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    Clinical Trial Results:
    A Randomised, Double-Blind, Double-Dummy, Placebo-Controlled, Dose-Ranging Phase II Study Assessing Ranolazine in the Maintenance of Sinus Rhythm after Electrical Cardioversion in Patients with Non-Permanent Atrial Fibrillation

    Summary
    EudraCT number
    		 2011-002789-18
    Trial protocol
    		 DE   ES   GB   IT  
    Global end of trial date
    30 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2021
    First version publication date
    20 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RAF-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01534962
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MENARINI RICERCHE S.P.A.
    Sponsor organisation address
    Via Sette Santi 1, Florence, Italy, 50131
    Public contact
    Corporate Clinical Sciences, MENARINI RICERCHE S.P.A., 0039 055-56809933, ACAPRIATI@MENARINI-RICERCHE.IT
    Scientific contact
    Corporate Clinical Sciences, MENARINI RICERCHE S.P.A., 0039 055-56809933, ACAPRIATI@MENARINI-RICERCHE.IT
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Ranolazine administered as 3 different doses regimens versus placebo in the maintenance of sinus rhythm after electrical cardioversion in patients with non-permanent Atrial Fibrillation (defined as a continuous Atrial Fibrillation with a minimum duration of 7 days to a maximum of 6 months or requiring termination by cardioversion).
    Protection of trial subjects
    If any event(s) related to the conduct of the study or the development of the IMP affects the safety of the study participants, the sponsor and the Investigator will take appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/ECs will be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance policy in accordance with local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jan 2012
    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
    Spain: 73
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Germany: 100
    Country: Number of subjects enrolled
    Italy: 57
    Worldwide total number of subjects
    241
    EEA total number of subjects
    241
    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)
    103
    From 65 to 84 years
    135
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was screened on 18 Jan 2012. The last patient completed the study on 30 Sep 2013. The study was conducted at 45 investigational sites in 4 European countries.

    Pre-assignment
    Screening details
    		 A total of 310 patients were screened and underwent cardioversion (CV). Of these, 241 were still in sinus rhythm 2 hours post-CV and could be enrolled. Three patients were randomised but did not take study medication. Finally, a total of 238 patients were randomised and took at least one dose of study (ITT population).

    Period 1
    Period 1 title
    Treatment and assessment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranolazine low dose
    Arm description
    		 375 mg, oral administration, BID; for a maximum of 16 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BID

    Arm title
    		 Ranolazine intermediate dose
    Arm description
    		 500 mg, oral administration, BID; for a maximum of 16 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BID

    Arm title
    		 Ranolazine high dose
    Arm description
    		 750 mg, oral administration, BID; for a maximum of 16 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BID

    Arm title
    		 Placebo
    Arm description
    		 Placebo (sugar pill), oral administration, BID; for a maximum of 16 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BID

    Number of subjects in period 1 [1]
    		Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo
    Started
    65
    60
    58
    55
    Completed
    30
    34
    34
    24
    Not completed
    35
    26
    24
    31
         Discontinued at AF recurrence
    35
    26
    24
    31
    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: A total of 310 patients were screened and underwent cardioversion. Of these, 241 were still in sinus rhythm 2 hours post-CV and could be enrolled. Three patients were randomised but did not take study medication. Finally, a total of 238 patients were randomised and took at least one dose of study, forming the ITT population and represent the baseline population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranolazine low dose
    Reporting group description
    		 375 mg, oral administration, BID; for a maximum of 16 weeks

    Reporting group title
    Ranolazine intermediate dose
    Reporting group description
    		 500 mg, oral administration, BID; for a maximum of 16 weeks

    Reporting group title
    Ranolazine high dose
    Reporting group description
    		 750 mg, oral administration, BID; for a maximum of 16 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (sugar pill), oral administration, BID; for a maximum of 16 weeks

    Reporting group values
    		 Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo Total
    Number of subjects
    		 65 60 58 55 238
    Age categorical
    Units: Subjects
    Age continuous
    Arithmetic mean age per reporting group in years and related standard deviation
    Units: years
        arithmetic mean (standard deviation)
    		 66.9 ( 11.8 ) 65.6 ( 8.5 ) 63.6 ( 11.3 ) 65.2 ( 9.5 ) -
    Gender categorical
    Caterorical gender (female, male) per reporting group.
    Units: Subjects
        Female
    		 19 9 12 14 54
        Male
    		 46 51 46 41 184
    Time since first AF
    Mean time since first atrial fibrillation (AF) diagnosis and related standad deviation.
    Units: months
        arithmetic mean (standard deviation)
    		 10.5 ( 24.0 ) 7.2 ( 12.9 ) 15.5 ( 28.2 ) 6.9 ( 13.5 ) -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT-population (all randomised patients who received at least one dose of study medication)

    Subject analysis sets values
    		 ITT population
    Number of subjects
    238
    Age categorical
    Units: Subjects
    Age continuous
    Arithmetic mean age per reporting group in years and related standard deviation
    Units: years
        arithmetic mean (standard deviation)
    65.3 ( 10.4 )
    Gender categorical
    Caterorical gender (female, male) per reporting group.
    Units: Subjects
        Female
    54
        Male
    184
    Time since first AF
    Mean time since first atrial fibrillation (AF) diagnosis and related standad deviation.
    Units: months
        arithmetic mean (standard deviation)
    10 ( 20.7 )

    End points

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    End points reporting groups
    Reporting group title
    Ranolazine low dose
    Reporting group description
    		 375 mg, oral administration, BID; for a maximum of 16 weeks

    Reporting group title
    Ranolazine intermediate dose
    Reporting group description
    		 500 mg, oral administration, BID; for a maximum of 16 weeks

    Reporting group title
    Ranolazine high dose
    Reporting group description
    		 750 mg, oral administration, BID; for a maximum of 16 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (sugar pill), oral administration, BID; for a maximum of 16 weeks

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT-population (all randomised patients who received at least one dose of study medication)

    Primary: Number of Patients with AF Recurrence

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    End point title
    		 Number of Patients with AF Recurrence
    End point description
    Number of patients with documented AF recurrence. Please note: The time to event related analysis, namely "Time to first documented AF recurrence" was hampered by a high variability of data that precluded the calculation of point estimates and confidence intervals and limited the capacity of this study to show unequivocal results.
    End point type
    Primary
    End point timeframe
    16 weeks (112 days)
    End point values
    		 Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo ITT population
    Number of subjects analysed
    65
    60
    58
    55
    238
    Units: patients
    37
    25
    23
    31
    116
    Statistical analysis title
    		 Descriptive statistics
    Statistical analysis description
    Descriptive statistics comparing verum groups vs placebo
    Comparison groups
    Ranolazine low dose v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.47
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Descriptive statistics
    Statistical analysis description
    Descriptive statistics comparing verum groups vs placebo
    Comparison groups
    Ranolazine intermediate dose v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.42
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Descriptive statistics
    Statistical analysis description
    Descriptive statistics comparing verum groups vs placebo
    Comparison groups
    Ranolazine high dose v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.28
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of AF recurrences

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    End point title
    		 Number of AF recurrences
    End point description
    Number of Documented and Confirmed AF Recurrences. Please note: The time to event related analysis, namely "Time to first documented and confirmed AF recurrence" was hampered by a high variability of data that precluded the calculation of point estimates and confidence intervals and limited the capacity of this study to show unequivocal results.
    End point type
    Secondary
    End point timeframe
    16 weeks (112 days)
    End point values
    		 Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo ITT population
    Number of subjects analysed
    65
    60
    58
    55
    238
    Units: Events
    31
    19
    16
    24
    90
    No statistical analyses for this end point

    Secondary: Documented AF Recurrence in Patients Still in Sinus Rhythm 2 Days After Cardioversion

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    End point title
    		 Documented AF Recurrence in Patients Still in Sinus Rhythm 2 Days After Cardioversion
    End point description
    Documented AF recurrences in those patients who did not experience early relapses (within 48 hours after cardioversion). Please note: The time to event related analysis, namely "Time to first documented AF recurrence in patients still in sinus rhythm 2 days post DCCV" was hampered by a high variability of data that precluded the calculation of point estimates and confidence intervals and limited the capacity of this study to show unequivocal results.
    End point type
    Secondary
    End point timeframe
    16 weeks (112 days)
    End point values
    		 Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo ITT population
    Number of subjects analysed
    65
    60
    58
    55
    238
    Units: Events
    32
    19
    21
    27
    99
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks (112 days)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Ranolazine low dose
    Reporting group description
    		 375 mg, oral administration, BID; for a maximum of 112 days

    Reporting group title
    Ranolazine intermediate dose
    Reporting group description
    		 500 mg, oral administration, BID; for a maximum of 112 days

    Reporting group title
    Ranolazine high dose
    Reporting group description
    		 750 mg, oral administration, BID; for a maximum of 112 days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (sugar pill), oral administration, BID; for a maximum of 112 days

    Serious adverse events
    		 Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 60 (5.00%)
    3 / 58 (5.17%)
    4 / 55 (7.27%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Pancreatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ranolazine low dose Ranolazine intermediate dose Ranolazine high dose Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 65 (78.46%)
    46 / 60 (76.67%)
    42 / 58 (72.41%)
    41 / 55 (74.55%)
    Investigations
    Blood creatine increased
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 60 (5.00%)
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    2
    3
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    29 / 65 (44.62%)
    24 / 60 (40.00%)
    23 / 58 (39.66%)
    27 / 55 (49.09%)
         occurrences all number
    31
    33
    27
    28
    Atrial flutter
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 60 (0.00%)
    3 / 58 (5.17%)
    2 / 55 (3.64%)
         occurrences all number
    2
    0
    3
    2
    Palpitations
         subjects affected / exposed
    9 / 65 (13.85%)
    11 / 60 (18.33%)
    11 / 58 (18.97%)
    6 / 55 (10.91%)
         occurrences all number
    11
    18
    19
    7
    Tachycardia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 60 (1.67%)
    3 / 58 (5.17%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    4
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 65 (9.23%)
    2 / 60 (3.33%)
    14 / 58 (24.14%)
    7 / 55 (12.73%)
         occurrences all number
    7
    4
    20
    8
    Headache
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 60 (3.33%)
    5 / 58 (8.62%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    5
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 60 (1.67%)
    5 / 58 (8.62%)
    2 / 55 (3.64%)
         occurrences all number
    4
    2
    5
    2
    Chest pain
         subjects affected / exposed
    8 / 65 (12.31%)
    7 / 60 (11.67%)
    4 / 58 (6.90%)
    6 / 55 (10.91%)
         occurrences all number
    9
    16
    4
    6
    Fatigue
         subjects affected / exposed
    11 / 65 (16.92%)
    10 / 60 (16.67%)
    9 / 58 (15.52%)
    5 / 55 (9.09%)
         occurrences all number
    13
    14
    10
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 60 (1.67%)
    4 / 58 (6.90%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    7
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 60 (3.33%)
    3 / 58 (5.17%)
    1 / 55 (1.82%)
         occurrences all number
    1
    2
    3
    1
    Nausea
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 60 (1.67%)
    4 / 58 (6.90%)
    0 / 55 (0.00%)
         occurrences all number
    7
    1
    7
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 65 (7.69%)
    7 / 60 (11.67%)
    5 / 58 (8.62%)
    6 / 55 (10.91%)
         occurrences all number
    6
    11
    5
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2011
    Addition of one sentence in den patient information v.1.2 dated 05.10.2011 approved. Addition of 3 new sites.
    14 Mar 2012
    Change of sentence in the following study documents: study protocol, patient information and informed consent form and TT-ECG handling manual, Addition of a new site.
    09 May 2012
    Change in SmPC and related documents: study protocol, patient information and informed consent, letter to general practitioner and investigators' brochure.
    03 Aug 2012
    Amendment to the site clinical trail agreement and addition of 3 new sites.
    07 Dec 2012
    Addition of a new site.

    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.
    Analysis of time to events endpoints were hampered by a high variability of data that precluded the calculation of point estimates and confidence intervals and limited the capacity of this study to show unequivocal results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25602175
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