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    Clinical Trial Results:
    A phase 2, proof of concept, randomised, placebo-controlled, parallel group study to evaluate the effect of ranolazine and dronedarone when given alone and in combination on atrial fibrillation burden in subjects with paroxysmal atrial fibrillation

    Summary
    EudraCT number
    2011-001134-42
    Trial protocol
    DE   GB   NL  
    Global end of trial date
    10 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-291-0102
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01522651
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    10 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the effect of ranolazine and of low dose dronedarone when given alone and in combination at different dose levels on atrial fibrillation burden (AFB) over 12 weeks of treatment. AFB was defined as the total time a subject is in atrial tachycardia/atrial fibrillation (AT/AF) expressed as a percentage of total recording time.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 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
    Israel: 25
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 60
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    134
    EEA total number of subjects
    86
    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)
    22
    From 65 to 84 years
    104
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in the United States, Poland, Germany, Israel, Italy, and the Netherlands. The first participant was screened on 24 January 2012. The last study visit occurred on 10 March 2014.

    Pre-assignment
    Screening details
    327 participants were screened.

    Period 1
    Period 1 title
    Overall study (overall period)
    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
    Placebo
    Arm description
    Placebo to match ranolazine (ran) + placebo to match dronedarone (dron) for 12 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    Ranolazine placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match ranolazine tablet administered orally twice daily

    Investigational medicinal product name
    Dronedarone placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match dronedarone capsule administered orally twice daily

    Arm title
    Ranolazine
    Arm description
    Ranolazine + placebo to match dronedarone for 12 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ranolazine 750 mg tablet administered orally twice daily

    Investigational medicinal product name
    Dronedarone placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match dronedarone capsule administered orally twice daily

    Arm title
    Dronedarone
    Arm description
    Placebo to match ranolazine + dronedarone 225 mg for 12 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Ranolazine placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match ranolazine tablet administered orally twice daily

    Investigational medicinal product name
    Dronedarone 225 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dronedarone 225 mg capsule administered orally twice daily

    Arm title
    Ranolazine+Dronedarone 225 mg
    Arm description
    Ranolazine + dronedarone 225 mg for 12 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ranolazine 750 mg tablet administered orally twice daily

    Investigational medicinal product name
    Dronedarone 225 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dronedarone 225 mg capsule administered orally twice daily

    Arm title
    Ranolazine+Dronedarone 150 mg
    Arm description
    Ranolazine + dronedarone 150 mg for 12 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ranolazine 750 mg tablet administered orally twice daily

    Investigational medicinal product name
    Dronedarone 150 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dronedarone 150 mg capsule administered orally twice daily

    Number of subjects in period 1 [1]
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg
    Started
    26
    26
    26
    27
    26
    Completed
    17
    19
    22
    20
    21
    Not completed
    9
    7
    4
    7
    5
         Device malfunction
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    3
    4
    4
    5
    4
         Protocol violation
    3
    -
    -
    -
    -
         Subject non-compliance
    1
    -
    -
    -
    -
         Discontinued from study by sponsor
    -
    -
    -
    1
    -
         Cardioversion
    1
    -
    -
    -
    -
         Withdrew consent
    1
    1
    -
    1
    1
         Investigator's discretion
    -
    1
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three participants who were randomized but not treated are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo to match ranolazine (ran) + placebo to match dronedarone (dron) for 12 weeks

    Reporting group title
    Ranolazine
    Reporting group description
    Ranolazine + placebo to match dronedarone for 12 weeks

    Reporting group title
    Dronedarone
    Reporting group description
    Placebo to match ranolazine + dronedarone 225 mg for 12 weeks

    Reporting group title
    Ranolazine+Dronedarone 225 mg
    Reporting group description
    Ranolazine + dronedarone 225 mg for 12 weeks

    Reporting group title
    Ranolazine+Dronedarone 150 mg
    Reporting group description
    Ranolazine + dronedarone 150 mg for 12 weeks

    Reporting group values
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg Total
    Number of subjects
    26 26 26 27 26 131
    Age categorical
    Units: Subjects
        < 65 years
    6 5 2 5 4 22
        ≥ 65 to < 75 years
    10 11 10 13 9 53
        ≥ 75 years
    10 10 14 9 13 56
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    72 ± 8.4 70 ± 10.8 75 ± 7.8 71 ± 7.1 73 ± 9.4 -
    Gender categorical
    Units: Subjects
        Female
    13 16 16 12 11 68
        Male
    13 10 10 15 15 63
    Race
    Units: Subjects
        Asian
    0 0 0 0 1 1
        White
    26 26 26 27 25 130
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 0 0 3 1 6
        Not Hispanic or Latino
    22 25 26 24 25 122
        Not Reported
    2 1 0 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo to match ranolazine (ran) + placebo to match dronedarone (dron) for 12 weeks

    Reporting group title
    Ranolazine
    Reporting group description
    Ranolazine + placebo to match dronedarone for 12 weeks

    Reporting group title
    Dronedarone
    Reporting group description
    Placebo to match ranolazine + dronedarone 225 mg for 12 weeks

    Reporting group title
    Ranolazine+Dronedarone 225 mg
    Reporting group description
    Ranolazine + dronedarone 225 mg for 12 weeks

    Reporting group title
    Ranolazine+Dronedarone 150 mg
    Reporting group description
    Ranolazine + dronedarone 150 mg for 12 weeks

    Primary: Percent change from baseline in atrial fibrillation burden (AFB) by Week 12

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    End point title
    Percent change from baseline in atrial fibrillation burden (AFB) by Week 12
    End point description
    AFB is defined as the total time a subject is in atrial tachycardia (AT)/atrial fibrillation (AF) expressed as a percentage of total recording time. Data are presented for baseline-adjusted AFB over 12 weeks of treatment.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg
    Number of subjects analysed
    18
    18
    23
    20
    22
    Units: percentage
        median (standard error)
    -5.9 ± 18
    -23 ± 21.17
    3.5 ± 15.68
    -59.1 ± 10.47
    -45.5 ± 10.73
    Statistical analysis title
    Ranolazine vs Placebo
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Placebo v Ranolazine
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.493
    Method
    F-test
    Parameter type
    Estimate
    Point estimate
    -19.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -57.5
         upper limit
    51.5
    Notes
    [1] - Comparative analysis
    Statistical analysis title
    Dronedarone vs Placebo
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Placebo v Dronedarone
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.78
    Method
    F-test
    Parameter type
    Estimate
    Point estimate
    8.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.2
         upper limit
    98.2
    Notes
    [2] - Comparative analysis
    Statistical analysis title
    Ranolazine+Dronedarone 225 mg vs Placebo
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Placebo v Ranolazine+Dronedarone 225 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.008
    Method
    F-test
    Parameter type
    Estimate
    Point estimate
    -57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -76.8
         upper limit
    -20.1
    Notes
    [3] - Comparative analysis
    Statistical analysis title
    Ranolazine+Dronedarone 150 mg vs Placebo
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Placebo v Ranolazine+Dronedarone 150 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.072
    Method
    F-test
    Parameter type
    Estimate
    Point estimate
    -42.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -68.7
         upper limit
    5.2
    Notes
    [4] - Comparative analysis
    Statistical analysis title
    Ranolazine vs Dronedarone
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Ranolazine v Dronedarone
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.315
    Method
    F-test
    Confidence interval
    Notes
    [5] - Comparative analysis
    Statistical analysis title
    Ranolazine vs Ranolazine+Dronedarone 225 mg
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Ranolazine v Ranolazine+Dronedarone 225 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.049
    Method
    F-test
    Confidence interval
    Notes
    [6] - Comparative analysis
    Statistical analysis title
    Dronedarone vs Ranolazine+Dronedarone 225 mg
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Dronedarone v Ranolazine+Dronedarone 225 mg
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.002
    Method
    F-test
    Confidence interval
    Notes
    [7] - Comparative analysis
    Statistical analysis title
    Dronedarone vs Ranolazine+Dronedarone 150 mg
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Dronedarone v Ranolazine+Dronedarone 150 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.028
    Method
    F-test
    Confidence interval
    Notes
    [8] - Comparative analysis
    Statistical analysis title
    Ran+Dron 225 mg vs Ran+Dron 150 mg
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Ranolazine+Dronedarone 150 mg v Ranolazine+Dronedarone 225 mg
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.334
    Method
    F-test
    Confidence interval
    Notes
    [9] - Comparative analysis
    Statistical analysis title
    All Treatment Groups Comparison
    Statistical analysis description
    An equal-slopes ANCOVA (analysis of covariance) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation. The global F-test of equality of all 5 treatment group means was followed by all pairwise comparisons.
    Comparison groups
    Ranolazine+Dronedarone 150 mg v Ranolazine+Dronedarone 225 mg v Placebo v Dronedarone v Ranolazine
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    = 0.012
    Method
    F-test
    Confidence interval
    Notes
    [10] - Comparative analysis

    Primary: Absolute change from baseline in AFB by Week 12

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    End point title
    Absolute change from baseline in AFB by Week 12 [11]
    End point description
    AFB is defined as the total time a subject is in atrial tachycardia (AT)/atrial fibrillation (AF) expressed as a percentage of total recording time. Data are presented for baseline-adjusted AFB over 12 weeks of treatment.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was performed for the percent change from baseline in AFB by Week 12. No statistical analysis was performed or presented on the absolute change from baseline.
    End point values
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg
    Number of subjects analysed
    18
    18
    23
    20
    22
    Units: percentage of total recording time
        arithmetic mean (standard error)
    4.6 ± 3.19
    -3.1 ± 2.17
    5.6 ± 2.65
    -4.7 ± 3.24
    -3.9 ± 3.11
    No statistical analyses for this end point

    Secondary: Percentage of participants who have ≥ 30%, ≥ 50%, or ≥ 70% reduction from baseline in AFB

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    End point title
    Percentage of participants who have ≥ 30%, ≥ 50%, or ≥ 70% reduction from baseline in AFB
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg
    Number of subjects analysed
    18
    18
    23
    20
    22
    Units: percentage of participants
    number (not applicable)
        ≥ 30%
    22.2
    50
    21.7
    45
    54.5
        ≥ 50%
    16.7
    22.2
    13
    45
    54.5
        ≥ 70%
    11.1
    16.7
    8.7
    45
    27.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 weeks plus 14 days; Serious adverse events (SAEs) that occurred later than 14 days after the last dose of study drugs and were considered related to study drug were also reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo to match ranolazine + placebo to match dronedarone for 12 weeks

    Reporting group title
    Ranolazine
    Reporting group description
    Ranolazine + placebo to match dronedarone for 12 weeks

    Reporting group title
    Dronedarone
    Reporting group description
    Placebo to match ranolazine + dronedarone 225 mg for 12 weeks

    Reporting group title
    Ranolazine+Dronedarone 225 mg
    Reporting group description
    Ranolazine + dronedarone 225 mg for 12 weeks

    Reporting group title
    Ranolazine+Dronedarone 150 mg
    Reporting group description
    Ranolazine + dronedarone 150 mg for 12 weeks

    Serious adverse events
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 26 (3.85%)
    7 / 26 (26.92%)
    2 / 26 (7.69%)
    5 / 27 (18.52%)
    1 / 26 (3.85%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Ranolazine Dronedarone Ranolazine+Dronedarone 225 mg Ranolazine+Dronedarone 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 26 (34.62%)
    15 / 26 (57.69%)
    14 / 26 (53.85%)
    12 / 27 (44.44%)
    14 / 26 (53.85%)
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    1
    1
    2
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    4
    3
    Haematoma
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    4 / 26 (15.38%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    2
    0
    4
    1
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 26 (11.54%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    3
    2
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    0
    2
    3
    Asthenia
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    1
    0
    0
    4
    Oedema peripheral
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    3
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    4 / 26 (15.38%)
         occurrences all number
    0
    1
    1
    1
    4
    Nausea
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    1
    2
    1
    Diarrhoea
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    2 / 26 (7.69%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    3
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    3
    2
    0
    Abdominal distension
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    2
    1
    1
    Cough
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    1
    1
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    1
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2011
    Increased the number of subjects per treatment group from 20 to 30, changed the study from single-blind to double-blind, and reduced the total number of treatment groups in the study by combining treatment groups.
    03 Apr 2012
    Changed AFB at randomization from: ≥ 3% and ≤ 50% to ≥ 2% and ≤ 70%.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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