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    Clinical Trial Results:
    A Randomized, Double Blind, Placebo-controlled, Parallel Group, Multicentre, Phase 2a Study to Assess Target Engagement, Safety and Tolerability of AZD4831 in Patients with Heart Failure with Preserved Ejection Fraction (HFpEF)

    Summary
    EudraCT number
    		 2018-002895-42
    Trial protocol
    		 SE   DK   FI   NL  
    Global end of trial date
    07 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2021
    First version publication date
    23 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D6580C00003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Astraallén, Södertälje, Sweden, 15185
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@astrazeneca.com
    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
    26 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of AZD4831 (an MPO inhibitor) on TE, by measuring MPO specific activity in plasma following ex vivo stimulation of fresh blood samples with zymosan, in patients with HFpEF. The study objectives also included evaluation of the safety and tolerability of AZD4831 in patients with HFpEF, and the incidence of Grade 3 maculopapular rash (maculopapular rash is an identified risk for AZD4831), and to assess the effect of AZD4831 on CFVR (as a measure of myocardial microvascular function) and 6MWD, in addition to assessing the PK of AZD4831 after repeated dosing.
    Protection of trial subjects
    Visit 4 and 6 may be performed as telephone contacts with the patient, if judged appropriate by investigator.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Sweden: 24
    Worldwide total number of subjects
    41
    EEA total number of subjects
    40
    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)
    2
    From 65 to 84 years
    38
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects may enter a screening period up to 28 days prior to randomization.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZD4831
    Arm description
    		 AZD4831 tablets taken orally for for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4831
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets taken orally for 90 days.
    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
    Once daily

    Number of subjects in period 1
    		AZD4831 Placebo
    Started
    27
    14
    Completed
    24
    9
    Not completed
    3
    5
         Subject meets exclusion criteria
    -
    1
         Dosing discontinued due to COVID-19
    3
    3
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZD4831
    Reporting group description
    		 AZD4831 tablets taken orally for for 90 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets taken orally for 90 days.

    Reporting group values
    		 AZD4831 Placebo Total
    Number of subjects
    		 27 14 41
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 1 2
        From 65-84 years
    		 25 13 38
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.8 ( 6.61 ) 73.5 ( 6.99 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 12 7 19
        Male
    		 15 7 22
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 27 13 40
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 27 14 41
        Unknown or Not Reported
    		 0 0 0
    Country
    Units: Subjects
        Denmark
    		 3 2 5
        Netherlands
    		 2 1 3
        USA
    		 0 1 1
        Finland
    		 5 3 8
        Sweden
    		 17 7 24

    End points

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    End points reporting groups
    Reporting group title
    AZD4831
    Reporting group description
    		 AZD4831 tablets taken orally for for 90 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets taken orally for 90 days.

    Primary: The change from baseline in MPO activity in % after AZD4831 treatment.

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    End point title
    		 The change from baseline in MPO activity in % after AZD4831 treatment.
    End point description
    To compare the effect of AZD4831 to placebo on target engagement
    End point type
    Primary
    End point timeframe
    Measurements on day 0, 10, 30 and 90.
    End point values
    		 AZD4831 Placebo
    Number of subjects analysed
    20
    14
    Units: Ratio
        least squares mean (confidence interval 95%)
    0.547 (0.379 to 0.790)
    2.177 (1.168 to 4.058)
    Statistical analysis title
    		 Relative change from baseline to end of treatment
    Comparison groups
    AZD4831 v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Means Ratio
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.52

    Secondary: Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE).

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    End point title
    		 Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE).
    End point description
    To compare the effect of AZD4831 to placebo on coronary flow velocity reserve (CFVR)
    End point type
    Secondary
    End point timeframe
    Measurement on day 0 and 90.
    End point values
    		 AZD4831 Placebo
    Number of subjects analysed
    18
    5
    Units: Ratio
        least squares mean (confidence interval 95%)
    0.975 (0.835 to 1.138)
    1.002 (0.747 to 1.344)
    Statistical analysis title
    		 Relative change from baseline to end of treatment
    Comparison groups
    AZD4831 v Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.568
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Means Ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.74
         upper limit
    		 -

    Secondary: Change from baseline in Walking distance

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    End point title
    		 Change from baseline in Walking distance
    End point description
    To compare the effect of AZD4831 to placebo on 6 minutes walking test (6MWT)
    End point type
    Secondary
    End point timeframe
    Measurement on day 0, 30 and 90.
    End point values
    		 AZD4831 Placebo
    Number of subjects analysed
    23
    11
    Units: Meters
        least squares mean (confidence interval 95%)
    47.4 (20.3 to 74.5)
    25.6 (-19.8 to 71.1)
    Statistical analysis title
    		 Change from baseline to end of treatment
    Comparison groups
    AZD4831 v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.407
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    21.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.5
         upper limit
    		 74.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events will be collected from the time of the first dose throughout the treatment period and including the follow-up period. Serious Adverse Events will be recorded from the time of signing the informed consent form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets taken orally for 90 days.

    Reporting group title
    AZD4831
    Reporting group description
    		 AZD4831 tablets taken orally for for 90 days.

    Serious adverse events
    		 Placebo AZD4831
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 27 (7.41%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (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: 1%
    Non-serious adverse events
    		 Placebo AZD4831
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 14 (64.29%)
    21 / 27 (77.78%)
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    Peripheral coldness
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Infusion site oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood urea increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Troponin T increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Head injury
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Scratch
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Cardiac failure
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 27 (11.11%)
         occurrences all number
    1
    3
    Headache
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Plicated tongue
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 27 (11.11%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Bursitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gingivitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Pyelonephritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2020
    Exclusion criteria 1 is updated to decrease eGFR from 45 to 30 ml/min/1.73m2, at screening visit.

    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.
    Due to premature study termination, the statistical assumptions for the study design according to the protocol could not be fulfilled, therefore, no statistical conclusions can be made based efficacy objectives.
    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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