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    Clinical Trial Results:
    Biomarker-guided implementation of angiotensin-II (AT-II) to reduce the occurrence of kidney damage after cardiac surgery

    Summary
    EudraCT number
    		 2021-003088-87
    Trial protocol
    		 DE  
    Global end of trial date
    21 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2024
    First version publication date
    04 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WWU20_0016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05199493
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Westfälische Wilhelms-Universität
    Sponsor organisation address
    Schlossplatz 2, Münster, Germany, 48149 Münster
    Public contact
    Dept. of Anesthesiology, University Hospital Muenster, +49 02518347252, aki@anit.uni-muenster.de
    Scientific contact
    Dept. of Anesthesiology, University Hospital Muenster, +49 02518347252, aki@anit.uni-muenster.de
    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
    15 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to investigate the efficacy of Angiotensin-II vs. standard of care on the biomarkers [TIMP-2]*[IGFBP7] in high-risk patients undergoing cardiac surgery.
    Protection of trial subjects
    All patients received standard intensive care therapy. None of the patients in both groups was exposed to additional risks. Participation in this study was voluntary. Written informed consent was obtained from patients. This study was performed in accordance with the revision of the declaration of Helsinki (2013). Study protocol, patient information and informed consent have been submitted to the ethics comittee of the University of Münster for approval prior to trial initiation. The treating investigator informed the patient about the nature of the trial, its aims, expected advantages as well as possible risks. Each patient had to consent in writing to participate in the study. The patient had to be given enough time and opportunity to decide on participation and to clarify any questions before the beginning of any study related procedure. The Data Safety Monitoring Board monitored the occurrence of serious adverse events. After the session, a recommendation was made regarding the continuation of the study.
    Background therapy
    		 The patient's primary physicians determined the remainder of patient management consistent with established best practice with the management of patients with cardiac surgery.
    Evidence for comparator
    		 Multiple pharmacologic interventions have shown promise in animal models of AKI, however no agents have been demonstrated to be efficacious in clinical practice. As a result, the management of AKI remains primarily supportive, with CRRT serving as the cornerstone of therapy in critically ill patients with severe AKI. To investigate whether angiotensin II reduces kidney damage in patients at high risk after cardiac surgery, we will randomly assign patients at high risk for AKI identified by biomarkers to receive either angiotensin II or a 0.9 sodium chloride solution as placebo to achieve a pre-defined mean arterial pressure.
    Actual start date of recruitment
    01 Oct 2021
    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
    Germany: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    21
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from January 2021 (First Patient In) until December 2022 and followed up until March 2023 (Last Patient out). 64 patients were enrolled and randomized to receive either Angiotensin II acetat (n=32) or control (saline) (n=32). One patient had to be excluded (drug was prepared but not administered due to his health condition)

    Pre-assignment
    Screening details
    		 419 patients were screened. 343 patients gave consent. 186 patients had no additional post-OP criterion (postoperative hypotension requiring vasopressors), 106 patients were excluded due to biomarker value < 3.7µU/ml 64 patients were randomized. One patient had to be excluded before administration of the study medication.

    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, Carer, Assessor
    Blinding implementation details
    Labeling and blinding was performed by medical staff who are independent from the AIDED investigational team. Fluids and matching placebo were packaged in identical drug syringes. Each package contained 250 ml of fluids and was labeled with the subject identification number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Angiotensin II acetat (AT II)
    Arm description
    		 Patients randomized to the intervention group received AT-II for 12 h after randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Giapreza
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose was 20 ng/kg/min and the dose was adjusted (up to 80 ng/kg/min) so that other vasopressors could completely be weaned and the mean arterial pressure was > 65 mmHg over 12 h after randomization.

    Arm title
    		 Control
    Arm description
    		 NaCl 0.9% after cardiac surgery
    Arm type
    		 Placebo

    Investigational medicinal product name
    Isotone Natriumchloridlösung 0,9 % injektionslösung
    Investigational medicinal product code
    Other name
    NaCl 0.9% after cardiac surgery
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The Placebo was added to the first-line vasopressor (norepinephrine) and the dose of the control substance was adjusted so that the mean arterial pressure is above 65 mm Hg.

    Number of subjects in period 1 [1]
    		Angiotensin II acetat (AT II) Control
    Started
    31
    32
    Completed
    31
    32
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One patient had to be excluded (drug was prepared but not administered due to his health condition)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Angiotensin II acetat (AT II)
    Reporting group description
    		 Patients randomized to the intervention group received AT-II for 12 h after randomization.

    Reporting group title
    Control
    Reporting group description
    		 NaCl 0.9% after cardiac surgery

    Reporting group values
    		 Angiotensin II acetat (AT II) Control Total
    Number of subjects
    		 31 32 63
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 12 21
        From 65-84 years
    		 22 20 42
    Gender categorical
    Units: Subjects
        Female
    		 7 7 14
        Male
    		 24 25 49

    End points

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    End points reporting groups
    Reporting group title
    Angiotensin II acetat (AT II)
    Reporting group description
    		 Patients randomized to the intervention group received AT-II for 12 h after randomization.

    Reporting group title
    Control
    Reporting group description
    		 NaCl 0.9% after cardiac surgery

    Primary: Difference of TIMP-2*IGFBP7 between time of randomization and 12 h after randomization

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    End point title
    		 Difference of TIMP-2*IGFBP7 between time of randomization and 12 h after randomization
    End point description
    End point type
    Primary
    End point timeframe
    Timepoint of randomization and 12 h after randomization
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: (ng/mL)^2/1000
        median (inter-quartile range (Q1-Q3))
    0.06 (-0.24 to 0.28)
    -0.08 (-0.35 to 0.14)
    Statistical analysis title
    		 Primary efficacy analysis
    Comparison groups
    Angiotensin II acetat (AT II) v Control
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Hodges-Lehmann
    Parameter type
    		 Location Shift
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.36

    Secondary: Occurence of AKI

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    End point title
    		 Occurence of AKI
    End point description
    Occurrence of AKI within 72h after cardiac surgery (according to the KDIGO criteria)
    End point type
    Secondary
    End point timeframe
    within 72h after cardiac surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: Number of patients with AKI
    9
    8
    No statistical analyses for this end point

    Secondary: Occurence of moderate and severe AKI

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    End point title
    		 Occurence of moderate and severe AKI
    End point description
    Occurrence of moderate and severe AKI within 72h after cardiac surgery (according to the KDIGO stage 2 and 3)
    End point type
    Secondary
    End point timeframe
    within 72h after cardiac surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: No of patients with AKI stage 2/3
    4
    3
    No statistical analyses for this end point

    Secondary: Amount of study medication application

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    End point title
    		 Amount of study medication application
    End point description
    Total amount of study medication application within 12 h after randomization [mL]
    End point type
    Secondary
    End point timeframe
    within 12 h after randomization
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: mL
        median (inter-quartile range (Q1-Q3))
    32 (22 to 100)
    259 (231 to 308)
    No statistical analyses for this end point

    Secondary: Fluid administration

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    End point title
    		 Fluid administration
    End point description
    End point type
    Secondary
    End point timeframe
    within 12 h after randomization
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: mL
        median (inter-quartile range (Q1-Q3))
    2946 (2358 to 3409)
    3341 (2775 to 4631)
    No statistical analyses for this end point

    Secondary: Noradrenaline equivalent dose

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    End point title
    		 Noradrenaline equivalent dose
    End point description
    Noradrenaline equivalent dose (total amount including Noradrenalin, Adrenalin, Vasopressin, Study medication)
    End point type
    Secondary
    End point timeframe
    During intervention (from randomization until 12 h after randomization)
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: mg
        median (inter-quartile range (Q1-Q3))
    1.61 (0.81 to 3.73)
    4.18 (1.40 to 6.21)
    No statistical analyses for this end point

    Secondary: Duration of vasopressor use

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    End point title
    		 Duration of vasopressor use
    End point description
    End point type
    Secondary
    End point timeframe
    During Hospital Stay
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: days
        median (inter-quartile range (Q1-Q3))
    3 (2 to 4)
    3.5 (2 to 5)
    No statistical analyses for this end point

    Secondary: Creatinine clearance on day one after cardiac surgery

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    End point title
    		 Creatinine clearance on day one after cardiac surgery
    End point description
    End point type
    Secondary
    End point timeframe
    On day after cardiac surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: mL/min
        median (inter-quartile range (Q1-Q3))
    89.3 (67.9 to 125.4)
    85.2 (64.2 to 118.7)
    No statistical analyses for this end point

    Secondary: Free-days through day 28 of vasoactive drugs and mechanical ventilation

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    End point title
    		 Free-days through day 28 of vasoactive drugs and mechanical ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    within 28 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: days
        median (inter-quartile range (Q1-Q3))
    26 (25 to 27)
    25.5 (22.5 to 27)
    No statistical analyses for this end point

    Secondary: Renal dysfunction on POD 90

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    End point title
    		 Renal dysfunction on POD 90
    End point description
    Patients with renal dysfunction on POD 90
    End point type
    Secondary
    End point timeframe
    90 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    28
    30
    Units: Number of patients
    1
    2
    No statistical analyses for this end point

    Secondary: 30-day mortality

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    End point title
    		 30-day mortality
    End point description
    Patient died before day 30
    End point type
    Secondary
    End point timeframe
    within 30 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: Number of patients
    1
    1
    No statistical analyses for this end point

    Secondary: 60-day mortality

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    End point title
    		 60-day mortality
    End point description
    Patient died before day 60
    End point type
    Secondary
    End point timeframe
    within 60 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: number of patients
    1
    1
    No statistical analyses for this end point

    Secondary: 90-days mortality

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    End point title
    		 90-days mortality
    End point description
    Patient died before day 90
    End point type
    Secondary
    End point timeframe
    90 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    29
    32
    Units: number of patients
    1
    2
    No statistical analyses for this end point

    Secondary: Length of ICU stay

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    End point title
    		 Length of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    during primary ICU stay
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: days
        median (inter-quartile range (Q1-Q3))
    2 (1 to 8)
    3.5 (1 to 7)
    No statistical analyses for this end point

    Secondary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    during primary hospital stay
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: days
        median (inter-quartile range (Q1-Q3))
    8 (7 to 14)
    8.5 (7 to 13)
    No statistical analyses for this end point

    Secondary: Use of renal replacement therapy within hospital stay

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    End point title
    		 Use of renal replacement therapy within hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    during hospital stay
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    31
    32
    Units: number of patients
    0
    0
    No statistical analyses for this end point

    Secondary: Use of renal replacement therapy at days 90

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    End point title
    		 Use of renal replacement therapy at days 90
    End point description
    End point type
    Secondary
    End point timeframe
    within 90 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    29
    29
    Units: number of patients
    0
    0
    No statistical analyses for this end point

    Secondary: MAKE90

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    End point title
    		 MAKE90
    End point description
    Major adverse kidney events consisting of mortality, dialysis dependency, persistent renal dysfunction (defined as serum creatinine ≥ 2x compared to baseline value at day 90)
    End point type
    Secondary
    End point timeframe
    90 days after surgery
    End point values
    		 Angiotensin II acetat (AT II) Control
    Number of subjects analysed
    29
    29
    Units: number of patients
    1
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events was recorded from the time the first dose of study drug was administered, up to and including follow-up-Visit d90
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Angiotensin II
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Serious adverse events
    		 Angiotensin II Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 31 (38.71%)
    15 / 32 (46.88%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemothorax
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brachial plexopathy
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebellar stroke
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         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
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         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
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Implant site infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (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
    3 / 31 (9.68%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Postoperative wound infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         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: 0%
    Non-serious adverse events
    		 Angiotensin II Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 31 (64.52%)
    22 / 32 (68.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Meningioma
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Bloody discharge
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Feeling hot
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 32 (6.25%)
         occurrences all number
    1
    3
    peripheral swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    swelling
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Hypercapnia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Increased bronchial secretion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    8 / 31 (25.81%)
    11 / 32 (34.38%)
         occurrences all number
    9
    19
    Pneumothorax
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Respiratory acidosis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    4 / 31 (12.90%)
    7 / 32 (21.88%)
         occurrences all number
    4
    8
    Investigations
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Blood glucose abnormal
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    blood glucose increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Blood lactic acid increased
         subjects affected / exposed
    4 / 31 (12.90%)
    0 / 32 (0.00%)
         occurrences all number
    5
    0
    Blood pressure decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Inflammatory marker increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Red blood cell count decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    3
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Surgical procedure repeated
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    4 / 31 (12.90%)
    3 / 32 (9.38%)
         occurrences all number
    4
    6
    Atrial flutter
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2
    Bradycardia
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 32 (12.50%)
         occurrences all number
    2
    4
    Cardiac failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Cardiomegaly
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Pericardial effusion
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 32 (12.50%)
         occurrences all number
    2
    4
    Tachyarrhythmia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    4
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Ventricular fibrillation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Brain injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Partial seizures
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Seizure like phenomena
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Eye disorders
    Anisocoria
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal rigidity
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Ascites
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    Constipation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Ulcerative gastritis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Erythema
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Joint warmth
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    3
    Chlamydial infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Coronavirus infection
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 32 (12.50%)
         occurrences all number
    1
    4
    endocarditis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Klebsiella urinary tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Laryngopharyngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hyperlactacidaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Hypervolaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38289858
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