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    Clinical Trial Results:
    TrimetaziDine as a Performance-enhancING drug in Heart Failure with Preserved Ejection Fraction (DoPING-HFpEF)

    Summary
    EudraCT number
    		 2018-002170-52
    Trial protocol
    		 NL  
    Global end of trial date
    22 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions
    Summary report(s)
    		 Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    66242
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VU University Medical Center (VUmc)
    Sponsor organisation address
    De Boelelaan 1117, Amsterdam, Netherlands, 1081HV
    Public contact
    dr. M.L. Handoko, cardiologist, VU University Medical Center (VUmc), 31 204440123, ml.handoko@vumc.nl
    Scientific contact
    dr. M.L. Handoko, cardiologist, VU University Medical Center (VUmc), 31 204440123, ml.handoko@vumc.nl
    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
    17 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assess the effect of a 3-month trimetazidine treatment in patients with HFpEF on LV diastology (change in exercise PCWP measured by exercise right heart catheterization or RHC)
    Protection of trial subjects
    Regular medical check ups, including assesment of (serious) adverse events and kidney function. Also, strict exclusion criteria were used to exclude patients with higher risks of adverse events due to the drug.
    Background therapy
    		 cardiofitness traject before study, weight reduction if possible, spironolacton and loop diuretics (in case of congestions).
    Evidence for comparator
    		 Placebo.
    Actual start date of recruitment
    29 Apr 2019
    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
    Netherlands: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    10
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the Amsterdam University Medical Centers outpatient dyspnea/HFpEF clinic and by referral from satellite hospitals. Between May 2019 and February 2021, 231 patients were screened, 30 patients were included and randomized, of whom 25 patients completed the trial. The last patient’s last follow-up visit was November 2021.

    Pre-assignment
    Screening details
    		 The key inclusion criteria were the diagnosis of clinically stable HFpEF with New York Heart Association (NYHA) functional class II or higher, despite optimal medical treatment. HFpEF was diagnosed based on symptoms of heart failure, LV ejection fraction ≥50% and evidence of LV diastolic dysfunction.

    Period 1
    Period 1 title
    First period: Trimetazidine or placebo
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trimetazidine
    Arm description
    		 trimetazidine 20mg trice dialy, or twice daily in case of moderate kidney dysfunction, for three months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    trimetazidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trimetazidine tablet was packed in a red capsule, indistinguishable from placebo

    Arm title
    		 Placebo
    Arm description
    		 Placebo trice daily (or twice daily in case of moderate kidney dysfunction) for three months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Powder for concentrate
    Routes of administration
    Oral use
    Dosage and administration details
    visually indistinguishable from trimetazidine. Powder consisted of microcrystalline cellulose powder.

    Number of subjects in period 1
    		Trimetazidine Placebo
    Started
    10
    20
    Completed
    10
    19
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1
    Period 2
    Period 2 title
    Second period: trimetazidine or placebo
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Trice or twice based on kidney function, for three months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Powder for concentrate
    Routes of administration
    Oral use
    Dosage and administration details
    visually indistinguishable from trimetazidine. Powder consisted of microcrystalline cellulose powder.

    Arm title
    		 Trimetazidine
    Arm description
    		 Trimetazidine 20mg trice (or twice daily in case of moderate kidney dysfunction) for three months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    trimetazidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trimetazidine tablet was packed in a red capsule, indistinguishable from placebo

    Number of subjects in period 2
    		Placebo Trimetazidine
    Started
    10
    19
    Completed
    8
    17
    Not completed
    2
    2
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First period: Trimetazidine or placebo
    Reporting group description
    		 -

    Reporting group values
    		 First period: Trimetazidine or placebo Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        Adults
    		 10 10
        Elderly
    		 20 20
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    Trimetazidine
    Reporting group description
    		 trimetazidine 20mg trice dialy, or twice daily in case of moderate kidney dysfunction, for three months.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo trice daily (or twice daily in case of moderate kidney dysfunction) for three months.
    Reporting group title
    Placebo
    Reporting group description
    		 Trice or twice based on kidney function, for three months

    Reporting group title
    Trimetazidine
    Reporting group description
    		 Trimetazidine 20mg trice (or twice daily in case of moderate kidney dysfunction) for three months.

    Primary: Change in Pulmonary Capillary Wedge Pressure at multiple levels of exercise

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    End point title
    		 Change in Pulmonary Capillary Wedge Pressure at multiple levels of exercise
    End point description
    End point type
    Primary
    End point timeframe
    at the end of the study periods
    End point values
    		 Trimetazidine Placebo Trimetazidine Placebo
    Number of subjects analysed
    8 [1]
    8 [2]
    17 [3]
    17 [4]
    Units: mmHg
        geometric mean (confidence interval 95%)
    0 (-2 to 2)
    0 (0 to 0)
    0 (-2 to 2)
    0 (0 to 0)
    Notes
    [1] - together with group 3. actual statistics is with mixed model but cannot be imputed here
    [2] - together with group 2. =baseline
    [3] - - average change (endpoint is measured with mixed model, but this cannot be imputed here). +group1
    [4] - baseline (compared to trim)
    Statistical analysis title
    		 mixed-model of repeated measures analyses
    Comparison groups
    Trimetazidine v Trimetazidine v Placebo v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - period 1 and period 2 trimetazidine were considered one group. Compared to period 1 and 2 placebo. In total 25 patients with complete follow up were included in this analyses

    Secondary: phosphocreatine (PCr) / adenosine triphosphate (ATP)

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    End point title
    		 phosphocreatine (PCr) / adenosine triphosphate (ATP)
    End point description
    measured with phosphorus-31 magnetic resonance spectroscopy.
    End point type
    Secondary
    End point timeframe
    Measured at the end of both study periods
    End point values
    		 Trimetazidine Placebo Trimetazidine Placebo
    Number of subjects analysed
    10 [6]
    10 [7]
    15 [8]
    15 [9]
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    1.08 (0.76 to 1.76)
    1.30 (0.95 to 1.86)
    1.08 (0.76 to 1.76)
    1.30 (0.95 to 1.86)
    Notes
    [6] - Trimetazidine
    [7] - Placebo
    [8] - Trimetazidine (together with group 1)
    [9] - together with group 2 placebo
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start screening until 4 weeks after latest drug administration
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Trimetazidine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 subjects affected by non-serious adverse events =23 , but cannot submit this number

    Serious adverse events
    		 Trimetazidine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 29 (10.34%)
    5 / 30 (16.67%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Bradyarrhythmia
    Additional description: Tachycardia-bradycardia requiring pacemaker
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendicitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
    Additional description: hospitalization
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         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: 5%
    Non-serious adverse events
    		 Trimetazidine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 29 (79.31%)
    20 / 30 (66.67%)
    Vascular disorders
    Raynaud's phenomenon
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    worsening of heart failure
    Additional description: requiring (extra) diuretics
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Angina pectoris
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Worsening of fatigue
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Headache
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Gastrointestinal pain
         subjects affected / exposed
    5 / 29 (17.24%)
    6 / 30 (20.00%)
         occurrences all number
    5
    6
    Musculoskeletal and connective tissue disorders
    Spasm/cramp
    alternative dictionary used: SNOMED CT 1
         subjects affected / exposed
    6 / 29 (20.69%)
    1 / 30 (3.33%)
         occurrences all number
    6
    1
    muscle pain
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    common cold
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2019
    Adjustment of exclusion criterium 2 (to increase inclusion rate); initially all patients with a history of myocardial infarction were excluded, this was changed to patients with suspected septal scar (for the inability to perform PCr/ATP assesment in these patients). Endpoint: assesment of white blood cell mitochondrial function was removed, as we were unable to perform this at our hospital.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 May 2020
    Inclusions were temporarily halted during the first COVID-19 outbreak.
    15 Jun 2020

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

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