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    Clinical Trial Results:
    A multicenter, prospective, randomized, open label study to assess the effect of serelaxin versus standard of care in acute heart failure (AHF) patients

    Summary
    EudraCT number
    		 2013-002513-35
    Trial protocol
    		 GB   AT   HU   IT   CZ   SK   BE   PT   BG   LT   PL   LV   EE   FI   SI   GR   ES   HR   DK   IS   FR  
    Global end of trial date
    25 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2018
    First version publication date
    10 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRLX030A3301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02064868
    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
    25 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of serelaxin as add-on therapy to standard of care (SOC) versus SOC alone in reducing in-hospital worsening heart failure (WHF) requiring rescue therapy or all-cause death, from randomization through Day 5.
    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
    31 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 56
    Country: Number of subjects enrolled
    Belgium: 87
    Country: Number of subjects enrolled
    Bulgaria: 74
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    Czech Republic: 78
    Country: Number of subjects enrolled
    Estonia: 26
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 239
    Country: Number of subjects enrolled
    Germany: 383
    Country: Number of subjects enrolled
    Greece: 49
    Country: Number of subjects enrolled
    Hungary: 149
    Country: Number of subjects enrolled
    Iceland: 8
    Country: Number of subjects enrolled
    Italy: 225
    Country: Number of subjects enrolled
    Latvia: 20
    Country: Number of subjects enrolled
    Lithuania: 40
    Country: Number of subjects enrolled
    Poland: 166
    Country: Number of subjects enrolled
    Portugal: 50
    Country: Number of subjects enrolled
    Romania: 95
    Country: Number of subjects enrolled
    Russian Federation: 382
    Country: Number of subjects enrolled
    Serbia: 176
    Country: Number of subjects enrolled
    Slovakia: 36
    Country: Number of subjects enrolled
    Slovenia: 17
    Country: Number of subjects enrolled
    Spain: 207
    Country: Number of subjects enrolled
    Switzerland: 34
    Country: Number of subjects enrolled
    United Kingdom: 41
    Worldwide total number of subjects
    2650
    EEA total number of subjects
    2058
    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)
    402
    From 65 to 84 years
    1751
    85 years and over
    497

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The initial target was to randomize 3183 patients. This study was prematurely terminated (due to the neutral read-out of study RELAX-AHF-2) after 2666 patients were randomized. 16 patients had not qualified for randomization but were inadvertently randomized. These 16 patients did not enter the treatment phase and were not counted as started.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Serelaxin + Standard of Care
    Arm description
    		 Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study drug was administered according to a weight-range adjusted dosing regimen at a nominal dose of 30 μg/kg/day, as a continuous intravenous infusion for 48 hours.

    Arm title
    		 Standard of Care (SOC)
    Arm description
    		 All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
    Arm type
    		 Standard of Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Serelaxin + Standard of Care Standard of Care (SOC)
    Started
    1756
    894
    Full Analysis Set
    1756
    894
    Safety Set
    1729
    894
    Completed
    1722
    881
    Not completed
    34
    13
         Physician decision
    1
    -
         Consent withdrawn by subject
    14
    3
         Technical Problems or Missing
    5
    2
         Lost to follow-up
    14
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Serelaxin + Standard of Care
    Reporting group description
    		 Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.

    Reporting group values
    		 Serelaxin + Standard of Care Standard of Care (SOC) Total
    Number of subjects
    		 1756 894 2650
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 281 121 402
        From 65-84 years
    		 1151 600 1751
        85 years and over
    		 324 173 497
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 75.24 ( 10.349 ) 75.95 ( 9.905 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 760 383 1143
        Male
    		 996 511 1507
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian|
    		 1706 869 2575
        Black|
    		 4 4 8
        Asian|
    		 5 2 7
        Unknown|
    		 16 7 23
        Other|
    		 25 12 37

    End points

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    End points reporting groups
    Reporting group title
    Serelaxin + Standard of Care
    Reporting group description
    		 Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.

    Primary: Worsening heart failure (WHF) / all cause of deaths through day 5

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    End point title
    		 Worsening heart failure (WHF) / all cause of deaths through day 5
    End point description
    In-hospital WHF through Day 5 post-randomization included worsening signs and/or symptoms of heart failure that required an intensification of intravenous therapy for heart failure or mechanical ventilation, renal or circulatory support. A central event adjudication committee was appointed to oversee the WHF primary endpoint adjudication.
    End point type
    Primary
    End point timeframe
    5 days
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1756
    894
    Units: Percentage of Participants
        number (not applicable)
    4.95
    6.94
    Statistical analysis title
    		 WHF / all cause of deaths
    Comparison groups
    Standard of Care (SOC) v Serelaxin + Standard of Care
    Number of subjects included in analysis
    2650
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0172 [1]
    Method
    		 Gehan’s generalized Wilcoxon test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.98
    Notes
    [1] - One-sided p-value

    Secondary: In-hospital worsening heart failure/all-cause death/readmission for heart failure through day 14

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    End point title
    		 In-hospital worsening heart failure/all-cause death/readmission for heart failure through day 14
    End point description
    WHF/death/readmission for heart failure through Day 14. WHF/deaths through Day 5 were adjudicated and confirmed by the Clinical Endpoint Committee, WHF/deaths after Day 5 through Day 14 and readmission through Day 14 were as reported by the investigators.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1756
    894
    Units: Percentage of Patients
        number (not applicable)
    8.49
    10.63
    Statistical analysis title
    		 WHF/death/readmission for heart failure
    Comparison groups
    Serelaxin + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    2650
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0634 [2]
    Method
    		 Gehan’s generalized Wilcoxon test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.02
    Notes
    [2] - Two-sided p-value

    Secondary: Persistent sign or symptoms of heart failure / non-improvement at any post baseline visit through day 5

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    End point title
    		 Persistent sign or symptoms of heart failure / non-improvement at any post baseline visit through day 5
    End point description
    Persistent or non-improvement in any signs or symptoms of HF at any post baseline visit up to Day 5.
    End point type
    Secondary
    End point timeframe
    5 days
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1744
    894
    Units: Percentage of Participants
        number (confidence interval 95%)
    86 (84 to 87)
    91 (89 to 93)
    Statistical analysis title
    		 Persistent or non-improvement in HF
    Comparison groups
    Serelaxin + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    2638
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Renal deterioration at any post baseline visit through day 14

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    End point title
    		 Renal deterioration at any post baseline visit through day 14
    End point description
    Renal deterioration is defined as > or = 0.3 mg/dL increase from screening in serum creatinine.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1740
    889
    Units: Percentage of Participants
        number (confidence interval 95%)
    36 (34 to 38)
    44 (40 to 47)
    Statistical analysis title
    		 Renal Deterioration
    Comparison groups
    Serelaxin + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    2629
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Length of index hospital stay

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    End point title
    		 Length of index hospital stay
    End point description
    Length of stay (in hours) is defined as the index hospitalization discharge date and time minus the index hospitalization start date and time.
    End point type
    Secondary
    End point timeframe
    30 Days
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1756
    894
    Units: hours
        arithmetic mean (standard deviation)
    251.28 ( 162.368 )
    243.59 ( 160.270 )
    Statistical analysis title
    		 Length of Index Hospital Stay
    Comparison groups
    Serelaxin + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    2650
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1392
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of patients reported with adverse events as assessment of safety and tolerability of Serelaxin in AHF patients

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    End point title
    		 Number of patients reported with adverse events as assessment of safety and tolerability of Serelaxin in AHF patients
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse Events (AE): 5 Days / Serious Adverse Events (SAE): 14 days / All cause deaths 30 days
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1729
    894
    Units: Percentage of participants
    number (not applicable)
        Patients with any AE through Day 5|
    58.13
    56.04
        Patients with any SAE through Day 14|
    12.38
    11.97
        All cause deaths through Day 5|
    0.58
    0.67
        All cause deaths through Day 14|
    1.91
    2.01
        All cause deaths through Day 30|
    3.30
    4.25
    No statistical analyses for this end point

    Secondary: Change from baseline in Health-related quality of life, assessed by EuroQoL EQ-5D-5L questionnaire.

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    End point title
    		 Change from baseline in Health-related quality of life, assessed by EuroQoL EQ-5D-5L questionnaire.
    End point description
    EQ-5D-5L is a questionnaire designed to assess health status in adults consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). The results were converted into a single index value using UK as the reference country for all countries. Range -0.3 (worst possible state) to 1 (best possible state).
    End point type
    Secondary
    End point timeframe
    Baseline, Day 5, Day 14
    End point values
    		 Serelaxin + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    1545 [3]
    793 [4]
    Units: Points
    arithmetic mean (standard deviation)
        Day 5|
    0.28 ( 0.298 )
    0.27 ( 0.292 )
        Day 14|
    0.32 ( 0.328 )
    0.31 ( 0.317 )
    Notes
    [3] - 1545 Subjects Analyzed at Day 5 1486 Subjects Analyzed at Day 14
    [4] - 793 Subjects Analyzed at Day 5 756 Subjects Analyzed at Day 14
    Statistical analysis title
    		 Change in EQ-5D-5L
    Statistical analysis description
    Day 5
    Comparison groups
    Serelaxin + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    2338
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3115
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Change in EQ-5D-5L
    Statistical analysis description
    Day 14
    Comparison groups
    Serelaxin + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    2338
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1236
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are collected from FPFV until LPLV.  All AEs are reported in this record from First Patient First Treatment until LPLV. For each patient AEs were collected to Day 5 and SAEs to Day 14. Deaths were reported only if an associated (S)AE was recorded.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the SAEs field “number of deaths resulting from adverse events” all those deaths, resulting from SAEs that are deemed to be causally related to treatment. 20 additional deaths in "Serelaxin + SOC" and 18 in "SOC" were recorded outside the reporting period of (S)AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Serelaxin + SOC
    Reporting group description
    		 Serelaxin + SOC

    Reporting group title
    Standard of Care
    Reporting group description
    		 Standard of care (SOC)

    Serious adverse events
    		 Serelaxin + SOC Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    214 / 1729 (12.38%)
    107 / 894 (11.97%)
         number of deaths (all causes)
    43
    25
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial disorder
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arteriovenous fistula
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femoral artery aneurysm
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1729 (0.12%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertensive crisis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    7 / 1729 (0.40%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Left atrial appendage occlusion
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (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
    Death
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organ failure
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    4 / 1729 (0.23%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    6 / 1729 (0.35%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 1729 (0.12%)
    3 / 894 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 1729 (0.06%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    3 / 1729 (0.17%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         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
    6 / 1729 (0.35%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio decreased
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fall
         subjects affected / exposed
    0 / 1729 (0.00%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria traumatic
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    6 / 1729 (0.35%)
    4 / 894 (0.45%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Angina pectoris
         subjects affected / exposed
    0 / 1729 (0.00%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 1729 (0.06%)
    4 / 894 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic valve incompetence
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 1729 (0.06%)
    3 / 894 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 1729 (0.35%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    3 / 1729 (0.17%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    7 / 1729 (0.40%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    6 / 1729 (0.35%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Cardiac failure
         subjects affected / exposed
    38 / 1729 (2.20%)
    26 / 894 (2.91%)
         occurrences causally related to treatment / all
    1 / 39
    0 / 26
         deaths causally related to treatment / all
    0 / 7
    0 / 8
    Cardiac failure acute
         subjects affected / exposed
    6 / 1729 (0.35%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    2 / 1729 (0.12%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 1729 (0.12%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac hypertrophy
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    3 / 1729 (0.17%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiorenal syndrome
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    7 / 1729 (0.40%)
    4 / 894 (0.45%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diastolic dysfunction
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mitral valve incompetence
         subjects affected / exposed
    5 / 1729 (0.29%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 1729 (0.12%)
    3 / 894 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus arrest
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    5 / 1729 (0.29%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    5 / 1729 (0.29%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnic coma
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 1729 (0.17%)
    4 / 894 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    3 / 1729 (0.17%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 1729 (0.52%)
    4 / 894 (0.45%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Acute prerenal failure
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    6 / 1729 (0.35%)
    3 / 894 (0.34%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Renal impairment
         subjects affected / exposed
    4 / 1729 (0.23%)
    5 / 894 (0.56%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal tubular necrosis
         subjects affected / exposed
    1 / 1729 (0.06%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chest wall haematoma
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (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
    Bacteraemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (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
    3 / 1729 (0.17%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngitis fungal
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (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
    11 / 1729 (0.64%)
    6 / 894 (0.67%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pneumonia influenzal
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (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
    2 / 1729 (0.12%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Skin bacterial infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 1729 (0.17%)
    4 / 894 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 1729 (0.12%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    0 / 894 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1729 (0.06%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 1729 (0.00%)
    2 / 894 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 1729 (0.00%)
    1 / 894 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1.5%
    Non-serious adverse events
    		 Serelaxin + SOC Standard of Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    637 / 1729 (36.84%)
    324 / 894 (36.24%)
    Investigations
    Blood pressure systolic decreased
         subjects affected / exposed
    49 / 1729 (2.83%)
    2 / 894 (0.22%)
         occurrences all number
    51
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    48 / 1729 (2.78%)
    18 / 894 (2.01%)
         occurrences all number
    49
    18
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    34 / 1729 (1.97%)
    23 / 894 (2.57%)
         occurrences all number
    34
    23
    Cardiac failure
         subjects affected / exposed
    81 / 1729 (4.68%)
    56 / 894 (6.26%)
         occurrences all number
    85
    58
    Mitral valve incompetence
         subjects affected / exposed
    28 / 1729 (1.62%)
    12 / 894 (1.34%)
         occurrences all number
    28
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    45 / 1729 (2.60%)
    18 / 894 (2.01%)
         occurrences all number
    45
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    49 / 1729 (2.83%)
    9 / 894 (1.01%)
         occurrences all number
    49
    9
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    24 / 1729 (1.39%)
    21 / 894 (2.35%)
         occurrences all number
    24
    21
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    74 / 1729 (4.28%)
    32 / 894 (3.58%)
         occurrences all number
    74
    32
    Diarrhoea
         subjects affected / exposed
    29 / 1729 (1.68%)
    21 / 894 (2.35%)
         occurrences all number
    29
    21
    Nausea
         subjects affected / exposed
    40 / 1729 (2.31%)
    17 / 894 (1.90%)
         occurrences all number
    40
    17
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    27 / 1729 (1.56%)
    16 / 894 (1.79%)
         occurrences all number
    28
    16
    Insomnia
         subjects affected / exposed
    58 / 1729 (3.35%)
    21 / 894 (2.35%)
         occurrences all number
    58
    21
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    18 / 1729 (1.04%)
    18 / 894 (2.01%)
         occurrences all number
    18
    18
    Renal impairment
         subjects affected / exposed
    30 / 1729 (1.74%)
    18 / 894 (2.01%)
         occurrences all number
    30
    18
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    28 / 1729 (1.62%)
    11 / 894 (1.23%)
         occurrences all number
    28
    11
    Muscle spasms
         subjects affected / exposed
    33 / 1729 (1.91%)
    8 / 894 (0.89%)
         occurrences all number
    33
    8
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    24 / 1729 (1.39%)
    14 / 894 (1.57%)
         occurrences all number
    24
    14
    Urinary tract infection
         subjects affected / exposed
    56 / 1729 (3.24%)
    26 / 894 (2.91%)
         occurrences all number
    56
    26
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    47 / 1729 (2.72%)
    35 / 894 (3.91%)
         occurrences all number
    47
    35
    Hypokalaemia
         subjects affected / exposed
    119 / 1729 (6.88%)
    73 / 894 (8.17%)
         occurrences all number
    120
    74

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2013
    Amendment 1 was initiated at the request of German Health Authorities and was applicable only to German sites participating in this trial. As part of the review process, German health authorities requested to amend the protocol with inclusion of the following 2 requirements: 1. As part of additional safety measures and to avoid any potential risk of hypotension with the infusion of serelaxin, it was recommended to clarify the use of an infusion pump, a drip or any other controllable infusion systems to ensure a constant infusion rate of serelaxin at 10ml/hour. 2. To further clarify the informed consent procedure related to the nature of the witness, an “independent second physician or nurse” was added who will co-sign the ICF and thereby confirm that the patient provided informed consent according to his/her own will following receipt of all study related information based on his/her ability to understand the trial procedures.
    19 Jun 2014
    Amendment 2 was introduced based on the initial feedback gathered from the investigators already screening and recruiting patients, the request for clarification from some local health authorities, and further discussions with the Executive Committee Board. These changes aimed at further strengthening the protocol, facilitating recruitment and ensuring possible data merging with other serelaxin studies like RELAX-AHF-2.
    24 Jun 2015
    Amendment 3: AHF is a complex and subjective clinical diagnosis. Since the diagnosis of AHF is primarily based on clinical observations that are interpreted bedside, in an urgent care environment, based on the clinical judgment of the investigator, the diagnosis is sometimes difficult to qualify. Therefore, the study Executive Committee recommended changes to better specify the criteria defining AHF in the patient population under investigation, correct inconsistencies and improve the overall clarity of the study.
    19 Oct 2016
    Amendment 4 was introduced since the Executive Committee recommended during its meeting held on 15th of June 2016 to increase the number of randomized patients from 2,685 to 3,183. The rationale for the increase was that the number of events constitutive of the primary endpoint was lower than expected. This decision was endorsed by the Data Monitoring Committee (DMC).

    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 following the neutral results from the Phase III RELAX-AHF-2 (CRLX030A2301) study which did not support further development of serelaxin in AHF.
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