypertension
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crush syndrome
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertonic bladder
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Micturition disorder
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device loosening
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 345 (0.58%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw cyst
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 345 (0.58%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Lactose intolerance
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute hepatitis C
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 345 (0.58%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chorioretinitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 345 (0.58%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HIV infection
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papilloma viral infection
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 345 (0.58%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 352 (0.57%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 352 (0.57%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 345 (0.29%)
    2 / 352 (0.57%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 352 (0.57%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 345 (0.87%)
    2 / 352 (0.57%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic rupture
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 345 (0.00%)
    2 / 352 (0.57%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Internal haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bartholin's cyst removal
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture reduction
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteosynthesis
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radical hysterectomy
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin lesion excision
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenectomy
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroidectomy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage II
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage II
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibrous histiocytoma
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of renal pelvis
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Neuroma
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    3 / 345 (0.87%)
    3 / 352 (0.85%)
    4 / 350 (1.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to metals
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    3 / 350 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix disorder
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    4 / 350 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menstrual disorder
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    2 / 350 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian haemorrhage
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic adhesions
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal cyst
         subjects affected / exposed
    1 / 345 (0.29%)
    0 / 352 (0.00%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paranasal cyst
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 345 (0.00%)
    0 / 352 (0.00%)
    1 / 350 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 345 (0.29%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 345 (0.00%)
    1 / 352 (0.28%)
    0 / 350 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Early laquinimod Switch from Avonex Switch from Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    215 / 345 (62.32%)
    194 / 352 (55.11%)
    205 / 350 (58.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 345 (5.22%)
    18 / 352 (5.11%)
    21 / 350 (6.00%)
         occurrences all number
    22
    18
    23
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    19 / 345 (5.51%)
    14 / 352 (3.98%)
    17 / 350 (4.86%)
         occurrences all number
    25
    16
    23
    Weight increased
         subjects affected / exposed
    19 / 345 (5.51%)
    9 / 352 (2.56%)
    11 / 350 (3.14%)
         occurrences all number
    23
    10
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    22 / 345 (6.38%)
    15 / 352 (4.26%)
    20 / 350 (5.71%)
         occurrences all number
    34
    18
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    44 / 345 (12.75%)
    74 / 352 (21.02%)
    60 / 350 (17.14%)
         occurrences all number
    84
    128
    121
    Psychiatric disorders
    Depression
         subjects affected / exposed
    26 / 345 (7.54%)
    17 / 352 (4.83%)
    20 / 350 (5.71%)
         occurrences all number
    26
    21
    21
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 345 (6.09%)
    28 / 352 (7.95%)
    23 / 350 (6.57%)
         occurrences all number
    27
    38
    27
    Back pain
         subjects affected / exposed
    49 / 345 (14.20%)
    50 / 352 (14.20%)
    49 / 350 (14.00%)
         occurrences all number
    74
    73
    72
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    24 / 345 (6.96%)
    16 / 352 (4.55%)
    23 / 350 (6.57%)
         occurrences all number
    26
    27
    29
    Influenza
         subjects affected / exposed
    27 / 345 (7.83%)
    22 / 352 (6.25%)
    25 / 350 (7.14%)
         occurrences all number
    34
    32
    38
    Nasopharyngitis
         subjects affected / exposed
    52 / 345 (15.07%)
    37 / 352 (10.51%)
    46 / 350 (13.14%)
         occurrences all number
    96
    58
    77
    Pharyngitis
         subjects affected / exposed
    11 / 345 (3.19%)
    11 / 352 (3.13%)
    18 / 350 (5.14%)
         occurrences all number
    18
    15
    24
    Respiratory tract infection viral
         subjects affected / exposed
    20 / 345 (5.80%)
    16 / 352 (4.55%)
    15 / 350 (4.29%)
         occurrences all number
    25
    20
    24
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 345 (10.43%)
    28 / 352 (7.95%)
    36 / 350 (10.29%)
         occurrences all number
    62
    59
    63
    Urinary tract infection
         subjects affected / exposed
    22 / 345 (6.38%)
    17 / 352 (4.83%)
    18 / 350 (5.14%)
         occurrences all number
    30
    22
    22

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2014
    Amendment 1 (dated 17 July 2014) to the protocol was issued when 822 subjects were ongoing in the study. Changes to the protocol were considered to have no negative impact on the safety of subjects already enrolled into the 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 2 was issued when 714 subjects were ongoing in the 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. These CV events resulted in the discontinuation of subjects treated with 1.2 and 1.5 mg from the respective studies in line with the Data Monitoring Committee (DMC) recommendations. The DMC also 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 reconsent to a revised form that included information on the CV risk findings at higher doses of laquinimod (1.2 and 1.5 mg). - Stopping rules were added for renal and hepatic impairment. - Glomerular filtration rate monitoring was 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, PK blood samples, and/or samples for potential biomarker analyses may have been collected at the discretion of the Investigator or Medical Monitor 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 are now classed as protocol-defined AEs for expedited reporting and were to be reported to the Sponsor within 48 hours, including completion of the corresponding dedicated CRF. - Subjects who were discontinued from study drug were encouraged to continue all scheduled visits and procedures until completion of the study (with the exception of procedures associated with drug dispensing and accountability, pregnancy testing, and GFR estimation).

    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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