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    Clinical Trial Results:
    A single blind, multicenter pilot study to investigate the safety and tolerability of a 14 day oral treatment with different doses of the chymase inhibitor BAY 1142524 in comparison to placebo in clinically stable patients with left-ventricular dysfunction after myocardial infarction

    Summary
    EudraCT number
    		 2014-005297-12
    Trial protocol
    		 DE   DK  
    Global end of trial date
    04 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Feb 2017
    First version publication date
    24 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1142524/17055
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02452515
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this pilot study was to investigate the safety and tolerability after multiple oral doses of BAY1142524 administered twice daily (BID) (using 3 dose groups) or once daily (OD) (using a 4th dose group) as combinations of 5 and 50 milligram (mg) immediate release (IR) tablets for 14 days in 12 subjects with left-ventricular dysfunction after myocardial infarction (9 verum and 3 placebo) per dose group in a randomized, single blind, placebo-controlled, parallel group, multicenter design.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 All patients received evidence-based standard therapy for left ventricular dysfunction after myocardial infarction (MI). This therapy has to include at least an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin receptor blockers (ARB). Beta-blockers, diuretics, magnetic resonance angiograms (MRAs), antiplatelet therapy, statins, and aspirin are to be used if indicated. Treatment with stable doses of ACE inhibitors or ARBs using at least half of the recommended target dose (as defined in the European Society of Cardiology [ESC] guidelines)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Italy: 12
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    27
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 9 active centers, enrolled subjects in 3 countries: Denmark, Germany and Italy between 08 July 2015 (first subject first visit) and 25 January 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 65 subjects were enrolled and screened. Of these, 16 subjects failed screening. The remaining 49 subjects were randomized and assigned to treatment.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to BAY1142524 5 mg, 10 mg, 25 mg IR tablets orally BID and 50 mg IR tablets orally OD for 14 days in the respective arms.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to BAY1142524 5 mg, 10 mg, 25 mg IR tablets orally BID and 50 mg IR tablets orally OD for 14 days.

    Arm title
    		 BAY1142524 5 mg BID
    Arm description
    		 Subjects received 5 mg of BAY1142524 orally BID (given as 1 * 5 mg IR tablet in the morning and in the evening) for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1142524
    Investigational medicinal product code
    BAY1142524
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5 mg of BAY1142524 orally BID (given as 1 * 5 mg IR tablet in the morning and in the evening) for 14 days.

    Arm title
    		 BAY1142524 10 mg BID
    Arm description
    		 Subjects received 10 mg of BAY1142524 orally BID (given as 2 * 5 mg IR tablets in the morning and in the evening) for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1142524
    Investigational medicinal product code
    BAY1142524
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg of BAY1142524 orally BID (given as 2 * 5 mg IR tablets in the morning and in the evening) for 14 days.

    Arm title
    		 BAY1142524 25 mg BID
    Arm description
    		 Subjects received 25 mg of BAY1142524 orally BID (given as 5 * 5 mg IR tablets in the morning and in the evening) for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1142524
    Investigational medicinal product code
    BAY1142524
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 25 mg of BAY1142524 orally BID (given as 5 * 5 mg IR tablets in the morning and in the evening) for 14 days.

    Arm title
    		 BAY1142524 50 mg OD
    Arm description
    		 Subjects received 50 mg of BAY1142524 orally OD (given as 1 * 50 mg IR tablet in the morning) for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1142524
    Investigational medicinal product code
    BAY1142524
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 50 mg of BAY1142524 orally OD (given as 1 * 50 mg IR tablet in the morning) for 14 days.

    Number of subjects in period 1
    		Placebo BAY1142524 5 mg BID BAY1142524 10 mg BID BAY1142524 25 mg BID BAY1142524 50 mg OD
    Started
    12
    9
    9
    10
    9
    Completed
    12
    9
    9
    9
    9
    Not completed
    0
    0
    0
    1
    0
         Withdrawal by subject
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to BAY1142524 5 mg, 10 mg, 25 mg IR tablets orally BID and 50 mg IR tablets orally OD for 14 days in the respective arms.

    Reporting group title
    BAY1142524 5 mg BID
    Reporting group description
    		 Subjects received 5 mg of BAY1142524 orally BID (given as 1 * 5 mg IR tablet in the morning and in the evening) for 14 days.

    Reporting group title
    BAY1142524 10 mg BID
    Reporting group description
    		 Subjects received 10 mg of BAY1142524 orally BID (given as 2 * 5 mg IR tablets in the morning and in the evening) for 14 days.

    Reporting group title
    BAY1142524 25 mg BID
    Reporting group description
    		 Subjects received 25 mg of BAY1142524 orally BID (given as 5 * 5 mg IR tablets in the morning and in the evening) for 14 days.

    Reporting group title
    BAY1142524 50 mg OD
    Reporting group description
    		 Subjects received 50 mg of BAY1142524 orally OD (given as 1 * 50 mg IR tablet in the morning) for 14 days.

    Reporting group values
    		 Placebo BAY1142524 5 mg BID BAY1142524 10 mg BID BAY1142524 25 mg BID BAY1142524 50 mg OD Total
    Number of subjects
    		 12 9 9 10 9 49
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.5 ± 9.7 61 ± 7.9 64.8 ± 7.7 59.3 ± 8.3 64.6 ± 7.1 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 2 2
        Male
    		 12 9 9 10 7 47

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to BAY1142524 5 mg, 10 mg, 25 mg IR tablets orally BID and 50 mg IR tablets orally OD for 14 days in the respective arms.

    Reporting group title
    BAY1142524 5 mg BID
    Reporting group description
    		 Subjects received 5 mg of BAY1142524 orally BID (given as 1 * 5 mg IR tablet in the morning and in the evening) for 14 days.

    Reporting group title
    BAY1142524 10 mg BID
    Reporting group description
    		 Subjects received 10 mg of BAY1142524 orally BID (given as 2 * 5 mg IR tablets in the morning and in the evening) for 14 days.

    Reporting group title
    BAY1142524 25 mg BID
    Reporting group description
    		 Subjects received 25 mg of BAY1142524 orally BID (given as 5 * 5 mg IR tablets in the morning and in the evening) for 14 days.

    Reporting group title
    BAY1142524 50 mg OD
    Reporting group description
    		 Subjects received 50 mg of BAY1142524 orally OD (given as 1 * 50 mg IR tablet in the morning) for 14 days.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N= 49) included all the subjects who received at least one dose of the study medication.

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) by Severity

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) by Severity [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly and another medical important serious event as judged by investigator. AE/SAEs that started or worsened after study drug treatment were recorded as TEAE/TESAEs. Mild: an AE that usually transient and might have required only minimal treatment or therapeutic intervention. This did not interfere with usual activities of daily living. Moderate: an AE that usually alleviated with additional specific therapeutic intervention. This interfered with usual activities of daily living, causing discomfort but posed no significant or permanent risk of harm.
    End point type
    Primary
    End point timeframe
    From the start of study treatment (Day 0) until end of follow-up (that is 7 to 9 days after last study drug administration on Day 13 and approximately 23 days after first study drug administration)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Placebo BAY1142524 5 mg BID BAY1142524 10 mg BID BAY1142524 25 mg BID BAY1142524 50 mg OD
    Number of subjects analysed
    12 [2]
    9 [3]
    9 [4]
    10 [5]
    9 [6]
    Units: subjects
        TEAEs
    7
    4
    2
    1
    3
        Mild TEAEs
    5
    2
    2
    1
    3
        Moderate TEAEs
    2
    2
    0
    0
    0
        TESAEs
    0
    0
    0
    0
    0
    Notes
    [2] - SAF
    [3] - SAF
    [4] - SAF
    [5] - SAF
    [6] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Potential Hemodynamic Effects (Blood Pressure, Pulse Rate)

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    End point title
    		 Number of Subjects With Clinically Significant Potential Hemodynamic Effects (Blood Pressure, Pulse Rate) [7]
    End point description
    The potential hemodynamic parameters included blood pressure and pulse rate. Blood pressure and pulse rate were measured by using semiautomatic devices after resting the subject in a supine position for at least 15 minutes.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 20
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Placebo BAY1142524 5 mg BID BAY1142524 10 mg BID BAY1142524 25 mg BID BAY1142524 50 mg OD
    Number of subjects analysed
    12 [8]
    9 [9]
    9 [10]
    10 [11]
    9 [12]
    Units: subjects
        Blood pressure
    0
    0
    0
    0
    0
        Pulse rate
    0
    0
    0
    0
    0
    Notes
    [8] - SAF
    [9] - SAF
    [10] - SAF
    [11] - SAF
    [12] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment with study drug (day 0) until end of follow-up (i.e. 7 to 9 days after last study drug administration on day 13 and approximately 23 days after first study drug administration)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BAY1142524 5 mg BID
    Reporting group description
    		 BAY1142524 5 mg BID

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    BAY1142524 25 mg BID
    Reporting group description
    		 BAY1142524 25 mg BID

    Reporting group title
    BAY1142524 50 mg OD
    Reporting group description
    		 BAY1142524 50 mg OD

    Reporting group title
    BAY1142524 10 mg BID
    Reporting group description
    		 BAY1142524 10 mg BID

    Serious adverse events
    		 BAY1142524 5 mg BID Placebo BAY1142524 25 mg BID BAY1142524 50 mg OD BAY1142524 10 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 BAY1142524 5 mg BID Placebo BAY1142524 25 mg BID BAY1142524 50 mg OD BAY1142524 10 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 9 (44.44%)
    7 / 12 (58.33%)
    1 / 10 (10.00%)
    3 / 9 (33.33%)
    2 / 9 (22.22%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Amylase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Glutamate dehydrogenase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    2
    Restless legs syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye disorders
    Oscillopsia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    Infections and infestations
    Vestibular neuronitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Anal abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2015
    This amendment included the following modifications: •Exclusion criterion was modified to reflect concomitantly prolonged corrected QT (QTc) interval values in subjects with complete bundle branch block and/or pacemaker, who were eligible for this study. •Additional exploratory metabolite measurements were to performed to investigate metabolite accumulation behaviour after multiple dosing. •An additional measurement for vital signs and electrocardiogram (ECG) on Day 13, pre-dose was added as it had been erroneously forgotten in the first version of the protocol. •Plasma choline esterase and bicarbonate assessment were eliminated from the list of parameters to be analyzed in the safety laboratory. •The paper velocity of the ECG devices to be used in this study was modified.

    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.
    Decimal places were automatically truncated if last decimal equals zero.
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