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    Clinical Trial Results:
    Effect on Ranolazine in Heart Failure Patients with Preserved Ejection Fraction

    Summary
    EudraCT number
    		 2011-000805-27
    Trial protocol
    		 GB   ES   IT  
    Global end of trial date
    22 Jan 2014

    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-Did/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
    Donatella Bemporad, A. Menarini Farmaceutica Internazionale S.R.L., 0039 055 5680685, dbemporad@menarini.it
    Scientific contact
    Donatella Bemporad, A. Menarini Farmaceutica Internazionale S.R.L., 0039 055 5680685, dbemporad@menarini.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
    22 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that ranolazine treatment results in a placebo corrected improvement in the 6-minute walk test (6MWT) after 28 weeks of treatment
    Protection of trial subjects
    This study has been carried out in compliance with the study protocol, the recommendations on biomedical research on human subjects of the declaration of Helsinki, International Conference of Harmonisation – Good Clinical Practice (ICH-GCP) Guidelines, EU-Directive 2001/20 of April 4, 2001, and national requirements of the participating countries.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 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: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    0
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Due to the prematurely end of the trial it was conducted in 4 investigational study sites (2 sites in Italy, 1 in the United Kingdom and 1 in Spain). First Patient First Visit: 30 May 2013 Early termination date: 22 January 2014 Phase 2 study

    Pre-assignment
    Screening details
    		 Screening visit (Visit 1, from day -7 to -1, +/- 3 days) patient eligibility was determined by inclusion/exclusion criteria. Overall, 13 patients were screened. Eight patients did not meet the inclusion/exclusion criteria and were not eligible for randomization. Another patient withdrew the consent before the baseline visit (Visit 2).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranolazine
    Arm description
    		 Ranolazine was administered at the initial dose of 500 mg BID. After 2 weeks, the dose was uptitrated to 750 mg BID in all patients (Visit 3). One further titration up to 1000 mg BID was to be performed after another 2 weeks (Visit 4), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg was not advisable because of safety or intolerability issues, patients had to continue with 500 or 750 mg, respectively, throughout the remain of the study. Adjustments (down-titration) to the dose of study drug were to be made in case of conditions occurred during the study treatment period according to study protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Titration of the study drug occurred according to the following schedule: · Visit 2 (Day 1): 500 mg BID; · Visit 3 (Week 2): 750 mg BID; · Visit 4 (Week 4): 1000 mg BID. If the up-titration to 750 mg or 1000 mg was not advisable because of safety or intolerability issues, patients had to continue with 500 or 750 mg, respectively, throughout the remain of the study. Ranolazine was provided as a PR tablet to be taken orally and to be swallowed whole, without breaking, chewing, or crushing. Study drug was to be taken BID, in the morning and in the evening, at around the same time each day, with a glass of water and with or without food.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo tablets were administered following the same route of Ranolazine with a virtual uptitration after 2 and 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was provided as a film-coated tablet to be taken orally and to be swallowed whole, without breaking, chewing, or crushing. Study drug was to be taken BID, in the morning and in the evening, at around the same time each day, with a glass of water and with or without food.

    Number of subjects in period 1
    		Ranolazine Placebo
    Started
    3
    1
    Completed
    1
    0
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    -
         Study Premature Ending
    1
    1

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Ranolazine
    Reporting group description
    		 Ranolazine was administered at the initial dose of 500 mg BID. After 2 weeks, the dose was uptitrated to 750 mg BID in all patients (Visit 3). One further titration up to 1000 mg BID was to be performed after another 2 weeks (Visit 4), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg was not advisable because of safety or intolerability issues, patients had to continue with 500 or 750 mg, respectively, throughout the remain of the study. Adjustments (down-titration) to the dose of study drug were to be made in case of conditions occurred during the study treatment period according to study protocol.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets were administered following the same route of Ranolazine with a virtual uptitration after 2 and 4 weeks.

    Primary: six-minute walking test

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    End point title
    		 six-minute walking test [1]
    End point description
    The study plan included a screening phase (one week), a randomised titration phase (4 weeks) and a randomised treatment phase (24 weeks). There were 6 clinic visits: screening (Visit 1, Day -7 to -1), randomisation (Visit 2, Day 1), 2 study drug titration visits (Visit 3, Week 2 and Visit 4, Week 4), and 2 treatment visits (Visit 5, Week 16 and Visit 6, Week 28). Due to early termination of the study only one subject completed all planned visits.
    End point type
    Primary
    End point timeframe
    The study plan included a randomised treatment phase of 24 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical and descriptive analysis were made. Only one subject completed the study.
    End point values
    		 Ranolazine Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: meter
        number (not applicable)
    Notes
    [2] - No statistical and descriptive analysis was made. Only one subject completed the study
    [3] - No statistical and descriptive analysis was made. No subjects completed the study
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent at Visit -1 (from day -7 to -1 day before treatment) to two weeks after the administration of the last treatment dose (Visit 6, 28 weeks of treatment). Total timeframe for Adverse event reporting was of 31 weeks.
    Adverse event reporting additional description
    Due to the premature closure of the study, data were not entered in a database and no coding of adverse events was performed. Therefore, the adverse events are reported as verbatim terms and narrative, without any coding as preferred term (PT) or system organ class (SOC).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 no dictionary
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Ranolazine
    Reporting group description
    		 Ranolazine was administered at the initial dose of 500 mg BID. After 2 weeks, the dose was uptitrated to 750 mg BID in all patients (Visit 3). One further titration up to 1000 mg BID was to be performed after another 2 weeks (Visit 4), if the drug was well tolerated. If the up-titration to 750 mg or 1000 mg was not advisable because of safety or intolerability issues, patients had to continue with 500 or 750 mg, respectively, throughout the remainder of the study. Adjustments (down-titration) to the dose of study drug were to be made in case of conditions occurred during the study treatment period according to study protocol.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets were administered following the same route of Ranolazine with a virtual uptitration after 2 and 4 weeks.

    Serious adverse events
    		 Ranolazine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrioventricular dissociation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (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: 0%
    Non-serious adverse events
    		 Ranolazine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    Investigations
    Laboratory test abnormal
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Somnolence
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastric disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2013
    Current amended protocol updated to incorporate all of the previous country specific changes into one global Protocol. The following were the main changes: * Section 16.2a included to incorporate the UK specific Informed consent in the Global Protocol. * Updated version of the Declaration Helsinki (2008) included. * Protocol amended to safely facilitate the enrollment of patients through the following changes : ** Inclusion criteria #2c and 2d combined to state that patients would qualify for inclusion if evidence of LV diastolic dysfunction or increased LV filling pressure were verified at screening by at least one of the following criteria: • NT-ProBNP> 200 pg/ml measured at the central laboratory • BNP> 80 pg/ml measured at the investigational site's local laboratory • Evidence of LV diastolic dysfunction or increased LV filling pressure in the last month (defined by at least one of the criteria listed further in the protocol) ** Exclusion criteria #6 adjusted allowing enrollment of patients with BMI > 35 kg/m2. ** Exclusion criteria #10 changed to reduce the time prior to screening that patients must have been on a stable cardiovascular medication from 4 weeks to 2 weeks. ** Screening period extended from 7 days to 14 days to allow more time for the completion of screening assessments. The 3-day window around Visit 1 has been removed. * Texts updated to clarify that no additional inclusion or exclusion criteria analysis will be performed at the Randomization visit (Visit 2). * Total duration of the study updated. * Allow dose reduction to 500 mg in case of intolerability of 750-mg dose. * Introduction of contraceptive methods in women of childbearing potential as enrollment criterion based on new reproductive toxicity information. * Record retention updated * Editorial changes made throughout the document to correct or clarify previously presented information for consistency.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Jan 2014
    Due to unexpected difficulties in the screening activities, particularly with regard to very specific and unusual characterization requirements of Heart Failure patients with Preserved Ejection Fraction (the "HFpEF"), only four (4) patients were randomized to the assigned treatment by the end of November 2013. This delay of approximately two years, as compared to the original timelines, would have had significant consequences both in terms of the study feasibility and of its expected scientific value. For the above reasons, the study sponsor decided to stop enrolling patients and to terminate the study. The decision to prematurely terminate the study was not taken due to any safety or drug-related reasons.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No reliable conclusions on efficacy and safety can be made due to the premature study interruption. 4 patients (3 Ranolazine, 1 Placebo) were treated, only one completed the study. Averse Drug Reactions were in line with the profile of Ranolazine.
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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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