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    Clinical Trial Results:
    The Effect of Trimetazidine on Mitochondrial Function, Myocardial Performance, and Invasive Hemodynamics in Patients Diagnosed with Wild-Type Transthyretin Cardiac Amyloidosis.

    Summary
    EudraCT number
    		 2020-001617-21
    Trial protocol
    		 DK  
    Global end of trial date
    07 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2024
    First version publication date
    29 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    72864
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus, Denmark,
    Public contact
    Department of Cardiology, Aarhus University Hospital, berlad@rm.dk
    Scientific contact
    Department of Cardiology, Aarhus University Hospital, berlad@rm.dk
    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
    10 Jul 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is: 1) to characterize the oxidative capacity of myocardial mitochondria as well as to investigate the treatment effect of Trimetazidine (TMZ) in patients with stage 1 cardiac amyloidosis in a double-blind, placebo-controlled cross-over study; 2) to examine the effect of TMZ at rest and during exercise on systolic and diastolic function measured by right heart catheterization (RHC) and advanced echocardiography; 3) to investigate and characterize the morphology of myocardial myocytes and mitochondria by electron microscopy; 4) to compare the oxidative capacity, morphology, and myocardial function of mitochondria in patients with early-stage asymptomatic disease versus patients with more advanced symptomatic disease.
    Protection of trial subjects
    Data monitoring was performed by the Good Clinical Practice Unit at Aarhus University. All subject were enrolled after providing written informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2020
    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
    Denmark: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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
    22
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with early-stage wild-type transthyretin cardiac amyloidosis were recruited at the department of cardiology at Aarhus University Hospital.

    Pre-assignment
    Screening details
    		 Inclusion criteria - Age ≥ 60 years for men. Age ≥ 70 years for women - TC99-DPD-scintigraphy positive for cardiac involvement - Negative serum immunofixation - Normal Kappa/Lambda ratio - NAC stage I (NT-proBNP ≤ 3000 ng/L, eGFR ≥ 45 mL/min) - NYHA-class I-IIa - Written informed consent

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Trimetazidine
    Arm description
    		 Trimetazidine 20 mg three times daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    trimetazidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg three times daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo three times daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo three times daily

    Number of subjects in period 1
    		Trimetazidine Placebo
    Started
    24
    24
    Completed
    22
    22
    Not completed
    2
    2
         Adverse event, non-fatal
    2
    2
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trimetazidine
    Arm description
    		 Trimetazidine 20 mg times three daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    trimetazidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg three times daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo capsule three times daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo three times daily

    Number of subjects in period 2
    		Trimetazidine Placebo
    Started
    24
    24
    Completed
    22
    22
    Not completed
    2
    2
         Adverse event, non-fatal
    2
    2

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 24 24
    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)
    		 0 0
        From 65-84 years
    		 24 24
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 23 23

    End points

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    End points reporting groups
    Reporting group title
    Trimetazidine
    Reporting group description
    		 Trimetazidine 20 mg three times daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo three times daily
    Reporting group title
    Trimetazidine
    Reporting group description
    		 Trimetazidine 20 mg times three daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo capsule three times daily

    Primary: Pulmonary artery wedge pressure at peak exercise

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    End point title
    		 Pulmonary artery wedge pressure at peak exercise
    End point description
    The primary end point was a difference in peak pulmonary artery wedge pressure at peak exercise between trimetazidine and placebo.
    End point type
    Primary
    End point timeframe
    ..
    End point values
    		 Trimetazidine Placebo
    Number of subjects analysed
    22
    22
    Units: mmHg
        arithmetic mean (standard deviation)
    31 ( 12 )
    31 ( 13 )
    Statistical analysis title
    		 Linear mixed model
    Comparison groups
    Trimetazidine v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 > 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Cardiac mitochondrial oxidative capacity

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    End point title
    		 Cardiac mitochondrial oxidative capacity
    End point description
    The secondary end point was cardiac mitochondrial oxidative phosphorylation capacity.
    End point type
    Secondary
    End point timeframe
    .
    End point values
    		 Trimetazidine Placebo
    Number of subjects analysed
    22
    22
    Units: pmol O2/(mg*s)
        arithmetic mean (standard deviation)
    73.4 ( 7.7 )
    75.3 ( 7.7 )
    Statistical analysis title
    		 Linear mixed model
    Comparison groups
    Trimetazidine v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 > 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    01Nov2020 to 01Aug2023
    Adverse event reporting additional description
    Collected by the study team and assessed by the investigator and supervisor.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 -

    Reporting group title
    Placebo arm
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Pericardial effusion
    Additional description: During biopsy procedure the patient suffered a pericardial effusion which was treated with pericardiocentesis.
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
    Additional description: After the procedures, the patient showed sustained VT on the telemetry.
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Treatment arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 24 (20.83%)
    5 / 24 (20.83%)
    Cardiac disorders
    Dizzyness
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Chest discomfort
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Stomach pain
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Infections and infestations
    Flu-like symptoms
         subjects affected / exposed
    0 / 24 (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? No

    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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    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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