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    Clinical Trial Results:
    A Phase 2, Multicenter, Randomised, Double-Blind, Placebo-Controlled Study to Assess the Hemodynamic Effects, Safety, Tolerability, and Pharmacokinetics of APD418 in Subjects with Heart Failure with Reduced Ejection Fraction

    Summary
    EudraCT number
    		 2020-006131-10
    Trial protocol
    		 PL  
    Global end of trial date
    19 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2023
    First version publication date
    30 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C5061001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05139615
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 APD418-201: Other study ID
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    01 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the effect of intravenous (IV) infusion of APD418 on hemodynamic status based on cardiac index (CI) in subjects with heart failure with reduced ejection fraction (HFrEF).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Dec 2021
    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: 1
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Serbia: 13
    Worldwide total number of subjects
    22
    EEA total number of subjects
    7
    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)
    13
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was planned to be conducted in two parts (Part A and B); however, study was terminated during Part A due to a business decision by Sponsor and Part B was not initiated and no subjects were enrolled in Part B.

    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, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1- 0.17 mg/kg/hr APD418
    Arm description
    		 Subjects were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    APD418
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.17 mg/kg/h (1 mg/kg) single 6-hour IV infusion

    Arm title
    		 Cohort 1- Placebo
    Arm description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose

    Arm title
    		 Cohort 2- 0.5 mg/kg/hr APD418
    Arm description
    		 Subjects were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    APD418
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.50 mg/kg/h (3 mg/kg) single 6-hour IV infusion

    Arm title
    		 Cohort 2- Placebo
    Arm description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single use

    Number of subjects in period 1
    		Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Started
    4
    3
    11
    4
    Completed
    4
    3
    11
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1- 0.17 mg/kg/hr APD418
    Reporting group description
    		 Subjects were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 1- Placebo
    Reporting group description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 2- 0.5 mg/kg/hr APD418
    Reporting group description
    		 Subjects were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 2- Placebo
    Reporting group description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo Total
    Number of subjects
    		 4 3 11 4 22
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 2 2 8 1 13
        From 65-84 years
    		 2 1 3 3 9
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.0 ± 9.56 62.0 ± 3.61 57.0 ± 10.82 68.0 ± 6.88 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 1 0 4 0 5
        Male
    		 3 3 7 4 17
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0
        White
    		 4 3 11 4 22
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 4 3 11 4 22
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1- 0.17 mg/kg/hr APD418
    Reporting group description
    		 Subjects were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 1- Placebo
    Reporting group description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 2- 0.5 mg/kg/hr APD418
    Reporting group description
    		 Subjects were administered a single dose of 0.5 mg/kg/hr (total dose of 3 mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 2- Placebo
    Reporting group description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Primary: Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterisation (RHC) From Baseline to end of Intravenous (IV) Infusion at 6 Hours

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    End point title
    		 Part A: Change in Cardiac Index (CI) Measured by Right Heart Catheterisation (RHC) From Baseline to end of Intravenous (IV) Infusion at 6 Hours [1]
    End point description
    Cardiac index (CI) is a hemodynamic parameter that relates the cardiac output (CO) from left ventricle in one minute to body surface area (BSA), thus relating heart performance to the body size of the subject. It was measured by RHC. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Primary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    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 analyses were planned for this primary end point.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Liter per minute per meter square
        arithmetic mean (standard deviation)
    0.33 ± 0.660
    0.10 ± 0.100
    0.25 ± 0.372
    0.10 ± 0.245
    No statistical analyses for this end point

    Secondary: Part A: Change in Stroke Volume (SV), Left Ventricular end-Systolic Volume (LVESV) and Left Ventricular end-Diastolic Volume (LVEDV) Measured by Echocardiogram (ECHO) From Baseline to end of IV Infusion at 6 Hours

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    End point title
    		 Part A: Change in Stroke Volume (SV), Left Ventricular end-Systolic Volume (LVESV) and Left Ventricular end-Diastolic Volume (LVEDV) Measured by Echocardiogram (ECHO) From Baseline to end of IV Infusion at 6 Hours
    End point description
    SV is the volume of blood pumped from the left ventricle per beat. LVESV is the volume of blood in the left ventricle at the end of contraction and at diastole. LVEDV is the amount of blood in the heart’s left ventricle just before the heart contracts. All these parameters were measured by ECHO. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    1
    9
    4
    Units: Milliliter
    arithmetic mean (standard deviation)
        Stroke Volume
    3.13 ± 10.623
    -0.80 ± 99999
    5.94 ± 10.183
    -3.15 ± 7.152
        LVESV
    -11.05 ± 22.837
    4.10 ± 99999
    8.28 ± 25.689
    8.92 ± 29.804
        LVEDV
    -7.92 ± 15.531
    3.30 ± 99999
    14.20 ± 31.021
    7.30 ± 38.006
    No statistical analyses for this end point

    Secondary: Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours

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    End point title
    		 Part A: Change in Stroke Volume Index (SVI) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours
    End point description
    SVI was calculated as stroke volume divided by BSA. This was measured by ECHO. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    1
    9
    4
    Units: Milliliter per meter square
        arithmetic mean (standard deviation)
    1.50 ± 5.518
    -0.30 ± 99999
    2.62 ± 4.615
    -2.00 ± 4.492
    No statistical analyses for this end point

    Secondary: Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours

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    End point title
    		 Part A: Change in Fractional Shortening (FS) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours
    End point description
    FS was calculated by measuring the percentage reduction in left ventricular diameter during systole. This was measured by ECHO. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Percentage reduction
        arithmetic mean (standard deviation)
    -2.60 ± 7.791
    0.47 ± 5.710
    -1.55 ± 1.924
    -4.50 ± 7.444
    No statistical analyses for this end point

    Secondary: Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours

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    End point title
    		 Part A: Change in Left Ventricular Ejection Fraction (LVEF) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours
    End point description
    LVEF is the central measure of left ventricular systolic function. LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). This was measured by ECHO. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Percentage of end diastolic volume
        arithmetic mean (standard deviation)
    1.90 ± 6.009
    0.47 ± 1.457
    1.14 ± 3.204
    -1.68 ± 0.900
    No statistical analyses for this end point

    Secondary: Part A: Change in Left Ventricular end-Systolic and Left Ventricular end-Diastolic Diameter Measured by ECHO From Baseline to end of IV Infusion at 6 Hours

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    End point title
    		 Part A: Change in Left Ventricular end-Systolic and Left Ventricular end-Diastolic Diameter Measured by ECHO From Baseline to end of IV Infusion at 6 Hours
    End point description
    Left ventricular end-systolic diameter and left ventricular end-diastolic diameter were measured using ECHO. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Centimeter (cm)
    arithmetic mean (standard deviation)
        Left ventricular end-systolic diameter
    0.10 ± 0.361
    -0.04 ± 0.384
    0.22 ± 0.321
    0.35 ± 0.544
        Left ventricular end-diastolic diameter
    -0.04 ± 0.087
    -0.02 ± 0.098
    0.15 ± 0.363
    0.16 ± 0.243
    No statistical analyses for this end point

    Secondary: Part A: Change in Left Ventricular Global Longitudinal Strain (LVGLS) and Left Ventricular Global Circumferential Strain (LVGCS) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours

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    End point title
    		 Part A: Change in Left Ventricular Global Longitudinal Strain (LVGLS) and Left Ventricular Global Circumferential Strain (LVGCS) Measured by ECHO From Baseline to end of IV Infusion at 6 Hours
    End point description
    LVGLS is the average strain of the cardiac chamber wall. LVGCS measured the chamber deformation along the circumference of the cardiac wall in a tangential xy-direction. Both the parameters were measured by ECHO. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint and ‘n’ signifies subjects evaluable for the specified rows.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration) up to 6 Hours (end of IV infusion)
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    1
    1
    5
    4
    Units: Percentage systolic deformation
    arithmetic mean (standard deviation)
        LVGLS (n= 1, 1, 4, 4)
    0.30 ± 99999
    -1.10 ± 99999
    1.10 ± 1.337
    -1.29 ± 0.987
        LVGCS (n= 1, 0, 5, 2)
    -6.70 ± 99999
    99999 ± 99999
    0.05 ± 2.105
    0.00 ± 3.111
    No statistical analyses for this end point

    Secondary: Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion

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    End point title
    		 Part A: Change in CI Measured by RHC at 0.5, 1, 2, 3, 4 and 5 Hours During 6 Hour IV Infusion
    End point description
    CI is a hemodynamic parameter that relates the CO from left ventricle in one minute to BSA, thus relating heart performance to the body size of the subject. It was measured by RHC. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4 and 5 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Liter per minute per meter square
    arithmetic mean (standard deviation)
        0.5 hours
    -0.05 ± 0.252
    0.27 ± 0.379
    0.10 ± 0.167
    -0.10 ± 0.183
        1 hour
    0.35 ± 0.252
    0.27 ± 0.379
    0.06 ± 0.112
    0.05 ± 0.208
        2 hours
    0.45 ± 0.370
    0.13 ± 0.058
    0.11 ± 0.104
    -0.08 ± 0.126
        3 hours
    0.68 ± 0.427
    0.20 ± 0.265
    0.20 ± 0.279
    0.15 ± 0.129
        4 hours
    0.25 ± 0.100
    0.10 ± 0.100
    0.09 ± 0.221
    0.10 ± 0.346
        5 hours
    0.23 ± 0.457
    0.17 ± 0.153
    0.11 ± 0.274
    0.08 ± 0.096
    No statistical analyses for this end point

    Secondary: Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Cardiac Output (CO) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    Change in CO measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this outcome measure. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Liter per minute
    arithmetic mean (standard deviation)
        0.5 hours
    -0.15 ± 0.420
    0.63 ± 0.777
    0.20 ± 0.329
    -0.15 ± 0.300
        1 hour
    0.68 ± 0.457
    0.67 ± 0.907
    0.15 ± 0.230
    0.13 ± 0.340
        2 hours
    0.90 ± 0.876
    0.43 ± 0.231
    0.21 ± 0.212
    -0.08 ± 0.189
        3 hours
    1.28 ± 0.877
    0.47 ± 0.643
    0.41 ± 0.568
    0.33 ± 0.299
        4 hours
    0.43 ± 0.222
    0.27 ± 0.231
    0.18 ± 0.467
    0.20 ± 0.560
        5 hours
    0.43 ± 0.911
    0.43 ± 0.379
    0.25 ± 0.559
    0.15 ± 0.191
        6 hours
    0.75 ± 1.420
    0.30 ± 0.346
    0.53 ± 0.742
    0.23 ± 0.499
    No statistical analyses for this end point

    Secondary: Part A: Change in Pulmonary Capillary Wedge Pressure (PCWP), Right Atrial Pressure (RAP), Systolic Pulmonary Arterial Pressure/Diastolic Pulmonary Arterial Pressure (PAS/PAD) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Pulmonary Capillary Wedge Pressure (PCWP), Right Atrial Pressure (RAP), Systolic Pulmonary Arterial Pressure/Diastolic Pulmonary Arterial Pressure (PAS/PAD) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    PCWP estimated the left atrial pressure and was the pressure measured by wedging a pulmonary artery catheter with an inflated balloon into a small pulmonary arterial branch. PCWP was assessed by 2 successive measurements at least 10 minutes apart. RAP is the blood pressure in the right atrium of the heart. Change in PCWP, RAP, PAS/PAD at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this endpoint. All the parameters were measured by RHC. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Millimeters of mercury
    arithmetic mean (standard deviation)
        PCWP: 0.5 hours (n= 4, 3, 9, 3)
    1.50 ± 2.887
    0.67 ± 3.055
    -0.78 ± 3.456
    -2.67 ± 4.726
        PCWP: 1 hour (n= 4, 3, 9, 3)
    -0.25 ± 8.808
    -2.33 ± 4.041
    -2.00 ± 2.828
    -2.67 ± 8.145
        PCWP: 2 hours (n= 4, 3, 9, 3)
    -1.50 ± 5.000
    -3.33 ± 1.528
    1.56 ± 3.609
    -0.67 ± 7.506
        PCWP: 3 hours (n= 4, 3, 9, 3)
    -3.75 ± 3.594
    -0.33 ± 4.509
    -3.67 ± 3.464
    -3.67 ± 7.506
        PCWP: 4 hours (4, 3, 10, 3)
    -2.75 ± 3.948
    -0.67 ± 5.033
    -2.90 ± 5.384
    -5.00 ± 9.165
        PCWP: 5 hours (n= 4, 3, 9, 3)
    -0.50 ± 6.137
    -1.33 ± 6.110
    -1.56 ± 2.698
    -3.33 ± 9.018
        PCWP: 6 hours (n= 4, 3, 8, 3)
    -0.75 ± 7.411
    -1.67 ± 5.686
    -1.25 ± 2.315
    -1.67 ± 9.504
        RAP: 0.5 hours (n= 4, 3, 10, 3)
    0.50 ± 1.291
    0.00 ± 1.732
    1.40 ± 3.836
    -1.33 ± 2.517
        RAP: 1 hour (n= 4, 3, 10, 3)
    2.50 ± 3.317
    0.33 ± 2.309
    0.00 ± 2.867
    3.33 ± 6.658
        RAP: 2 hours (n= 4, 3, 10, 3)
    1.00 ± 0.816
    -1.00 ± 1.000
    1.00 ± 4.397
    2.67 ± 7.234
        RAP: 3 hours (n= 4, 3, 10, 3)
    -0.25 ± 1.258
    0.33 ± 2.517
    0.40 ± 2.366
    3.33 ± 8.505
        RAP: 4 hours (n= 4, 3, 10, 3)
    -0.75 ± 4.500
    -0.67 ± 1.155
    -0.20 ± 4.315
    4.00 ± 6.083
        RAP: 5 hours (n= 4, 3, 10, 3)
    -1.50 ± 3.416
    -2.67 ± 1.155
    0.50 ± 4.301
    1.67 ± 8.327
        RAP: 6 hours (n= 3, 3, 10, 3)
    -0.67 ± 4.041
    -1.67 ± 1.528
    -0.50 ± 5.233
    4.00 ± 8.660
        PAS: 0.5 hours (n= 4, 3, 10, 3)
    1.50 ± 5.196
    -1.00 ± 2.646
    0.20 ± 6.033
    -0.67 ± 6.110
        PAS: 1 hour (n= 4, 3, 10, 3)
    4.50 ± 9.147
    -0.67 ± 4.041
    -1.50 ± 4.859
    -0.67 ± 6.028
        PAS: 2 hours (n= 4, 3, 10, 3)
    6.25 ± 4.717
    0.67 ± 0.577
    0.90 ± 6.740
    0.33 ± 4.933
        PAS: 3 hours (n= 4, 3, 10, 3)
    7.25 ± 6.185
    1.67 ± 5.033
    -1.40 ± 9.383
    -3.33 ± 9.292
        PAS: 4 hours (n= 4, 3, 10, 3)
    5.75 ± 13.525
    2.00 ± 4.359
    -1.70 ± 6.201
    -8.33 ± 15.631
        PAS: 5 hours (n= 4, 3, 10, 3)
    6.00 ± 11.195
    5.00 ± 1.000
    -1.30 ± 6.945
    -1.33 ± 6.658
        PAS: 6 hours (n= 4, 3, 10, 3)
    4.25 ± 9.179
    2.67 ± 2.309
    -0.90 ± 8.569
    -4.33 ± 9.609
        PAD: 0.5 hours (n= 4, 3, 10, 3)
    -1.25 ± 3.500
    0.00 ± 0.000
    -1.00 ± 2.789
    0.33 ± 4.509
        PAD: 1 hour (n= 4, 3, 10, 3)
    0.50 ± 2.646
    -1.33 ± 0.577
    -0.90 ± 3.872
    -1.67 ± 4.041
        PAD: 2 hours (n= 4, 3, 10, 3)
    -0.25 ± 2.217
    -0.67 ± 2.517
    -0.70 ± 3.860
    -1.00 ± 3.000
        PAD: 3 hours (n= 4, 3, 10, 3)
    -1.25 ± 4.193
    1.00 ± 2.646
    -3.60 ± 5.168
    0.00 ± 6.245
        PAD: 4 hours (n= 4, 3, 10, 3)
    -3.50 ± 8.888
    1.33 ± 1.155
    -2.40 ± 4.061
    -3.00 ± 7.937
        PAD: 5 hours (n= 4, 3, 10, 3)
    -2.50 ± 4.041
    1.00 ± 2.646
    -2.40 ± 3.688
    1.33 ± 5.033
        PAD: 6 hours (n= 4, 3, 10, 3)
    -4.00 ± 5.831
    1.33 ± 3.215
    -1.80 ± 4.984
    0.67 ± 5.686
    No statistical analyses for this end point

    Secondary: Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Pulmonary Artery Pulsatility Index (PAPi) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    PAPi is a hemodynamic parameter that is derived from right atrial and pulmonary artery pulse pressures. PAPi = (PAS − PAD)/right atrial pressure. Change in PAPi measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this endpoint. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Ratio
    arithmetic mean (standard deviation)
        PAPi: 0.5 hours (n= 4, 3, 10, 3)
    0.28 ± 0.411
    -0.17 ± 0.833
    -0.11 ± 0.713
    0.37 ± 1.343
        PAPi: 1 hour (n= 4, 3, 10, 3)
    -0.08 ± 0.562
    0.17 ± 0.306
    -0.21 ± 0.835
    -0.17 ± 0.603
        PAPi: 2 hours (n= 4, 3, 10, 3)
    0.38 ± 0.435
    0.33 ± 0.058
    -0.14 ± 1.011
    0.20 ± 0.900
        PAPi: 3 hours (n= 4, 3, 10, 3)
    0.65 ± 0.624
    0.43 ± 0.777
    0.03 ± 0.897
    -0.33 ± 0.611
        PAPi: 4 hours (n= 4, 3, 10, 3)
    1.35 ± 1.838
    0.83 ± 1.834
    0.27 ± 1.203
    -1.03 ± 0.907
        PAPi: 5 hours (n= 4, 3, 10, 3)
    0.95 ± 0.597
    2.33 ± 1.818
    -0.01 ± 0.872
    0.87 ± 2.639
        PAPi: 6 hour (n= 3, 3, 10, 3)
    0.93 ± 0.929
    1.27 ± 0.929
    0.77 ± 2.470
    -0.90 ± 0.173
    No statistical analyses for this end point

    Secondary: Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Systemic Vascular Resistance Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    Systemic vascular resistance is the amount of force exerted on circulating blood by the vasculature of the body. SVR was calculated as 80*(mean arterial pressure - mean venous pressure) divided by cardiac output. Change in SVR measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6-hour IV infusion was reported in this endpoint. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Millimeter of mercury*minute/milliliter
    arithmetic mean (standard deviation)
        SVR: 0.5 hours (n= 4, 3, 10, 3)
    10.30 ± 74.776
    -71.27 ± 55.492
    -47.30 ± 139.874
    74.13 ± 198.427
        SVR: 1 hour (n= 4, 3, 10, 3)
    -80.50 ± 57.295
    -86.30 ± 80.694
    16.71 ± 231.657
    -131.93 ± 91.886
        SVR: 2 hours (n= 4, 3, 10, 3)
    -48.83 ± 71.811
    -46.23 ± 28.762
    -42.16 ± 205.772
    -49.40 ± 136.124
        SVR: 3 hours (n= 4, 3, 10, 3)
    -67.63 ± 56.169
    -8.10 ± 102.327
    -101.20 ± 188.863
    -195.77 ± 101.041
        SVR: 4 hours (n= 4, 3, 10, 3)
    -27.20 ± 104.351
    73.90 ± 136.245
    -33.91 ± 241.040
    -311.03 ± 145.094
        SVR: 5 hours (n= 4, 3, 10, 3)
    21.10 ± 112.824
    132.63 ± 171.630
    -92.29 ± 94.834
    -110.57 ± 222.498
        SVR: 6 hours (n= 3, 3, 10, 3)
    33.10 ± 106.652
    90.37 ± 137.576
    -70.00 ± 116.681
    -104.23 ± 90.537
    No statistical analyses for this end point

    Secondary: Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Systemic Vascular Resistance Index (SVRI) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    SVRI was calculated by dividing the difference between mean arterial pressure and central venous pressure by cardiac index and multiplying by 80. Change in SVRI measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6 hour IV infusion was reported in this endpoint. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Dynes*second*meter^2 per centimeter^5
    arithmetic mean (standard deviation)
        SVRI: 0.5 hours (n= 4, 3, 10, 3)
    5.00 ± 157.514
    -171.20 ± 154.962
    -98.41 ± 270.327
    107.83 ± 428.022
        SVRI: 1 hour (n= 4, 3, 10, 3)
    -156.58 ± 105.011
    -202.73 ± 185.527
    16.20 ± 404.144
    -289.57 ± 102.838
        SVRI: 2 hours (n= 4, 3, 10, 3)
    -115.13 ± 165.795
    -85.30 ± 63.286
    -94.82 ± 407.893
    -64.77 ± 281.682
        SVRI: 3 hours (n= 4, 3, 10, 3)
    -152.98 ± 108.934
    -42.57 ± 192.932
    -190.53 ± 315.500
    -403.47 ± 271.919
        SVRI: 4 hours (n= 4, 3, 10, 3)
    -85.05 ± 224.198
    201.20 ± 357.587
    -31.66 ± 414.786
    -649.80 ± 360.988
        SVRI: 5 hours (n= 4, 3, 10, 3)
    12.80 ± 208.554
    350.47 ± 458.646
    -172.77 ± 186.678
    -260.83 ± 484.601
        SVRI: 6 hours (n= 3, 3, 10, 3)
    61.47 ± 205.227
    152.63 ± 171.695
    -94.08 ± 306.599
    -227.17 ± 126.337
    No statistical analyses for this end point

    Secondary: Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Pulmonary Vascular Resistance (PVR) Measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    PVR is the resistance against blood flow from the pulmonary artery to the left atrium. Change in PVR measured by RHC at 0.5, 1, 2, 3, 4, 5 and 6 hours during the 6 hour IV infusion was reported in this endpoint. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: dynes*second per centimeter^5
    arithmetic mean (standard deviation)
        PVR: 0.5 hours (n= 4, 3, 9, 3)
    -28.98 ± 21.955
    -97.13 ± 134.474
    14.83 ± 115.974
    83.40 ± 80.442
        PVR: 1 hour (n= 4, 3, 9, 3)
    5.80 ± 108.571
    -37.57 ± 102.284
    78.37 ± 235.884
    6.40 ± 115.783
        PVR: 2 hours (n= 4, 3, 9, 3)
    37.68 ± 106.364
    46.43 ± 27.918
    -1.64 ± 290.121
    -0.10 ± 136.989
        PVR: 3 hours (n= 4, 3, 9, 3)
    29.70 ± 99.607
    -11.60 ± 69.295
    36.04 ± 171.091
    18.13 ± 107.316
        PVR: 4 hours (n= 4, 3, 9, 3)
    32.28 ± 190.279
    10.03 ± 72.673
    32.44 ± 191.341
    -44.03 ± 121.310
        PVR: 5 hours (n= 4, 3, 9, 3)
    29.08 ± 163.825
    44.57 ± 38.099
    22.61 ± 195.626
    53.70 ± 211.590
        PVR: 6 hours (n= 4, 3, 8, 3)
    2.70 ± 150.529
    54.57 ± 15.245
    38.10 ± 291.188
    19.53 ± 86.649
    No statistical analyses for this end point

    Secondary: Part A: Change in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    SBP, DBP and MAP were measured in a supine or seated position after subject had at least 5 minutes of rest. MAP is the average pressure of the blood circulating through a subject's arteries during the cardiac cycle. MAP was derived by using the following formula: DBP + 1/3(SBP-DBP). Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Millimeters of mercury
    arithmetic mean (standard deviation)
        SBP: 0.5 hours
    7.3 ± 10.21
    -11.0 ± 10.15
    -2.2 ± 11.47
    -0.5 ± 6.35
        SBP: 1 hour
    6.8 ± 10.56
    -7.3 ± 1.53
    -3.8 ± 9.44
    -0.8 ± 6.18
        SBP: 2 hours
    8.0 ± 14.54
    -6.3 ± 9.81
    -2.6 ± 11.21
    0.5 ± 6.14
        SBP: 3 hours
    -1.0 ± 14.07
    -4.7 ± 7.77
    -3.9 ± 10.35
    -1.0 ± 10.30
        SBP: 4 hours
    2.5 ± 15.11
    -2.7 ± 8.33
    -3.9 ± 9.66
    0.5 ± 14.93
        SBP: 5 hours
    5.5 ± 14.82
    1.0 ± 12.12
    -8.3 ± 11.86
    1.5 ± 13.03
        SBP: 6 hours
    9.8 ± 12.45
    -5.0 ± 6.00
    -1.4 ± 8.90
    -1.0 ± 12.57
        DBP: 0.5 hours
    3.0 ± 16.06
    -6.7 ± 7.02
    -0.2 ± 4.92
    0.0 ± 4.24
        DBP: 1 hour
    3.0 ± 14.85
    -4.0 ± 5.29
    -2.2 ± 5.74
    7.0 ± 18.20
        DBP: 2 hours
    10.0 ± 16.12
    -7.0 ± 2.65
    0.0 ± 7.92
    -1.5 ± 5.92
        DBP: 3 hours
    -4.0 ± 12.46
    -3.3 ± 5.13
    -4.8 ± 9.26
    -1.0 ± 7.79
        DBP: 4 hours
    -2.8 ± 13.10
    0.3 ± 7.77
    -6.3 ± 5.76
    -1.0 ± 5.72
        DBP: 5 hours
    -0.8 ± 13.67
    -2.0 ± 1.73
    -6.8 ± 6.52
    -1.0 ± 6.98
        DBP: 6 hours
    1.3 ± 13.57
    1.3 ± 2.08
    -0.3 ± 6.87
    3.8 ± 7.93
        MAP: 0.5 hours
    4.42 ± 13.723
    -8.11 ± 8.002
    -0.85 ± 4.994
    -0.17 ± 4.041
        MAP: 1 hour
    4.25 ± 12.971
    -5.11 ± 3.097
    -2.73 ± 4.718
    4.42 ± 10.651
        MAP: 2 hours
    9.33 ± 13.891
    -6.78 ± 4.623
    -0.88 ± 6.634
    -0.83 ± 5.828
        MAP: 3 hours
    -3.00 ± 12.640
    -3.78 ± 5.274
    -4.52 ± 7.752
    -1.00 ± 8.551
        MAP: 4 hours
    -1.00 ± 13.101
    -0.67 ± 6.960
    -5.48 ± 5.768
    -0.50 ± 8.131
        MAP: 5 hours
    1.33 ± 13.570
    -1.00 ± 5.196
    -7.30 ± 5.742
    -0.17 ± 7.466
        MAP: 6 hours
    4.08 ± 12.900
    -0.78 ± 1.388
    -0.64 ± 5.934
    2.17 ± 9.406
    No statistical analyses for this end point

    Secondary: Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours

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    End point title
    		 Part A: Change in Heart Rate at 0.5, 1, 2, 3, 4, 5 and 6 Hours
    End point description
    Heart rate was measured in a supine or seated position after subject had at least 5 minutes of rest. Full analysis set included all randomised subjects, irrespective of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (within 2 hours prior to start of study treatment administration), 0.5, 1, 2, 3, 4, 5 and 6 hours of IV infusion
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Beats per minute
    arithmetic mean (standard deviation)
        0.5 hours
    -8.8 ± 9.00
    -7.3 ± 12.66
    0.0 ± 5.93
    3.5 ± 9.11
        1 hour
    -2.5 ± 2.65
    -3.3 ± 14.19
    -1.6 ± 4.86
    -9.0 ± 13.29
        2 hours
    -2.3 ± 5.32
    -0.7 ± 9.07
    -1.5 ± 6.62
    -7.0 ± 13.49
        3 hours
    2.0 ± 8.87
    0.0 ± 9.17
    -0.6 ± 8.31
    -5.3 ± 11.18
        4 hours
    -0.5 ± 6.24
    0.3 ± 14.22
    -1.1 ± 5.80
    1.0 ± 20.02
        5 hours
    -6.3 ± 6.08
    -1.7 ± 5.86
    -1.5 ± 5.77
    -5.0 ± 13.49
        6 hours
    4.5 ± 9.00
    1.0 ± 5.57
    4.2 ± 9.22
    -1.5 ± 17.82
    No statistical analyses for this end point

    Secondary: Part A: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Part A: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An AE was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAEs were defined as those AEs with onset after start date/timepoint of study drug administration. Safety set included all randomised subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From start of study treatment on Day 1 up to Day 9
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 1- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 2- Placebo
    Number of subjects analysed
    4
    3
    11
    4
    Units: Subjects
    1
    1
    3
    1
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD418

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    End point title
    		 Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUCLast) of APD418 [2]
    End point description
    AUClast was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Hours*nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    9410 ± 84.3
    9230 ± 164
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD418

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    End point title
    		 Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 6 Hours (AUC[0-6]) of APD418 [3]
    End point description
    AUC [0-6] was reported in this endpoint. Pharmacokinetic (PK) set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Hours*nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    6620 ± 68.7
    5970 ± 268
    No statistical analyses for this end point

    Secondary: Part A: Maximum Observed Plasma Concentration (Cmax) of APD418

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    End point title
    		 Part A: Maximum Observed Plasma Concentration (Cmax) of APD418 [4]
    End point description
    Cmax of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    1540 ± 88.8
    1480 ± 277
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD418

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    End point title
    		 Part A: Area Under the Plasma Concentration Time Curve From Time Zero up to Infinity (AUC[0-Infinity]) of APD418 [5]
    End point description
    AUC [0-infinity] was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    9
    Units: Hours*nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    9660 ± 87.0
    13400 ± 34.5
    No statistical analyses for this end point

    Secondary: Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD418

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    End point title
    		 Part A: Time to Maximum Observed Plasma Concentration (Tmax) for APD418 [6]
    End point description
    Tmax of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Hours
        median (full range (min-max))
    5.42 (4.00 to 6.08)
    5.00 (0.500 to 6.18)
    No statistical analyses for this end point

    Secondary: Part A: Distributional Half-Life (t1/2a) for APD418

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    End point title
    		 Part A: Distributional Half-Life (t1/2a) for APD418 [7]
    End point description
    Distributional t1/2 of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    3
    9
    Units: Hours
        arithmetic mean (standard deviation)
    0.579 ± 0.381
    0.381 ± 0.119
    No statistical analyses for this end point

    Secondary: Part A: Terminal Elimination Half-Life (t1/2) for APD418

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    End point title
    		 Part A: Terminal Elimination Half-Life (t1/2) for APD418 [8]
    End point description
    Terminal t1/2 of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    9
    Units: Hours
        arithmetic mean (standard deviation)
    5.26 ± 0.960
    5.26 ± 0.998
    No statistical analyses for this end point

    Secondary: Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD418

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    End point title
    		 Part A: Mean Residence Time From Time Zero to Time of Last Quantifiable Plasma Concentration (MRTlast) for APD418 [9]
    End point description
    MRTlast of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Hours
        geometric mean (geometric coefficient of variation)
    2.44 ± 33.6
    2.54 ± 74.3
    No statistical analyses for this end point

    Secondary: Part A: Volume of Distribution at Steady State (Vdss) for APD418

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    End point title
    		 Part A: Volume of Distribution at Steady State (Vdss) for APD418 [10]
    End point description
    Vdss of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    9
    Units: Liter
        geometric mean (geometric coefficient of variation)
    27.7 ± 42.2
    46.0 ± 34.5
    No statistical analyses for this end point

    Secondary: Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD418

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    End point title
    		 Part A: Total Volume of Distribution Based on the Terminal Phase (Vdz) for APD418 [11]
    End point description
    Vdz of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    9
    Units: Liter
        geometric mean (geometric coefficient of variation)
    68.6 ± 74.5
    133 ± 28.6
    No statistical analyses for this end point

    Secondary: Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP418

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    End point title
    		 Part A: Average Plasma Concentration During Dosing Interval (Cave) for ADP418 [12]
    End point description
    Average plasma concentration calculated over the 6-hour infusion time was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6 hours post infusion start
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    1100 ± 68.7
    996 ± 268
    No statistical analyses for this end point

    Secondary: Part A: Total Clearance (CL) for APD418

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    End point title
    		 Part A: Total Clearance (CL) for APD418 [13]
    End point description
    IV CL of APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement. Here, ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 6.083, 6.167, 6.25, 6.5, 7, 8, 10, 18 and 24 hours post infusion start
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    9
    Units: Liter per hour
        geometric mean (geometric coefficient of variation)
    9.16 ± 92.7
    17.8 ± 23.2
    No statistical analyses for this end point

    Secondary: Part A: Renal Clearance (CLr) for ADP418

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    End point title
    		 Part A: Renal Clearance (CLr) for ADP418 [14]
    End point description
    CLr for APD418 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0) to 24 hours post infusion start, collected over 0 to 6 hour, 6 to 10 hour and 10 to 24-hour intervals
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Liter per hour
        geometric mean (geometric coefficient of variation)
    2.14 ± 55.3
    3.78 ± 54.8
    No statistical analyses for this end point

    Other pre-specified: Part A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae])

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    End point title
    		 Part A: Total Amount of Unchanged Drug Excreted in Urine Over the Collection Period (Amount Excreted [Ae]) [15]
    End point description
    Total amount of unchanged drug excreted in urine over the collection period was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0) to 24 hours post infusion start, collected over 0 to 6 hour, 6 to 10 hour and 10 to 24-hour intervals
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Milligrams
        geometric mean (geometric coefficient of variation)
    20.1 ± 28.8
    48.5 ± 38.0
    No statistical analyses for this end point

    Other pre-specified: Part A: Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2)

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    End point title
    		 Part A: Amount of Unchanged Drug Excreted in Urine During Each Collection Interval From t1 to t2 (Aet1-t2) [16]
    End point description
    Amount of unchanged drug excreted in urine during each collection interval from t1 to t2 was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Other pre-specified
    End point timeframe
    Anytime between 0 to 6 hours, 6 to 10 hours and 10 to 24 hours post infusion start
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Milligrams
    geometric mean (geometric coefficient of variation)
        Ae 0-6
    11.8 ± 26.7
    25.6 ± 56.9
        Ae 6-10
    4.47 ± 27.3
    7.68 ± 68.4
        Ae 10-24
    2.83 ± 136
    7.93 ± 172
    No statistical analyses for this end point

    Other pre-specified: Part A: Fraction of Drug Excreted Unchanged (Fe) in Urine

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    End point title
    		 Part A: Fraction of Drug Excreted Unchanged (Fe) in Urine [17]
    End point description
    Fraction of drug excreted in urine was reported in this endpoint. PK set included all subjects in the safety set with at least 1 post-dose PK measurement.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0) to 24 hours post infusion start, collected over 0 to 6 hour, 6 to 10 hour and 10 to 24-hour intervals
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting statistics for the arms specified.
    End point values
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- 0.5 mg/kg/hr APD418
    Number of subjects analysed
    4
    11
    Units: Percentage of unchanged drug
        geometric mean (geometric coefficient of variation)
    22.7 ± 31.2
    19.7 ± 39.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment on Day 1 up to Day 9
    Adverse event reporting additional description
    Safety set included all randomised subjects who received at least one dose of study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Cohort 1- 0.17 mg/kg/hr APD418
    Reporting group description
    		 Subjects were administered a single dose of 0.17 milligrams per kilogram per hour (mg/kg/hr) (total dose of 1 mg/kg) APD418 as an intravenous (IV) infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 2- Placebo
    Reporting group description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 2- 0.5 mg/kg/hr APD418
    Reporting group description
    		 Subjects were administered a single dose of 0.5 mg/kg/hr (total dose of 3mg/kg) APD418 as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Reporting group title
    Cohort 1- Placebo
    Reporting group description
    		 Subjects were administered a single dose of matching placebo as an IV infusion over a duration of 6 hours on Day 1 (Dosing Period) followed by an 18 to 24-hour in-clinic observation period.

    Serious adverse events
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 1- Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1- 0.17 mg/kg/hr APD418 Cohort 2- Placebo Cohort 2- 0.5 mg/kg/hr APD418 Cohort 1- Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    3 / 11 (27.27%)
    1 / 3 (33.33%)
    Investigations
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Vein rupture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2021
    Updates to the exclusion criteria. Prolonged the screening period for Part A to 21 days prior to and including Day 1 (Days - 21 to 1).
    19 Oct 2021
    Updates to provide additional guidance for IV administration and interruption procedures, and selection and monitoring of the infusion site. For exclusion criteria, new criterion was added for conditions that in the opinion of the Investigator may have increased the risk of infusion site reactions (ISRs) and/or compromised subject assessment of the ISRs. Revised reasons in which the study must have been terminated and those that may have terminated the study for clarity. Added safety related criteria for stopping study treatment. Provided further clarification for dose escalation stopping criteria.
    26 Apr 2022
    Modified eligibility criteria that were not safety related. Added organic-anion-transporting polypeptide (OATP) genotype assessment to the exploratory objectives.

    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.
    This study was terminated early due to a business decision that was not due to any safety concerns. The number of subjects was smaller than originally planned and only summary statistics were therefore generated for primary and secondary endpoints.
    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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