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    Clinical Trial Results:
    A Phase 2b randomised, double blind, placebo-controlled trial of trimetazidine therapy in patients with non-obstructive hypertrophic cardiomyopathy.

    Summary
    EudraCT number
    2011-000038-12
    Trial protocol
    GB  
    Global end of trial date
    30 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Dec 2018
    First version publication date
    05 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    10/0216
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01696370
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint UCLH/UCL Biomedical Research Unit, 1st Floor Maple House, 149 Tottenham Court Road, London, United Kingdom, W1T 7NF
    Public contact
    Margaret Norton, BRC Office Manager, Joint UCLH/UCL Biomedical Research Unit, 1st Floor Maple House, 149 Tottenham Court Road, London, +44 2031087907, m.norton@ucl.ac.uk
    Scientific contact
    Professor Perry Elliott, Chief Investigator, Joint UCLH/UCL Biomedical Research Unit, 1st Floor Maple House, 149 Tottenham Court Road, London, +44 2031087907, perry.elliott@ucl.ac.uk
    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
    04 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Principle question: Does trimetazidine improve exercise capacity in patients with HCM? We will test trimetazidine against placebo (dummy drug) in patients who have symptoms despite standard treatment.
    Protection of trial subjects
    Adherence to Good Clinical Practice and UK clinical trials regulations
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 51
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    45
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    recruitment at a single UK site. Participants were recruited between 31st may 2012 and 13th Aug 2014

    Pre-assignment
    Screening details
    Screening criteria: able to consent, Age 18 or over, diagnosis of HCM, on optimal medical therapy, peak VO2 <= 80% predicted for age and gender, LVOT gradient < 50mmHg, NYHA Class >=2, resting heart rate < 90bpm, willing to use contraception.

    Pre-assignment period milestones
    Number of subjects started
    51
    Number of subjects completed
    51

    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
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trimetazidine
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Trimetazidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg three times daily

    Arm title
    placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Trimetazidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule three times daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule three times daily

    Number of subjects in period 1
    Trimetazidine placebo
    Started
    27
    24
    Completed
    26
    23
    Not completed
    1
    1
         Protocol deviation
    1
    -
         Physician decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trimetazidine
    Reporting group description
    -

    Reporting group title
    placebo
    Reporting group description
    -

    Reporting group values
    Trimetazidine placebo Total
    Number of subjects
    27 24 51
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49 ± 13 51 ± 14 -
    Gender categorical
    Units: Subjects
        Female
    9 6 15
        Male
    18 18 36
    Ethnicity
    Units: Subjects
        Caucasian
    17 19 36
        Non-Caucasian
    10 5 15

    End points

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    End points reporting groups
    Reporting group title
    Trimetazidine
    Reporting group description
    -

    Reporting group title
    placebo
    Reporting group description
    -

    Primary: peak oxygen consumption

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    End point title
    peak oxygen consumption
    End point description
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    Trimetazidine placebo
    Number of subjects analysed
    26
    23
    Units: mls/kg/min
        arithmetic mean (standard deviation)
    17.66 ± 3.53
    19.01 ± 4.68
    Statistical analysis title
    Primary end point
    Comparison groups
    Trimetazidine v placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.033
    Method
    Regression, Linear
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening visit to 10 days after end of trial
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    SNOMED CT
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Trimetazidine
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Trimetazidine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Chest pain
    Additional description: Requiring hospital admission
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Trimetazidine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 27 (59.26%)
    12 / 24 (50.00%)
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Palpitations
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 27 (14.81%)
    6 / 24 (25.00%)
         occurrences all number
    7
    6
    Eye disorders
    Conjunctival disorder
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Back pain
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Bite
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    Lethargy
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences all number
    2
    4
    Peripheral swelling
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         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
    09 Aug 2011
    Changes to protocol V2.0: • Section 1 Trial Personnel: Updated investigator team telephone numbers. • Section 8.2. Delete “Minimisation will be used to balance groups according to age and gender. This will reduce the imbalance between the active treatment and placebo groups” This was removed as the investigator and the statistician decided minimisation was not necessary. • Section 8.2: Delete” Brecon Pharmaceuticals” and change “UCLH” to “The Heart Hospital, UCLH Pharmacy”. Brecon Pharmaceuticals were left in the protocol in error as we had originally planned to use them. As per the CTA application form we will be using RFH Pharmacy Production. Changes to all other documents: Updated investigator team telephone numbers.
    19 Nov 2012
    Changes to protocol V3.0: Section 3.2.1 (Clinical Particulars): Updates made to therapeutic indications, contraindications and side effect table in light of updates to the SmPc Section 2.0 (Summary) and Section 6.1 (Inclusion Criteria): Updates made to the inclusion criteria to include patients with atrial fibrillation and also to clarify that patients who are fitted with a pacemaker are eligible. Expanded the inclusion criteria to include patients with atrial fibrillation as it is considered that this will increase recruitment by 10-20%. These individuals are usually asymptomatic and challenging to treat, so their inclusion is of clinical relevance. We have also clarified that patients with a pacemaker fitted are also eligible for the trial. Section 6.2 (Exclusion Criteria) Added ‘Participant has Parkinson’s disease or Parkinsonism’ as an exclusion in line with the updated SmPc. Annex 1 updated in line with changes to protocol. Non-substantial amendment documents also sent.
    10 Apr 2013
    Protocol V4.0 Creation of advert and patient invitation letter to increase recruitment rate to the trial. Protocol updated to incorporate use of advert and recruitment plan.
    15 Jan 2014
    Changes to protocol V5.0: • Addition of 3 PIC sites to enhance the recruitment rate to the trial. Sites will potentially be • The Royal Brompton & Harefield NHS Foundation Trust • Barts Health NHS Trust • Guys and St Thomas’ NHS Foundation Trust
    01 Apr 2014
    Protocol V6.0 Change to the inclusion criteria: • No significant left ventricular outflow tract obstruction on echocardiography at rest or during exercise (gradient < 50 mmHg) as determined at screening (if not done within previous 2 years).

    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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