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    Clinical Trial Results:
    A randomized, subject and investigator-blind, placebo controlled study of CLR325 in chronic stable heart failure patients

    Summary
    EudraCT number
    		 2016-001387-12
    Trial protocol
    		 DE   BE   NL  
    Global end of trial date
    14 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCLR325X2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02696967
    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)
    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
    14 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safety and tolerability of an 18-hour i.v. infusion of CLR325 in patients with stable heart failure
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2016
    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: 3
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    26
    EEA total number of subjects
    6
    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)
    21
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 11 centers in 5 countries: Belgium (1), Germany (2), Netherlands (1), Singapore (1) and USA (6).

    Pre-assignment
    Screening details
    		 Patients were assigned to one of the 2 treatment arms in fixed randomization ratio (CLR325: Placebo): • Cohort 1: Single dose of CLR325 2.5 µg/kg/min (i.v.) or placebo (i.v.) • Cohort 2: Single dose of CLR325 0.25 µg/kg/min (i.v.) or placebo (i.v.) • Cohort 3: Single dose of CLR325 8 µg/kg/min (i.v.) or placebo (i.v.)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CLR325 0.25 mcg/kg/min
    Arm description
    		 Patients randomized to this arm received single dose of CLR325 0.25 mcg/kg/min (i.v.) in double blind manner.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR325
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CLR325 120 mg/10 mL (liquid in vial)

    Arm title
    		 CLR325 2.5 mcg/kg/min
    Arm description
    		 Patients randomized to this arm received single dose of CLR325 2.5 mcg/kg/min (i.v.) in double blind manner.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR325
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CLR325 120 mg/10 mL (liquid in vial)

    Arm title
    		 CLR325 8 mcg/kg/min
    Arm description
    		 Patients randomized to this arm received single dose of CLR325 8 mcg/kg/min (i.v.) in double blind manner.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR325
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CLR325 120 mg/10 mL (liquid in vial)

    Arm title
    		 Placebo
    Arm description
    		 Patients randomized to this arm received single dose of Placebo (i.v.) in double blind manner.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo to CLR325 120mg/10mL

    Number of subjects in period 1
    		CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min Placebo
    Started
    4
    6
    6
    10
    Pharmacokinetic (PK) analysis set
    4
    6
    4 [1]
    0 [2]
    Completed
    4
    6
    6
    10
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    [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: Pharmacokinetic sampling only performed on CLR325 treatment arms (does not apply to placebo randomized patients)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CLR325 0.25 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 0.25 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    CLR325 2.5 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 2.5 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    CLR325 8 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 8 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomized to this arm received single dose of Placebo (i.v.) in double blind manner.

    Reporting group values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min Placebo Total
    Number of subjects
    		 4 6 6 10 26
    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)
    		 4 5 3 9 21
        From 65-84 years
    		 0 1 3 1 5
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.5 ( 3.1 ) 55.2 ( 13.0 ) 63.5 ( 11.8 ) 54.2 ( 9.2 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 1 0 2 0 3
        Male
    		 3 6 4 10 23
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 4 3 4 8 19
        Black
    		 0 2 2 1 5
        Asian
    		 0 1 0 1 2

    End points

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    End points reporting groups
    Reporting group title
    CLR325 0.25 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 0.25 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    CLR325 2.5 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 2.5 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    CLR325 8 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 8 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomized to this arm received single dose of Placebo (i.v.) in double blind manner.

    Primary: Number of patients with adverse events, serious adverse events and death

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    End point title
    		 Number of patients with adverse events, serious adverse events and death [1]
    End point description
    Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) in each treatment arm to demonstrate that CLR325 is safe for the treatment of chronic stable heart-failure patients through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Primary
    End point timeframe
    Day 1 to 28
    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: Only descriptive analysis performed
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min Placebo
    Number of subjects analysed
    4
    6
    6
    10
    Units: Participants
        On-treatment Adverse Event (AEs)
    1
    3
    4
    7
        On-treatment Serious Adverse Event (SAEs)
    0
    2
    2
    0
        On-treatment Deaths
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to 18 hours (AUC0-18hr)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to 18 hours (AUC0-18hr) [2]
    End point description
    AUC0-18hr is the area under the plasma concentration-time curve from time zero to 18 hours after the start of CLR325 infusion. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, and 18 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        CLR 325
    1220 ( 10.4 )
    18500 ( 31.6 )
    79700 ( 32.5 )
        CQJ295
    999 ( 999 )
    623 ( 102.3 )
    5560 ( 46.7 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from from time zero to 28 hours (AUC0-28hrs)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from from time zero to 28 hours (AUC0-28hrs) [3]
    End point description
    AUC0-28hr is the area under the plasma concentration-time curve from time zero to 28 hours after the start of CLR325 infusion. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        CLR325
    1460 ( 12.8 )
    21500 ( 32.9 )
    100000 ( 28.2 )
        CQJ295
    999 ( 999 )
    838 ( 106.2 )
    8390 ( 43.5 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to infinity (AUCinf)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to infinity (AUCinf) [4]
    End point description
    AUCinf is the area under the plasma concentration-time curve from time zero to infinity. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        CLR325
    1510 ( 4.7 )
    21900 ( 34.0 )
    103000 ( 26.1 )
        CQJ295
    999 ( 999 )
    843 ( 49.9 )
    9660 ( 38.5 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) [5]
    End point description
    AUClast is the area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        CLR325
    1450 ( 13.0 )
    21500 ( 32.9 )
    100000 ( 28.2 )
        CQJ295
    3.10 ( 999 )
    836 ( 107.1 )
    8380 ( 43.6 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325: clearance from plasma (CL) following drug administration

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    End point title
    		 Pharmacokinetic of CLR325: clearance from plasma (CL) following drug administration [6]
    End point description
    CL is the systemic (or total body) clearance from plasma following CLR325 infusion. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: mL/hr
        geometric mean (geometric coefficient of variation)
    15200 ( 6.1 )
    13200 ( 54.9 )
    7460 ( 15.4 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: observed maximum plasma concentration following drug administration at steady state (Cmax,ss)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: observed maximum plasma concentration following drug administration at steady state (Cmax,ss) [7]
    End point description
    Cmax,ss is the observed maximum plasma concentration following drug administration at steady state. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        CLR325
    103 ( 11.2 )
    1370 ( 36.0 )
    6080 ( 38.4 )
        CQJ295
    999 ( 999 )
    54.2 ( 91.0 )
    468 ( 54.0 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: terminal elimination half-life (T1/2)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: terminal elimination half-life (T1/2) [8]
    End point description
    T^1/2 is the elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: hr
    arithmetic mean (standard deviation)
        CLR325
    1.86 ( 0.197 )
    2.99 ( 0.520 )
    2.96 ( 0.992 )
        CQJ295
    999 ( 999 )
    3.12 ( 0.275 )
    5.73 ( 3.38 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: time to reach the maximum concentration after drug administration (TMax)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: time to reach the maximum concentration after drug administration (TMax) [9]
    End point description
    Tmax is the time to reach maximum plasma concentration after single dose administration. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: hr
    median (full range (min-max))
        CLR325
    14.0 (4.93 to 18.0)
    12.0 (8.05 to 12.1)
    14.9 (8.08 to 17.9)
        CQJ295
    0 (0 to 5.03)
    15.1 (7.92 to 18.1)
    17.9 (8.33 to 18.1)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325: volume of distribution at steady state following intravenous administration (Vss)

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    End point title
    		 Pharmacokinetic of CLR325: volume of distribution at steady state following intravenous administration (Vss) [10]
    End point description
    Vss is the volume of distribution at steady state following intravenous administration. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: mL
        geometric mean (geometric coefficient of variation)
    51600 ( 19.6 )
    32500 ( 47.6 )
    28000 ( 33.3 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: Amount of drug (or defined metabolite) excreted into the urine from time (Ae 0-28 hours)

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: Amount of drug (or defined metabolite) excreted into the urine from time (Ae 0-28 hours) [11]
    End point description
    Ae 0-28 hours is the amount of drug (or defined metabolite) excreted into the urine from time zero to 28 hours after the start of CLR325 infusion. The urine PK parameters were measured using an non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0-28 hours on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: ng
    geometric mean (geometric coefficient of variation)
        CLR325
    999 ( 999 )
    19500000 ( 125.2 )
    41300000 ( 253.3 )
        CQJ295
    999 ( 999 )
    7620000 ( 27.2 )
    4040000 ( 999 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic of CLR325 and CQJ295: renal clearance from plasma (CLr) following drug administration

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    End point title
    		 Pharmacokinetic of CLR325 and CQJ295: renal clearance from plasma (CLr) following drug administration [12]
    End point description
    CLr is the renal clearance from urine following CLR325 infusion. The urine PK parameters were measured using an non-compartmental methods. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    0-28 hours on Day 1
    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: Pharmacokinetic (PK) analysis set = At least one dose of study drug and one evaluable PK concentration measurement
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min
    Number of subjects analysed
    4
    6
    4
    Units: mL/hr
    geometric mean (geometric coefficient of variation)
        CLR325
    999 ( 999 )
    904 ( 199.4 )
    411 ( 395.1 )
        CQJ295
    999 ( 999 )
    5620 ( 71.7 )
    258 ( 999 )
    No statistical analyses for this end point

    Secondary: Number of patients with increase in anti-CLR325 and anti-apelin antibodies in serum

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    End point title
    		 Number of patients with increase in anti-CLR325 and anti-apelin antibodies in serum
    End point description
    Anti-CLR325 anti-apelin antibodies in serum were analyzed predose, Day 10 and Day 28 to determine the immunogenicity of an 18-hour i.v. infusion of CLR325 in heart failure patients.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 10 and Day 28
    End point values
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min Placebo
    Number of subjects analysed
    4
    6
    6
    10
    Units: Participants
        BL anti-Apelin antibody|Antibody detected = Yes
    0
    0
    0
    0
        BL anti-CLR325 antibody|Antibody detected = Yes
    0
    0
    0
    0
        D10 anti-Apelin antibody|Antibody detected = Yes
    0
    0
    0
    0
        D10 anti-CLR325 antibody|Antibody detected = Yes
    0
    0
    0
    0
        D28 anti-Apelin antibody|Antibody detected = Yes
    0
    0
    0
    0
        D28 anti-CLR325 antibody|Antibody detected = Yes
    0
    0
    0
    0
        BL anti-Apelin antibody|Antibody detected = No
    1
    1
    1
    0
        BL anti-CLR325 antibody|Antibody detected = No
    4
    5
    5
    10
        D10 anti-Apelin antibody|Antibody detected = No
    0
    0
    1
    1
        D10 anti-CLR325 antibody|Antibody detected = No
    3
    4
    6
    7
        D28 anti-Apelin antibody|Antibody detected = No
    1
    0
    1
    0
        D28 anti-CLR325 antibody|Antibody detected = No
    3
    5
    5
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from first dose of study treatment until end of study treatment plus 30 days post-treatment, up to maximum duration of 1 month.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    CLR325 0.25 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 0.25 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    CLR325 2.5 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 2.5 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    CLR325 8 mcg/kg/min
    Reporting group description
    		 Patients randomized to this arm received single dose of CLR325 8 mcg/kg/min (i.v.) in double blind manner.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomized to this arm received single dose of Placebo (i.v.) in double blind manner.

    Serious adverse events
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 CLR325 0.25 mcg/kg/min CLR325 2.5 mcg/kg/min CLR325 8 mcg/kg/min Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    7 / 10 (70.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Feeling hot
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Generalised oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infusion site pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Liver function test increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Pulmonary arterial wedge pressure decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Cardiogenic shock
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    0
    0
    3
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ileus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Azotaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    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
    21 Apr 2016
    Amendment 1 was issued to: • To reduce patient burden and improve patient safety, the measurement of right ventricular pressures using the pulmonary artery catheter was made optional. • To reduce patient burden, non-invasive hemodynamic monitoring was made optional at select sites. This will reduce the number of electrodes on the patient’s chest and improve overall patient comfort during the study. • To reduce patient burden, the screening period has been expanded to Day 1 to allow a patient to be screened and enrolled in the study in the same day, reducing the need for multiple patient visits to the site to participate in this study.
    05 Aug 2016
    Amendment 2: • The primary purpose of this amendment was to enhance patient safety in response to a suspected, unexpected, SAE (occurred in a subject who experienced a rise in liver function tests during infusion of study drug that reversed without intervention following termination of the infusion). The etiology of this event could be related to prior underlying liver disease or to a volume-depleted state (as indicated by a low PCWP at baseline) in this subject. An exclusion criterion was added to exclude patients with underlying liver disease or with relative volume depletion. • This protocol amendment also clarified criteria around pulse rate and anticoagulation management and monitoring of coagulation laboratories as requested by BfArM.
    07 Feb 2017
    Amendment 3: • The primary purpose of this protocol amendment is to reduce patient burden by establishing additional cohorts that utilized echocardiography rather than invasive hemodynamics to monitor changes in cardiac index during infusion of study medication. This allowed chronic stable heart failure patients to be enrolled in this study without the placement of a pulmonary artery catheter, thus reducing the risk to patients from catheter-related complications (e.g., bleeding, arrhythmias). The number of additional cohorts that can be recruited in this study was increased from 3 to 4 and the randomization ratio is modified to 1:1 for all additional cohorts to increase power to detect changes in hemodynamics during study drug infusion.
    31 Oct 2017
    Amendment 4: • Experience from the first cohort (n = 8) of patients with chronic stable heart failure treated with CLR325 indicated that CLR325 was generally well tolerated. The AEs were few and balanced between CLR325 and placebo treated patients. Given this acceptable safety profile with CLR325 in chronic stable heart failure patients, the inclusion and exclusion criteria was modified to allow the recruitment of stabilized, acutely decompensated heart failure patients. As such, these patients would be a population, which more closely reflects the target population for the development of CLR325 as a novel cardiac inotrope. • The protocol also clarified regarding the exclusion criteria on echocardiographic assessment of volume status (exclusion criteria #17). This criterion was included to exclude those patients with low PCWP (<10 mm Hg) as described in Amendment 2.
    27 Aug 2018
    Amendment 5: • Based on a review of the data, this amendment was designed to reduce patient and site burden by eliminating the requirement to obtain thermodilution cardiac outputs. Elimination of thermodilution cardiac outputs reduced the volume load given to each patient during the course of the study. Finally, removal of thermodilution cardiac outputs also reduced burden on the sites, as these determinations are very labor intensive. • The screening window was expanded, updated withdrawal of consent language, and clarified criteria for laboratory tests, replacement patients, and urine PK collection to improve site operations.

    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 EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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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