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    Clinical Trial Results:
    RANOLAZINE IN PATIENTS WITH SYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY: A PILOT STUDY ASSESSING THE EFFECTS ON EXERCISE CAPACITY, DIASTOLIC FUNCTION AND SYMPTOMATIC STATUS

    Summary
    EudraCT number
    2011-004507-20
    Trial protocol
    ES   DE   IT  
    Global end of trial date
    14 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    25 May 2016
    First version publication date
    25 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEIN/11/RAN-HCM/001
    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
    Menarini International Operations Luxembourg S.A., Medical Scientific Management, +352 264976,
    Scientific contact
    Menarini Corporate Medical Department, Menarini Industrie Farmaceutiche Riunite, +39 055 56801,
    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
    12 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary study objective is to demonstrate the efficacy of ranolazine in improving the Exercise capacity in patients affected by symptomatic hypertrophic cardiomyopathy (SHCM) using the V02 peak technique
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jul 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: 13
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 53
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    66
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Total recruitment period (first patient in to last patient in) : 02.07.2012-12.06.2014

    Pre-assignment
    Screening details
    Between 02 Jul 2012 and 12 Jun 2014, a total of 119 patients were screened for inclusion in the MEIN/11/RAN HCM/001 study. These included 39 patients (32.8%) who failed screening and were not included in the study.

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    Patients were blinded to the study drug they received. The blinding was assured by using matching placebo to guarantee the maintenance of double-blind conditions. The ranolazine PR tablets and the matching placebo tablets were manufactured with the same shape and attributes (appearance, colour, etc.) in order to maintain the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ranolazine 500/750/1000
    Arm description
    Ranolazine PR (prolonged release) was administered at the initial dose of 500 mg/ bid. After 7 days, the dose was up-titrated to 750 mg bid, if the drug was well tolerated (Visit 2). One further titration up to 1000 mg bid was performed after another 7 days (Visit 3), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg bid was not advisable, patients continued with 500 or 750 mg bid, respectively, throughout the remainder of the study. After the titration phase (2 weeks, Visits 2 and 3) the treatment phase was composed of 3 visits (Visits 4, 5, and 6) at Week 4, Week 12 and Week 20 respectively,
    Arm type
    Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ranolazine was provided as prolonged release (PR) tablets to be taken orally and to be swallowed whole, without breaking, chewing, or crushing. Study drug was taken twice daily (bid), in the morning and in the evening, at approximately the same time each day, with a glass of water and with or without food. Ranolazine PR was administered at the initial dose of 500 mg/ bid. After 7 days, the dose was up-titrated to 750 mg bid, if the drug was well tolerated (Visit 2). One further titration up to 1000 mg bid was performed after another 7 days (Visit 3), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg bid was not advisable, patients continued with 500 or 750 mg bid, respectively, throughout the remainder of the study. Ranolazine was provided in 3 dosage strengths: • 500 mg tablet • 750 mg tablet • 1000 mg tablet

    Arm title
    Placebo 500/750/1000
    Arm description
    The matching placebo tablets (Placebo to Match, PTM) were provided in the same manner as 3 solid dosage film-coated, biconvex tablets. The 3 placebo tablets included: • 500 mg tablet • 750 mg tablet • 1000 mg tablet
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The matching placebo tablets (Placebo to Match, PTM) were provided in the same manner as 3 solid dosage film-coated, biconvex tablets. The 3 placebo tablets included: • 500 mg tablet • 750 mg tablet • 1000 mg tablet Placebo was provided as prolonged release (PR) tablets to be taken orally and swallowed whole, without breaking, chewing, or crushing. It was taken twice daily (bid), in the morning and in the evening, at approximately the same time each day, with a glass of water and with or without food. It was administered at the initial dose of 500 mg/ bid. After 7 days, the dose was up-titrated to 750 mg bid, if it was well tolerated (Visit 2). One further titration up to 1000 mg bid was performed after another 7 days (Visit 3) if well tolerated

    Number of subjects in period 1
    Ranolazine 500/750/1000 Placebo 500/750/1000
    Started
    40
    40
    Completed
    35
    34
    Not completed
    5
    6
         Consent withdrawn by subject
    3
    -
         Adverse event, non-fatal
    -
    2
         non compliance with study drug
    1
    1
         Investigator decision
    1
    1
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranolazine 500/750/1000
    Reporting group description
    Ranolazine PR (prolonged release) was administered at the initial dose of 500 mg/ bid. After 7 days, the dose was up-titrated to 750 mg bid, if the drug was well tolerated (Visit 2). One further titration up to 1000 mg bid was performed after another 7 days (Visit 3), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg bid was not advisable, patients continued with 500 or 750 mg bid, respectively, throughout the remainder of the study. After the titration phase (2 weeks, Visits 2 and 3) the treatment phase was composed of 3 visits (Visits 4, 5, and 6) at Week 4, Week 12 and Week 20 respectively,

    Reporting group title
    Placebo 500/750/1000
    Reporting group description
    The matching placebo tablets (Placebo to Match, PTM) were provided in the same manner as 3 solid dosage film-coated, biconvex tablets. The 3 placebo tablets included: • 500 mg tablet • 750 mg tablet • 1000 mg tablet

    Reporting group values
    Ranolazine 500/750/1000 Placebo 500/750/1000 Total
    Number of subjects
    40 40 80
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    32 34 66
        From 65-84 years
    8 6 14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.7 ( 13.92 ) 52.1 ( 13.46 ) -
    Gender categorical
    Units: Subjects
        Female
    16 18 34
        Male
    24 22 46
    Subject analysis sets

    Subject analysis set title
    Ranolazine ITT/Safety population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population included all randomized patients. Patients erroneously registered twice or more into the study were accounted for only once. Patients were analyzed according to the treatment assigned at the end of the randomization procedure. For patients registered twice or more the first assigned treatment was taken as reference. The safety population included all randomized patients who received at least 1 dose of the study drugs. Patients were analysed according to the treatment actually received. In this particular study the safety population corresponds to the ITT population where this latter is considered the population that included all randomized patients.

    Subject analysis set title
    Ranolazine PP population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population consisted of the randomized patients who: i) did not have major deviations from inclusion and exclusion criteria; ii) received at least 80% and not more than 120% of the expected amount of the treatment assigned at the end of the randomization procedure; iii) completed all the planned study visits and were evaluated for the primary endpoint of the study at the final visit. Patients were analyzed according to the treatment they actually received.

    Subject analysis set title
    Placebo ITT/Safety population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population included all randomized patients. Patients erroneously registered twice or more into the study were accounted for only once. Patients were analyzed according to the treatment assigned at the end of the randomization procedure. For patients registered twice or more the first assigned treatment was taken as reference. The safety population included all randomized patients who received at least 1 dose of the study drugs. Patients were analysed according to the treatment actually received

    Subject analysis set title
    Placebo PP population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population consisted of the randomized patients who: i) did not have major deviations from inclusion and exclusion criteria; ii) received at least 80% and not more than 120% of the expected amount of the treatment assigned at the end of the randomization procedure; iii) completed all the planned study visits and were evaluated for the primary endpoint of the study at the final visit. Patients were analyzed according to the treatment they actually received.

    Subject analysis sets values
    Ranolazine ITT/Safety population Ranolazine PP population Placebo ITT/Safety population Placebo PP population
    Number of subjects
    40
    31
    40
    29
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    32
    25
    34
    25
        From 65-84 years
    8
    6
    6
    4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.7 ( 13.92 )
    53.8 ( 14.65 )
    52.1 ( 13.46 )
    51.3 ( 13.48 )
    Gender categorical
    Units: Subjects
        Female
    16
    12
    18
    14
        Male
    24
    19
    22
    15

    End points

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    End points reporting groups
    Reporting group title
    Ranolazine 500/750/1000
    Reporting group description
    Ranolazine PR (prolonged release) was administered at the initial dose of 500 mg/ bid. After 7 days, the dose was up-titrated to 750 mg bid, if the drug was well tolerated (Visit 2). One further titration up to 1000 mg bid was performed after another 7 days (Visit 3), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg bid was not advisable, patients continued with 500 or 750 mg bid, respectively, throughout the remainder of the study. After the titration phase (2 weeks, Visits 2 and 3) the treatment phase was composed of 3 visits (Visits 4, 5, and 6) at Week 4, Week 12 and Week 20 respectively,

    Reporting group title
    Placebo 500/750/1000
    Reporting group description
    The matching placebo tablets (Placebo to Match, PTM) were provided in the same manner as 3 solid dosage film-coated, biconvex tablets. The 3 placebo tablets included: • 500 mg tablet • 750 mg tablet • 1000 mg tablet

    Subject analysis set title
    Ranolazine ITT/Safety population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population included all randomized patients. Patients erroneously registered twice or more into the study were accounted for only once. Patients were analyzed according to the treatment assigned at the end of the randomization procedure. For patients registered twice or more the first assigned treatment was taken as reference. The safety population included all randomized patients who received at least 1 dose of the study drugs. Patients were analysed according to the treatment actually received. In this particular study the safety population corresponds to the ITT population where this latter is considered the population that included all randomized patients.

    Subject analysis set title
    Ranolazine PP population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population consisted of the randomized patients who: i) did not have major deviations from inclusion and exclusion criteria; ii) received at least 80% and not more than 120% of the expected amount of the treatment assigned at the end of the randomization procedure; iii) completed all the planned study visits and were evaluated for the primary endpoint of the study at the final visit. Patients were analyzed according to the treatment they actually received.

    Subject analysis set title
    Placebo ITT/Safety population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population included all randomized patients. Patients erroneously registered twice or more into the study were accounted for only once. Patients were analyzed according to the treatment assigned at the end of the randomization procedure. For patients registered twice or more the first assigned treatment was taken as reference. The safety population included all randomized patients who received at least 1 dose of the study drugs. Patients were analysed according to the treatment actually received

    Subject analysis set title
    Placebo PP population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population consisted of the randomized patients who: i) did not have major deviations from inclusion and exclusion criteria; ii) received at least 80% and not more than 120% of the expected amount of the treatment assigned at the end of the randomization procedure; iii) completed all the planned study visits and were evaluated for the primary endpoint of the study at the final visit. Patients were analyzed according to the treatment they actually received.

    Primary: Change of VO2 peak after 5 months of treatment

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    End point title
    Change of VO2 peak after 5 months of treatment
    End point description
    The primary efficacy assessment was VO2 peak evaluation using the cardiorespiratory test technique, after5 months at the maximum reached dosage of ranolazine, or placebo.
    End point type
    Primary
    End point timeframe
    After 20 weeks of treatment (visit 6)
    End point values
    Ranolazine PP population Placebo PP population
    Number of subjects analysed
    31
    29
    Units: mL/Kg/min
        arithmetic mean (standard deviation)
    -0.35 ( 3.917 )
    0.01 ( 4.579 )
    Statistical analysis title
    Ranolazine vs Placebo
    Statistical analysis description
    This was a superiority study: the treatment with ranolazine would be considered superior to placebo if the comparison between treatments at the end of the study obtained statistical significance in the analysis of covariance (ANCOVA)
    Comparison groups
    Ranolazine PP population v Placebo PP population
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.746
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - The hypothesis was tested using the F test (two-way ANCOVA, with treatment and baseline values as covariates), using a two-sided alpha level of 5%.

    Secondary: Change in E/E’ ratio (lateral)

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    End point title
    Change in E/E’ ratio (lateral)
    End point description
    Evaluation of E/E’ ratio (ratio between the early mitral valve flow velocity and the early diastolic lengthening velocities) changes with treatment using the tissue Doppler (TD) technique at the lateral annulus
    End point type
    Secondary
    End point timeframe
    After 20 weeks of treatment (visit 6)
    End point values
    Ranolazine PP population Placebo PP population
    Number of subjects analysed
    31
    29
    Units: ratio
        arithmetic mean (standard deviation)
    -0.32 ( 3.571 )
    -0.78 ( 4.564 )
    No statistical analyses for this end point

    Secondary: Change in concentration of prohormone brain natriuretic peptide (proBNP)

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    End point title
    Change in concentration of prohormone brain natriuretic peptide (proBNP)
    End point description
    The change in proBNP concentration after 5 months of treatment with ranolazine or placebo was a secondary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    After 20 weeks of treatment (visit 6)
    End point values
    Ranolazine PP population Placebo PP population
    Number of subjects analysed
    31
    29
    Units: pg/mL
        arithmetic mean (standard deviation)
    -241.3 ( 1233.9 )
    -20.5 ( 515.26 )
    No statistical analyses for this end point

    Secondary: Change in MLWHFQ total score

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    End point title
    Change in MLWHFQ total score
    End point description
    The change in symptomatic status evaluation as determined with the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) after 5 months of treatment with ranolazine or placebo was a secondary endpoint.
    End point type
    Secondary
    End point timeframe
    After 20 weeks of treatment (visit 6)
    End point values
    Ranolazine PP population Placebo PP population
    Number of subjects analysed
    31
    29
    Units: number
        arithmetic mean (standard deviation)
    -8.71 ( 15.231 )
    6.63 ( 14.46 )
    No statistical analyses for this end point

    Secondary: Change in E/E’ ratio (septal)

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    End point title
    Change in E/E’ ratio (septal)
    End point description
    Evaluation of E/E’ ratio (ratio between the early mitral valve flow velocity and the early diastolic lengthening velocities) changes with treatment using the tissue Doppler (TD) technique at the septal annulus
    End point type
    Secondary
    End point timeframe
    After 20 weeks of treatment (visit 6)
    End point values
    Ranolazine PP population Placebo PP population
    Number of subjects analysed
    31
    29
    Units: ratio
        arithmetic mean (standard deviation)
    -0.5 ( 3.271 )
    -1.54 ( 5.888 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety measurements are recorded at each visit from Visit 2 (-7 days) to Visit 6 (20 weeks; end of study) during the treatment phase
    Adverse event reporting additional description
    At each visit the investigator assessed any occurring subjective or objective AE. Adverse events communicated by the patient or by the patient’s relatives or delegates through phone calls, letters or e-mails were also recorded.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Ranolazine 500/750/1000
    Reporting group description
    Ranolazine PR (prolonged release) was administered at the initial dose of 500 mg/ bid. After 7 days, the dose was up-titrated to 750 mg bid, if the drug was well tolerated (Visit 2). One further titration up to 1000 mg bid was performed after another 7 days (Visit 3), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg bid was not advisable, patients continued with 500 or 750 mg bid, respectively, throughout the remainder of the study. After the titration phase (2 weeks, Visits 2 and 3) the treatment phase was composed of 3 visits (Visits 4, 5, and 6) at Week 4, Week 12 and Week 20 respectively,

    Reporting group title
    Placebo 500/750/1000
    Reporting group description
    The matching placebo tablets were provided in the same manner as 3 solid dosage film-coated, biconvex tablets. The 3 placebo tablets included: • 500 mg tablet • 750 mg tablet • 1000 mg tablet

    Serious adverse events
    Ranolazine 500/750/1000 Placebo 500/750/1000
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 40 (10.00%)
    5 / 40 (12.50%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Intraocular pressure test
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoperfusion
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Glaucoma surgery
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ranolazine 500/750/1000 Placebo 500/750/1000
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 40 (67.50%)
    30 / 40 (75.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Hypotension
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 40 (12.50%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Vomiting
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Diarrhoea
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2011
    This protocol amendment was implemented to provide contact details for the study pharmacovigilance representative at the CRO, and to add the name of the Study Medical Expert to the Investigator’s Approval page. In addition, typographical errors were corrected, including an incorrect mathematical symbol in the description of the null hypothesis.
    13 Jan 2012
    This protocol amendment was implemented in order to implement changes requested by Ethics Committees and Health Authorities during the approval phase, and to increase compliance with the SmPC. Changes were made to the eligibility criteria, including exclusion of patients using CYP3A4 inducers and patients who were hypersensitive to ranolazine (or its excipients), modification of the definition of alcoholism, and introduction of mandatory GFR calculation as part of the assessment of renal impairment. The parameters to be assessed during clinical laboratory assessment were clarified. Prohibition of grapefruit juice and CYP3A4 inducers was added due to their capacity to affect ranolazine metabolism. The severity of newly developed renal sufficiency requiring dose reduction was changed from mild severe to mild-moderate. The description of adverse reactions was updated to reflect the description provided in the updated SmPC. Verification of eligibility criteria (including laboratory tests) within 3 days of screening was introduced prior to provision of the patients’ drug supply. The description of the efficacy variables was clarified to indicate that efficacy variables should be assessed at the maximum dosage reached. The description of the Modified Bruce exercise treadmill test protocol was amended to clarify that testing was to be carried out by suitably qualified individuals with training in basic life support, and with the requirement of a written emergency plan. In addition, changes were made to reflect changes in the study team, to clarify text and correct typographical errors.
    12 Mar 2012
    This protocol amendment was implemented following the availability of new data on ranolazine drug interactions, and to change the cardiopulmonary assessment from a treadmill test to a cycle ergometer. In addition, the title of the study was modified to include the “RESTYLE-HCM” name. Based on recent data showing that ranolazine can increase plasma concentrations of metformin by 1.8-fold, a maximum daily dose of 1000 mg metformin was introduced. In addition, the dose of simvastatin was limited to 20 mg once daily, due to the involvement of CYP3A4 in its metabolism. Eligibility criteria were modified accordingly. The description of the procedure for unblinding was clarified. The schedule of events was modified to clarify that physical examinations, ECGs, and assessments of E/E’ ratio and pro-BNP were to take place before the VO2 peak evaluation, and to add recording of concomitant diseases and medications to Visits 2 and 3. The cardiopulmonary test to be employed was changed from the Treadmill test (Bruce modified) to the Cyclo ergometer test, based on the majority of study sites being more familiar with this test; both techniques were considered to be equally appropriate and comparable with regard to the determination of VO2 peak. In addition, changes were made to clarify text and correct typographical errors.
    03 Dec 2013
    This PA was implemented in order to add details to text describing certain evaluations (Holter ECG monitoring, pro-BNP analysis, etc), to extend the enrolment period further, to update the protocol according to the updated ranolazine SmPC, and to describe administrative changes. The enrolment period was increased from 18 months to 24 months. Clarification was made in the exclusion criteria that QTc would be calculated according to the Bazets method (...). A central review was introduced for ECG parameters (...), whilst clarifying that local evaluations should also be maintained. Details were provided on the data to be collected during the cardiopulmonary exercise test and VO2 peak evaluation. The definition of SAE was amended to include medically important conditions, and clarification was made that hospitalizations planned at the time of obtaining informed consent would not be reported as SAEs. It was also clarified that assessments of expectedness of AEs were to be made based on the ranolazine SmPC rather than the IB, as the SmPC is updated more frequently. The definition of SUSAR was also updated to reflect the definition provided in CT3. Clarification was made that clinically significant abnormal laboratory findings were to be considered as AEs. In addition, the text describing SAE reporting and AE management was updated. Descriptions of 24-h Holter ECG monitoring and proBNP evaluation were added (...). (...)Text describing AR was updated according to the most recent version of the ranolazine SmPC. (...) In addition, atorvastatin was added to the list of drugs metabolised by CYP3A4 that could undergo a dose reduction when co-administered with ranolazine. (...) Details of the study team were updated. (...) The appendices were updated with the most recent version of the Declaration of Helsinki, and with a list of CROs and Consultants involved in the study conduct. Changes were made to clarify text and correct typographical errors.

    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.
    No limitations or caveats are applicable to this summary
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