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    Clinical Trial Results:
    A European multicenre double-blind placebo controlled phase III trial of nilvadipine in mild to moderate Alzheimer's disease.

    Summary
    EudraCT number
    2012-002764-27
    Trial protocol
    GB   IE   SE   HU   GR   NL   IT   DE  
    Global end of trial date
    16 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Aug 2018
    First version publication date
    30 Aug 2018
    Other versions
    Summary report(s)
    NILVAD Clinical Study Report Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    NILVAD2012
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02017340
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    St James's Hospital
    Sponsor organisation address
    James's Street, Dublin, Ireland, Dublin 8
    Public contact
    Brian Lawlor, St James's Hospital, 353 18968524, lawlorba@tcd.ie
    Scientific contact
    Brian Lawlor, St James's Hospital, 353 18968524, lawlorba@tcd.ie
    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
    09 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of Nilvadipine as a disease course modifying treatment for mild to moderate AD in a phase III double-blind placebo-controlled study.
    Protection of trial subjects
    Safety was assessed by physical examination, blood pressure measurements and clinical laboratory tests. Each subject partaking in the study had a blood sample taken for safety purposes, which underwent a series of clinical laboratory tests. Safety blood tests were carried out at the Screening Visit and at Week 78. All subjects had sitting and standing blood pressure (BP) measurements performed at screening, Week 0, Week 6, Week 13, Week 26, Week 39, Week 52, Week 65 and Week 78. The research clinician performed a routine physical examination and neurological examination of each subject at the screening visit. Routine evaluation of general health and wellbeing were conducted at the baseline visit and were repeated at each of the subsequent visits. These and other safety measurements as required were conducted more frequently if clinically indicated or at the discretion of the Investigator. The reason for additional observations was noted in the case report form. Any clinically significant complaints, symptoms, or other abnormalities were followed by appropriate tests and/or procedures until these values returned to normal or to clinically acceptable levels or could be attributed to causes other than the test drug(s). The investigator explained all abnormal findings in the case report form (CRF). All adverse events required reporting. Different reporting procedures were applied for differing types of adverse events. All non serious adverse events events were captured in the AE section of the CRF and sent to the Data Management coordinating centre on a regular basis for entry into the Clinical Database and inclusion in the Annual Safety Reports. All serious adverse events and suspected unexpected serious adverse events were reported to a dedicated email address at the coordinating office in Dublin in an expedited manner. Safety data was reviewed every 6 months by the independent Data Management and Safety Monitoring Board (DMSB).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 78
    Country: Number of subjects enrolled
    Sweden: 21
    Country: Number of subjects enrolled
    United Kingdom: 65
    Country: Number of subjects enrolled
    France: 58
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Greece: 100
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Ireland: 111
    Country: Number of subjects enrolled
    Italy: 55
    Worldwide total number of subjects
    511
    EEA total number of subjects
    511
    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)
    92
    From 65 to 84 years
    393
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    There were 23 recruiting clinical sites in total with 2 sites in Ireland, 1 in the UK, 7 in France, 4 in Italy, 1 in Hungary, 3 in Greece, 1 in Germany, 1 in Sweden and 3 in the Netherlands. The first subject was enrolled on 15th May 2013 and the last subject last visit was 2nd November 2016.

    Pre-assignment
    Screening details
    Subjects diagnosed with mild to moderate AD who were suitable for treatment with nilvadipine were screened. Patients were screened within a 6 week period before the baseline evaluation. Clinical laboratory tests were conducted after informed consent was completed to determine eligibility. Once deemed eligible subjects proceeded to a baseline visit.

    Pre-assignment period milestones
    Number of subjects started
    511
    Number of subjects completed
    498

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    No follow-up assessment: 12
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nilvadipine
    Arm description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.
    Arm type
    Experimental

    Investigational medicinal product name
    Nilvadipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Arm title
    Placebo
    Arm description
    Subjects randomised to placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Number of subjects in period 1 [1]
    Nilvadipine Placebo
    Started
    247
    251
    Completed
    247
    251
    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: 13 participants who were included in the worldwide enrollment figure were excluded from the mITT group. One participant withdrew consent after enrollment and 12 participants were excluded from the mITT group due to not completing follow-up assessments. Please see the subject non-completion reasons described in the pre-assignment period section. Please note that the mITT groups are defined by the ADAS-Cog endpoint alone, and there were additional subjects who underwent secondary assessments.
    Period 2
    Period 2 title
    Week 13
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nilvadipine
    Arm description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.
    Arm type
    Experimental

    Investigational medicinal product name
    Nilvadipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Arm title
    Placebo
    Arm description
    Subjects randomised to placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Number of subjects in period 2
    Nilvadipine Placebo
    Started
    247
    251
    Completed
    247
    249
    Not completed
    0
    2
         Physician decision
    -
    1
         Consent withdrawn by subject
    -
    1
    Period 3
    Period 3 title
    Week 52
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nilvadipine
    Arm description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.
    Arm type
    Experimental

    Investigational medicinal product name
    Nilvadipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Arm title
    Placebo
    Arm description
    Subjects randomised to placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Number of subjects in period 3
    Nilvadipine Placebo
    Started
    247
    249
    Completed
    232
    235
    Not completed
    15
    14
         Protocol deviation
    -
    1
         Death
    2
    3
         Adverse event, non-fatal
    5
    2
         Consent withdrawn by subject
    7
    8
         Lost to follow-up
    1
    -
    Period 4
    Period 4 title
    Week 78
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nilvadipine
    Arm description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.
    Arm type
    Experimental

    Investigational medicinal product name
    Nilvadipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Arm title
    Placebo
    Arm description
    Subjects randomised to placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration taken once daily after breakfast.

    Number of subjects in period 4
    Nilvadipine Placebo
    Started
    232
    235
    Completed
    222
    225
    Not completed
    10
    10
         Protocol deviation
    1
    -
         Death
    1
    1
         Adverse event, non-fatal
    4
    3
         Consent withdrawn by subject
    4
    5
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nilvadipine
    Reporting group description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomised to placebo.

    Reporting group values
    Nilvadipine Placebo Total
    Number of subjects
    247 251 498
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    73.1 ± 8.66 72.8 ± 7.84 -
    Gender categorical
    Units: Subjects
        Female
    161 147 308
        Male
    86 104 190
    SMMSE
    Standardised Mini-Mental State Examination (SMMSE) (Standish & Molloy, 1997)
    Units: Subjects
        SMMSE < 20
    93 94 187
        SMMSE ≥ 20
    154 157 311

    End points

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    End points reporting groups
    Reporting group title
    Nilvadipine
    Reporting group description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomised to placebo.
    Reporting group title
    Nilvadipine
    Reporting group description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomised to placebo.
    Reporting group title
    Nilvadipine
    Reporting group description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomised to placebo.
    Reporting group title
    Nilvadipine
    Reporting group description
    The test drug was an over-encapsulated 8 mg slow release nilvadipine taken orally once a day after breakfast.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomised to placebo.

    Subject analysis set title
    Modified intention-to-treat
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    An intention-to-treat analysis set, with the additional criterion that participants must have been successfully assessed both at baseline, and at at least one other period of the trial.

    Primary: ADAS-cog 12

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    End point title
    ADAS-cog 12
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, week 13, week 52 and week 78.
    End point values
    Nilvadipine Placebo Nilvadipine Placebo Nilvadipine Placebo Nilvadipine Placebo
    Number of subjects analysed
    247
    251
    247
    245
    215
    225
    205
    208
    Units: Arbitrary
        arithmetic mean (standard deviation)
    34.4 ± 10.5
    34.5 ± 10.8
    35.2 ± 11.3
    35.3 ± 11.6
    39.4 ± 13.1
    40.3 ± 13.9
    41.9 ± 14.6
    41.9 ± 14.5
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    This is the primary analysis result, which if statistically significant (p<0.05) will gate the conduct of secondary endpoints promoted to the status of co-primary end-points.
    Comparison groups
    Placebo v Nilvadipine v Placebo v Nilvadipine v Placebo v Nilvadipine v Placebo v Nilvadipine
    Number of subjects included in analysis
    1843
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.465
    Method
    Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Date of first subject enrollment (05th May 2013) to last patient last visit (02nd November 2016).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Nilvadipine
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Nilvadipine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 252 (19.44%)
    42 / 257 (16.34%)
         number of deaths (all causes)
    3
    7
         number of deaths resulting from adverse events
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interventional procedure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral bladder resection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign anorectal neoplasm
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone cancer
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Polyp
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropsychiatric symptoms
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    7 / 252 (2.78%)
    5 / 257 (1.95%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorder
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    4 / 252 (1.59%)
    3 / 257 (1.17%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphonia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngo-oesophageal diverticulum
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent placement
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral bladder resection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Femur fracture
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    4 / 252 (1.59%)
    2 / 257 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Nilvadipine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    206 / 252 (81.75%)
    201 / 257 (78.21%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Alcohol poisoning
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Ankle fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    5 / 252 (1.98%)
    3 / 257 (1.17%)
         occurrences all number
    5
    4
    Facial bones fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    40 / 252 (15.87%)
    38 / 257 (14.79%)
         occurrences all number
    50
    66
    Femur fracture
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Head injury
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 257 (1.17%)
         occurrences all number
    2
    3
    Hip fracture
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 257 (1.17%)
         occurrences all number
    2
    3
    Humerus fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Injury
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Joint dislocation
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Joint injury
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 257 (1.17%)
         occurrences all number
    2
    3
    Laceration
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Ligament sprain
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 257 (1.17%)
         occurrences all number
    2
    3
    Limb injury
         subjects affected / exposed
    3 / 252 (1.19%)
    2 / 257 (0.78%)
         occurrences all number
    4
    2
    Muscle strain
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Overdose
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    5
    Poisoning
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Procedural pain
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Radius fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Rib fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Skeletal injury
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 257 (1.17%)
         occurrences all number
    0
    3
    Skin wound
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Spinal fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Toxicity to various agents
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Upper limb fracture
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Wound
         subjects affected / exposed
    4 / 252 (1.59%)
    3 / 257 (1.17%)
         occurrences all number
    4
    3
    Wrist fracture
         subjects affected / exposed
    3 / 252 (1.19%)
    2 / 257 (0.78%)
         occurrences all number
    3
    3
    Investigations
    Amylase
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Bence Jones protein urine present
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Biopsy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Biopsy colon
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Blood folate decreased
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Blood iron decreased
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Blood magnesium abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Blood potassium abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Blood pressure abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Blood pressure measurement
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    3
    Blood sodium decreased
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Blood triglycerides abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Body temperature increased
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Cardiac murmur
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Colonoscopy
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    1
    Electrocardiogram ambulatory
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Full blood count abnormal
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Gastrointestinal examination
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Heart rate decreased
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Heart rate increased
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Heart rate irregular
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Heart sounds abnormal
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Prostatic specific antigen increased
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Red blood cell sedimentation rate abnormal
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Spinal X-ray
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Thyroid function test abnormal
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Vitamin B12 abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    5 / 252 (1.98%)
    8 / 257 (3.11%)
         occurrences all number
    8
    10
    Weight increased
         subjects affected / exposed
    4 / 252 (1.59%)
    3 / 257 (1.17%)
         occurrences all number
    4
    3
    X-ray of pelvis and hip
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Angina pectoris
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Atrial Fibrillation
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Atrioventricular block complete
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Atrioventricular block first degree
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Bradycardia
         subjects affected / exposed
    4 / 252 (1.59%)
    1 / 257 (0.39%)
         occurrences all number
    4
    1
    Cardiac arrest
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cardiac disorder
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cardiac failure
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cardiac fibrillation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Coronary artery disease
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Mitral valve incompetence
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Myocardial infarction
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Palpitations
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Sinus bradycardia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    2 / 252 (0.79%)
    4 / 257 (1.56%)
         occurrences all number
    2
    6
    Congenital, familial and genetic disorders
    Type V hyperlipidaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    4 / 257 (1.56%)
         occurrences all number
    0
    5
    Anaemia macrocytic
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Lymphadenitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Pernicious anaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 257 (1.17%)
         occurrences all number
    0
    3
    Aphasia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Aphonia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Apraxia
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Ataxia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    4 / 252 (1.59%)
    2 / 257 (0.78%)
         occurrences all number
    4
    2
    Burning sensation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Clonus
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Cognitive disorder
         subjects affected / exposed
    10 / 252 (3.97%)
    13 / 257 (5.06%)
         occurrences all number
    12
    13
    Dementia Alzheimer's type
         subjects affected / exposed
    5 / 252 (1.98%)
    6 / 257 (2.33%)
         occurrences all number
    6
    9
    Depressed level of consciousness
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    30 / 252 (11.90%)
    29 / 257 (11.28%)
         occurrences all number
    39
    40
    Drooling
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Dysarthria
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Dyspraxia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Epilepsy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Facial paralysis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    20 / 252 (7.94%)
    19 / 257 (7.39%)
         occurrences all number
    27
    22
    Hypersomnia
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Hyporeflexia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hypotonia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Loss of consciousness
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    3
    Memory impairment
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 257 (1.17%)
         occurrences all number
    1
    3
    Migraine
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    2
    Myoclonus
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Paraesthesia
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Poor quality sleep
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    3
    2
    Reduced facial expression
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Resting tremor
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences all number
    7
    0
    Sleep phase rhythm disturbance
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    3 / 252 (1.19%)
    4 / 257 (1.56%)
         occurrences all number
    3
    4
    Speech disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Syncope
         subjects affected / exposed
    12 / 252 (4.76%)
    9 / 257 (3.50%)
         occurrences all number
    18
    13
    Tension headache
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Transient ischaemic attack
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    1
    Tremor
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 257 (1.17%)
         occurrences all number
    1
    3
    Visual field defect
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Eye disorders
    Amblyopia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cataract
         subjects affected / exposed
    5 / 252 (1.98%)
    2 / 257 (0.78%)
         occurrences all number
    6
    2
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Eye allergy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Eye haemorrhage
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Eye irritation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Eye movement disorder
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Eye pain
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Glaucoma
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Myopia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Presbyopia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Ear pain
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Excessive cerumen production
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hypoacusis
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Sudden hearing loss
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    1 / 252 (0.40%)
    4 / 257 (1.56%)
         occurrences all number
    1
    4
    Vertigo
         subjects affected / exposed
    5 / 252 (1.98%)
    2 / 257 (0.78%)
         occurrences all number
    7
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 252 (0.79%)
    5 / 257 (1.95%)
         occurrences all number
    3
    8
    Abdominal distension
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    7 / 252 (2.78%)
    6 / 257 (2.33%)
         occurrences all number
    8
    6
    Abdominal pain lower
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    4
    1
    Abdominal tenderness
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Anal incontinence
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Coeliac disease
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    5 / 252 (1.98%)
    4 / 257 (1.56%)
         occurrences all number
    5
    5
    Diarrhoea
         subjects affected / exposed
    19 / 252 (7.54%)
    16 / 257 (6.23%)
         occurrences all number
    20
    19
    Dry mouth
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Duodenogastric reflux
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Dysphagia
         subjects affected / exposed
    4 / 252 (1.59%)
    3 / 257 (1.17%)
         occurrences all number
    4
    3
    Eructation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Haemorrhoids
         subjects affected / exposed
    4 / 252 (1.59%)
    1 / 257 (0.39%)
         occurrences all number
    4
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Intestinal metaplasia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    15 / 252 (5.95%)
    12 / 257 (4.67%)
         occurrences all number
    16
    15
    Occult blood
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Pharyngo-oesophageal diverticulum
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Proctalgia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Stomatitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    19 / 252 (7.54%)
    15 / 257 (5.84%)
         occurrences all number
    19
    23
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Bladder prolapse
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Globus urinary bladder
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Incontinence
         subjects affected / exposed
    3 / 252 (1.19%)
    4 / 257 (1.56%)
         occurrences all number
    3
    4
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Micturition urgency
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Pollakiuria
         subjects affected / exposed
    3 / 252 (1.19%)
    6 / 257 (2.33%)
         occurrences all number
    3
    6
    Renal cyst
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Renal impairment
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Renal pain
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Ureterolithiasis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    5 / 252 (1.98%)
    5 / 257 (1.95%)
         occurrences all number
    5
    5
    Urinary tract disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Dry skin
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Eczema
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 257 (1.17%)
         occurrences all number
    0
    3
    Ingrowing nail
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Pemphigoid
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    3
    2
    Psoriasis
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Rash
         subjects affected / exposed
    5 / 252 (1.98%)
    9 / 257 (3.50%)
         occurrences all number
    5
    10
    Rash macular
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Skin discolouration
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Skin disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Skin fissures
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Skin irritation
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Skin lesion
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Skin ulcer
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Skin warm
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Stasis dermatitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Xeroderma
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 252 (5.56%)
    16 / 257 (6.23%)
         occurrences all number
    17
    20
    Arthritis
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    8 / 252 (3.17%)
    10 / 257 (3.89%)
         occurrences all number
    9
    13
    Bursitis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Coccydynia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Fistula
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Flank pain
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Joint effusion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Joint stiffness
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Joint swelling
         subjects affected / exposed
    7 / 252 (2.78%)
    1 / 257 (0.39%)
         occurrences all number
    7
    1
    Low back pain
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 257 (1.17%)
         occurrences all number
    0
    3
    Muscle haemorrhage
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 257 (1.17%)
         occurrences all number
    3
    4
    Muscular weakness
         subjects affected / exposed
    3 / 252 (1.19%)
    2 / 257 (0.78%)
         occurrences all number
    3
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 252 (1.19%)
    5 / 257 (1.95%)
         occurrences all number
    3
    5
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Neck pain
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Osteoarthritis
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Osteoporosis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    8 / 252 (3.17%)
    7 / 257 (2.72%)
         occurrences all number
    9
    7
    Pain in jaw
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Posture abnormal
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Spinal pain
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Tendonitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hypothyroidism
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 252 (1.19%)
    2 / 257 (0.78%)
         occurrences all number
    3
    2
    Dehydration
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Fluid intake reduced
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Fluid overload
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Folate deficiency
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 252 (1.98%)
    3 / 257 (1.17%)
         occurrences all number
    7
    4
    Hyperglycaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Polydipsia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 252 (2.78%)
    9 / 257 (3.50%)
         occurrences all number
    9
    10
    Cellulitis
         subjects affected / exposed
    5 / 252 (1.98%)
    0 / 257 (0.00%)
         occurrences all number
    9
    0
    Cystitis
         subjects affected / exposed
    4 / 252 (1.59%)
    3 / 257 (1.17%)
         occurrences all number
    5
    4
    Dental abscess
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Erysipelas
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Eye infection bacterial
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Fungal infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 252 (1.59%)
    2 / 257 (0.78%)
         occurrences all number
    4
    5
    Gastroenteritis viral
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Gingivitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Haematoma infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Hordeolum
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Influenza
         subjects affected / exposed
    17 / 252 (6.75%)
    11 / 257 (4.28%)
         occurrences all number
    19
    15
    Kidney infection
         subjects affected / exposed
    7 / 252 (2.78%)
    1 / 257 (0.39%)
         occurrences all number
    8
    1
    Labyrinthitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Localised infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    10 / 252 (3.97%)
    7 / 257 (2.72%)
         occurrences all number
    14
    8
    Nail bed infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Onychomycosis
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Oral herpes
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Paronychia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    3
    3
    Pneumonia
         subjects affected / exposed
    4 / 252 (1.59%)
    0 / 257 (0.00%)
         occurrences all number
    4
    0
    Pseudomonas infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Pyelonephritis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    4
    Sepsis
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 257 (1.17%)
         occurrences all number
    3
    3
    Sinusitis
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Skin infection
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 257 (1.17%)
         occurrences all number
    0
    3
    Tinea versicolour
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Tracheitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    25 / 252 (9.92%)
    24 / 257 (9.34%)
         occurrences all number
    41
    40
    Urosepsis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    19 / 252 (7.54%)
    24 / 257 (9.34%)
         occurrences all number
    21
    27
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Wound infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Flushing
         subjects affected / exposed
    5 / 252 (1.98%)
    5 / 257 (1.95%)
         occurrences all number
    6
    5
    Haematoma
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Hot flush
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    9 / 252 (3.57%)
    13 / 257 (5.06%)
         occurrences all number
    11
    17
    Hypotension
         subjects affected / exposed
    20 / 252 (7.94%)
    14 / 257 (5.45%)
         occurrences all number
    26
    16
    Labile blood pressure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    2
    Pallor
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Periphlebitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Varicose vein
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Antibiotic prophylaxis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Bladder neoplasm surgery
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Cardiac pacemaker insertion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Dental implantation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hernia repair
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hip arthroplasty
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hip surgery
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hysterectomy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Interventional procedure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Knee operation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Large intestinal polypectomy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Percutaneous coronary intervention
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Plastic surgery to the face
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Prostatectomy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Skin graft
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Skin neoplasm excision
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Stent placement
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Suture insertion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Tooth extraction
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 257 (1.17%)
         occurrences all number
    2
    3
    Transurethral bladder resection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Transurethral prostatectomy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Urethral stent removal
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Varicose vein operation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Benign anorectal neoplasm
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Bladder cancer
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Bladder neoplasm
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Bone cancer
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Colon adenoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Metastasis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Neoplasm progression
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Neoplasm swelling
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Skin cancer
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Skin papilloma
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Ureteral neoplasm
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Seasonal allergy
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    1
    Social circumstances
    Bereavement
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Decrease of autonomy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 252 (2.38%)
    7 / 257 (2.72%)
         occurrences all number
    7
    9
    Chest discomfort
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Chest pain
         subjects affected / exposed
    1 / 252 (0.40%)
    4 / 257 (1.56%)
         occurrences all number
    1
    4
    Chills
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    3
    2
    Condition aggravated
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Cyst
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Facial pain
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    10 / 252 (3.97%)
    11 / 257 (4.28%)
         occurrences all number
    12
    13
    Feeling cold
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Gait disturbance
         subjects affected / exposed
    5 / 252 (1.98%)
    2 / 257 (0.78%)
         occurrences all number
    6
    2
    Hernia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Malaise
         subjects affected / exposed
    6 / 252 (2.38%)
    7 / 257 (2.72%)
         occurrences all number
    7
    8
    Oedema
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Oedema peripheral
         subjects affected / exposed
    14 / 252 (5.56%)
    3 / 257 (1.17%)
         occurrences all number
    15
    3
    Pain
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Peripheral swelling
         subjects affected / exposed
    6 / 252 (2.38%)
    1 / 257 (0.39%)
         occurrences all number
    6
    1
    Pyrexia
         subjects affected / exposed
    5 / 252 (1.98%)
    2 / 257 (0.78%)
         occurrences all number
    6
    2
    Sensation of foreign body
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    5 / 252 (1.98%)
    4 / 257 (1.56%)
         occurrences all number
    5
    5
    Abnormal dreams
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Affective disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Aggression
         subjects affected / exposed
    5 / 252 (1.98%)
    9 / 257 (3.50%)
         occurrences all number
    7
    11
    Agitation
         subjects affected / exposed
    15 / 252 (5.95%)
    21 / 257 (8.17%)
         occurrences all number
    21
    23
    Alexithymia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Anger
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    2
    Anxiety
         subjects affected / exposed
    9 / 252 (3.57%)
    10 / 257 (3.89%)
         occurrences all number
    9
    10
    Borderline personality disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    13 / 252 (5.16%)
    11 / 257 (4.28%)
         occurrences all number
    14
    13
    Delirium
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    1
    Delusion
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 257 (1.17%)
         occurrences all number
    1
    3
    Depressed mood
         subjects affected / exposed
    5 / 252 (1.98%)
    11 / 257 (4.28%)
         occurrences all number
    5
    12
    Depression
         subjects affected / exposed
    7 / 252 (2.78%)
    2 / 257 (0.78%)
         occurrences all number
    7
    2
    Dermatillomania
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Disorientation
         subjects affected / exposed
    6 / 252 (2.38%)
    2 / 257 (0.78%)
         occurrences all number
    7
    2
    Dissociative amnesia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Emotional disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Emotional distress
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Fear
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Frustration tolerance decreased
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    1
    Hallucination, auditory
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Hallucination, visual
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 257 (1.17%)
         occurrences all number
    1
    3
    Insomnia
         subjects affected / exposed
    11 / 252 (4.37%)
    3 / 257 (1.17%)
         occurrences all number
    13
    3
    Logorrhoea
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Mood swings
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Neuropsychiatric symptoms
         subjects affected / exposed
    8 / 252 (3.17%)
    7 / 257 (2.72%)
         occurrences all number
    11
    8
    Obsessive-compulsive disorder
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Panic attack
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Paranoia
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Psychotic disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    5 / 252 (1.98%)
    8 / 257 (3.11%)
         occurrences all number
    10
    9
    Sleep disorder
         subjects affected / exposed
    4 / 252 (1.59%)
    1 / 257 (0.39%)
         occurrences all number
    6
    1
    Suicidal ideation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Tearfulness
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 257 (0.78%)
         occurrences all number
    2
    2
    Pruritus genital
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 257 (0.39%)
         occurrences all number
    1
    1
    Testicular cyst
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Vulvovaginal burning sensation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal pain
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Choking
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 257 (0.78%)
         occurrences all number
    0
    2
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    3
    0
    Cough
         subjects affected / exposed
    24 / 252 (9.52%)
    13 / 257 (5.06%)
         occurrences all number
    29
    17
    Dysphonia
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 257 (0.39%)
         occurrences all number
    3
    1
    Epistaxis
         subjects affected / exposed
    3 / 252 (1.19%)
    2 / 257 (0.78%)
         occurrences all number
    4
    3
    Increased upper airway secretion
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Nasal polyps
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 257 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 252 (1.19%)
    4 / 257 (1.56%)
         occurrences all number
    3
    4
    Productive cough
         subjects affected / exposed
    6 / 252 (2.38%)
    4 / 257 (1.56%)
         occurrences all number
    6
    5
    Pulmonary embolism
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Rales
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 257 (0.39%)
         occurrences all number
    0
    1
    Respiratory disorder
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 257 (1.17%)
         occurrences all number
    0
    3
    Wheezing
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 257 (0.78%)
         occurrences all number
    1
    2
    Hepatobiliary disorders
    Hepatic cyst
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 257 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2013
    Inclusion of the NILVAD substudy protocols as amendments to the main protocol.
    14 Mar 2013
    The timing of when the study medication is to be taken was changed from with lunch to after breakfast. An explanatory note was added to the sample size estimation. The medical food Souvenaid was excluded from the study. The length of time that a CT/MRI report is valid was extended from 2 to 4 years. The unscheduled termination section was updated to state that removal of patients from the study must be discussed with the Principal Investigator and the Project Coordinator rather than the Scientific Project Manager.
    20 Sep 2013
    Combine all of the NILVAD protocols into one NILVAD Complete Protocol (including the main and substudy protocols). To increase the time frame between the screening visit and baseline visit from 21 days to 6 weeks. To specify that patients can be re-screened at any point in the recruitment window. To specify that the principal investigator or study clinician can sign off the Eligibility Screening Form.
    11 Feb 2014
    Amendment to the exclusion criteria and approval to enroll subjects requiring more than one agent to control blood pressure. This resulted from international consensus guidelines on the management of hypertension which advocated the use of low dose combination antihypertensive (AH) therapy rather than monotherapy to achieve target blood pressure control in hypertensive patients.
    17 Sep 2015
    Addition of the event syncope as an expected adverse reaction to the investigator’s brochure.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27436668
    http://www.ncbi.nlm.nih.gov/pubmed/25300460
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