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    Clinical Trial Results:
    Conservative vs. Liberal Approach to fluid therapy of Septic Shock in Intensive Care

    Summary
    EudraCT number
    2014-000902-37
    Trial protocol
    DK  
    Global end of trial date
    04 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2017
    First version publication date
    12 Aug 2017
    Other versions
    Summary report(s)
    main results and paper

    Trial information

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    Trial identification
    Sponsor protocol code
    RH-ITA-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02079402
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Dept. of Intensive Care 4131, Copenhagen University Hospital, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Prof. Anders Perner, Dept. of Intensive Care Rigshospitalet, 45 35458333, anders.perner@regionh.dk
    Scientific contact
    Prof. Anders Perner, Dept. of Intensive Care Rigshospitalet, 45 35458333, anders.perner@regionh.dk
    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 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to assess the feasibility of a trial comparing two approaches to fluid resuscitation of septic shock after initial resuscitation; a trigger guided approach vs. a target guided approach, the latter reflecting standard care
    Protection of trial subjects
    All trial subjects received the highest standard of care with high degree of monitoring. Also, fluid therapy is an intervention abundantly used across the world.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Denmark: 143
    Worldwide total number of subjects
    151
    EEA total number of subjects
    151
    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)
    65
    From 65 to 84 years
    80
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment was performed on schedule.

    Pre-assignment
    Screening details
    Inclusion: adults with septic shock who had received the initial fluid management. 203 fulfilled inclusion criteria and were screened; 153 were randomised; 151 were analysed.

    Period 1
    Period 1 title
    Intervention period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Open-label trial. Trial statistician was blinded to allocation

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fluid restriction group
    Arm description
    isotonic crystalloid (saline or Ringer’s solutions) fluid boluses of 250–500 mL could be given intravenously during ICU stay in the case of severe hypoperfusion
    Arm type
    Experimental

    Investigational medicinal product name
    pr1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    patient specific

    Arm title
    Standard Care
    Arm description
    isotonic crystalloid (saline or Ringer’s solutions) fluid boluses could be given intravenously during ICU stay as long as haemodynamic variables improved
    Arm type
    Active comparator

    Investigational medicinal product name
    pr1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    patient specific dosing

    Number of subjects in period 1
    Fluid restriction group Standard Care
    Started
    75
    76
    Completed
    75
    76

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fluid restriction group
    Reporting group description
    isotonic crystalloid (saline or Ringer’s solutions) fluid boluses of 250–500 mL could be given intravenously during ICU stay in the case of severe hypoperfusion

    Reporting group title
    Standard Care
    Reporting group description
    isotonic crystalloid (saline or Ringer’s solutions) fluid boluses could be given intravenously during ICU stay as long as haemodynamic variables improved

    Reporting group values
    Fluid restriction group Standard Care Total
    Number of subjects
    75 76 151
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    69 (61 to 76) 73 (67 to 77) -
    Gender categorical
    Units: Subjects
        Female
    23 29 52
        Male
    52 47 99

    End points

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    End points reporting groups
    Reporting group title
    Fluid restriction group
    Reporting group description
    isotonic crystalloid (saline or Ringer’s solutions) fluid boluses of 250–500 mL could be given intravenously during ICU stay in the case of severe hypoperfusion

    Reporting group title
    Standard Care
    Reporting group description
    isotonic crystalloid (saline or Ringer’s solutions) fluid boluses could be given intravenously during ICU stay as long as haemodynamic variables improved

    Primary: resuscitation fluid first 5 days after rando

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    End point title
    resuscitation fluid first 5 days after rando
    End point description
    See other outcome measures in the attached published article
    End point type
    Primary
    End point timeframe
    5 days
    End point values
    Fluid restriction group Standard Care
    Number of subjects analysed
    75
    76
    Units: ml
        median (inter-quartile range (Q1-Q3))
    500 (0 to 2500)
    2000 (1000 to 4100)
    Statistical analysis title
    primary analysis
    Comparison groups
    Fluid restriction group v Standard Care
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: resusciation fluid during entire ICU stay

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    End point title
    resusciation fluid during entire ICU stay
    End point description
    End point type
    Primary
    End point timeframe
    entire ICU stay
    End point values
    Fluid restriction group Standard Care
    Number of subjects analysed
    75
    76
    Units: ml
        median (inter-quartile range (Q1-Q3))
    500 (0 to 3250)
    2200 (1000 to 4750)
    Statistical analysis title
    co-primary analysis
    Comparison groups
    Fluid restriction group v Standard Care
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    During ICU stay up to 90 days from randomisation
    Adverse event reporting additional description
    serious adverse events were predefined outcome measures in the trial. See the attached published paper for full description
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0%
    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: Serious adverse events (SAEs) will not be recorded as an entity, because the majority of septic ICU patients will experience several SAEs during their critical illness. The most important SAEs will be captured in the exploratory outcome measures and in the daily SOFA-scoring. Patient charts will contain daily registrations of clinical data, which can be obtained on request from the medical authorities.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2015
    Action: Promotion of a secondary outcome to a co-primary outcome. Applied for: June 19th 2015 Approved by Ethics Committee and Medicines Agency: July 31st 2015 Outcome: Amount of resuscitation fluid during ICU stay
    25 Sep 2015
    Change: The definition of circulatory impairment in the inclusion criterion “Suspected or confirmed circulatory impairment (hypotension/hypoperfusion/hypovolemia) for no more than 12 hours including the hours preceding ICU admission” was revised. Previous protocol version: 4.2 June 4th 2014 New (final) protocol version: 4.3 September 25th 2014 Applied for: September 25th 2014 Approved by Ethics Committee and Medicines Agency and effectuated: October 30th 2014

    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/27686349
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