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    Clinical Trial Results:
    The efficacy and safety of olmesartan medoxomil/amlodipine fixed combination in patients with grade 1 to grade 2 arterial hypertension. An international randomized, double-blind, 10-week multi-factorial clinical study.

    Summary
    EudraCT number
    		 2014-003470-17
    Trial protocol
    		 DE   HU   RO  
    Global end of trial date
    10 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Oct 2016
    First version publication date
    27 Oct 2016
    Other versions
    Summary report(s)
    		 Summary of Integrated clinical study report

    Trial information

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    Trial identification
    Sponsor protocol code
    KKL172014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Krka, d. d., Novo mesto
    Sponsor organisation address
    Šmarješka cesta 6, Novo mesto, Slovenia, 8501
    Public contact
    Infopoint KKL172014, Krka, d.d. Novo mesto, +386 73312111, info@krka.biz
    Scientific contact
    Infopoint KKL172014, Krka, d.d. Novo mesto, +386 14751489, Clinical.trials@krka.biz
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective is to compare the treatment effect of fixed-dose combinations of olmesartan medoxomil/amlodipine (TIMP) to those of the component monotherapies (RIMPs) and placebo in subjects with grade 1 or grade 2 arterial hypertension. Within the primary objective the superiority of the treatment effect of TIMPs over each RIMP of respective strength and placebo is expected to be demonstrated.
    Protection of trial subjects
    This study was conducted in accordance with the Note for Guidance on GCP, the general guidelines indicated in the Declaration of Helsinki and all applicable regulatory requirements. Before initiating the study, the written and dated approvals/favorable opinions were obtained from the competent national Ethical Committees for the study protocol, amendments, and the informed consent form (ICF). Investigators explained the benefits and risks of study participation to each subject or the subject’s legal representative. Written informed consent was obtained before the subject entered the study and before initiation of any study-related procedure. During the active treatment phase, there was a possibility of rescue medication in case of marked lack of efficacy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Feb 2015
    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
    Poland: 328
    Country: Number of subjects enrolled
    Romania: 418
    Country: Number of subjects enrolled
    Germany: 96
    Country: Number of subjects enrolled
    Hungary: 155
    Worldwide total number of subjects
    997
    EEA total number of subjects
    997
    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)
    811
    From 65 to 84 years
    186
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At the screening visit, subjects' eligibility was assessed after ICF signature. Eligible subjects were enrolled in 2-week washout/ placebo run-in period (Period I). Overall 997 subjects were screened.

    Period 1
    Period 1 title
    Washout/run-in period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Placebo
    Arm description
    		 This was a pre-randomization period. All enrolled subjects were assigned to this placebo arm prior to randomization.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Plac
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Number of subjects in period 1
    		Placebo
    Started
    997
    Completed
    841
    Not completed
    156
         Consent withdrawn by subject
    41
         Adverse event, non-fatal
    13
         Inclusion/Exclusion criteria violation
    97
         Other
    3
         Lost to follow-up
    2
    Period 2
    Period 2 title
    Active treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The study blind is assured by encapsulation of all the IMPs in identical test capsules. The identity of the IMP is not revealed on the labels.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OA 20/5
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    olmesartan medoxomil 20 mg/amlodipine 5 mg
    Investigational medicinal product code
    OA 20/5
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One Olmesartan medoxomil/amlodipine 20/5 mg encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 OA 40/5
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olmesartan medoxomil/amlodipine 40/5 mg film-coated tablets
    Investigational medicinal product code
    OA 40/5
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One Olmesartan medoxomil/amlodipine 40/5 mg encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 OA 40/10
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olmesartan medoxomil/amlodipine 40/10 mg film-coated tablets
    Investigational medicinal product code
    OA 40/10
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One Olmesartan medoxomil/amlodipine 40/10 mg encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 Olmesartan 20
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olmesartan 20 mg
    Investigational medicinal product code
    O20
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One olmesartan medoxomil 20 mg encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 Olmesartan 40
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olmesartan medoxomil 40 mg
    Investigational medicinal product code
    O40
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One olmesartan medoxomil 40 mg encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 Amlodipine 5
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amlodipine 5 mg
    Investigational medicinal product code
    A5
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One amlodipine 5 mg encapsulated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 Amlodipine 10
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amlodipine 10 mg
    Investigational medicinal product code
    A10
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One amlodipine 10 mg encapsulated tablet administered once daily at about the same time each day, orally.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Plac
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo encapsulated film-coated tablet administered once daily at about the same time each day, orally.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 was a washout/placebo run-in period, during which all enrolled subjects received placebo prior to randomization. Baseline period was Period II, during which all randomized patients received active treatment or placebo.
    Number of subjects in period 2 [2]
    		OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Started
    129
    130
    129
    97
    96
    97
    98
    65
    Completed
    124
    125
    125
    93
    92
    94
    86
    61
    Not completed
    5
    5
    4
    4
    4
    3
    12
    4
         Consent withdrawn by subject
    -
    -
    2
    1
    -
    -
    4
    3
         Adverse event, non-fatal
    2
    -
    -
    3
    1
    -
    3
    -
         Other
    -
    1
    -
    -
    -
    1
    3
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    1
    -
    -
         Protocol deviation
    3
    4
    1
    -
    3
    1
    2
    1
    Notes
    [2] - 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: The baseline period was Period II, during which all randomized patients (841 in total) received active treatment. Not all enrolled patients (997 in total) were randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OA 20/5
    Reporting group description
    		 -

    Reporting group title
    OA 40/5
    Reporting group description
    		 -

    Reporting group title
    OA 40/10
    Reporting group description
    		 -

    Reporting group title
    Olmesartan 20
    Reporting group description
    		 -

    Reporting group title
    Olmesartan 40
    Reporting group description
    		 -

    Reporting group title
    Amlodipine 5
    Reporting group description
    		 -

    Reporting group title
    Amlodipine 10
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo Total
    Number of subjects
    		 129 130 129 97 96 97 98 65 841
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 109 104 107 77 76 80 82 56 691
        From 65-84 years
    		 20 26 22 20 20 17 16 9 150
        85 years and over
    		 0 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.6 ± 11.1 55 ± 10.8 52.3 ± 11.7 54.7 ± 10.9 54.6 ± 10.8 53.9 ± 11 54.1 ± 11 53.6 ± 9.6 -
    Gender categorical
    Units: Subjects
        Female
    		 58 54 61 48 44 48 47 24 384
        Male
    		 71 76 68 49 52 49 51 41 457
    Previous antihypertensive therapy
    Units: Subjects
        Received previous AH therapy
    		 75 75 68 51 52 50 55 42 468
        No previous AH therapy
    		 54 55 61 46 44 47 43 23 373
    Smoking
    Units: Subjects
        Non-smokers
    		 100 107 103 83 79 77 79 53 681
        Regular smokers
    		 29 23 26 14 17 20 19 12 160
    Mean baseline SeDBP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 96.9 ± 4.3 97.3 ± 4.5 97.5 ± 4.8 97.8 ± 4.8 97.2 ± 4.8 97.5 ± 4.6 97.1 ± 4.6 96.6 ± 4.1 -
    Mean baseline SeSBP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 152.1 ± 10.9 153.3 ± 13.1 154.2 ± 12.4 153.2 ± 10.9 152.8 ± 10.4 154.3 ± 10.4 153.1 ± 11.3 152.2 ± 11.7 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 This was a pre-randomization period. All enrolled subjects were assigned to this placebo arm prior to randomization.
    Reporting group title
    OA 20/5
    Reporting group description
    		 -

    Reporting group title
    OA 40/5
    Reporting group description
    		 -

    Reporting group title
    OA 40/10
    Reporting group description
    		 -

    Reporting group title
    Olmesartan 20
    Reporting group description
    		 -

    Reporting group title
    Olmesartan 40
    Reporting group description
    		 -

    Reporting group title
    Amlodipine 5
    Reporting group description
    		 -

    Reporting group title
    Amlodipine 10
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS was defined as all randomized subjects who completed the placebo run-in period and received at least one dose of the study medication during the double-blind period, with both baseline value and at least one post-baseline value of efficacy assessment.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT was defined as all randomized subjects who completed the placebo run-in period.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP was defined as all randomized subjects without major protocol violations who receive study-directed treatment and have all assessments for all efficacy endpoints during the study.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set was defined as all randomized subjects who received at least one dose of the study medication during the double-blind period.

    Primary: Mean change from baseline in SeDBP at week 8

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    End point title
    		 Mean change from baseline in SeDBP at week 8
    End point description
    For each combination it was required to show its superiority over the respective monotherapies and placebo. Three families of hypotheses were formed based on active monocomponent's strengths (first family included highest strengths; third family included lowest strengths). In order to continue with the next family of hypotheses all null hypotheses in the previous family had to be rejected. Since not all the null hypotheses in the first family were rejected, the further hypothesis testing could not be evaluated. Therefore only the first family results are presented.
    End point type
    Primary
    End point timeframe
    Start and end of active treatment period (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    Units: mmHg
        least squares mean (confidence interval 95%)
    -12.8 (-14 to 11.5)
    -15.5 (-16.9 to 14.1)
    -13.4 (-14.9 to 12)
    -11.1 (-12.7 to -9.5)
    -14.6 (-16.4 to 12.9)
    -12.1 (-13.7 to 10.5)
    -12.8 (-14.5 to 11.2)
    -6.1 (-8.5 to -3.8)
    Statistical analysis title
    		 Treatment difference OA 40/10 vs PLAC
    Comparison groups
    Placebo v OA 40/10
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.39
         upper limit
    		 -4.6
    Statistical analysis title
    		 Treatment difference A10 vs PLAC
    Comparison groups
    Placebo v Amlodipine 10
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 -2.91
    Statistical analysis title
    		 Treatment difference OA 40/10 vs O40
    Comparison groups
    OA 40/10 v Olmesartan 40
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.494
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 2.81
    Statistical analysis title
    		 Treatment difference OA 40/10 vs A10
    Comparison groups
    OA 40/10 v Amlodipine 10
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.155
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.66
         upper limit
    		 0.58
    Statistical analysis title
    		 Treatment difference O40 vs PLAC
    Comparison groups
    Placebo v Olmesartan 40
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.24
         upper limit
    		 -5.2

    Secondary: Mean change from baseline in SeSBP at week 8

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    End point title
    		 Mean change from baseline in SeSBP at week 8
    End point description
    As for the primary efficacy endpoint, three families of hypotheses were formed based on active monocomponent's strengths (first family included highest strengths; third family included lowest strengths). In order to continue with the next family of hypotheses all null hypotheses in the previous family had to be rejected. Since not all the null hypotheses in the first family were rejected, the further hypothesis testing could not be evaluated. Therefore only the first family results are presented.
    End point type
    Secondary
    End point timeframe
    Start and end of active treatment period (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    Units: mmHg
        least squares mean (confidence interval 95%)
    -20.7 (-23.3 to -18.2)
    -22.6 (-25.4 to -19.7)
    -20.6 (-23.1 to -18.1)
    -18.9 (-21.3 to -16.5)
    -19.9 (-23.1 to -16.7)
    -17.5 (-19.6 to -15.3)
    -20.6 (-23.2 to -17.9)
    -9 (-11.8 to -6.1)
    Statistical analysis title
    		 Treatment difference OA 40/10 vs PLAC
    Comparison groups
    OA 40/10 v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.31
         upper limit
    		 -6.91
    Statistical analysis title
    		 Treatment difference O40 vs PLAC
    Comparison groups
    Placebo v Olmesartan 40
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.86
         upper limit
    		 -7.06
    Statistical analysis title
    		 Treatment difference A10 vs PLAC
    Comparison groups
    Placebo v Amlodipine 10
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.8
         upper limit
    		 -5.92
    Statistical analysis title
    		 Treatment difference OA 40/10 vs O40
    Comparison groups
    OA 40/10 v Olmesartan 40
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.833
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.92
         upper limit
    		 3.62
    Statistical analysis title
    		 Treatment difference OA 40/10 vs A10
    Comparison groups
    OA 40/10 v Amlodipine 10
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.659
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.07
         upper limit
    		 2.57

    Secondary: Mean change from baseline in SeDBP at week 2

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    End point title
    		 Mean change from baseline in SeDBP at week 2
    End point description
    End point type
    Secondary
    End point timeframe
    From start of active treatment (baseline) to week 2
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    Units: mmHg
        least squares mean (confidence interval 95%)
    -10.5 (-11.8 to -9.2)
    -11.4 (-12.5 to -10.2)
    -9.6 (-11.2 to -8)
    -9.7 (-11.3 to -8.1)
    -10.3 (-12 to -8.6)
    -8.8 (-10.2 to -7.3)
    -10.1 (-11.6 to -8.7)
    -4.3 (-6.3 to -2.3)
    No statistical analyses for this end point

    Secondary: Mean change from baseline in SeDBP at week 4

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    End point title
    		 Mean change from baseline in SeDBP at week 4
    End point description
    End point type
    Secondary
    End point timeframe
    From start of active treatment (baseline) to week 4
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    Units: mmHg
        least squares mean (confidence interval 95%)
    -12.8 (-13.9 to -11.6)
    -14.2 (-15.4 to -13.1)
    -12.3 (-13.7 to -10.9)
    -11.4 (-13 to -9.8)
    -12.9 (-14.7 to -11.1)
    -10.6 (-12.1 to -9)
    -11.5 (-13.1 to -10)
    -6.5 (-8.6 to -4.5)
    No statistical analyses for this end point

    Secondary: Mean change from baseline in SeSBP at week 2

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    End point title
    		 Mean change from baseline in SeSBP at week 2
    End point description
    End point type
    Secondary
    End point timeframe
    From start of active treatment (baseline) to week 2
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    Units: mmHg
        least squares mean (confidence interval 95%)
    -15.7 (-17.8 to -13.5)
    -16.5 (-18.5 to -14.4)
    -14 (-16.3 to -11.7)
    -13.1 (-15.6 to -10.6)
    -13.4 (-16.7 to -10.1)
    -11.8 (-14.1 to -9.6)
    -17.1 (-21.1 to -16.2)
    -5.5 (-8.3 to -2.8)
    No statistical analyses for this end point

    Secondary: Mean change from baseline in SeSBP at week 4

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    End point title
    		 Mean change from baseline in SeSBP at week 4
    End point description
    End point type
    Secondary
    End point timeframe
    From start of active treatment (baseline) to week 4
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    Units: mmHg
        least squares mean (confidence interval 95%)
    -19.7 (-22 to -17.5)
    -20.6 (-22.8 to -18.5)
    -19.8 (-22.3 to -17.2)
    -17.5 (-19.9 to -15)
    -16.4 (-19.6 to -13.3)
    -15.7 (-18 to -13.4)
    -18.6 (-21.1 to -16.2)
    -8.9 (-11.7 to -6.1)
    No statistical analyses for this end point

    Secondary: Proportion of subjects with SeSBP reduction from baseline ≥ 20 mm Hg at week 8

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    End point title
    		 Proportion of subjects with SeSBP reduction from baseline ≥ 20 mm Hg at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    Start and end of active treatment period (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo FAS
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    828
    Units: Subjects
    64
    74
    64
    49
    53
    42
    50
    13
    409
    No statistical analyses for this end point

    Secondary: Proportion of subjects with SeDBP reduction from baseline ≥ 10 mm Hg at week 8

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    End point title
    		 Proportion of subjects with SeDBP reduction from baseline ≥ 10 mm Hg at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    Start and end of active treatment period (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo FAS
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    828
    Units: Subjects
    85
    99
    83
    55
    66
    55
    59
    18
    520
    No statistical analyses for this end point

    Secondary: Proportion of subjects with BP goal of less than 140/90 mmHg at week 2

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    End point title
    		 Proportion of subjects with BP goal of less than 140/90 mmHg at week 2
    End point description
    End point type
    Secondary
    End point timeframe
    From start of active treatment (baseline) to week 2.
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo FAS
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    828
    Units: Subjects
    60
    75
    52
    42
    48
    41
    43
    9
    370
    No statistical analyses for this end point

    Secondary: Proportion of subjects with BP goal of less than 140/90 mmHg at week 4

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    End point title
    		 Proportion of subjects with BP goal of less than 140/90 mmHg at week 4
    End point description
    End point type
    Secondary
    End point timeframe
    From start of active treatment (baseline) to week 4
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo FAS
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    828
    Units: Subjects
    89
    93
    77
    59
    59
    59
    53
    21
    510
    No statistical analyses for this end point

    Secondary: Proportion of subjects with BP goal of less than 140/90 mmHg at week 8

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    End point title
    		 Proportion of subjects with BP goal of less than 140/90 mmHg at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of active treatment (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo FAS
    Number of subjects analysed
    128
    128
    127
    97
    93
    96
    94
    65
    828
    Units: Subjects
    89
    97
    81
    59
    64
    68
    66
    23
    547
    No statistical analyses for this end point

    Secondary: Mean change from baseline in average 24-hour SBP at week 8

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    End point title
    		 Mean change from baseline in average 24-hour SBP at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of active treatment (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    61
    54
    52
    42
    41
    46
    38
    25
    Units: mmHg
        least squares mean (confidence interval 95%)
    -15.3 (-18.9 to -11.7)
    -13.9 (-18.9 to -8.9)
    -14.6 (-19 to -10.2)
    -12.3 (-16.7 to -7.9)
    -16.3 (-21 to -11.6)
    -6 (-10.9 to -1.1)
    -16.9 (-22.1 to -11.8)
    -1.2 (-8.2 to 5.9)
    No statistical analyses for this end point

    Secondary: Mean change from baseline in average 24-hour DBP at week 8

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    End point title
    		 Mean change from baseline in average 24-hour DBP at week 8
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of active treatment (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    61
    54
    52
    42
    41
    46
    38
    25
    Units: mmHg
        least squares mean (confidence interval 95%)
    -9.1 (-12 to -6.3)
    -8.6 (-11.6 to -5.6)
    -9.4 (-12.4 to -6.5)
    -8.7 (-11.8 to -5.6)
    -12 (-15.2 to -8.7)
    -4.9 (-8 to -1.8)
    -8.7 (-11.9 to -5.4)
    -0.8 (-4.4 to 2.7)
    No statistical analyses for this end point

    Other pre-specified: A number/percent of subjects unable to finish the clinical assessment due to clinically significant adverse reaction

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    End point title
    		 A number/percent of subjects unable to finish the clinical assessment due to clinically significant adverse reaction
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start to end of active treatment (baseline, week 8).
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo Safety
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    841
    Units: Subject
    2
    0
    0
    3
    1
    0
    3
    0
    9
    No statistical analyses for this end point

    Other pre-specified: Mean change from baseline in AST at week 8

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    End point title
    		 Mean change from baseline in AST at week 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start to end of active treatment (baseline, week 8).
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    Units: U/L
        arithmetic mean (standard deviation)
    0 ± 9.7
    -0.8 ± 7.9
    -0.9 ± 11.6
    -0.6 ± 8.5
    1 ± 7.2
    1.6 ± 11.5
    -1.5 ± 9.4
    -0.4 ± 8.3
    No statistical analyses for this end point

    Other pre-specified: Mean change from baseline in ALT at week 8

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    End point title
    		 Mean change from baseline in ALT at week 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start to end of active treatment (baseline, week 8)
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    Units: U/L
        arithmetic mean (standard deviation)
    0 ± 13.2
    0.7 ± 16.8
    -0.9 ± 16.6
    -0.2 ± 11.1
    0.9 ± 14.4
    4.2 ± 18.9
    -2.4 ± 13.7
    0.7 ± 12.1
    No statistical analyses for this end point

    Other pre-specified: Mean change from baseline in Serum Creatinine at week 8

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    End point title
    		 Mean change from baseline in Serum Creatinine at week 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start to end of active treatment (baseline, week 8).
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    Units: umol/L
        arithmetic mean (standard deviation)
    2.2 ± 12.5
    1.1 ± 12.8
    0.3 ± 12.8
    0.9 ± 11.5
    1.1 ± 13.4
    2.6 ± 15.2
    2 ± 11.8
    1.5 ± 12.7
    No statistical analyses for this end point

    Other pre-specified: Mean change from baseline in Serum Urea at week 8

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    End point title
    		 Mean change from baseline in Serum Urea at week 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start to end of active treatment (baseline, week 8).
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.4 ± 2.6
    0.3 ± 3.7
    -0.3 ± 3.9
    -0.3 ± 3.5
    0.8 ± 3.3
    -0.7 ± 2.5
    -0.3 ± 2.8
    -0.1 ± 1.8
    No statistical analyses for this end point

    Other pre-specified: Mean change from baseline in Serum Potassium at week 8

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    End point title
    		 Mean change from baseline in Serum Potassium at week 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start to end of active treatment (baseline, week 8).
    End point values
    		 OA 20/5 OA 40/5 OA 40/10 Olmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 Placebo
    Number of subjects analysed
    129
    130
    129
    97
    96
    97
    98
    65
    Units: mmol/L
        arithmetic mean (standard deviation)
    0 ± 0.5
    0.1 ± 0.5
    0 ± 0.5
    0.1 ± 0.6
    0 ± 0.6
    0.1 ± 0.9
    0.1 ± 0.6
    0 ± 0.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 10 weeks (from ICF signature to the end of trial).
    Adverse event reporting additional description
    All randomised subjects who received at least one dose of study medication during the double-blind period were included in the Safety set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    OA 20/5
    Reporting group description
    		 Participants who received OA 20/5 along the entire active treatment period.

    Reporting group title
    OA 40/5
    Reporting group description
    		 Participants who received OA 40/5 along the entire active treatment period.

    Reporting group title
    OA 40/10
    Reporting group description
    		 Participants who received OA 40/10 along the entire active treatment period.

    Reporting group title
    0lmesartan 20
    Reporting group description
    		 Participants who received O20 along the entire active treatment period.

    Reporting group title
    Olmesartan 40
    Reporting group description
    		 Participants who received O40 along the entire active treatment period.

    Reporting group title
    Amlodipine 5
    Reporting group description
    		 Participants who received A5 along the entire active treatment period.

    Reporting group title
    Amlodipine 10
    Reporting group description
    		 Participants who received A10 along the entire active treatment period.

    Reporting group title
    PLAC
    Reporting group description
    		 Participants who received placebo along the entire active treatment period.

    Serious adverse events
    		 OA 20/5 OA 40/5 OA 40/10 0lmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 PLAC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 OA 20/5 OA 40/5 OA 40/10 0lmesartan 20 Olmesartan 40 Amlodipine 5 Amlodipine 10 PLAC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 129 (16.28%)
    24 / 130 (18.46%)
    38 / 129 (29.46%)
    23 / 97 (23.71%)
    21 / 96 (21.88%)
    13 / 97 (13.40%)
    32 / 98 (32.65%)
    12 / 65 (18.46%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 130 (0.77%)
    3 / 129 (2.33%)
    1 / 97 (1.03%)
    2 / 96 (2.08%)
    1 / 97 (1.03%)
    1 / 98 (1.02%)
    2 / 65 (3.08%)
         occurrences all number
    1
    1
    3
    1
    2
    1
    1
    2
    Hypotension
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Flushing
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    9 / 129 (6.98%)
    0 / 97 (0.00%)
    4 / 96 (4.17%)
    4 / 97 (4.12%)
    12 / 98 (12.24%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    10
    0
    4
    4
    12
    0
    Asthenia
         subjects affected / exposed
    1 / 129 (0.78%)
    3 / 130 (2.31%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    2 / 96 (2.08%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    1
    3
    0
    1
    2
    0
    1
    0
    Local swelling
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    0
    No adverse event
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    2 / 129 (1.55%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Oedema
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Sinobronchitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Investigations
    ALT increased
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Arthroscopy
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    AST increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Blood pressure decreased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Red blood cell count decreased
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    2 / 129 (1.55%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    2 / 97 (2.06%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 130 (1.54%)
    7 / 129 (5.43%)
    1 / 97 (1.03%)
    2 / 96 (2.08%)
    2 / 97 (2.06%)
    2 / 98 (2.04%)
    4 / 65 (6.15%)
         occurrences all number
    2
    2
    7
    1
    2
    2
    2
    5
    Dizziness
         subjects affected / exposed
    5 / 129 (3.88%)
    3 / 130 (2.31%)
    6 / 129 (4.65%)
    1 / 97 (1.03%)
    3 / 96 (3.13%)
    1 / 97 (1.03%)
    2 / 98 (2.04%)
    0 / 65 (0.00%)
         occurrences all number
    5
    3
    6
    1
    3
    1
    2
    0
    Somnolence
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    2 / 96 (2.08%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hypotonia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    2 / 96 (2.08%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    0
    0
    Ear discomfort
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Vertigo positional
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    2 / 98 (2.04%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Anal haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Ileus paralytic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    2 / 98 (2.04%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Psoriasis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin irritation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Haemoglobinuria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Calculus ureteric
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Glycosuria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Renal colic
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    3 / 129 (2.33%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    4 / 98 (4.08%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    0
    4
    0
    Back pain
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 130 (1.54%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    1
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    2 / 98 (2.04%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    2
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 130 (0.77%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Acute tonsillitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 130 (1.54%)
    0 / 129 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 130 (0.77%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    1 / 129 (0.78%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 130 (0.00%)
    0 / 129 (0.00%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2014
    Amendment was requested by the competent German regulatory authority (BfArm) and included additional information/clarification on the contraception and pregnancy testing methology in accordance with "HMA/CTFG Recommendations related to contraception and pregnancy testing in clinical trials. Final version, 2014-09-15". Hence, Exclusion criteria were reformulated and additional pregnancy tests were included for female subjects of childbearing potential.

    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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