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

    Summary
    EudraCT number
    2018-000404-42
    Trial protocol
    DK   SE   CZ   ES   BE   FI   IT  
    Global end of trial date
    16 Nov 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Oct 2023
    First version publication date
    13 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RH-ITA-007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03668236
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Department of Intensive Care, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Anders Perner, Dept. of Intensive Care, Copenhagen University Hospital - Rigshospitalet, DK. , +45 35458333, anders.perner@regionh.dk
    Scientific contact
    Anders Perner, Dept. of Intensive Care, Copenhagen University Hospital - Rigshospitalet, DK. , +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
    18 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the CLASSIC trial is to assess benefits and harms of IV fluid restriction vs. standard of care on patient-important outcome measures in adult ICU patients with septic shock.
    Protection of trial subjects
    Parts of the protocol were tested in a feasibility RCT which included safety measures (NCT02079402).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Nov 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 50
    Country: Number of subjects enrolled
    Denmark: 951
    Country: Number of subjects enrolled
    Italy: 54
    Country: Number of subjects enrolled
    Norway: 233
    Country: Number of subjects enrolled
    Sweden: 130
    Country: Number of subjects enrolled
    Switzerland: 117
    Worldwide total number of subjects
    1554
    EEA total number of subjects
    1419
    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)
    1554
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    We recruited patients from November 27, 2018 to November 16, 2021.

    Pre-assignment
    Screening details
    We screened 2223, excluded 669, randomized 1554 and included 1545 patients in the primary analysis.

    Period 1
    Period 1 title
    Intervention period (overall period)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Treatment allocation was concealed for the Data Monitoring and Safety Committee, the trial statistician, and for the management committee until the first version of the abstract had been drafted.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Standard fluid group
    Arm description
    No upper limit for the use of IV fluid. 1) IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. 2) IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3) IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol

    Investigational medicinal product name
    Ringers Acetate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Plasmalyte
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Ringers Lactate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Arm title
    Restrictive fluid group
    Arm description
    No IV fluids unless one of the below extenuating circumstances occurs; 1)In case of severe hypoperfusion or severe circulatory impairment defined by either: - Lactate 4 mmol/L or above - Mean arterial blood pressure below 50 mmHg (with or without vasopressor/inotrope) - Mottling beyond the kneecap (mottling score >2) OR - Urinary output less 0.1 mL/kg bodyweight/h, but only in the first 2 hrs after randomisation A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation. 2)In case of overt fluid losses (e.g. aspirates) IV fluid may be given to correct for the loss, but not above the volume lost. 3)In case the oral for water or electrolyte solutions is contraindicated , IV fluids may be given to: - Correct dehydration or electrolyte deficiencies. - Ensure a total fluid input of 1 L per 24 h (fluids with medications and nutrition count as input).
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol

    Investigational medicinal product name
    Ringers Acetate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Plasmalyte
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Ringers Lactate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Number of subjects in period 1
    Standard fluid group Restrictive fluid group
    Started
    784
    770
    Completed
    781
    764
    Not completed
    3
    6
         Consent withdrawn by subject
    2
    3
         Lost to follow-up
    1
    3
    Period 2
    Period 2 title
    Baseline period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Standard fluid group
    Arm description
    No upper limit for the use of IV fluid. 1) IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. 2) IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3) IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol

    Investigational medicinal product name
    Ringers Acetate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Plasmalyte
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Ringers Lactate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Arm title
    Restrictive fluid group
    Arm description
    No IV fluids unless one of the below extenuating circumstances occurs; 1)In case of severe hypoperfusion or severe circulatory impairment defined by either: - Lactate 4 mmol/L or above - Mean arterial blood pressure below 50 mmHg (with or without vasopressor/inotrope) - Mottling beyond the kneecap (mottling score >2) OR - Urinary output less 0.1 mL/kg bodyweight/h, but only in the first 2 hrs after randomisation A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation. 2)In case of overt fluid losses (e.g. aspirates) IV fluid may be given to correct for the loss, but not above the volume lost. 3)In case the oral for water or electrolyte solutions is contraindicated , IV fluids may be given to: - Correct dehydration or electrolyte deficiencies. - Ensure a total fluid input of 1 L per 24 h (fluids with medications and nutrition count as input).
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol

    Investigational medicinal product name
    Ringers Acetate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Plasmalyte
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Investigational medicinal product name
    Ringers Lactate
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As specified in the protocol.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the total number of patients randomised in the trial minus those who withdrew consent for the use of their data.
    Number of subjects in period 2 [2] [3]
    Standard fluid group Restrictive fluid group
    Started
    776
    755
    Completed
    776
    755
    Notes
    [2] - 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: All baseline values were missing in 15 patients in the restrictive-fluid group and 8 patients in the standard-fluid group.
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 3 patients in the restrictive-fluid group and 2 in the standard-fluid group withdrew consent for the use of data. For additional 11 patients in the restrictive fluid group and 6 in the standard-fluid group, consent was only granted for the use of allocation and 90-day follow-up. Thus, all baseline values were missing in 15 patients in the restrictive-fluid group and 8 patients in the standard-fluid group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard fluid group
    Reporting group description
    No upper limit for the use of IV fluid. 1) IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. 2) IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3) IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements

    Reporting group title
    Restrictive fluid group
    Reporting group description
    No IV fluids unless one of the below extenuating circumstances occurs; 1)In case of severe hypoperfusion or severe circulatory impairment defined by either: - Lactate 4 mmol/L or above - Mean arterial blood pressure below 50 mmHg (with or without vasopressor/inotrope) - Mottling beyond the kneecap (mottling score >2) OR - Urinary output less 0.1 mL/kg bodyweight/h, but only in the first 2 hrs after randomisation A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation. 2)In case of overt fluid losses (e.g. aspirates) IV fluid may be given to correct for the loss, but not above the volume lost. 3)In case the oral for water or electrolyte solutions is contraindicated , IV fluids may be given to: - Correct dehydration or electrolyte deficiencies. - Ensure a total fluid input of 1 L per 24 h (fluids with medications and nutrition count as input).

    Reporting group values
    Standard fluid group Restrictive fluid group Total
    Number of subjects
    776 755 1531
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    280 243 523
        From 65-84 years
    442 455 897
        85 years and over
    54 57 111
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    70 (60 to 77) 71 (62 to 77) -
    Gender categorical
    Units: Subjects
        Female
    324 303 627
        Male
    452 452 904

    End points

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    End points reporting groups
    Reporting group title
    Standard fluid group
    Reporting group description
    No upper limit for the use of IV fluid. 1) IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. 2) IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3) IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements

    Reporting group title
    Restrictive fluid group
    Reporting group description
    No IV fluids unless one of the below extenuating circumstances occurs; 1)In case of severe hypoperfusion or severe circulatory impairment defined by either: - Lactate 4 mmol/L or above - Mean arterial blood pressure below 50 mmHg (with or without vasopressor/inotrope) - Mottling beyond the kneecap (mottling score >2) OR - Urinary output less 0.1 mL/kg bodyweight/h, but only in the first 2 hrs after randomisation A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation. 2)In case of overt fluid losses (e.g. aspirates) IV fluid may be given to correct for the loss, but not above the volume lost. 3)In case the oral for water or electrolyte solutions is contraindicated , IV fluids may be given to: - Correct dehydration or electrolyte deficiencies. - Ensure a total fluid input of 1 L per 24 h (fluids with medications and nutrition count as input).
    Reporting group title
    Standard fluid group
    Reporting group description
    No upper limit for the use of IV fluid. 1) IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. 2) IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3) IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements

    Reporting group title
    Restrictive fluid group
    Reporting group description
    No IV fluids unless one of the below extenuating circumstances occurs; 1)In case of severe hypoperfusion or severe circulatory impairment defined by either: - Lactate 4 mmol/L or above - Mean arterial blood pressure below 50 mmHg (with or without vasopressor/inotrope) - Mottling beyond the kneecap (mottling score >2) OR - Urinary output less 0.1 mL/kg bodyweight/h, but only in the first 2 hrs after randomisation A bolus of 250-500 ml of IV crystalloid solution may be given followed by re-evaluation. 2)In case of overt fluid losses (e.g. aspirates) IV fluid may be given to correct for the loss, but not above the volume lost. 3)In case the oral for water or electrolyte solutions is contraindicated , IV fluids may be given to: - Correct dehydration or electrolyte deficiencies. - Ensure a total fluid input of 1 L per 24 h (fluids with medications and nutrition count as input).

    Primary: 90-day mortality

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    End point title
    90-day mortality
    End point description
    End point type
    Primary
    End point timeframe
    After randomisation up to a maximum of 90 days.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    781
    764
    Units: number of patients
    329
    323
    Statistical analysis title
    Adjusted absolute difference
    Statistical analysis description
    Logistic regression analysis adjusted for the stratification variables (site and hematologic or metastatic cancer) in the intention-to-treat population.
    Comparison groups
    Restrictive fluid group v Standard fluid group
    Number of subjects included in analysis
    1545
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Absolute difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.7
         upper limit
    4.9

    Secondary: Serious adverse events

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    End point title
    Serious adverse events
    End point description
    *Number of patients with one or more serious adverse events (SAEs). Composite outcome defined by cerebral ischemia, myocardial ischemia, intestinal ischemia, limb ischemia and severe acute kidney injury. The single components of the composite outcome are reported in the primary publication (PMID: 35709019). All secondary outcome data were missing for 23 patients (15 in restrictive group, 8 in standard group). For SAEs, 4 patients (in addition to the 23) had missing data in the composite outcome.
    End point type
    Secondary
    End point timeframe
    During ICU stay until a maximum of 90 days.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    772
    751
    Units: number of patients*
    238
    221
    Statistical analysis title
    Adjusted absolute difference
    Statistical analysis description
    Logistic regression analysis adjusted for the stratification variables (site and metastatic or hematologic cancer) in the ITT population. The parameter estimate with corresponding confidence interval is for the comparison of the restrictive fluid group vs standard fluid group.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1523
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Absolute difference, percentage points
    Point estimate
    -1.7
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -7.7
         upper limit
    4.3

    Secondary: Number of days alive without life support

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    End point title
    Number of days alive without life support
    End point description
    Number of days alive without the use of invasive mechanical ventilation, circulatory support, or any form of renal replacement therapy. All secondary outcome data were missing for 23 patients (15 in restrictive group, 8 in standard group).
    End point type
    Secondary
    End point timeframe
    After randomisation until a maximum of 90 days.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    776
    755
    Units: days
        median (inter-quartile range (Q1-Q3))
    77 (1 to 87)
    77 (1 to 87)
    Statistical analysis title
    Adjusted absolute difference
    Statistical analysis description
    The parameter estimate with corresponding confidence interval is for the comparison of the restrictive fluid group vs standard fluid group.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1531
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -11
         upper limit
    11
    Notes
    [1] - Calculated by Van Elteren test after adjustment for site.

    Secondary: Serious adverse reactions

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    End point title
    Serious adverse reactions
    End point description
    Number of patients with one or more serious adverse reactions (SARs). Composite outcome defined by severe hypernatremia, generalised tonic-clonic seizures, anaphylactic reactions, central pontine myelinolysis, severe hyperchloremic acidosis, or severe metabolic alkalosis. All secondary outcome data were missing for 23 patients (15 in restrictive group, 8 in standard group). The single components of the composite outcome are reported in the primary publication (PMID: 35709019).
    End point type
    Secondary
    End point timeframe
    During ICU stay until a maximum of 90 days.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    776
    755
    Units: number of patients
    32
    31
    Statistical analysis title
    Adjusted absolute difference
    Statistical analysis description
    Logistic regression analysis adjusted for the stratification variables (site and metastatic or hematologic cancer) in the ITT population. The parameter estimate with corresponding confidence interval is for the comparison of the restrictive fluid group vs standard fluid group.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1531
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Absolute difference, percentage points
    Point estimate
    -0.1
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    2.6

    Secondary: Number of days alive and out of hospital

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    End point title
    Number of days alive and out of hospital
    End point description
    Including any readmissions during the 90-day follow-up period. All secondary outcome data were missing for 23 patients (15 in restrictive group, 8 in standard group).
    End point type
    Secondary
    End point timeframe
    After randomisation until a maximum of 90 days.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    776
    755
    Units: days
        median (inter-quartile range (Q1-Q3))
    33 (0 to 70)
    21 (0 to 69)
    Statistical analysis title
    Adjusted absolute difference
    Statistical analysis description
    The parameter estimate with corresponding confidence interval is for the comparison of the restrictive fluid group vs standard fluid group.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1531
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    -12
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -30
         upper limit
    6
    Notes
    [2] - Calculated by Van Elteren test after adjustment for site.

    Secondary: 1-year mortality

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    End point title
    1-year mortality
    End point description
    End point type
    Secondary
    End point timeframe
    After randomisation up to a maximum of 1 year.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    767 [3]
    750 [4]
    Units: Number of patients
    383
    385
    Notes
    [3] - 2 patients withdrew consent for 90-day follow-up and 15 patients for 1-year follow-up.
    [4] - 3 patients withdrew consent for 90-day follow-up and 17 patients for 1-year follow-up.
    Statistical analysis title
    Adjusted risk difference
    Statistical analysis description
    Adjusted absolute risk difference for 1-year mortality in the restrictive group versus standard group. Adjusted for stratification variables (site and hematologic malignancy or metastatic cancer).
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1517
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.5
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -4.8
         upper limit
    7.8

    Secondary: Health related quality of life

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    End point title
    Health related quality of life
    End point description
    EQ-5D-5L: EuroQol 5 domains 5 levels health-related quality of life scale with non-surviviors at 1 year included with the value 0. Index values calculated using country-specific value sets.
    End point type
    Secondary
    End point timeframe
    Collected 1 year after randomisation.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    712 [5]
    704 [6]
    Units: EQ-5D-5L index values
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0.81)
    0 (0 to 0.82)
    Notes
    [5] - 2 and 15 patients withdrew consent for 90-day and 1-year follow-up, and 55 had missing data.
    [6] - 3 and 17 patients withdrew consent for 90-day and 1-year follow-up, and 46 had missing data.
    Statistical analysis title
    Adjusted mean difference
    Statistical analysis description
    Adjusted mean difference with 99% CI for Eq-5D-5L index values in the restrictive fluid group versus the standard fluid group.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1416
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -0.06
         upper limit
    0.05

    Secondary: Cognitive function

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    End point title
    Cognitive function
    End point description
    Cognitive function assessed by Mini MoCA Montreal cognitive assessment. Non-survivors at 1 year included with the worst possible values.
    End point type
    Secondary
    End point timeframe
    1 year after randomisation.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    669 [7]
    668 [8]
    Units: Mini MoCA values
        median (inter-quartile range (Q1-Q3))
    0 (0 to 22)
    0 (0 to 22)
    Notes
    [7] - 2 and 15 patients withdrew consent for 90-day and 1-year follow-up and 98 had missing data.
    [8] - 3 and 17 patients withdrew consent for 90-day and 1-year follow-up and 82 had missing data.
    Statistical analysis title
    Adjusted mean difference
    Statistical analysis description
    Adjusted mean difference for the Mini Moca values in the restrictive fluid group versus standard fluid group. Ajusted for stratification variables.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1337
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -1.59
         upper limit
    1.31

    Secondary: Health related quality of life

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    End point title
    Health related quality of life
    End point description
    EuroQol EQ visual analogue scale (VAS)
    End point type
    Secondary
    End point timeframe
    Collected 1 year after randomisation. Non-survivors at 1 year included with the worst possible values.
    End point values
    Standard fluid group Restrictive fluid group
    Number of subjects analysed
    690 [9]
    687 [10]
    Units: EQ-VAS
        median (inter-quartile range (Q1-Q3))
    0 (0 to 70)
    0 (0 to 70)
    Notes
    [9] - 2 and 15 patients withdrew consent for 90-day and 1-year follow-up, and 77 had missing values.
    [10] - 3 and 17 patients withdrew consent for 90-day and 1-year follow-up, and 63 had missing values.
    Statistical analysis title
    Adjusted mean difference
    Statistical analysis description
    Adjusted mean difference with 99% CI for EQ VAS values in the restrictive fluid group versus the standard fluid group.
    Comparison groups
    Standard fluid group v Restrictive fluid group
    Number of subjects included in analysis
    1377
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -5.4
         upper limit
    4.08

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    While the patient was in the ICU. From randomisation to a maximum of 90-days
    Adverse event reporting additional description
    Any serious adverse reaction/event not covered in the secondary outcomes adjudicated to be related to the intervention by the investigator, was to be reported within 24 hours to the Sponsor. If deemed a SUSAR by the Sponsor, it was to be reported to the Danish Medicine Agency.
    Assessment type
    Non-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: No non-serious adverse events were recorded, but the patient charts 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? 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.
    Patients and personnel were aware of group assignments. Protocol violations occurred in 21.5% in the restrictive fluid group and 13.0% in the standard group. Different results may be obtained in settings where more IV fluid is used in standard care.
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