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    Clinical Trial Results:
    Albumin To prevenT Infection in chronic liveR failurE (ATTIRE)

    Summary
    EudraCT number
    2014-002300-24
    Trial protocol
    GB  
    Global end of trial date
    11 Dec 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    09 May 2021
    First version publication date
    09 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    6.0
    Additional study identifiers
    ISRCTN number
    ISRCTN14174793
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London (UCL)
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    CCTU Enquiry Desk, University College London (UCL), CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, University College London (UCL), CCTU-enquiries@ucl.ac.uk
    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
    11 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a phase III randomised controlled trial to verify whether targeting a serum albumin level of >30g/l in patients hospitalised with acutely decompensated cirrhosis using repeated 20% HAS infusions will reduce incidence of infection, renal dysfunction and mortality for the treatment period (maximum 14 days or until discharge/assessed as medically fit for discharge prior to 14 days) compared to standard medical care. In AD patients, the frequent course of events is that infection precipitates organ dysfunction and this combination is the commonest cause of hospital mortality. Equally data are emerging to indicate that even in survivors, long term mortality is also substantially reduced i.e. this represents a “tipping point” in the clinical course of cirrhosis. Preventing infection and subsequent organ dysfunction would be expected to therefore improve short and long term mortality.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures (SOPs), the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). International sites complied with the approved protocol, UCL CCTU SOPs, the principles of GCP as laid down by ICH topic E6 (Note for Guidance on GCP), Commission Directive 2005/28/EC, the European Directive 2001/20/EC (where applicable) and other national and local applicable regulations. While HAS is routinely given to patients with liver disease and its safety is well established, provision for stopping in the rare event of severe reactions (such as shock) was made in the trial protocol. In case of hypersensitivity or allergic reactions, in some cases severe anaphylaxis, it was noted in the protocol that epinephrine would be available immediately to treat any acute hypersensitivity reaction. Albumin was prescribed to participants on the 20% HAS arm, as per the suggested protocol, which could be amended by the prescribing clinician with the clinical reasons for this recorded in the trial documentation. If the prescribing clinician or the ward staff administering the 20% HAS had safety concerns with the continuation of treatment, infusions could be halted until/if it was deemed safe to resume treatment. Where 20% HAS was halted due to safety concerns this was not considered to be a protocol deviation. Three reasons was provided in the trial protocol for albumen being given in the standard of care arm: Large Volume Paracentesis (LVP), Spontaneous Bacterial Peritonitis (SBP), Hepatorenal Syndrome (HRS).
    Background therapy
    In the original protocol re-randomization was permitted >30 days after completing trial treatment, accounting for albumin’s 21 day half-life. However, as ATTIRE was not blinded, knowledge of original treatment could influence the decision to participate again and only survivors could do so, introducing potential bias. Therefore, primary randomisations are presented here, and analyses that included re-randomizations are reported in the Supplementary Appendix.
    Evidence for comparator
    -
    Actual start date of recruitment
    30 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
    United Kingdom: 777
    Worldwide total number of subjects
    777
    EEA total number of subjects
    0
    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)
    667
    From 65 to 84 years
    108
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The eligibility of the patient were reviewed on the observations and bloods taken for screening. Blood tests required for screening and randomisation were part of standard of care when an AD patient is admitted to hospital (FBC, LFTs, U&Es, CRP and INR).

    Pre-assignment
    Screening details
    This trial used a two stage consent process. Written informed consent to be randomised into the RCT were obtained, after explanation of the aims, methods, benefits and potential hazards of the trial and BEFORE any trial-specific procedures were performed or any samples are taken for the trial.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Albumin
    Arm description
    20% Human Albumin Solution (HAS)
    Arm type
    Experimental

    Investigational medicinal product name
    20% Human Albumin Solution (HAS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20% HAS prescribed daily according to the patient’s serum albumin concentration that day (or closest previous measurement). A suggested dosing protocol was: a. If serum albumin 30-34g/l, give 100mls 20% HAS b. If serum albumin 26-29g/l, give 200mls 20% HAS c. If serum albumin 20-25g/l, give 300mls 20% HAS d. If serum albumin <20g/l, give 400mls 20% HAS This is based on clinical experience and also the reported regimen used in the ALBIOS study (that examines the repeated use of albumin infusions in patients with sepsis on intensive care). HAS may be prescribed using another regimen as long as the aim is to raise albumin level to >30g/l, but this must be fully recorded in the Case Reports Forms (CRF) and medical notes. Equally differing regimens may be used to cover paracentesis procedures or treat HRS and SBP as per local trial site and national guidelines but HAS must be prescribed and given if serum albumin <35g/l, unless there are any safety concerns.

    Arm title
    Standard Care
    Arm description
    Hospitalized decompensated cirrhosis patients with serum albumin <30g/L at enrollment received standard care.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Albumin Standard Care
    Started
    380
    397
    Completed
    380
    397
    Period 2
    Period 2 title
    Endpoints
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Albumin
    Arm description
    20% Human Albumin Solution (HAS)
    Arm type
    Active comparator

    Investigational medicinal product name
    20% Human Albumin Solution (HAS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20% HAS prescribed daily according to the patient’s serum albumin concentration that day (or closest previous measurement). A suggested dosing protocol was: a. If serum albumin 30-34g/l, give 100mls 20% HAS b. If serum albumin 26-29g/l, give 200mls 20% HAS c. If serum albumin 20-25g/l, give 300mls 20% HAS d. If serum albumin <20g/l, give 400mls 20% HAS This is based on clinical experience and also the reported regimen used in the ALBIOS study (that examines the repeated use of albumin infusions in patients with sepsis on intensive care). HAS may be prescribed using another regimen as long as the aim is to raise albumin level to >30g/l, but this must be fully recorded in the Case Reports Forms (CRF) and medical notes. Equally differing regimens may be used to cover paracentesis procedures or treat HRS and SBP as per local trial site and national guidelines but HAS must be prescribed and given if serum albumin <35g/l, unless there are any safety concerns.

    Arm title
    Standard Care
    Arm description
    Hospitalized decompensated cirrhosis patients with serum albumin <30g/L at enrollment will receive standard care.
    Arm type
    Standard Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Albumin Standard Care
    Started
    380
    397
    Completed
    380
    397

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Albumin
    Reporting group description
    20% Human Albumin Solution (HAS)

    Reporting group title
    Standard Care
    Reporting group description
    Hospitalized decompensated cirrhosis patients with serum albumin <30g/L at enrollment received standard care.

    Reporting group values
    Albumin Standard Care Total
    Number of subjects
    380 397 777
    Age categorical
    Units: Subjects
    Age continuous
    Age Mean (s.d.) 1 Missing observation with no data for age
    Units: years
        arithmetic mean (standard deviation)
    53.8 ± 10.6 53.8 ± 10.7 -
    Gender categorical
    Sex
    Units: Subjects
        Female
    123 104 227
        Male
    257 293 550
    Admitted to ward – no.
    Units: Subjects
        Yes
    370 384 754
        No
    10 13 23
    Admitted to Intensive Care Unit – no.
    Units: Subjects
        Yes
    8 10 18
        No
    372 387 759
    Alcohol
    Aetiology of cirrhosis - no.
    Units: Subjects
        Yes
    347 350 697
        No
    33 47 80
    Hepatitis C
    Aetiology of cirrhosis† - no.
    Units: Subjects
        Yes
    24 35 59
        No
    356 362 718
    NAFLD
    Aetiology of cirrhosis - no.
    Units: Subjects
        Yes
    26 29 55
        No
    354 368 722
    Encephalopathy
    Reason for decompensation admission† - no.
    Units: Subjects
        Yes
    80 69 149
        No
    300 328 628
    Suspected variceal Bleed
    Reason for decompensation admission† - no.
    Units: Subjects
        Yes
    52 63 115
        No
    328 334 662
    New onset or worsening ascites
    Reason for decompensation admission† - no.
    Units: Subjects
        Yes
    236 281 517
        No
    144 116 260
    Diagnosed with infection‡
    Infection - no.
    Units: Subjects
        Yes
    98 113 211
        No
    282 284 566
    Prescribed antibiotics
    Infection - no.
    Units: Subjects
        Yes
    195 199 394
        No
    185 198 383
    Serum albumin level – no.
    Units: Subjects
        <20 g/L
    61 60 121
        20-25 g/L
    207 224 431
        26-29 g/L
    112 113 225
    Cerebral: >Grade III Hepatic Encephalopathy
    Baseline Organ Dysfunction
    Units: Subjects
        Yes
    10 8 18
        No
    370 389 759
    Circulatory: Mean Arterial Pressure <60 mmHg
    Baseline Organ Dysfunction
    Units: Subjects
        Yes
    10 6 16
        No
    370 391 761
    Respiratory: Sp02 / Fi02
    Units: Subjects
        0 (>357)
    345 367 712
        1 (>214 ≤357)
    29 23 52
        2 (≤214 or Mechanical Ventilation)
    5 5 10
        Not recorded
    1 2 3
    Renal: Creatinine >1.5mg/dl
    Units: Subjects
        Yes
    36 46 82
        No
    344 351 695
    Physiological variable – median (IQR)
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0) 0 (0 to 0) -
    Bilirubin (mg/dl)
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    5.70 (2.75 to 10.47) 5.56 (2.63 to 9.68) -
    INR
    International Normalised Ratio
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    1.6 (1.4 to 1.9) 1.6 (1.4 to 1.9) -
    MELD Score
    Model for end stage liver disease https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/ range <9 to >40, higher values indicate higher 3-month mortality.
    Units: MELD score
        median (inter-quartile range (Q1-Q3))
    19.6 (15.4 to 22.9) 19.5 (15.4 to 23.4) -
    Creatinine (mg/dl)
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    0.75 (0.58 to 0.97) 0.78 (0.64 to 1.06) -

    End points

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    End points reporting groups
    Reporting group title
    Albumin
    Reporting group description
    20% Human Albumin Solution (HAS)

    Reporting group title
    Standard Care
    Reporting group description
    Hospitalized decompensated cirrhosis patients with serum albumin <30g/L at enrollment received standard care.
    Reporting group title
    Albumin
    Reporting group description
    20% Human Albumin Solution (HAS)

    Reporting group title
    Standard Care
    Reporting group description
    Hospitalized decompensated cirrhosis patients with serum albumin <30g/L at enrollment will receive standard care.

    Primary: Primary outcome

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    End point title
    Primary outcome
    End point description
    A composite endpoint comprising incidence of infection, renal dysfunction and mortality occurring between treatment day 3 and day 15 (end of treatment period), or date of discharge/being assessed as medically fit for discharge if prior to day 15. The definition of the three components of the endpoint are: 1. New Infection: indicated by clinician diagnosis and clinical evidence provided on completed infection CRFs. 2. Renal Dysfunction: indicated by a serum creatinine increase of ≥50% as compared to serum creatinine at randomisation OR the patient initiated on renal replacement support (either haemodialysis or haemofiltration) OR a rise in serum creatinine of ≥26.5 μmol/L within 48hours. If patients are on renal replacement support at baseline, they will not be able to reach this outcome. 3. Death
    End point type
    Primary
    End point timeframe
    A composite endpoint comprising incidence of infection, renal dysfunction and mortality occurring between treatment day 3 and day 15 (end of treatment period), or date of discharge/being assessed as medically fit for discharge if prior to day 15.
    End point values
    Albumin Standard Care
    Number of subjects analysed
    380
    397
    Units: number (%)
        Primary outcome – no.
    113
    120
        Composite endpoint components
    0
    0
        Incidence of new Infection
    79
    71
        Incidence of renal dysfunction
    40
    57
        Incidence of death
    30
    33
        Mortality at 28 days
    53
    62
        Mortality at 3 months
    92
    93
        Mortality at 6 months
    132
    119
        Total Albumin infused per patient (g)ǁ
    200
    20
    Attachments
    Revised.Supplementary Appendix.24.11.20.pdf
    Statistical analysis title
    Primary outcome
    Statistical analysis description
    For the primary outcome, we fitted a mixed-effects logistic regression model, with binary treatment indicator and stratification variables included as fixed effects, and random intercepts for sites. We also performed a time to event analysis, with patients censored at the earliest of: hospital discharge, day deemed fit for discharge, or study day 15.
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.87 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.33
    Notes
    [1] - ATTIRE was a superiority trial, the primary purpose of which was to demonstrate that repeated 20% HAS infusions, according to the ATTIRE protocol, reduces the incidence of new infection, renal dysfunction, and death on days 3 to 15 of the trial, compared to standard care.
    [2] - All applicable statistical tests were 2-sided and will be performed using a 5% significance level, unless otherwise specified. All confidence intervals presented were 95% and two-sided.
    Statistical analysis title
    Composite endpoint components‡:
    Statistical analysis description
    Incidence of new Infection
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.75
    Statistical analysis title
    Composite endpoint components
    Statistical analysis description
    Incidence of renal dysfunction
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.11
    Statistical analysis title
    Composite endpoint components
    Statistical analysis description
    Incidence of death
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.59
    Statistical analysis title
    Mortality at 28 days
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.3
    Statistical analysis title
    Mortality at 3 months
    Comparison groups
    Standard Care v Albumin
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.48
    Statistical analysis title
    Mortality at 6 months
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    1.73
    Statistical analysis title
    Total Albumin infused per patient (g)ǁ
    Comparison groups
    Albumin v Standard Care
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    142.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    127
         upper limit
    158.2

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Investigators would notify UCL CCTU of any SAEs occurring from the time of enrolment until the last protocol treatment administration. SARs and SUSARs notified to UCL CCTU until trial closure.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Albumin
    Reporting group description
    20% Human Albumin Solution (HAS)

    Reporting group title
    Standard Care
    Reporting group description
    Hospitalized decompensated cirrhosis patients with serum albumin <30g/L at enrollment will receive standard care.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Adverse events were not collected by the investigators (only Serious Adverse Events).
    Serious adverse events
    Albumin Standard Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 380 (22.89%)
    66 / 397 (16.62%)
         number of deaths (all causes)
    42
    48
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome
         subjects affected / exposed
    0 / 380 (0.00%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 380 (0.26%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 380 (0.26%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary edema
         subjects affected / exposed
    15 / 380 (3.95%)
    4 / 397 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Any mention of pulmonary edema or fluid overload
    Additional description: Serious Adverse Events mentioning pulmonary edema or GI bleeding*** *** SAEs were individually labelled with a primary event but could have a mention of other contributing events
         subjects affected / exposed
    23 / 380 (6.05%)
    8 / 397 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 380 (0.26%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    4 / 380 (1.05%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    23 / 380 (6.05%)
    31 / 397 (7.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Esophageal varices hemorrhage
         subjects affected / exposed
    5 / 380 (1.32%)
    6 / 397 (1.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    5 / 380 (1.32%)
    4 / 397 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Any mention of GI bleeding
    Additional description: Serious Adverse Events mentioning pulmonary edema or GI bleeding*** *** SAEs were individually labelled with a primary event but could have a mention of other contributing events
         subjects affected / exposed
    11 / 380 (2.89%)
    13 / 397 (3.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 380 (0.53%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations - Other: SBP
         subjects affected / exposed
    0 / 380 (0.00%)
    5 / 397 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    15 / 380 (3.95%)
    8 / 397 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 380 (1.05%)
    3 / 397 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Albumin Standard Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 380 (0.00%)
    0 / 397 (0.00%)

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2015
    Protocol update to v2.0 - first version of the protocol that was approved for use.
    17 Jul 2015
    Protocol update to v3.0 - allowed for co-enrolment in CI approved CTIMP; Clarification of Standard guidelines for administration of HAS ; Clarification of dosing requirements; Change to reporting of SAEs for Stage 1 (only reporting up to end of treatment).
    26 Aug 2015
    Protocol update to v4.0 - Change was made in response to the non-acceptance from the MHRA; Change of SAR and SUSAR reporting until trial closure instead of 30 days post last protocol treatment.
    14 Jun 2016
    Protocol update to v5.0 - Clarified the outcomes for the RCT; Allow blood, urine and stool samples to be collected from patients who provide additional consent.
    15 Jan 2018
    Protocol update to v6.0 - Change in definition of primary outcome; Incidence of extra-Hepatic organ dysfunctions added as secondary outcome; Removal and clarification of a some of the secondary and exploratory outcomes; Highlighting throughout that IMP administration can be halted if there are safety concerns by members of trial or ward staff; Change in format of glossary and introduction section.

    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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