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    Clinical Trial Results:
    A randomized, placebo-controlled, investigator- and participant-blinded study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of HSY244 in participants with atrial fibrillation

    Summary
    EudraCT number
    2020-004327-17
    Trial protocol
    DE  
    Global end of trial date
    11 Jul 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CHSY244X2201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04582409
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Study Director  , Novartis Pharmaceuticals  , 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Study Director  , Novartis Pharmaceuticals  , 41 613241111, Novartis.email@Novartis.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
    11 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of HSY244 to restore sinus rhythm in participants with Atrial Fibrillation (AF)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Nov 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
    Germany: 9
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    13
    EEA total number of subjects
    9
    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
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A screening period of up to 3 days (72 hours) was used to assess eligibility.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    HSY244
    Arm description
    HSY244 150 mg concentrate solution for injection via intravenous infusion
    Arm type
    Experimental

    Investigational medicinal product name
    HSY244
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    HSY244 150 mg i.v. infusion over 15 minutes

    Arm title
    Placebo
    Arm description
    Placebo concentrate solution for injection via intravenous infusion
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo i.v. infusion over 15 minutes

    Number of subjects in period 1
    HSY244 Placebo
    Started
    7
    6
    Completed
    7
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HSY244
    Reporting group description
    HSY244 150 mg concentrate solution for injection via intravenous infusion

    Reporting group title
    Placebo
    Reporting group description
    Placebo concentrate solution for injection via intravenous infusion

    Reporting group values
    HSY244 Placebo Total
    Number of subjects
    7 6 13
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    5 5 10
        From 65-84 years
    2 1 3
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.6 ± 9.73 60.0 ± 4.05 -
    Sex: Female, Male
    Units: participants
        Female
    1 0 1
        Male
    6 6 12
    Race/Ethnicity, Customized
    Units: Subjects
        White
    7 5 12
        Other
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    HSY244
    Reporting group description
    HSY244 150 mg concentrate solution for injection via intravenous infusion

    Reporting group title
    Placebo
    Reporting group description
    Placebo concentrate solution for injection via intravenous infusion

    Primary: Number of participants with conversion to sinus rhythm for at least 1 minute within 90 minutes from the start of study drug administration.

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    End point title
    Number of participants with conversion to sinus rhythm for at least 1 minute within 90 minutes from the start of study drug administration. [1]
    End point description
    Conversion to sinus rhythm was monitored using a Holter monitoring device through 90 minutes after the start of study drug administration. If a participant had been monitored for at least 45 minutes and did not convert to sinus rhythm for at least one minute, the primary endpoint was defined as ‘no’. If a participant converted to sinus rhythm for at least one minute at any time during the post-treatment 90 minutes observation period, regardless of the length of time monitored, the primary endpoint was to be defined as ‘yes’.
    End point type
    Primary
    End point timeframe
    90 minutes from the start of study drug administration
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The planned statistical analyses could not be completed as no primary outcome events occurred.
    End point values
    HSY244 Placebo
    Number of subjects analysed
    7
    6
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    Maximum Observed Plasma Concentration (Cmax)
    End point description
    The Cmax is the maximum (peak) observed plasma drug concentration after single-dose administration. Actual recorded sampling times were taken into consideration for PK calculations.
    End point type
    Secondary
    End point timeframe
    Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
    End point values
    HSY244 Placebo
    Number of subjects analysed
    7
    0 [2]
    Units: ng/mL
        arithmetic mean (standard deviation)
    4800 ± 3890
    ±
    Notes
    [2] - Only participants who received the investigational product were evaluated
    No statistical analyses for this end point

    Secondary: Time to Reach the Maximum Concentration After Drug Administration (Tmax)

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    End point title
    Time to Reach the Maximum Concentration After Drug Administration (Tmax)
    End point description
    Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). Actual recorded sampling times were taken into consideration for PK calculations.
    End point type
    Secondary
    End point timeframe
    Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
    End point values
    HSY244 Placebo
    Number of subjects analysed
    7
    0 [3]
    Units: Hour
        median (full range (min-max))
    0.28 (0.25 to 0.30)
    ( to )
    Notes
    [3] - Only participants who received the investigational product were evaluated
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve (AUClast)

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    End point title
    Area under the plasma concentration-time curve (AUClast)
    End point description
    AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast). Actual recorded sampling times were taken into consideration for PK calculations.
    End point type
    Secondary
    End point timeframe
    Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
    End point values
    HSY244 Placebo
    Number of subjects analysed
    6
    0 [4]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    2960 ± 1510
    ±
    Notes
    [4] - Only participants who received the investigational product were evaluated
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 31 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    HSY244 150 mg
    Reporting group description
    HSY244 150 mg

    Reporting group title
    Total
    Reporting group description
    Total

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Serious adverse events
    HSY244 150 mg Total Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    HSY244 150 mg Total Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    11 / 13 (84.62%)
    5 / 6 (83.33%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 13 (15.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Blood urine present
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    Procedural hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 13 (15.38%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Burning sensation
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Tremor
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 13 (23.08%)
    2 / 6 (33.33%)
         occurrences all number
    1
    3
    2
    Limb discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle tightness
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 13 (15.38%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2020
    The purpose of this amendment was to correct the EUDRACT number on the cover page.
    12 Jan 2021
    The primary purpose of this amendment was to address requests for protocol amendments from Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM). BfArM requests include the following: 1) to clarify the maximum number of replacement participants per cohort, and to clarify that only those participants would be replaced which have not discontinued due to adverse drug reactions or adverse events based on study procedures, 2) to clarify that a protocol amendment would be submitted to the Competent Authorities and IRB/IECs for approval to start Cohort 2 if a decision to initiate Cohort 2 was due to safety concerns from Cohort 1, 3) to clarify that Competent Authorities, IRB/IECs, and PIs would be informed if the study met a study stopping rule criteria, and approval was required by Competent Authorities and IRB/IECs to restart the study and 4) to clarify that only participants who were capable of providing informed consent themselves would be included in the study.
    26 Aug 2021
    The primary purpose of this amendment was to update the eligibility criteria. The changes to the eligibility criteria were based on sites’ feedback, which facilitated better representation of the study population to that of patients with atrial fibrillation and a clinical indication for cardioversion. These updates were not expected to increase risk to patient safety or result in meaningful decreases in study drug efficacy. In addition, the protocol text was updated to clarify the study duration. The study duration is unchanged (96 hours or 4 days post-dose) with end of study (EOS) visit occurring on Day 5.
    04 Apr 2022
    The primary purposes of this amendment were to reduce participant burden, reduce site burden, expand eligibility, and expedite study completion. At the time of writing this amendment, eight participants had been enrolled in Cohort 1. Through discussions with investigators and site staff about enrollment challenges it was determined that the protocol needed to be updated to decrease burden and to better represent the patient population with atrial fibrillation (AF) meeting a clinical indication for cardioversion. With these changes, enrollment was expected to increase and expedite study completion, while not increasing the risk to participant safety during the trial.

    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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