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    Clinical Trial Results:
    EFFICACY OF RANOLAZINE IN PATIENTS WITH CORONARY ARTERY DISEASE (CAD)

    Summary
    EudraCT number
    2011-001278-24
    Trial protocol
    GR   ES   IE   GB   DE   AT   IT   BG  
    Global end of trial date
    06 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Nov 2018
    First version publication date
    11 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEIN/10/Ran-Cad/003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Menarini International Operations Luxembourg S.A
    Sponsor organisation address
    1, Avenue de la Gare, Luxembourg, Luxembourg, L-1611
    Public contact
    Study Medical Expert (SME), Menarini International Operations Luxembourg SA, 0039 02516555236, dzava@lusofarmaco.it
    Scientific contact
    Study Medical Expert (SME), Menarini International Operations Luxembourg SA, 0039 02516555236, dzava@lusofarmaco.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
    05 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective will be to verify whether ranolazine 750 mg b.i.d. is effective in increasing exercise capacity (exercise treadmill time at peak).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and local law requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Sep 2011
    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: 68
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 152
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Ireland: 19
    Country: Number of subjects enrolled
    Italy: 116
    Country: Number of subjects enrolled
    Romania: 67
    Country: Number of subjects enrolled
    Russian Federation: 124
    Worldwide total number of subjects
    651
    EEA total number of subjects
    527
    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)
    288
    From 65 to 84 years
    363
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    1004 subjetcs have been screened at Visit 0.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment arm
    Arm description
    Ranolazine arm: ranolazine tablets 375 mg b.i.d for 2 weeks + ranolazione tablets 500 mg b.i.d for the next 2 weeks and finally ranolazine tablets 750 mg b.i.d for 24 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 375 mg b.i.d for 2 weeks - Ranolazine 500 mg b.i.d for 2 weeks - Ranolazine 750 mg b.i.d for 24 weeks

    Arm title
    Placebo arm
    Arm description
    Placebo 1 tablet b.i.d. for 28 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    Placeboo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Other use
    Dosage and administration details
    1 tablet b.i.d. for 28 weeks

    Number of subjects in period 1
    Treatment arm Placebo arm
    Started
    324
    327
    Completed
    302
    299
    Not completed
    22
    28
         Protocol deviation
    22
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Ranolazine arm: ranolazine tablets 375 mg b.i.d for 2 weeks + ranolazione tablets 500 mg b.i.d for the next 2 weeks and finally ranolazine tablets 750 mg b.i.d for 24 weeks.

    Reporting group title
    Placebo arm
    Reporting group description
    Placebo 1 tablet b.i.d. for 28 weeks

    Reporting group values
    Treatment arm Placebo arm Total
    Number of subjects
    324 327 651
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    140 148 288
        From 65-84 years
    184 179 363
        85 years and over
    0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    64.5 ± 9.22 63.3 ± 9.33 -
    Gender categorical
    Units: Subjects
        Female
    75 76 151
        Male
    249 251 500
    Subject analysis sets

    Subject analysis set title
    Ranolazine Therapy
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    IIT population who have taken IMP

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    IIT population who have taken placebo

    Subject analysis sets values
    Ranolazine Therapy Placebo
    Number of subjects
    302
    299
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    132
    137
        From 65-84 years
    167
    165
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (standard deviation)
    64.6 ± 9.08
    63.1 ± 9.12
    Gender categorical
    Units: Subjects
        Female
    68
    70
        Male
    234
    229

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Ranolazine arm: ranolazine tablets 375 mg b.i.d for 2 weeks + ranolazione tablets 500 mg b.i.d for the next 2 weeks and finally ranolazine tablets 750 mg b.i.d for 24 weeks.

    Reporting group title
    Placebo arm
    Reporting group description
    Placebo 1 tablet b.i.d. for 28 weeks

    Subject analysis set title
    Ranolazine Therapy
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    IIT population who have taken IMP

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    IIT population who have taken placebo

    Primary: Change in treadmill total exercise duration

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    End point title
    Change in treadmill total exercise duration
    End point description
    The study aim was to demonstrate the effect of ranolazine in patients with CAD characterized by angina and limited exercise capacity on treadmill test (3-9 min on modified Bruce protocol).
    End point type
    Primary
    End point timeframe
    28 weeks of treatment (from V1 to V8)
    End point values
    Treatment arm Placebo arm Ranolazine Therapy Placebo
    Number of subjects analysed
    324
    327
    302
    299
    Units: seconds
    324
    327
    302
    299
    Statistical analysis title
    Ranolazine vs Placebo in the TED after 28 weeks
    Statistical analysis description
    change from baseline in the Total Exercise Duration (TED) with ranolazine or placebo in the two study groups.
    Comparison groups
    Ranolazine Therapy v Placebo
    Number of subjects included in analysis
    601
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.008
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    29.601
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.734
         upper limit
    51.467
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.134
    Notes
    [1] - H0: μ ranolazine - μ placebo ≤ 0 [mL • Kg -1 • min -1] versus H1: μ ranolazine - μ placebo > 0 [mL • Kg -1 • min -1] The hypothesis are tested using the F test (two-way ANCOVA, with treatment and baseline values as covariates), using a two-sided alpha level of 5%.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from Visit 1 to V8 (from Informed Consent signed to final visit).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Ranolazine arm: ranolazine tablets 375 mg b.i.d for 2 weeks + ranolazione tablets 500 mg b.i.d for the next 2 weeks and finally ranolazine tablets 750 mg b.i.d for 24 weeks.

    Reporting group title
    Placebo arm
    Reporting group description
    Placebo 1 tablet b.i.d. for 28 weeks

    Serious adverse events
    Treatment arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 324 (6.79%)
    15 / 327 (4.59%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Vascular disorders
    Angina pectoris aggravated
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Arterial stenosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Surgical and medical procedures
    Bypass surgery
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Percutaneous coronary intervention
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Thromboendarterectomy
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Chest pain non cardiac
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Concomitant disease aggravated
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    2 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Investigations
    Coronary angiograph
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Endoscopy
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Injury, poisoning and procedural complications
    Vertebral fracture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Vertebral injury
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Angina pectoris
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    2 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Angina pectoris unstable
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atrial fibrillation
         subjects affected / exposed
    1 / 324 (0.31%)
    4 / 327 (1.22%)
         occurrences causally related to treatment / all
    1 / 39
    4 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiovascular disorder
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Left heart failure
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Non ST segment elevation myocardial infarction
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    2 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Paroxysmal atrial fibrillation
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    2 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Silent myocardial ischemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Unstable angina
         subjects affected / exposed
    3 / 324 (0.93%)
    6 / 327 (1.83%)
         occurrences causally related to treatment / all
    3 / 39
    6 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Ventricular ectopic beats
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Ventricular tachycardia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Middle cerebral artery stroke
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Syncope
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    2 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Transient ischemic attacks
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Vertigo
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Blood and lymphatic system disorders
    Anaemia aggravated
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Eye disorders
    Detached retina
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastrointestinal disorders
    Atrophic gastritis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Epigastric pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hypersecretion gastric
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Reflux esophagitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Vomiting
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    2 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Musculoskeletal and connective tissue disorders
    Contusion of multiple site of trunk
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Infections and infestations
    Respiratory infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 324 (25.00%)
    72 / 327 (22.02%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Blood pressure inadequately controlled
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    hypertension aggraveted
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Surgical and medical procedures
    Coronary angioplasty
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    General disorders and administration site conditions
    General Body Pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Performance status decreased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Sickness
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Oedema
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Asthenia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Malaise
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Increased shortness of breath
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Investigations
    Coronary Angiograph
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Weight increased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Cardiac disorders
    Angina pectoris aggravated
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Atrial fibrillation paroxysmal
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Left bundle branch block
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Paroxysmal atrial fibrillation
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Tachycardia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Headache
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 327 (0.61%)
         occurrences all number
    200
    135
    Presyncope
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Parkinson's disease
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Ear and labyrinth disorders
    Hearing loss
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    otalgia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Wax in ear
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 327 (0.61%)
         occurrences all number
    200
    135
    Cataract
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 324 (1.23%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Diarrhoea
         subjects affected / exposed
    3 / 324 (0.93%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Gastrointestinal bleeding
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Inguinal hernia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Nausea
         subjects affected / exposed
    2 / 324 (0.62%)
    3 / 327 (0.92%)
         occurrences all number
    200
    135
    Obstipation
         subjects affected / exposed
    3 / 324 (0.93%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Vomiting
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Odynophagia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 327 (0.61%)
         occurrences all number
    200
    135
    Erythema
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 327 (0.61%)
         occurrences all number
    200
    135
    Exacerbation of psoriasis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Hair Loss
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 327 (0.61%)
         occurrences all number
    200
    135
    Endocrine disorders
    Iodine hyperthyroidims
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Secondary hyperthyroidism
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Musculoskeletal and connective tissue disorders
    Leg Pain
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Joint pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Infections and infestations
    Acute diverticulitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 327 (0.31%)
         occurrences all number
    200
    135
    Acute gastroenteritis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Cold
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    Flu
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135
    gastroenteritis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 327 (0.00%)
         occurrences all number
    200
    135

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2012
    - To better clarify tha characteristics of patients to be include - To exclude inclusion of patients with already planned revascularization - To exclude inclusion of patients with implant of a pacemaker - To add in exclusion criteria the list of medication not permitted - To exclude patients who participiedto other clinical trials in the previous three month before enrolment - To exclude patients who are prescribed and using off-label medications - To adapt paragraph of concomitant medications not permitted during the study according to new update version of SmPC (April 2012)
    20 Jan 2014
    - Better clarify inclusion/exclusion criteria - How to notify new safety information - More details in paragraph "Methods" - More details in paragraph "Objective" - Changes in paragraph "Secondary Endpoint"

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 May 2015
    Menarini International Operations Luxembourg S.A. decided to early terminate the CAD study. Due to an higher than expected screening failure rate and to the clinical management changes driven by new guidelines with respect to these specific patients, although new Investigational Sites have been opened we have faced many difficulties in recruiting patients and only about half of the expecteed patients have been randomized. No safety or drug related reasons are related to the decision of study closure.
    -

    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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