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    Clinical Trial Results:
    Efficacy and safety of eslicarbazepine acetate (BIA 2-093) as monotherapy for patients with newly diagnosed partial-onset seizures: a double-blind, randomized, active-controlled, parallel-group, multicenter clinical study — Open-label ESL extension —

    Summary
    EudraCT number
    		 2015-001243-36
    Trial protocol
    		 DE   GB   HU   LT   CZ   LV   PT   BE   FR   ES   SE   EE   AT   BG   SK   FI   HR   IT  
    Global end of trial date
    19 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions
    Summary report(s)
    		 BIA-2093-311/EXT

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-2093-311/EXT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02484001
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BIAL - Portela & Ca, S.A.
    Sponsor organisation address
    À Av. Siderurgia Nacional, Coronado, Portugal, 4745-457
    Public contact
    Helena Gama, BIAL - Portela & Cª, S.A., 00351 229866100, helena.gama@bial.com
    Scientific contact
    Helena Gama, BIAL - Portela & Cª, S.A., 00351 229866100, helena.gama@bial.com
    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
    30 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To confirm maintenance of efficacy of eslicarbazepine acetate (ESL, 800 mg to 1600 mg once daily [QD]) monotherapy during long-term treatment in adults (≥18 years) with recently diagnosed epilepsy experiencing partial-onset seizures.
    Protection of trial subjects
    This study was conducted in compliance with International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Good Clinical Practice, including the archiving of essential documents.
    Background therapy
    		 Concomitant AED therapy (1 or 2 AEDs).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Latvia: 13
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Ukraine: 13
    Worldwide total number of subjects
    207
    EEA total number of subjects
    111
    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)
    186
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adults (≥18 years) with recently diagnosed epilepsy experiencing partial-onset seizures who were under treatment in the double-blind study BIA-2093-311.

    Pre-assignment
    Screening details
    		 Subjects who met all inclusion criteria and none of the exclusion criteria. 207 subjects were enrolled to the trial and 1 subject was a screening failure.

    Pre-assignment period milestones
    Number of subjects started
    		 207
    Number of subjects completed
    		 206

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligibility: 1
    Period 1
    Period 1 title
    Open-label ESL extension (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall ESL
    Arm description
    		 Subjects already treated with ESL continued with their last evaluated dose (ESL 800 mg, 1200 mg or 1600 mg QD). Subjects previously treated with CBZ-CR started with ESL 400 mg QD for one week followed by up-titration to the ESL target dose which was equivalent to the last evaluated CBZ-CR dose level (i.e. CBZ-CR 200 mg BID -> ESL 800 mg QD; CBZ-CR 400 mg BID -> ESL 1200 mg QD; CBZ-CR 600 mg BID -> ESL 1600 mg QD) in steps of 400 mg dose increase per week.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    ESL
    Other name
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects already treated with ESL will continue with their last evaluated dose (ESL 800 mg, 1200 mg or 1600 mg QD). Subjects previously treated with CBZ-CR will start with ESL 400 mg QD for one week followed by up-titration to the ESL target dose which is equivalent to the last evaluated CBZ-CR dose level (i.e. CBZ-CR 200 mg BID -> ESL 800 mg QD; CBZ-CR 400 mg BID -> ESL 1200 mg QD; CBZ-CR 600 mg BID -> ESL 1600 mg QD) in steps of 400 mg dose increase per week. In case of new seizures, the ESL dose can be increased to a maximum dose of ESL 1600 mg QD [dose level C], depending on the investigator`s decision. Any up-titration should be performed in weekly steps of 400 mg. If deemed necessary by the investigator, e.g. due to occurrence of adverse events, the dose of ESL can be reduced according to investigator’s discretion, as long as the dose remains in the range of 800 mg QD to 1600mg QD. Down-titration of ESL as required should be performed in steps of 400 mg decrease per week.

    Number of subjects in period 1 [1]
    		Overall ESL
    Started
    206
    Completed
    172
    Not completed
    34
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    9
         Physician decision
    3
         Hyponatremia <125 mmol/L
    1
         Adverse event, non-fatal
    7
         Subject non-compliance
    4
         Other
    5
         Adverse event, serious non-fatal
    2
         Lack of efficacy
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline period does not include 1 subject who was a screening failure.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall ESL
    Reporting group description
    		 Subjects already treated with ESL continued with their last evaluated dose (ESL 800 mg, 1200 mg or 1600 mg QD). Subjects previously treated with CBZ-CR started with ESL 400 mg QD for one week followed by up-titration to the ESL target dose which was equivalent to the last evaluated CBZ-CR dose level (i.e. CBZ-CR 200 mg BID -> ESL 800 mg QD; CBZ-CR 400 mg BID -> ESL 1200 mg QD; CBZ-CR 600 mg BID -> ESL 1600 mg QD) in steps of 400 mg dose increase per week.

    Reporting group values
    		 Overall ESL Total
    Number of subjects
    		 206 206
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0
        Newborns (0-27days)
    		 0 0
        Infants and toddlers (28days – 23months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 year)
    		 0 0
        From 18 - 64 years
    		 185 185
        From 65 – 84 years
    		 21 21
        Over 85 years
    		 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 42.6 ( 15.89 ) -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 98 98
        Male
    		 108 108

    End points

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    End points reporting groups
    Reporting group title
    Overall ESL
    Reporting group description
    		 Subjects already treated with ESL continued with their last evaluated dose (ESL 800 mg, 1200 mg or 1600 mg QD). Subjects previously treated with CBZ-CR started with ESL 400 mg QD for one week followed by up-titration to the ESL target dose which was equivalent to the last evaluated CBZ-CR dose level (i.e. CBZ-CR 200 mg BID -> ESL 800 mg QD; CBZ-CR 400 mg BID -> ESL 1200 mg QD; CBZ-CR 600 mg BID -> ESL 1600 mg QD) in steps of 400 mg dose increase per week.

    Subject analysis set title
    Overall ESL x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects enrolled who received at least 1 dose of ESL during the open-label extension study.

    Subject analysis set title
    Overall ESL x FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects enrolled and treated with at least 1 dose of ESL during the open-label extension study and date of withdrawal of ESL or last day of ESL intake available allowing to calculate the derived variables “time to treatment failure” or “treatment retention time” including censoring.

    Subject analysis set title
    Overall ESL x Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the OL FAS without any major protocol deviation. Subjects will be excluded from the PP set for the following reasons: -Treated with ESL outside the range of 800-1600 mg QD except of treatment with ESL 400 mg QD during the first week of transition when switching from CBZ-CR treatment. -Intake of prohibited therapies. -Poor compliance for completion of the subject diary (i.e. they do not adequately report seizure information or diaries are not returned). -Poor compliance for taking ESL (i.e. confirmed compliance <80% or >120% of the scheduled total dose). -Other events occur that may have a relevant impact on the efficacy evaluations. Such study conditions, which may or may not represent a protocol deviation or violation, will be identified during the data review meeting.

    Subject analysis set title
    Overall ESL x Per Protocol Subset
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the OL PP set, excluding all subjects switching from CBZ-CR who discontinue the open-label extension study before they have completed CBZ-CR down-titration for any reasons not linked to efficacy.

    Primary: Monthly failure rates of time to treatment failure (TTF) / treatment retention time (TRT)

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    End point title
    		 Monthly failure rates of time to treatment failure (TTF) / treatment retention time (TRT) [1]
    End point description
    Estimates of monthly failure rates of time to treatment failure (TTF) / treatment retention time (TRT). Time to treatment failure (TTF) is defined as the time from OL Baseline (OL Visit 1) until withdrawal of ESL due to AE or lack of efficacy (i.e. inadequate seizure control) in subjects who received ESL already during the DB phase. Treatment retention time (TRT) is defined as the time from OL Baseline (OL Visit 1) until withdrawal of ESL due to AE or lack of efficacy (i.e. inadequate seizure control) in all subjects including those subjects who received CBZ-CR during the DB phase.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Failure Probability
    number (confidence interval)
        +30 days
    0.0049000000 (0.0007 to 0.0340)
        +60 days
    0.0146 (0.0047 to 0.0445)
        +90 days
    0.0194000000 (0.0073 to 0.0509)
        +120 days
    0.0194000000 (0.0073 to 0.0509)
        +150 days
    0.0194000000 (0.0073 to 0.0509)
        +180 days
    0.0194000000 (0.0073 to 0.0509)
        +210 days
    0.0194000000 (0.0073 to 0.0509)
        +240 days
    0.0194000000 (0.0073 to 0.0509)
        +270 days
    0.0194000000 (0.0073 to 0.0509)
        +300 days
    0.0244000000 (0.0102 to 0.0576)
        +330 days
    0.0293 (0.0133 to 0.0642)
        +360 days
    0.0293 (0.0133 to 0.0642)
        +390 days
    0.0394000000 (0.0199 to 0.0772)
        +420 days
    0.0394000000 (0.0199 to 0.0772)
        +450 days
    0.0394000000 (0.0199 to 0.0772)
        +480 days
    0.0548000000 (0.0307 to 0.0968)
        +510 days
    0.0548000000 (0.0307 to 0.0968)
        +540 days
    0.0548000000 (0.0307 to 0.0968)
        +570 days
    0.0548000000 (0.0307 to 0.0968)
        +600 days
    0.0548000000 (0.0307 to 0.0968)
        +630 days
    0.0548000000 (0.0307 to 0.0968)
        +660 days
    0.0548000000 (0.0307 to 0.0968)
        +690 days
    0.0548000000 (0.0307 to 0.0968)
        +720 days
    0.0602000000 (0.0346 to 0.1037)
        +750 days
    0.0602000000 (0.0346 to 0.1037)
    No statistical analyses for this end point

    Primary: Monthly withdrawal rates of time to withdrawal for any reason TTW

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    End point title
    		 Monthly withdrawal rates of time to withdrawal for any reason TTW [2]
    End point description
    Estimates of monthly withdrawal rates of time to withdrawal for any reason is defined as the time from OL Baseline OL Visit 1 until withdrawal of ESL.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [2] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Withdrawal Rate
    number (not applicable)
        +30 days
    0.0049000000
        +60 days
    0.0146
        +90 days
    0.0194000000
        +120 days
    0.0243000000
        +150 days
    0.0291000000
        +180 days
    0.0291000000
        +210 days
    0.0340000000
        +240 days
    0.0388000000
        +270 days
    0.0388000000
        +300 days
    0.0485000000
        +330 days
    0.0534000000
        +360 days
    0.0583000000
        +390 days
    0.0777000000
        +420 days
    0.0777000000
        +450 days
    0.0825000000
        +480 days
    0.1117000000
        +510 days
    0.1165000000
        +540 days
    0.1262000000
        +570 days
    0.1311000000
        +600 days
    0.1359000000
        +630 days
    0.1359000000
        +660 days
    0.1359000000
        +690 days
    0.1505000000
        +720 days
    0.1553000000
        +750 days
    0.1746000000
    No statistical analyses for this end point

    Primary: Seizure freedom

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    End point title
    		 Seizure freedom [3]
    End point description
    Number of subjects without seizures (seizure freedom) while treated during the open-label extension study.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [3] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Seizure Freedom
    number (not applicable)
        Seizure Freedom
    167
    No statistical analyses for this end point

    Primary: Subjects with seizures by seizure type

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    End point title
    		 Subjects with seizures by seizure type [4]
    End point description
    The number of subjects with seizures while treated during the open-label extension study classified by seizure type.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [4] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Subjects
    number (not applicable)
        Total seizures
    39
        Simple partial
    12
        Complex partial
    17
        Partial evolving to secondary
    19
        Generalized
    2
        Unclassifiable
    3
        Other seizure type
    0
    No statistical analyses for this end point

    Primary: Subjects with seizures by seizure duration

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    End point title
    		 Subjects with seizures by seizure duration [5]
    End point description
    The number of subjects with seizures while treated during the open-label extension study classified by seizure duration.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Subjects
    number (not applicable)
        < 30 sec.
    4
        ≥ 30 sec. - < 1 min.
    11
        ≥ 1 min. - < 5 min.
    26
        ≥ 5 min.
    17
        Unknown
    1
        More than 1 day
    0
        Ongoing
    0
    No statistical analyses for this end point

    Primary: Standardized seizure frequency

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    End point title
    		 Standardized seizure frequency [6]
    End point description
    Standardised seizure frequency (ssf), calculated as 28 days * (number of seizures in interval T/length of T in days) summarised by open-label ESL study.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [6] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: SSF
    number (standard deviation)
        OL Baseline
    206
        OL Visit 2
    204
        OL Treatment Visit 1
    201
        OL Treatment Visit 2
    199
        OL Treatment Visit 3
    195
        OL Treatment Visit 4
    191
        OL Treatment Visit 5
    184
        OL Treatment Visit 6
    178
        OL Treatment Visit 7
    178
        OL EOS
    172
        OL EDV
    26
        OL PSV
    193
    No statistical analyses for this end point

    Primary: Number of responders

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    End point title
    		 Number of responders [7]
    End point description
    A responder is defined as a subject with ≥50% reduction in seizure frequency compared to the seizure frequency at double blind study Baseline.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [7] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Subjects
    number (not applicable)
        OL Baseline
    206
        OL Visit 2
    201
        OL Treatment Visit 1
    195
        OL Treatment Visit 2
    193
        OL Treatment Visit 3
    192
        OL Treatment Visit 4
    191
        OL Treatment Visit 5
    181
        OL Treatment Visit 6
    175
        OL Treatment Visit 7
    174
        OL EOS
    171
        OL EDV
    24
        OL PSV
    186
        Overall
    206
    No statistical analyses for this end point

    Primary: Frequency of responders

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    End point title
    		 Frequency of responders [8]
    End point description
    A responder is defined as a subject with ≥50% reduction in seizure frequency compared to the seizure frequency at double blind study Baseline.
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [8] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Percentage of responders
    number (not applicable)
        OL Baseline
    100
        OL Visit 2
    97.6
        OL Treatment Visit 1
    94.7
        OL Treatment Visit 2
    93.7
        OL Treatment Visit 3
    93.2
        OL Treatment Visit 4
    92.7
        OL Treatment Visit 5
    87.9
        OL Treatment Visit 6
    85
        OL Treatment Visit 7
    84.5
        OL EOS
    83
        OL EDV
    11.7
        OL PSV
    90.3
        Overall
    100
    No statistical analyses for this end point

    Primary: Quality of life assessed using the QOLIE-31

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    End point title
    		 Quality of life assessed using the QOLIE-31 [9]
    End point description
    Score of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31).
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [9] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: QOLIE-31 Score
    number (standard deviation)
        OL Baseline
    205
        OL Visit 2
    201
        OL Treatment Visit 2
    199
        OL Treatment Visit 4
    191
        OL Treatment Visit 6
    178
        OL EOS
    172
        OL EDV
    23
    No statistical analyses for this end point

    Primary: Treatment satisfaction by the Subject

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    End point title
    		 Treatment satisfaction by the Subject [10]
    End point description
    Subject rating of treatment satisfaction (assessed on a 4-point-scale).
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [10] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Treatment satisfaction
    number (not applicable)
        OL Visit 2 x Very good
    118
        OL Visit 2 x Good
    79
        OL Visit 2 x Fair
    6
        OL Visit 2 x Poor
    1
        OL Treatment Visit 1 x Very good
    129
        OL Treatment Visit 1 x Good
    69
        OL Treatment Visit 1 x Fair
    2
        OL Treatment Visit 1 x Poor
    0
        OL Treatment Visit 1 x Missing
    1
        OL Treatment Visit 2 x Very good
    139
        OL Treatment Visit 2 x Good
    54
        OL Treatment Visit 2 x Fair
    6
        OL Treatment Visit 2 x Poor
    0
        OL Treatment Visit 3 x Very good
    140
        OL Treatment Visit 3 x Good
    51
        OL Treatment Visit 3 x Fair
    4
        OL Treatment Visit 3 x Poor
    0
        OL Treatment Visit 4 x Very good
    133
        OL Treatment Visit 4 x Good
    55
        OL Treatment Visit 4 x Fair
    3
        OL Treatment Visit 4 x Poor
    0
        OL Treatment Visit 5 x Very good
    130
        OL Treatment Visit 5 x Good
    50
        OL Treatment Visit 5 x Fair
    2
        OL Treatment Visit 5 x Poor
    2
        OL Treatment Visit 6 x Very good
    126
        OL Treatment Visit 6 x Good
    48
        OL Treatment Visit 6 x Fair
    4
        OL Treatment Visit 6 x Poor
    0
        OL Treatment Visit 7 x Very good
    122
        OL Treatment Visit 7 x Good
    53
        OL Treatment Visit 7 x Fair
    3
        OL Treatment Visit 7 x Poor
    0
        OL EOS x Very good
    121
        OL EOS x Good
    49
        OL EOS x Fair
    2
        OL EOS x Poor
    0
        OL EDV x Very good
    10
        OL EDV x Good
    9
        OL EDV x Fair
    5
        OL EDV x Poor
    1
    No statistical analyses for this end point

    Primary: Treatment satisfaction by the Investigator

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    End point title
    		 Treatment satisfaction by the Investigator [11]
    End point description
    Investigator rating of treatment satisfaction (assessed on a 4-point-scale).
    End point type
    Primary
    End point timeframe
    Visit 1 untill the end of open-label ESL extension
    Notes
    [11] - 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 statistical analyses have been performed for this primary end point.
    End point values
    		 Overall ESL x FAS
    Number of subjects analysed
    206
    Units: Treatment satisfaction
    number (not applicable)
        OL Visit 2 x Very good
    128
        OL Visit 2 x Good
    72
        OL Visit 2 x Fair
    2
        OL Visit 2 x Poor
    2
        OL Treatment Visit 1 x Very good
    133
        OL Treatment Visit 1 x Good
    64
        OL Treatment Visit 1 x Fair
    3
        OL Treatment Visit 1 x Poor
    0
        OL Treatment Visit 1 x Missing
    1
        OL Treatment Visit 2 x Very good
    140
        OL Treatment Visit 2 x Good
    54
        OL Treatment Visit 2 x Fair
    5
        OL Treatment Visit 2 x Poor
    0
        OL Treatment Visit 3 x Very good
    139
        OL Treatment Visit 3 x Good
    53
        OL Treatment Visit 3 x Fair
    3
        OL Treatment Visit 3 x Poor
    0
        OL Treatment Visit 4 x Very good
    137
        OL Treatment Visit 4 x Good
    52
        OL Treatment Visit 4 x Fair
    2
        OL Treatment Visit 4 x Poor
    0
        OL Treatment Visit 5 x Very good
    132
        OL Treatment Visit 5 x Good
    49
        OL Treatment Visit 5 x Fair
    3
        OL Treatment Visit 5 x Poor
    0
        OL Treatment Visit 6 x Very good
    130
        OL Treatment Visit 6 x Good
    45
        OL Treatment Visit 6 x Fair
    3
        OL Treatment Visit 6 x Poor
    0
        OL Treatment Visit 7 x Very good
    126
        OL Treatment Visit 7 x Good
    49
        OL Treatment Visit 7 x Fair
    3
        OL Treatment Visit 7 x Poor
    0
        OL EOS x Very good
    122
        OL EOS x Good
    49
        OL EOS x Fair
    14
        OL EOS x Poor
    0
        OL EDV x Very good
    12
        OL EDV x Good
    7
        OL EDV x Fair
    4
        OL EDV x Poor
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Visit 1 until post study visit (4 weeks after OL EOS or OL EDV).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Overall ESL x Safety
    Reporting group description
    		 Subjects in the Safety set treated with ESL

    Serious adverse events
    		 Overall ESL x Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 206 (8.25%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Aortic dilatation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall ESL x Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    124 / 206 (60.19%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Thyroid neoplasm
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Arteriosclerosis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    11 / 206 (5.34%)
         occurrences all number
    11
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Asthenia
         subjects affected / exposed
    5 / 206 (2.43%)
         occurrences all number
    5
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Allergy to plants
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    6 / 206 (2.91%)
         occurrences all number
    6
    Pleurisy
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    5
    Lung disorder
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Sinus polyp
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Alcohol abuse
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Disorientation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Confusional state
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Bradyphrenia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    3
    Irritability
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Mood disorder due to a general medical condition
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Blood chloride decreased
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    13 / 206 (6.31%)
         occurrences all number
    15
    Blood creatinine decreased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Blood parathyroid hormone increased
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Blood pressure decreased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Blood sodium decreased
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Blood urea increased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    International normalised ratio increased
         subjects affected / exposed
    7 / 206 (3.40%)
         occurrences all number
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 206 (2.91%)
         occurrences all number
    8
    C-reactive protein increased
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Body mass index increased
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    N-telopeptide
         subjects affected / exposed
    5 / 206 (2.43%)
         occurrences all number
    5
    Osteocalcin decreased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Thyroid hormones decreased
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Thyroxine decreased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Thyroxine free decreased
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Weight decreased
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    4
    Weight increased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    4
    Hand fracture
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Foot fracture
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    2
    Craniocerebral injury
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Head injury
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Ligament rupture
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Muscle injury
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Overdose
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Rib fracture
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Upper limb fracture
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Tooth fracture
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Tongue injury
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Cardiac failure
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    2
    Coronary artery disease
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Cardiac failure chronic
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Left ventricular failure
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Extrasystoles
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Myocardial infarction
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Ataxia
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Balance disorder
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Cerebellar syndrome
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Coordination abnormal
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Disturbance in attention
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    3
    Dizziness
         subjects affected / exposed
    10 / 206 (4.85%)
         occurrences all number
    12
    Epilepsy
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    4
    Drop attacks
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    10 / 206 (4.85%)
         occurrences all number
    17
    Hypoaesthesia
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    8
    Hyporeflexia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Memory impairment
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Hyperreflexia
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Migraine
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    4
    Morton's neuralgia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Migraine without aura
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Parkinson's disease
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Postictal paralysis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Sciatica
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Seizure
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    9 / 206 (4.37%)
         occurrences all number
    11
    Syncope
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    7
    Tension headache
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Eosinopenia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    4
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    4
    Tinnitus
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Dry age-related macular degeneration
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Pterygium
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Myopia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    2
    Eyelid dermatochalasis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Visual impairment
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Colitis ulcerative
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    2
    Colitis ischaemic
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Duodenogastric reflux
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    2
    Large intestine polyp
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    6
    Pancreatitis chronic
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Salivary gland mucocoele
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Steatohepatitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Rash erythematous
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Skin depigmentation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Chronic kidney disease
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Haematuria
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Renal artery thrombosis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Renal cyst
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Primary hypothyroidism
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    11 / 206 (5.34%)
         occurrences all number
    11
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Posture abnormal
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Spinal pain
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Spinal osteoarthritis
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Infections and infestations
    Cystitis
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    4
    Bronchitis
         subjects affected / exposed
    7 / 206 (3.40%)
         occurrences all number
    8
    Erysipelas
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Gingivitis
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    5
    Herpes zoster
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    13 / 206 (6.31%)
         occurrences all number
    19
    Laryngitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Labyrinthitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Nasal herpes
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Otitis externa
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Otitis media acute
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    12 / 206 (5.83%)
         occurrences all number
    14
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Pharyngitis bacterial
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Pulpitis dental
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Respiratory tract infection viral
         subjects affected / exposed
    4 / 206 (1.94%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    4
    Tooth infection
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Tonsillitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Tinea cruris
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Tracheitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Diabetes mellitus
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Dyslipidaemia
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences all number
    2
    Hyponatraemia
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Obesity
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences all number
    3
    Vitamin D deficiency
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Vitamin C deficiency
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1
    Zinc deficiency
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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