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    Clinical Trial Results:
    Multicenter, open-label, dose escalation study to evaluate safety, tolerability and pharmacokinetics of RLX030 in addition to standard of care in pediatric patients from birth to <18 years of age, hospitalized with acute heart failure

    Summary
    EudraCT number
    2013-002847-28
    Trial protocol
    DE  
    Global end of trial date
    03 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRLX030A2208
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02151383
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001168-PIP01-11
    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
    03 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    -To evaluate the safety and tolerability of an iv serelaxin infusion in addition to standard of care in hospitalized pediatric patients with AHF -To investigate the effects of age on the pharmacokinetics of serelaxin given as iv infusion in addition to standard of care in hospitalized pediatric patients with AHF
    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. The investigator could prescribe any medications and/or supportive care during the study based on clinical needs.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Sep 2014
    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: 4
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    12
    EEA total number of subjects
    5
    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)
    2
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 18 patients were assigned to study treatment. 6 patients were identified with GCP violations; hence, only 12 patients were included in disposition.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Serelaxin: Cohort 1
    Arm description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 1, patients in age group of 6 to <18 years were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. Both the low-dose and high- dose groups were planned to receive equal number of patients.
    Arm type
    Experimental

    Investigational medicinal product name
    Serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The study drug was provided as a 1 mg/mL solution in 6 mL vials (with 3.5 mL fill). The required dose (μg/kg) was calculated for each patient at the assigned dose titration level.

    Arm title
    Serelaxin: Cohort 2
    Arm description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 2, patients in age group of 1 to <6 years were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. Both the low-dose and high- dose groups were planned to receive equal number of patients.
    Arm type
    Experimental

    Investigational medicinal product name
    Serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The study drug was provided as a 1 mg/mL solution in 6 mL vials (with 3.5 mL fill). The required dose (μg/kg) was calculated for each patient at the assigned dose titration level.

    Arm title
    Serelaxin: Cohort 3
    Arm description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 3, patients in age group of 1 month to <1 year were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. In this cohort, high- dose group was planned to receive twice the number of patients in low-dose group.
    Arm type
    Experimental

    Investigational medicinal product name
    Serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The study drug was provided as a 1 mg/mL solution in 6 mL vials (with 3.5 mL fill). The required dose (μg/kg) was calculated for each patient at the assigned dose titration level.

    Number of subjects in period 1
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Started
    8
    3
    1
    Low-dose
    2 [1]
    3
    1
    High-dose
    6 [2]
    0 [3]
    0 [4]
    Completed
    8
    3
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are fix dose titration groups for the cohort where the cohort patients are assigned to either of these 2 groups.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are fix dose titration groups for the cohort where the cohort patients are assigned to either of these 2 groups.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are fix dose titration groups for the cohort where the cohort patients are assigned to either of these 2 groups.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are fix dose titration groups for the cohort where the cohort patients are assigned to either of these 2 groups.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    These 12 patients are in enrolled and safety set which exclude the 6 patients identified with GCP violations

    Reporting group values
    Overall Study Total
    Number of subjects
    12 12
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    2 2
        Children (2-11 years)
    5 5
        Adolescents (12-17 years)
    5 5
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    8.1 ± 5.17 -
    Gender, Male/Female
    Units: Subjects
        Female
    1 1
        Male
    11 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 2
        Not Hispanic or Latino
    7 7
        Unknown or Not Reported
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Serelaxin: Cohort 1
    Reporting group description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 1, patients in age group of 6 to <18 years were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. Both the low-dose and high- dose groups were planned to receive equal number of patients.

    Reporting group title
    Serelaxin: Cohort 2
    Reporting group description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 2, patients in age group of 1 to <6 years were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. Both the low-dose and high- dose groups were planned to receive equal number of patients.

    Reporting group title
    Serelaxin: Cohort 3
    Reporting group description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 3, patients in age group of 1 month to <1 year were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. In this cohort, high- dose group was planned to receive twice the number of patients in low-dose group.

    Primary: Number of patients reported with treatment emergent any adverse events, serious adverse events and death

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    End point title
    Number of patients reported with treatment emergent any adverse events, serious adverse events and death [1]
    End point description
    Number of patients with treatment emergent adverse events (including confirmed systolic blood pressure decreases and worsening heart failure), serious adverse events and death is reported.
    End point type
    Primary
    End point timeframe
    through 28 days + 30 days SAE follow up after completion or discontinuation from the study
    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: No statistical hypothesis was planned to be tested.
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    8
    3
    1
    Units: Patients
        at least one Adverse Event
    6
    3
    0
        Serious Adverse Event
    3
    1
    0
        Death
    0
    0
    0
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameter: Css (steady state concentration)

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    End point title
    Pharmacokinetic parameter: Css (steady state concentration) [2]
    End point description
    Steady state concentration was planned to be estimated by 16 hour, 32 hour and 48 hour concentration for each dose level.
    End point type
    Primary
    End point timeframe
    at 0, 2, 16, 22, 32, 40, 48 hr. during the infusion, at 0.5, 4, 8 hours post infusion or study drug discontinuation, and on day 28
    Notes
    [2] - 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: No statistical hypothesis was planned to be tested.
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [3] - PK data was considered too limited for a meaningful interpretation
    [4] - PK data was considered too limited for a meaningful interpretation
    [5] - PK data was considered too limited for a meaningful interpretation
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameter: CL (clearance)

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    End point title
    Pharmacokinetic parameter: CL (clearance) [6]
    End point description
    Clearance(CL) was planned to be estimated using steady state concentration (Css) and rate of infusion.
    End point type
    Primary
    End point timeframe
    at 0, 2, 16, 22, 32, 40, 48 hr. during the infusion, at 0.5, 4, 8 hours post infusion or study drug discontinuation, and on day 28
    Notes
    [6] - 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: No statistical hypothesis was planned to be tested.
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: mL/hr
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [7] - PK data was considered too limited for a meaningful interpretation
    [8] - PK data was considered too limited for a meaningful interpretation
    [9] - PK data was considered too limited for a meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of arterial blood pressure

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    End point title
    Change from baseline of arterial blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [10] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [11] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [12] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of central venous pressure (CVP)

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    End point title
    Change from baseline of central venous pressure (CVP)
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [13] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [14] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [15] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of left atrial pressure (LAP)

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    End point title
    Change from baseline of left atrial pressure (LAP)
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [16] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [17] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [18] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of pulmonary artery pressure (PAP– systolic and diastolic)

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    End point title
    Change from baseline of pulmonary artery pressure (PAP– systolic and diastolic)
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [19] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [20] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [21] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of central venous and arterial oxygen saturation

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    End point title
    Change from baseline of central venous and arterial oxygen saturation
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [22]
    0 [23]
    0 [24]
    Units: percentage
        number (not applicable)
    Notes
    [22] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [23] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [24] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of urine output

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    End point title
    Change from baseline of urine output
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    Units: ml/kg/hour
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [25] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [26] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [27] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Secondary: Change from baseline of blood lactate levels

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    End point title
    Change from baseline of blood lactate levels
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, prior to each dose escalation, and at 24 hr. post end of infusion
    End point values
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Number of subjects analysed
    0 [28]
    0 [29]
    0 [30]
    Units: mmol/L
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [28] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [29] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    [30] - Data analysis was not done as limited set of data would preclude meaningful interpretation
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Serelaxin: Cohort 1
    Reporting group description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 1, patients in age group of 6 to <18 years were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. Both the low-dose and high- dose groups were planned to receive equal number of patients.

    Reporting group title
    Serelaxin: Cohort 2
    Reporting group description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 2, patients in age group of 1 to <6 years were enrolled either into a low-dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. Both the low-dose and high- dose groups were planned to receive equal number of patients.

    Reporting group title
    Serelaxin: Cohort 3
    Reporting group description
    Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours. In Cohort 3, patients in age group of 1 month to <1 year were enrolled either into a low dose or a high-dose group. During this 48-hour treatment period, the serelaxin dose rates to be administered were 3 μg/kg/day, 10 μg/kg/day and 30 μg/kg/day in the low -dose group; 10 μg/kg/day, 30 μg/kg/day and 100 μg/kg/day in the high-dose group. In this cohort, high- dose group was planned to receive twice the number of patients in low-dose group.

    Serious adverse events
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    Serelaxin: Cohort 1 Serelaxin: Cohort 2 Serelaxin: Cohort 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    3 / 3 (100.00%)
    0 / 1 (0.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood pressure systolic decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Cardioactive drug level increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Skin oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Pneumonia viral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2014
    No patients had entered this study at the time of this amendment. Health Authority review of the original protocol resulted in study design changes regarding the starting dose (low dose group was added) and the patient sample size. Additional analyses were added with regard to vital signs and adverse events. Feedback from pediatric cardiology experts led to small changes to the exclusion criteria and clarification regarding the criteria for inclusion of patients with a chest x-ray done as part of their standard-of-care.
    20 Aug 2014
    No patients had entered the study at the time this amendment was prepared. This amendment mainly described the sub-study regarding additional data collection that was to be conducted in a small number of participating study sites (1-2 sites), which would enable a more in depth exploration of serelaxin’s PK-PD relationship
    30 Sep 2016
    Fourteen patients had been enrolled in the study at the time this amendment was prepared. The protocol was amended to incorporate changes to enhance the recruitment feasibility for the study without compromising the study objectives or patient safety.

    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 the early termination of the study, the planned analyses were not performed as the limited set of data would preclude meaningful interpretation.
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