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    Clinical Trial Results:
    Prospective, Double-Blind, Multicenter Study Evaluating the Safety of Repeat Doses of IV Serelaxin in Subjects with Chronic Heart Failure 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.novfor complete trial results.

    Summary
    EudraCT number
    		 2013-002781-39
    Trial protocol
    		 DE   IT   FI   ES   SE   NO   RO   NL   CZ  
    Global end of trial date
    23 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2018
    First version publication date
    06 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRLX030A2209
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01982292
    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,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    23 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the proportion of patients with CHF who develop anti-serelaxin antibodies at any time following repeat administration of three IV continuous infusions of serelaxin administered for up to 48 hours in four week intervals.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. The Investigator could prescribe any medications and/or supportive care during the study based on clinical needs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Czech Republic: 41
    Country: Number of subjects enrolled
    Germany: 120
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Romania: 24
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Turkey: 23
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    323
    EEA total number of subjects
    245
    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)
    127
    From 65 to 84 years
    190
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 323 patients were randomized to the serelaxin or placebo treatment in a 2:1 ratio. 2 patients from serelaxin were mis-randomized, hence 321 received study drug.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RLX030 (serelaxin)
    Arm description
    		 Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    RLX030 (serelaxin) was administered according to a weight-range adjusted dosing regimen at a nominal dose of 30 μg/kg/day as a continuous IV infusion for 48 hours.

    Arm title
    		 Placebo
    Arm description
    		 Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo of RLX030 (serelaxin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo of serelaxin was administered as a continuous IV infusion for 48 hours.

    Number of subjects in period 1
    		RLX030 (serelaxin) Placebo
    Started
    215
    108
    Full analaysis set (FAS)
    213
    108
    Safety set
    212
    108
    Completed
    203
    107
    Not completed
    12
    1
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    2
    -
         Protocol Deviation
    1
    -
         Patient/Guardian Decision
    3
    1
         Technical Problems
    2
    -
         Non-Compliance With Study Treatment
    1
    -
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RLX030 (serelaxin)
    Reporting group description
    		 Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8

    Reporting group values
    		 RLX030 (serelaxin) Placebo Total
    Number of subjects
    		 215 108 323
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 79 48 127
        From 65-84 years
    		 133 57 190
        85 years and over
    		 3 3 6
    Gender, Male/Female
    Units: Subjects
        Female
    		 46 26 72
        Male
    		 169 82 251

    End points

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    End points reporting groups
    Reporting group title
    RLX030 (serelaxin)
    Reporting group description
    		 Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8

    Primary: Percentage of participants with chronic heart failure (CHF) who develop anti-serelaxin antibodies at any time following repeat administration of IV continuous infusions of serelaxin administered for up to 48 hours in 16 weeks

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    End point title
    		 Percentage of participants with chronic heart failure (CHF) who develop anti-serelaxin antibodies at any time following repeat administration of IV continuous infusions of serelaxin administered for up to 48 hours in 16 weeks
    End point description
    A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. A patient is considered antibody negative during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were negative. A patient’s antibody status is considered to be undetermined during the study if it is not defined as positive or negative.
    End point type
    Primary
    End point timeframe
    16 weeks
    End point values
    		 RLX030 (serelaxin) Placebo
    Number of subjects analysed
    200
    106
    Units: Percentage of participants
    number (confidence interval 90%)
        Positive
    0.5 (0.03 to 2.35)
    0 (0 to 2.79)
        Negative
    99.5 (97.65 to 99.97)
    100 (97.21 to 100)
    Statistical analysis title
    		 Difference in % of pts with +ve antibody status
    Statistical analysis description
    Difference in percentage of patients with positive antibody status
    Comparison groups
    RLX030 (serelaxin) v Placebo
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentage
    Point estimate
    0.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.38
         upper limit
    		 10.38
    Statistical analysis title
    		 Difference in % of pts with - ve antibody status
    Statistical analysis description
    Difference in percentage of patients with negative antibody status
    Comparison groups
    RLX030 (serelaxin) v Placebo
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -0.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -10.38
         upper limit
    		 9.38

    Secondary: Percentage of participants with chronic heart failure who develop positive anti-serelaxin antibodies after a single infusion of serelaxin over time up to week 16

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    End point title
    		 Percentage of participants with chronic heart failure who develop positive anti-serelaxin antibodies after a single infusion of serelaxin over time up to week 16
    End point description
    A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. Each time period is defined as the time frame from study drug initiation (or the visit if there is no infusion) to prior to study drug initiation of the next period (or the visit if no there is no infusion). n= The total number of subjects with evaluable antibody status during the defined period.
    End point type
    Secondary
    End point timeframe
    Randomization to Week 4, Week 4 to Week 8, Week 8 to Week 12, week 12 to week 16
    End point values
    		 RLX030 (serelaxin) Placebo
    Number of subjects analysed
    212
    108
    Units: Percentage of patients
    number (confidence interval 90%)
        Randomization to week 4 (n= 209, 107)
    0.48 (0.02 to 2.25)
    0 (0 to 2.76)
        Week 4 to week 8 (n= 204, 108)
    0.49 (0.03 to 2.3)
    0 (0 to 2.74)
        Week 8 to week 12 (n= 204, 107)
    0.49 (0.03 to 2.3)
    0 (0 to 2.76)
        Week 12 to week 16 (n= 2, 2)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Antibody titers in participants with chronic heart failure who develop anti-serelaxin antibodies (neutralizing, non-neutralizing or both) at any time following 3 repeated infusions and at Week 4, Week 8 and Week 12.

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    End point title
    		 Antibody titers in participants with chronic heart failure who develop anti-serelaxin antibodies (neutralizing, non-neutralizing or both) at any time following 3 repeated infusions and at Week 4, Week 8 and Week 12.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8, Week 12
    End point values
    		 RLX030 (serelaxin) Placebo
    Number of subjects analysed
    1 [1]
    0 [2]
    Units: In international Units
        arithmetic mean (standard deviation)
    9999 ( 99.99 )
    ( )
    Notes
    [1] - Antibody titers unavailable as positive anti-bodies patients were very low in number
    [2] - Antibody titers is unavailable because there was no positive anti-body patient
    No statistical analyses for this end point

    Secondary: Percentage of participants with chronic heart failure with positive antibody status who develop non-neutralizing anti-serelaxin antibodies following 3 repeated infusions (i.e. at Week 4, Week 8, and Week 12)

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    End point title
    		 Percentage of participants with chronic heart failure with positive antibody status who develop non-neutralizing anti-serelaxin antibodies following 3 repeated infusions (i.e. at Week 4, Week 8, and Week 12)
    End point description
    A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. n = the total number of subjects with evaluable antibody status after specified number of infusions
    End point type
    Secondary
    End point timeframe
    At Week 4, Week 8, Week 12
    End point values
    		 RLX030 (serelaxin) Placebo
    Number of subjects analysed
    212
    108
    Units: Percentage of participants
    number (confidence interval 90%)
        after 1 infusion (at week 4) [n=209,108]
    0.48 (0.02 to 2.25)
    0 (0 to 2.74)
        after 2 infusions (at week 8) [n=200,106]
    0.5 (0.03 to 2.35)
    0 (0 to 2.79)
        after 3 infusions (at week 12) [n=184, 102]
    0.54 (0.03 to 2.55)
    0 (0 to 2.89)
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events such as adjudicated potential hypersensitivity or infusion reactions

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    End point title
    		 Number of participants with adverse events such as adjudicated potential hypersensitivity or infusion reactions
    End point description
    Incidence rate of special interest, indicative of hypersensitivity reactions which occur during and after administration of repeated infusions of serelaxin relative to placebo in subjects with chronic heart failure is reported. Hypersensitivity reactions or infusion reactions can be headache, nausea, fever, chills, dizziness, flush, pruritus, chest and/or back pain.
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 RLX030 (serelaxin) Placebo
    Number of subjects analysed
    212
    108
    Units: Participants
        Submitted for adjudication
    32
    14
        Confirmed with no hypersensitivity reactions
    32
    14
        Hypersensitivity reactions confirmed
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of RLX030: Area under the plasma concentration time curve from time zero up to 48 hours post dose (AUC 0-48)

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    End point title
    		 Pharmacokinetics of RLX030: Area under the plasma concentration time curve from time zero up to 48 hours post dose (AUC 0-48) [3]
    End point description
    Due to sparse PK sampling, AUC 0-48 hours was not analyzed.
    End point type
    Secondary
    End point timeframe
    pre-infusion and 8, 24 and 48 hours post each infusion.
    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: PK gets measured on study drug, not on placebo
    End point values
    		 RLX030 (serelaxin)
    Number of subjects analysed
    0 [4]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    ( )
    Notes
    [4] - Due to sparse PK sampling, AUC 0-48 hours was not analyzed.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of RLXL030: actual concentrations at steady state (Css)

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    End point title
    		 Pharmacokinetics of RLXL030: actual concentrations at steady state (Css) [5]
    End point description
    Concentration at steady state (Css) was estimated using C48 or C24 for patients who received the intended rate of infusion for at least 24hours. n: Number of patients with valid PK parameters available
    End point type
    Secondary
    End point timeframe
    pre-infusion and 24, 48 hours post each infusion
    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: PK gets measured on study drug, not on placebo
    End point values
    		 RLX030 (serelaxin)
    Number of subjects analysed
    211
    Units: ng/ml
    arithmetic mean (standard deviation)
        First infusion (n=174)
    31.6 ( 70.1 )
        Second Infusion (n=174)
    53.5 ( 234 )
        Third (n = 181)
    38.9 ( 95.2 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of RLX030: Cmax steady state (Cmaxss) concentration at 48 hours

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    End point title
    		 Pharmacokinetics of RLX030: Cmax steady state (Cmaxss) concentration at 48 hours [6]
    End point description
    This analysis was not done due to sparse PK sampling.
    End point type
    Secondary
    End point timeframe
    48 hours post each infusion
    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: PK gets measured on study drug, not on placebo
    End point values
    		 RLX030 (serelaxin)
    Number of subjects analysed
    0 [7]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    Notes
    [7] - This analysis was not done due to sparse PK sampling.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of RLX030: clearance of serelaxin (CL)

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    End point title
    		 Pharmacokinetics of RLX030: clearance of serelaxin (CL) [8]
    End point description
    Clearance (CL) was calculated using concentration at steady state (Css) and the actual delivered dose rate. n: Number of patients with valid PK parameters available within 48 hours post each infusion.
    End point type
    Secondary
    End point timeframe
    48 hours post each infusion
    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: PK gets measured on study drug, not on placebo
    End point values
    		 RLX030 (serelaxin)
    Number of subjects analysed
    211
    Units: mL/hr/kg
    arithmetic mean (standard deviation)
        First Infusion (n= 173)
    106 ( 55.8 )
        Second Infusion (n=173)
    97.4 ( 41.4 )
        Third Infusion (n= 180)
    202 ( 1290 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    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
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8

    Reporting group title
    Serelaxin
    Reporting group description
    		 Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8

    Serious adverse events
    		 Placebo Serelaxin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 108 (13.89%)
    30 / 212 (14.15%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE EMERGENCY
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    MEDICAL DEVICE SITE PAIN
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    ACUTE PSYCHOSIS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ALCOHOL POISONING
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK SECOND DEGREE
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    2 / 108 (1.85%)
    4 / 212 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIOGENIC SHOCK
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    SYNCOPE
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 212 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAROTID ARTERY STENOSIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOCAL CORD PARALYSIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    DIARRHOEA INFECTIOUS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPIDIDYMITIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONSILLAR ABSCESS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA STREPTOCOCCAL
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 212 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STREPTOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Serelaxin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 108 (36.11%)
    65 / 212 (30.66%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    5 / 108 (4.63%)
    7 / 212 (3.30%)
         occurrences all number
    6
    8
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    3 / 108 (2.78%)
    9 / 212 (4.25%)
         occurrences all number
    4
    10
    DIZZINESS
         subjects affected / exposed
    1 / 108 (0.93%)
    10 / 212 (4.72%)
         occurrences all number
    1
    10
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 108 (1.85%)
    6 / 212 (2.83%)
         occurrences all number
    2
    6
    General disorders and administration site conditions
    INFUSION SITE EXTRAVASATION
         subjects affected / exposed
    1 / 108 (0.93%)
    5 / 212 (2.36%)
         occurrences all number
    1
    6
    OEDEMA PERIPHERAL
         subjects affected / exposed
    3 / 108 (2.78%)
    4 / 212 (1.89%)
         occurrences all number
    3
    4
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 108 (0.93%)
    6 / 212 (2.83%)
         occurrences all number
    1
    8
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    3 / 108 (2.78%)
    3 / 212 (1.42%)
         occurrences all number
    3
    3
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    3 / 108 (2.78%)
    3 / 212 (1.42%)
         occurrences all number
    5
    5
    Musculoskeletal and connective tissue disorders
    MUSCLE SPASMS
         subjects affected / exposed
    3 / 108 (2.78%)
    4 / 212 (1.89%)
         occurrences all number
    3
    5
    BACK PAIN
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 212 (0.47%)
         occurrences all number
    4
    1
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 212 (0.47%)
         occurrences all number
    3
    1
    NASOPHARYNGITIS
         subjects affected / exposed
    8 / 108 (7.41%)
    18 / 212 (8.49%)
         occurrences all number
    8
    21
    BRONCHITIS
         subjects affected / exposed
    4 / 108 (3.70%)
    2 / 212 (0.94%)
         occurrences all number
    4
    2
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    5 / 108 (4.63%)
    3 / 212 (1.42%)
         occurrences all number
    6
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2014
    This amendment issued before the study initiation (first patient first visit), introduced the following changes:  - Addition of the brand name for the infusion filter  - A sentence was added to clarify that the use of other 250 mL infusion bags containing 5% dextrose were permitted  -the liver monitoring sections of the protocol were updated to match the program and company standard wording and process
    21 Mar 2014
    This amendment issued before the study initiation (first patient first visit), introduced the following change(s): - One exclusion criteria was corrected to indicate that women of child-bearing potential must use highly effective methods of contraception. - A section in the protocol was modified to clarify the various methods utilized to ensure protocol and GCP compliance and the quality/integrity of the sites’ data. - Per request of German Health Authority as part of additional safety measures to avoid any potential risk of hypotension with the infusion of serelaxin, particular section of the protocol clarified that an infusion pump, a drip or any other controllable infusion system would be used to ensure a constant infusion rate of serelaxin at 10 mL/hr.
    28 Jul 2014
    This amendment issued when less than 20 patients were randomized introduced the following change(s): - One exclusion criteria was modified with following sentence “The exception to this exclusion criteria are the low potency topical corticosteroids and inhaled glucocorticoids used for anti-inflammatory effect, e.g. asthma, contact dermatitis, etc”. The rationale for allowing low potency topical corticosteroids and inhaled glucocorticoids used for antiinflammatory effects was that these products had no known or negligible systemic effects if used in accordance to approved dosing and in line with medical recommendation. Since the immunomodulating/immunosuppressive actions were minimal and were not expected to affect the objectives of this study, patients requiring such treatment could be enrolled into the study as long as all other inclusion and exclusion criteria have been fulfilled. - One exclusion criteria was modified by adding ‘Visit 2’ for clarity. - Tables and appendices were updated and modified for clarity.

    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.novfor 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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