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    Clinical Trial Results:
    EVOlocumab in stable Heart Failure with reduced ejection fraction of ischemic etiology: EVO-HF Pilot

    Summary
    EudraCT number
    		 2017-004656-30
    Trial protocol
    		 ES  
    Global end of trial date
    20 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Apr 2024
    First version publication date
    24 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ICOR-2016-05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    FUNDACIÓ INSTITUT D’INVESTIGACIÓ EN CIÈNCIES DE LA SALUT GERMANS TRIAS I PUJOL (IGTP)
    Sponsor organisation address
    Carretera de Canyet s/n, Badalona, Spain, 08916
    Public contact
    ScienHub Research Support, FUNDACIÓ INSTITUT D’INVESTIGACIÓ EN CIÈNCIES DE LA SALUT GERMANS TRIAS I PUJOL (IGTP), +34 934978414, info@scienhub.org
    Scientific contact
    ScienHub Research Support, FUNDACIÓ INSTITUT D’INVESTIGACIÓ EN CIÈNCIES DE LA SALUT GERMANS TRIAS I PUJOL (IGTP), +34 934978414, info@scienhub.org
    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 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess if LDL-C lowering at 1 year with monthly subcutaneous (SC) evolocumab 420 mg for 1 year will result in a significant reduction of high-sensitivity troponin T (hs-TnT), surrogate marker of myocyte injury and atherosclerosis progression, compared with current Standard of care (SOC) in subjects with elevated LDL-C, stable coronary artery disease (CAD) and stable heart failure with reduced ejection fraction (HFrEF).
    Protection of trial subjects
    Not specified
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2018
    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: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    12
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The participants were recruited in three Spanish Sites: - Hospital Universitario Germans Trias i Pujol. - Hospital Clínico Universitario de Valencia. - Hospital Universitario Virgen del Rocío de Sevilla

    Pre-assignment
    Screening details
    		 1. Signing of the informed consent 2. Patient ≥18 years and ≤80 years of age 3. LVEF <40% 4. Ischemic etiology (evidence of at least one acute coronary event and/or CAD by coronary angiography or multi slice CT) 5. New York Heart Association (NYHA) class II 6. NT-proBNP ≥400 pg/mL 7. Hs-TnT ≥10 pg/mL 8. LDL ≥ 70 mg/dL 9. Stable CAD

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Investigators will be blinded for the biomarkers results

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Evolocumab + GDMT
    Arm description
    		 Patients in arm 1 will receive 12 subcutaneous injections of 420 mg of evolocumab, once every month, along with GDMT during 1 year.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    evolocumab 420 mg/month on top of guideline-driven medical treatment (GDMT)

    Arm title
    		 GDMT
    Arm description
    		 Guideline-driven medical treatment according to each participant
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Evolocumab + GDMT GDMT
    Started
    17
    22
    Completed
    16
    22
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 39 39
    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)
    		 12 12
        From 65-84 years
    		 27 27
        85 years and over
    		 0 0
        Subjects
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 67.7 ± 9.7 -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 31 31

    End points

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    End points reporting groups
    Reporting group title
    Evolocumab + GDMT
    Reporting group description
    		 Patients in arm 1 will receive 12 subcutaneous injections of 420 mg of evolocumab, once every month, along with GDMT during 1 year.

    Reporting group title
    GDMT
    Reporting group description
    		 Guideline-driven medical treatment according to each participant

    Primary: The Change in hs-TnT levels at 1 year

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    End point title
    		 The Change in hs-TnT levels at 1 year
    End point description
    Statistical differences among patients in each treatment group were compared using the paired Student’s t-test or Wilcoxon test according to normal or non-normal distribution of the observed changes. No significant changes in hs-TnT levels were measured at 1 year in either of the two groups.
    End point type
    Primary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: hs-TnT levels
        median (standard deviation)
    0.63 ± 8.6
    1.42 ± 7.3
    Statistical analysis title
    		 Paired Student’s t-test
    Statistical analysis description
    Mean±standard deviation was used only when all of the values for one variable had a normal distribution, including changes between baseline and 1 year. Statistical differences among patients in each treatment group were compared using the paired Student’s t-test or Wilcoxon test according to normal or non-normal distribution of the observed changes.
    Comparison groups
    GDMT v Evolocumab + GDMT
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.539
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Change in NT-proBNP levels

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    End point title
    		 Change in NT-proBNP levels
    End point description
    The NT-proBNP levels decreased only in the evolocumab plus GDMT group (p=0.045), but the differences between treatment groups were non-significant.
    End point type
    Secondary
    End point timeframe
    at 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: NT-proBNP levels
        log mean (standard deviation)
    -882 ± 1676
    -117 ± 545
    No statistical analyses for this end point

    Secondary: Change in hs-CRP levels

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    End point title
    		 Change in hs-CRP levels
    End point description
    There were no significant changes in hs-CRP in either of the two groups
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: hs-CRP levels
        median (inter-quartile range (Q1-Q3))
    -0.3 (-3.55 to 0.15)
    -0.7 (-3.75 to 0.235)
    No statistical analyses for this end point

    Secondary: Change in LDL-C levels

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    End point title
    		 Change in LDL-C levels
    End point description
    Changes in total cholesterol and LDL-C were significantly different between groups, with higher decrease in the GDMT plus evolocumab group (p=0.003).
    End point type
    Secondary
    End point timeframe
    at 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: LDL-C levels
        log mean (standard deviation)
    -46.1 ± 35
    -15.3 ± 23.7
    No statistical analyses for this end point

    Secondary: Change LDLR levels

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    End point title
    		 Change LDLR levels
    End point description
    There were no significant changes in LDLR in either of the two groups
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: LDLR levels
        log mean (standard deviation)
    7.5 ± 23.1
    1.04 ± 12.6
    No statistical analyses for this end point

    Secondary: Change in HDL-C levels

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    End point title
    		 Change in HDL-C levels
    End point description
    There were no significant changes in HDL-C in either of the two groups
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: HDL-C levels
        log mean (standard deviation)
    -0.98 ± 9.4
    1.86 ± 9.1
    No statistical analyses for this end point

    Secondary: Change in PCSK9 Levels

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    End point title
    		 Change in PCSK9 Levels
    End point description
    PCSK9 blood levels increased only in the intervention group
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: PCSK9 Levels
        log mean (standard deviation)
    2307 ± 1366
    111.6 ± 479
    No statistical analyses for this end point

    Secondary: Change in 6 minutes walking test

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    End point title
    		 Change in 6 minutes walking test
    End point description
    No significant differences were measured in the distance walked in the 6-min walking test between groups
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: meters
        log mean (standard deviation)
    371 ± 120
    367 ± 104
    No statistical analyses for this end point

    Secondary: Change in quality of life test (KCCQ)

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    End point title
    		 Change in quality of life test (KCCQ)
    End point description
    There were also no significant changes in the scoring on the KCCQ. However, a non-significant trend for better evolution in quality of life perception in the intervention group was observed.
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: score
        log mean (standard deviation)
    74.9 ± 18.7
    78.7 ± 18.1
    No statistical analyses for this end point

    Secondary: Change in ST2 levels

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    End point title
    		 Change in ST2 levels
    End point description
    ST2 levels decreased significantly in the evolocumab plus GDMT group (p=0.008) and not in the GDMT alone group, and the difference between groups was significant (p=0.013).
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    		 Evolocumab + GDMT GDMT
    Number of subjects analysed
    17
    22
    Units: ST2 levels
        median (inter-quartile range (Q1-Q3))
    -3 (-7.5 to 0)
    1 (-3 to 2.25)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All adverse events that occur during the period comprehended from the time of enrollment of the patient in the study (signing of the consent form) to 30 days after discontinuation of the investigational products will be recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Experimental Group
    Reporting group description
    		 -

    Reporting group title
    Control Group
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The AEs report is not included in the EudraCT results. In total 14 non-serious AEs have been recorded by the control group and 18 non-serious AEs have been recorded by the experimental group. In total 32 non-serious AEs have been recorded during the study.
    Serious adverse events
    		 Experimental Group Control Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 17 (29.41%)
    5 / 22 (22.73%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Cardiac disorders
    Sustained ventricular tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 22 (13.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac dysfunction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart Failure
    Additional description: NYHA Class III
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Temporal artery stenosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia by covid-19
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden onset dyspnea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haematoma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal gland operation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical Herniation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental Group Control Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2019
    Two changes in the criteria inclusion. The value of LDL cholesterol will be reduced to &#8805; 70 mg/dL and the troponin T (Hs-TnT) value high sensitivity will be reduced to #8805; 10 pg/ml. It is decided to reduce These two criteria values inclusion to be able to include more patients in the study and benefit of the treatment, and extrapolate further faithfully the results of the study the real population.
    13 Feb 2020
    Change of inclusion criterion #6, duration update study and addition of a new site recruiter
    11 Feb 2021
    Update of the number of subjects of the rehearsal and communication of the termination of collaboration AMGEN in the study

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Jul 2021
    The corresponding competent authority requested the sponsor the verification of compliance with Good Manufacturing Standards by the Pharmacy Service Hospital involved in the manufacture of Investigational Drug(s) after the AMGEN discontinuation in the study.
    14 Sep 2021

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    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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