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    Clinical Trial Results:
    A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy and Safety Study of NEOD001 Plus Standard of Care vs. Placebo Plus Standard of Care in Subjects with Light Chain (AL) Amyloidosis

    Summary
    EudraCT number
    		 2014-003865-11
    Trial protocol
    		 DE   AT   ES   BE   NL   FR   GB   GR   PL   DK   IT  
    Global end of trial date
    08 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2019
    First version publication date
    28 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NEOD001-CL002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02312206
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Prothena Therapeutics Limited, now merged into Prothena Biosciences Limited
    Sponsor organisation address
    77 Sir John Rogerson's Quay, Block C, Grand Canal Docklands, Dublin 2, Ireland, D02 T804
    Public contact
    Communications Office, Prothena Biosciences Inc, info@prothena.com
    Scientific contact
    Clinical Trials Office, Prothena Biosciences Inc, info@prothena.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
    30 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of NEOD001 plus standard of care (SOC) vs. placebo plus standard of care when administered intravenously in subjects with AL amyloidosis by assessing time to all- cause mortality or cardiac hospitalization
    Protection of trial subjects
    This study was conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practice, the principles of the Declaration of Helsinki, and with the laws of the countries in which the study was conducted. The Investigator had the ability to break the blind for a specific subject in the event of an immediate medical emergency, wherein knowledge of the subject’s treatment (NEOD001 or placebo) needed to be known in order to provide adequate medical treatment. In these situations, the breaking of the blind was to be reported to the Sponsor or its designee within 24 hours. An independent DMC was in place to safeguard the interests of subjects in the study and to help ensure the integrity and credibility of the study.
    Background therapy
    		 All subjects received concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion. Antiviral prophylaxis was required.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 2015
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    United States: 142
    Worldwide total number of subjects
    260
    EEA total number of subjects
    92
    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)
    139
    From 65 to 84 years
    117
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 260 subjects were enrolled in the study, 130 randomly assigned to receive NEOD001 and 130 randomly assigned to receive placebo.

    Pre-assignment
    Screening details
    		 Screening evaluations and procedures were performed within 28 days prior to the first study drug administration on Month 1-Day 1. Individual test results that did not meet eligibility requirements could be repeated, with the exception of 6MWT; full rescreening was only allowed once per subject.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NEOD001 24 mg/kg plus SOC
    Arm description
    		 NEOD001, 24 mg/kg IV every 4 weeks with concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NEOD001 24 mg/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study drug administered intravenously every 4 weeks for 12 months, starting at the Month 1-Day 1 Visit.

    Arm title
    		 Placebo plus SOC
    Arm description
    		 Placebo, 0.9% Saline IV every 4 weeks with concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion.
    Arm type
    		 Placebo

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

    Number of subjects in period 1
    		NEOD001 24 mg/kg plus SOC Placebo plus SOC
    Started
    130
    130
    Informed Consent Obtained
    130
    130
    Not Completed
    130
    130
    Completed
    0
    0
    Not completed
    130
    130
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    7
    6
         Physician decision
    7
    6
         Disease progression
    1
    -
         Patient progression and institution of new therapy
    1
    -
         Subject missed three consecutive treatment visits
    -
    1
         Adverse event, non-fatal
    2
    6
         Death
    30
    36
         Study Terminated by Sponsor
    81
    74
         Patient transferred to hospice
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NEOD001 24 mg/kg plus SOC
    Reporting group description
    		 NEOD001, 24 mg/kg IV every 4 weeks with concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion.

    Reporting group title
    Placebo plus SOC
    Reporting group description
    		 Placebo, 0.9% Saline IV every 4 weeks with concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion.

    Reporting group values
    		 NEOD001 24 mg/kg plus SOC Placebo plus SOC Total
    Number of subjects
    		 130 130 260
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 69 70 139
        From 65-84 years
    		 61 56 117
        85 years and over
    		 0 4 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.69 ( 9.478 ) 63.24 ( 9.708 ) -
    Gender categorical
    Units: Subjects
        Female
    		 48 40 88
        Male
    		 82 90 172
    Race
    Units: Subjects
        White
    		 118 120 238
        Black or African American
    		 9 3 12
        Not reported
    		 1 5 6
        Asian
    		 2 2 4
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 4
        Not Hispanic or Latino
    		 116 122 238
        Not reported
    		 12 6 18
    Subject analysis sets

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (Safety Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population includes all subjects who received any amount of study drug

    Subject analysis set title
    Placebo plus SOC (Safety Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Population includes all subjects who received any amount of study drug

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (ITT Population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT Population includes all randomized subjects who received any amount of study drug

    Subject analysis set title
    Placebo plus SOC (ITT Population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT Population includes all randomized subjects who received any amount of study drug

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (Renal Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Renal Evaluable Population includes all ITT subjects who had a baseline proteinuria >0.5 g/24 hours and at least one postbaseline assessment of 24 hour protein

    Subject analysis set title
    Placebo plus SOC (Renal Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Renal Evaluable Population includes all ITT subjects who had a baseline proteinuria >0.5 g/24 hours and at least one postbaseline assessment of 24 hour protein

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (PN Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Peripheral Neuropathy (PN) Evaluable Population includes all ITT subjects who had ascending sensorimotor neuropathy due to AL amyloidosis at screening and had a baseline NIS-LL total score >= 2 and at least one postbaseline NIS-LL total score assessment

    Subject analysis set title
    Placebo plus SOC (PN Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Peripheral Neuropathy (PN) Evaluable Population includes all ITT subjects who had ascending sensorimotor neuropathy due to AL amyloidosis at screening and had a baseline NIS-LL total score >= 2 and at least one postbaseline NIS-LL total score assessment

    Subject analysis sets values
    		 NEOD001 24 mg/kg plus SOC (Safety Population) Placebo plus SOC (Safety Population) NEOD001 24 mg/kg plus SOC (ITT Population) Placebo plus SOC (ITT Population) NEOD001 24 mg/kg plus SOC (Renal Evaluable Population) Placebo plus SOC (Renal Evaluable Population) NEOD001 24 mg/kg plus SOC (PN Evaluable Population) Placebo plus SOC (PN Evaluable Population)
    Number of subjects
    130
    130
    130
    130
    64
    45
    15
    14
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    69
    70
    69
    70
    34
    28
    8
    7
        From 65-84 years
    61
    56
    61
    56
    30
    16
    7
    7
        85 years and over
    0
    4
    0
    4
    0
    1
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.69 ( 9.478 )
    63.24 ( 9.708 )
    63.69 ( 9.478 )
    63.24 ( 9.708 )
    63.57 ( 8.256 )
    60.62 ( 10.100 )
    65.13 ( 10.158 )
    64.56 ( 8.372 )
    Gender categorical
    Units: Subjects
        Female
    48
    40
    48
    40
    18
    13
    2
    3
        Male
    82
    90
    82
    90
    46
    32
    13
    11
    Race
    Units: Subjects
        White
    118
    120
    118
    120
    59
    44
    15
    13
        Black or African American
    9
    3
    9
    3
    2
    0
    0
    0
        Not reported
    1
    5
    1
    5
    1
    1
    0
    1
        Asian
    2
    2
    2
    2
    2
    0
    0
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2
    2
    2
    2
    2
    0
    0
    0
        Not Hispanic or Latino
    116
    122
    116
    122
    56
    43
    14
    14
        Not reported
    12
    6
    12
    6
    6
    2
    1
    0

    End points

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    End points reporting groups
    Reporting group title
    NEOD001 24 mg/kg plus SOC
    Reporting group description
    		 NEOD001, 24 mg/kg IV every 4 weeks with concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion.

    Reporting group title
    Placebo plus SOC
    Reporting group description
    		 Placebo, 0.9% Saline IV every 4 weeks with concomitant standard of care chemotherapy, which must have included bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may have been prescribed as per standard of care at the Investigator’s discretion.

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (Safety Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population includes all subjects who received any amount of study drug

    Subject analysis set title
    Placebo plus SOC (Safety Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Population includes all subjects who received any amount of study drug

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (ITT Population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT Population includes all randomized subjects who received any amount of study drug

    Subject analysis set title
    Placebo plus SOC (ITT Population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT Population includes all randomized subjects who received any amount of study drug

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (Renal Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Renal Evaluable Population includes all ITT subjects who had a baseline proteinuria >0.5 g/24 hours and at least one postbaseline assessment of 24 hour protein

    Subject analysis set title
    Placebo plus SOC (Renal Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Renal Evaluable Population includes all ITT subjects who had a baseline proteinuria >0.5 g/24 hours and at least one postbaseline assessment of 24 hour protein

    Subject analysis set title
    NEOD001 24 mg/kg plus SOC (PN Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Peripheral Neuropathy (PN) Evaluable Population includes all ITT subjects who had ascending sensorimotor neuropathy due to AL amyloidosis at screening and had a baseline NIS-LL total score >= 2 and at least one postbaseline NIS-LL total score assessment

    Subject analysis set title
    Placebo plus SOC (PN Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Peripheral Neuropathy (PN) Evaluable Population includes all ITT subjects who had ascending sensorimotor neuropathy due to AL amyloidosis at screening and had a baseline NIS-LL total score >= 2 and at least one postbaseline NIS-LL total score assessment

    Primary: Time to composite of all-cause mortality or cardiac hospitalization

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    End point title
    		 Time to composite of all-cause mortality or cardiac hospitalization
    End point description
    Time to all-cause mortality death occurring after the first infusion of study drug or cardiac hospitalization as adjudicated by the CEC occurring at least 91 days after a first infusion of study drug through last subject last visit, whichever came first
    End point type
    Primary
    End point timeframe
    Randomization until the date of death or cardiac hospitalization
    End point values
    		 NEOD001 24 mg/kg plus SOC (ITT Population) Placebo plus SOC (ITT Population)
    Number of subjects analysed
    130
    130
    Units: Subjects
        Died or cardiac hospitalization - Yes
    56
    62
        Died or cardiac hospitalization - No
    74
    68
    Statistical analysis title
    		 Time to comp. all-cause mortality or cardiac hosp
    Statistical analysis description
    Test to determine if the survival distribution of the time-to all-cause mortality or cardiac hospitalization is the same or different between placebo and NEOD001.
    Comparison groups
    NEOD001 24 mg/kg plus SOC (ITT Population) v Placebo plus SOC (ITT Population)
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.835
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5799
         upper limit
    		 1.2011

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Initiation of study drug through the last study visit or up to 30 days after last dose, whichever is later.
    Adverse event reporting additional description
    AE that newly appears, increases in frequency, or worsens in severity following initiation of study drug and through the last study visit or up to 30 days after date of last dose, whichever is later.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    NEOD001 24 mg/kg plus SOC
    Reporting group description
    		 NEOD001 24 mg/kg IV every 4 weeks

    Reporting group title
    Placebo plus SOC
    Reporting group description
    		 Placebo, 0.9% Saline IV every 4 weeks

    Reporting group title
    Total
    Reporting group description
    		 Total NEOD001 + Placebo

    Serious adverse events
    		 NEOD001 24 mg/kg plus SOC Placebo plus SOC Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    88 / 130 (67.69%)
    91 / 130 (70.00%)
    179 / 260 (68.85%)
         number of deaths (all causes)
    41
    42
    83
         number of deaths resulting from adverse events
    20
    32
    52
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 130 (2.31%)
    6 / 130 (4.62%)
    9 / 260 (3.46%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    2 / 130 (1.54%)
    3 / 130 (2.31%)
    5 / 260 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 130 (1.54%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 130 (2.31%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Oedema
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 130 (1.54%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Sudden death
         subjects affected / exposed
    1 / 130 (0.77%)
    3 / 130 (2.31%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 130 (2.31%)
    0 / 130 (0.00%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 130 (2.31%)
    0 / 130 (0.00%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 130 (0.77%)
    3 / 130 (2.31%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 130 (1.54%)
    6 / 130 (4.62%)
    8 / 260 (3.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 130 (0.77%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary amyloidosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial necrosis marker increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 130 (0.77%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Atrial fibrillation
         subjects affected / exposed
    6 / 130 (4.62%)
    6 / 130 (4.62%)
    12 / 260 (4.62%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac amyloidosis
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Cardiac arrest
         subjects affected / exposed
    9 / 130 (6.92%)
    10 / 130 (7.69%)
    19 / 260 (7.31%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 13
    0 / 23
         deaths causally related to treatment / all
    0 / 5
    0 / 6
    0 / 11
    Cardiac failure
         subjects affected / exposed
    17 / 130 (13.08%)
    28 / 130 (21.54%)
    45 / 260 (17.31%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 35
    0 / 70
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    0 / 6
    Cardiac failure acute
         subjects affected / exposed
    6 / 130 (4.62%)
    5 / 130 (3.85%)
    11 / 260 (4.23%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    17 / 130 (13.08%)
    9 / 130 (6.92%)
    26 / 260 (10.00%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 11
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 130 (0.77%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    2 / 130 (1.54%)
    5 / 130 (3.85%)
    7 / 260 (2.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 130 (1.54%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    11 / 130 (8.46%)
    7 / 130 (5.38%)
    18 / 260 (6.92%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 130 (1.54%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulation factor deficiency
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 130 (1.54%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 130 (3.08%)
    0 / 130 (0.00%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic pseudo-obstruction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 130 (2.31%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 130 (0.77%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 130 (0.77%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 130 (0.77%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 130 (1.54%)
    2 / 130 (1.54%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic hepatic cyst
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Hepatic haematoma
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatosplenomegaly
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    7 / 130 (5.38%)
    9 / 130 (6.92%)
    16 / 260 (6.15%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 10
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 130 (1.54%)
    4 / 130 (3.08%)
    6 / 260 (2.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 130 (2.31%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 130 (0.77%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 130 (1.54%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Injection site cellulitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 130 (2.31%)
    0 / 130 (0.00%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 130 (2.31%)
    4 / 130 (3.08%)
    7 / 260 (2.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pasteurella infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    11 / 130 (8.46%)
    9 / 130 (6.92%)
    20 / 260 (7.69%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
    0 / 26
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Pneumonia viral
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 130 (2.31%)
    2 / 130 (1.54%)
    5 / 260 (1.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    4 / 130 (3.08%)
    1 / 130 (0.77%)
    5 / 260 (1.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
    Soft tissue infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 130 (3.08%)
    0 / 130 (0.00%)
    4 / 260 (1.54%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 130 (1.54%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cell death
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 130 (2.31%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 130 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    5 / 130 (3.85%)
    4 / 130 (3.08%)
    9 / 260 (3.46%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 130 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 130 (0.77%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 130 (0.77%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 130 (0.77%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    5 / 130 (3.85%)
    3 / 130 (2.31%)
    8 / 260 (3.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 130 (0.77%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NEOD001 24 mg/kg plus SOC Placebo plus SOC Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    122 / 130 (93.85%)
    123 / 130 (94.62%)
    245 / 260 (94.23%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    20 / 130 (15.38%)
    29 / 130 (22.31%)
    49 / 260 (18.85%)
         occurrences all number
    29
    54
    83
    Orthostatic hypotension
         subjects affected / exposed
    9 / 130 (6.92%)
    13 / 130 (10.00%)
    22 / 260 (8.46%)
         occurrences all number
    13
    13
    26
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 130 (6.92%)
    9 / 130 (6.92%)
    18 / 260 (6.92%)
         occurrences all number
    18
    10
    28
    Chills
         subjects affected / exposed
    9 / 130 (6.92%)
    4 / 130 (3.08%)
    13 / 260 (5.00%)
         occurrences all number
    11
    4
    15
    Fatigue
         subjects affected / exposed
    57 / 130 (43.85%)
    52 / 130 (40.00%)
    109 / 260 (41.92%)
         occurrences all number
    125
    90
    215
    Oedema peripheral
         subjects affected / exposed
    55 / 130 (42.31%)
    56 / 130 (43.08%)
    111 / 260 (42.69%)
         occurrences all number
    112
    88
    200
    Pyrexia
         subjects affected / exposed
    12 / 130 (9.23%)
    11 / 130 (8.46%)
    23 / 260 (8.85%)
         occurrences all number
    18
    13
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 130 (23.85%)
    27 / 130 (20.77%)
    58 / 260 (22.31%)
         occurrences all number
    46
    33
    79
    Dyspnoea
         subjects affected / exposed
    38 / 130 (29.23%)
    40 / 130 (30.77%)
    78 / 260 (30.00%)
         occurrences all number
    63
    68
    131
    Dyspnoea exertional
         subjects affected / exposed
    11 / 130 (8.46%)
    7 / 130 (5.38%)
    18 / 260 (6.92%)
         occurrences all number
    13
    13
    26
    Epistaxis
         subjects affected / exposed
    8 / 130 (6.15%)
    7 / 130 (5.38%)
    15 / 260 (5.77%)
         occurrences all number
    9
    7
    16
    Pleural effusion
         subjects affected / exposed
    8 / 130 (6.15%)
    13 / 130 (10.00%)
    21 / 260 (8.08%)
         occurrences all number
    10
    15
    25
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 130 (8.46%)
    3 / 130 (2.31%)
    14 / 260 (5.38%)
         occurrences all number
    11
    3
    14
    Depression
         subjects affected / exposed
    11 / 130 (8.46%)
    7 / 130 (5.38%)
    18 / 260 (6.92%)
         occurrences all number
    13
    8
    21
    Insomnia
         subjects affected / exposed
    39 / 130 (30.00%)
    30 / 130 (23.08%)
    69 / 260 (26.54%)
         occurrences all number
    41
    35
    76
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 130 (3.85%)
    8 / 130 (6.15%)
    13 / 260 (5.00%)
         occurrences all number
    5
    10
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 130 (8.46%)
    8 / 130 (6.15%)
    19 / 260 (7.31%)
         occurrences all number
    13
    14
    27
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 130 (9.23%)
    5 / 130 (3.85%)
    17 / 260 (6.54%)
         occurrences all number
    36
    7
    43
    Blood creatinine increased
         subjects affected / exposed
    22 / 130 (16.92%)
    11 / 130 (8.46%)
    33 / 260 (12.69%)
         occurrences all number
    55
    21
    76
    Platelet count decreased
         subjects affected / exposed
    4 / 130 (3.08%)
    10 / 130 (7.69%)
    14 / 260 (5.38%)
         occurrences all number
    11
    20
    31
    Weight decreased
         subjects affected / exposed
    19 / 130 (14.62%)
    16 / 130 (12.31%)
    35 / 260 (13.46%)
         occurrences all number
    25
    23
    48
    Weight increased
         subjects affected / exposed
    6 / 130 (4.62%)
    11 / 130 (8.46%)
    17 / 260 (6.54%)
         occurrences all number
    12
    12
    24
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    8 / 130 (6.15%)
    10 / 130 (7.69%)
    18 / 260 (6.92%)
         occurrences all number
    10
    12
    22
    Fall
         subjects affected / exposed
    14 / 130 (10.77%)
    10 / 130 (7.69%)
    24 / 260 (9.23%)
         occurrences all number
    18
    14
    32
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 130 (6.15%)
    10 / 130 (7.69%)
    18 / 260 (6.92%)
         occurrences all number
    10
    15
    25
    Cardiac failure
         subjects affected / exposed
    9 / 130 (6.92%)
    6 / 130 (4.62%)
    15 / 260 (5.77%)
         occurrences all number
    13
    6
    19
    Palpitations
         subjects affected / exposed
    3 / 130 (2.31%)
    11 / 130 (8.46%)
    14 / 260 (5.38%)
         occurrences all number
    3
    15
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    25 / 130 (19.23%)
    38 / 130 (29.23%)
    63 / 260 (24.23%)
         occurrences all number
    35
    54
    89
    Dysgeusia
         subjects affected / exposed
    10 / 130 (7.69%)
    12 / 130 (9.23%)
    22 / 260 (8.46%)
         occurrences all number
    12
    12
    24
    Headache
         subjects affected / exposed
    17 / 130 (13.08%)
    16 / 130 (12.31%)
    33 / 260 (12.69%)
         occurrences all number
    20
    21
    41
    Neuropathy peripheral
         subjects affected / exposed
    30 / 130 (23.08%)
    17 / 130 (13.08%)
    47 / 260 (18.08%)
         occurrences all number
    43
    27
    70
    Paraesthesia
         subjects affected / exposed
    10 / 130 (7.69%)
    13 / 130 (10.00%)
    23 / 260 (8.85%)
         occurrences all number
    14
    18
    32
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 130 (10.77%)
    13 / 130 (10.00%)
    27 / 260 (10.38%)
         occurrences all number
    23
    23
    46
    Syncope
         subjects affected / exposed
    7 / 130 (5.38%)
    11 / 130 (8.46%)
    18 / 260 (6.92%)
         occurrences all number
    10
    17
    27
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 130 (16.15%)
    27 / 130 (20.77%)
    48 / 260 (18.46%)
         occurrences all number
    43
    67
    110
    Lymphopenia
         subjects affected / exposed
    6 / 130 (4.62%)
    7 / 130 (5.38%)
    13 / 260 (5.00%)
         occurrences all number
    19
    18
    37
    Thrombocytopenia
         subjects affected / exposed
    10 / 130 (7.69%)
    9 / 130 (6.92%)
    19 / 260 (7.31%)
         occurrences all number
    17
    19
    36
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    15 / 130 (11.54%)
    15 / 130 (11.54%)
    30 / 260 (11.54%)
         occurrences all number
    23
    17
    40
    Abdominal pain
         subjects affected / exposed
    13 / 130 (10.00%)
    15 / 130 (11.54%)
    28 / 260 (10.77%)
         occurrences all number
    19
    16
    35
    Abdominal pain upper
         subjects affected / exposed
    6 / 130 (4.62%)
    8 / 130 (6.15%)
    14 / 260 (5.38%)
         occurrences all number
    6
    8
    14
    Constipation
         subjects affected / exposed
    55 / 130 (42.31%)
    55 / 130 (42.31%)
    110 / 260 (42.31%)
         occurrences all number
    75
    82
    157
    Diarrhoea
         subjects affected / exposed
    51 / 130 (39.23%)
    54 / 130 (41.54%)
    105 / 260 (40.38%)
         occurrences all number
    110
    82
    192
    Nausea
         subjects affected / exposed
    56 / 130 (43.08%)
    43 / 130 (33.08%)
    99 / 260 (38.08%)
         occurrences all number
    86
    71
    157
    Stomatitis
         subjects affected / exposed
    7 / 130 (5.38%)
    8 / 130 (6.15%)
    15 / 260 (5.77%)
         occurrences all number
    7
    9
    16
    Vomiting
         subjects affected / exposed
    27 / 130 (20.77%)
    20 / 130 (15.38%)
    47 / 260 (18.08%)
         occurrences all number
    42
    32
    74
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    7 / 130 (5.38%)
    7 / 130 (5.38%)
    14 / 260 (5.38%)
         occurrences all number
    7
    7
    14
    Ecchymosis
         subjects affected / exposed
    7 / 130 (5.38%)
    8 / 130 (6.15%)
    15 / 260 (5.77%)
         occurrences all number
    7
    8
    15
    Pruritus
         subjects affected / exposed
    14 / 130 (10.77%)
    12 / 130 (9.23%)
    26 / 260 (10.00%)
         occurrences all number
    19
    14
    33
    Rash
         subjects affected / exposed
    15 / 130 (11.54%)
    18 / 130 (13.85%)
    33 / 260 (12.69%)
         occurrences all number
    16
    24
    40
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 130 (6.92%)
    4 / 130 (3.08%)
    13 / 260 (5.00%)
         occurrences all number
    16
    9
    25
    Chronic kidney disease
         subjects affected / exposed
    7 / 130 (5.38%)
    6 / 130 (4.62%)
    13 / 260 (5.00%)
         occurrences all number
    17
    10
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 130 (9.23%)
    6 / 130 (4.62%)
    18 / 260 (6.92%)
         occurrences all number
    18
    7
    25
    Back pain
         subjects affected / exposed
    15 / 130 (11.54%)
    12 / 130 (9.23%)
    27 / 260 (10.38%)
         occurrences all number
    17
    12
    29
    Muscle spasms
         subjects affected / exposed
    15 / 130 (11.54%)
    7 / 130 (5.38%)
    22 / 260 (8.46%)
         occurrences all number
    17
    8
    25
    Muscular weakness
         subjects affected / exposed
    9 / 130 (6.92%)
    5 / 130 (3.85%)
    14 / 260 (5.38%)
         occurrences all number
    12
    9
    21
    Pain in extremity
         subjects affected / exposed
    14 / 130 (10.77%)
    8 / 130 (6.15%)
    22 / 260 (8.46%)
         occurrences all number
    16
    11
    27
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 130 (6.15%)
    10 / 130 (7.69%)
    18 / 260 (6.92%)
         occurrences all number
    9
    14
    23
    Pneumonia
         subjects affected / exposed
    8 / 130 (6.15%)
    8 / 130 (6.15%)
    16 / 260 (6.15%)
         occurrences all number
    11
    8
    19
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 130 (17.69%)
    25 / 130 (19.23%)
    48 / 260 (18.46%)
         occurrences all number
    28
    34
    62
    Urinary tract infection
         subjects affected / exposed
    14 / 130 (10.77%)
    6 / 130 (4.62%)
    20 / 260 (7.69%)
         occurrences all number
    17
    8
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    27 / 130 (20.77%)
    20 / 130 (15.38%)
    47 / 260 (18.08%)
         occurrences all number
    34
    28
    62
    Hyperglycaemia
         subjects affected / exposed
    8 / 130 (6.15%)
    8 / 130 (6.15%)
    16 / 260 (6.15%)
         occurrences all number
    47
    11
    58
    Hyperkalaemia
         subjects affected / exposed
    9 / 130 (6.92%)
    8 / 130 (6.15%)
    17 / 260 (6.54%)
         occurrences all number
    15
    16
    31
    Hyperuricaemia
         subjects affected / exposed
    9 / 130 (6.92%)
    13 / 130 (10.00%)
    22 / 260 (8.46%)
         occurrences all number
    18
    17
    35
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 130 (5.38%)
    6 / 130 (4.62%)
    13 / 260 (5.00%)
         occurrences all number
    24
    11
    35
    Hypokalaemia
         subjects affected / exposed
    24 / 130 (18.46%)
    26 / 130 (20.00%)
    50 / 260 (19.23%)
         occurrences all number
    72
    47
    119
    Hyponatraemia
         subjects affected / exposed
    16 / 130 (12.31%)
    17 / 130 (13.08%)
    33 / 260 (12.69%)
         occurrences all number
    46
    42
    88

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2016
    This global protocol amendment incorporates changes that were made during several country-specific amendments, which were issued between the finalization of Amendment 1 and this global Amendment 2.
    06 Nov 2017
    Overview of Major/Substantial Changes:  Aligned with updated case report form and statistical analysis plan  Removed requirement for monthly collection of additional coagulation indices  Removed sample collection for quantitative/renal biomarkers  Allowed postbaseline 6MWT to be administered on the same calendar day that study drug is administered  Increased the number of subjects  Clarified timing of serious adverse event collection

    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.
    None reported
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    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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