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    Clinical Trial Results:
    Forced fluid removal vs. usual care in intensive care patients with high-risk acute kidney injury and severe fluid overload (FFAKI) – A randomized clinical trial

    Summary
    EudraCT number
    		 2015-001701-13
    Trial protocol
    		 DK  
    Global end of trial date
    15 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2018
    First version publication date
    13 May 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    FFAKI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02458157
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nordsjællands Hospital. Dept. of Anaesthesiology and Intensive Care.
    Sponsor organisation address
    Dyrehavevej 29, Hillerød, Denmark, 3400
    Public contact
    Dept. of Anaesthesiology, Nordsjællands Hospital, +45 48294829,
    Scientific contact
    Dept. of Anaesthesiology, Nordsjællands Hospital, +45 48294829,
    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 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this pilot trial was to assess the feasibility of forced fluid removal in high-risk AKI patients with severe fluid overload. Fluid removal was done with furosemide and/or continuous renal replacement therapy aiming at net negative fluid balance > 1 ml/kg ideal body weight/hour until cumulative fluid balance calculated from ICU admission reached less than 1000 ml. The intervention was compared to standard of care as reflected in the KDIGO guidelines.
    Protection of trial subjects
    Patients included in the trial was admitted to the ICU and received all relevant critical care, no other measures were implemented to protect patients during the trial.
    Background therapy
    		 The management of AKI is complex with multiple interventions. These interventions must be provided equally and according to the KDIGO guidelines in both interventions arms. The KDIGO recommendations consist of maintenance of adequate renal perfusion pressure (MAP > 65) through crystalloid fluids and vasopressor use, avoidance of hyperglycaemia, reduction and/or avoidance of further harm by nephrotoxic antibiotics and avoidance of contrast media unless absolutely indicated. Severe sepsis and septic shock is a frequently associated with AKI, and the management of sepsis should be performed according to the SSC-guidelines [23] in both intervention arms. Overt fluid losses (e.g. bleeding, diarrhoea, ascites and pulmonary effusion) may be substituted in both intervention arms.
    Evidence for comparator
    		 The primary outcome of the FFAKI trial was cumulative fluid balance 5 days after ramdomisation. This comparator was chosen to reflect both the efficacy of the trial treatment (forced fluid removal) and protocol adherence, since failure of either of these would likely result in failure to remove fluids from the patients and lack of difference in the main outcome.
    Actual start date of recruitment
    01 Aug 2015
    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
    Denmark: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    4
    From 65 to 84 years
    18
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited for the trial in three different Danish ICU's. Nordsjællands Hospital, Rigshospitalet and Aalborg Universitets Hospital. Screening began on October 10th 2015 and the trial was terminated for futility because of very low recruitment rates on June 8th 2017

    Pre-assignment
    Screening details
    		 We screened patients for the development of fluid overload during the first 5 days of admission to the ICU and used peak serum creatinine from time of ICU admission ± 24 hours and urine output from the first full ICU-day to determine presence of acute kidney injury and calculate renal recovery score.

    Period 1
    Period 1 title
    Inclusion and randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Forced fluid removal
    Arm description
    		 The eksperimental treatment arm. Patients were allocated to forced fluid removal targeted at a negative fluid balance of at least 1 ml/kg/h using furosemide or CRRT
    Arm type
    		 Experimental

    Investigational medicinal product name
    Furosemide
    Investigational medicinal product code
    C 03 CA 01
    Other name
    Furix
    Pharmaceutical forms
    Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Furosemide infusion • Contraindications: anuria, allergy to sulphonamides or furosemide, hepatic coma or pregnancy • Dose: 40 mg I.V. bolus followed by continuous infusion titrated to achieve the therapeutic goal with a maximum infusion rate of 40 mg/h • Furosemide is used according to the indication and dosing described in the SmPC. No modification will be made to the packaging or labelling and no placebo will be used in the trial. The preparation of furosemide to be used as a trial drug will be double controlled. • Start time, end time, hourly infusion rate and any bolus dose of furosemide is registered in the source-data (ICU-observation charts) and will be transferred to the CRF. • The electronic medicine module EPM will be used to register furosemide used in the trial.

    Arm title
    		 Standard Care
    Arm description
    		 Control group recieving standard care. Renal replacement therapy: - Supportive therapy with RRT is indicated when life-threatening complications in fluid, electrolyte and acid-base balance occur: - Hyperkalaemia (p-K+ > 6 mmol/l) - Severe metabolic acidosis attributable to AKI (pH < 7.25 and SBE < -10 mmol/l) resistant to IV bicarbonate infusion - Severe respiratory failure with PaO2/FiO2 < 13 kPa and bilateral infiltrates/oedema on the chest x-ray. - Aside from these absolute indications, RRT may be provided in case of progressive azotaemia and plasma BUN > 25 mmol/l. Fluid therapy: Fluid administration at the discretion of the treating clinicians, using hemodynamic goal of choice Fluid removal: Pharmacological fluid removal (furosemide) will be done at the discretion of the treating clinicians.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Forced fluid removal Standard Care
    Started
    9
    14
    Completed
    7
    13
    Not completed
    2
    1
         Violation of exclusion criteria
    1
    -
         Violation of inclusion criteria
    1
    -
         Patient discharged within 1 hour of inclusion
    -
    1
    Period 2
    Period 2 title
    Intervention
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Forced fluid removal
    Arm description
    		 The eksperimental treatment arm. Patients were allocated to forced fluid removal targeted at a negative fluid balance of at least 1 ml/kg/h using furosemide or CRRT
    Arm type
    		 Experimental

    Investigational medicinal product name
    Furosemide
    Investigational medicinal product code
    C 03 CA 01
    Other name
    Furix
    Pharmaceutical forms
    Solution for injection, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Furosemide infusion • Contraindications: anuria, allergy to sulphonamides or furosemide, hepatic coma or pregnancy • Dose: 40 mg I.V. bolus followed by continuous infusion titrated to achieve the therapeutic goal with a maximum infusion rate of 40 mg/h • Furosemide is used according to the indication and dosing described in the SmPC. No modification will be made to the packaging or labelling and no placebo will be used in the trial. The preparation of furosemide to be used as a trial drug will be double controlled. • Start time, end time, hourly infusion rate and any bolus dose of furosemide is registered in the source-data (ICU-observation charts) and will be transferred to the CRF. • The electronic medicine module EPM will be used to register furosemide used in the trial.

    Arm title
    		 Standard Care
    Arm description
    		 Control group recieving standard care. Renal replacement therapy: - Supportive therapy with RRT is indicated when life-threatening complications in fluid, electrolyte and acid-base balance occur: - Hyperkalaemia (p-K+ > 6 mmol/l) - Severe metabolic acidosis attributable to AKI (pH < 7.25 and SBE < -10 mmol/l) resistant to IV bicarbonate infusion - Severe respiratory failure with PaO2/FiO2 < 13 kPa and bilateral infiltrates/oedema on the chest x-ray. - Aside from these absolute indications, RRT may be provided in case of progressive azotaemia and plasma BUN > 25 mmol/l. Fluid therapy: Fluid administration at the discretion of the treating clinicians, using hemodynamic goal of choice Fluid removal: Pharmacological fluid removal (furosemide) at the discretion of the treating clinicians.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Three patients were withdrawn from the trial without receiving the allocated intervention. The reasons for withdrawal was: Violation of inclusion criteria, violation of exclusion criteria and the last patient was discharged within one our from randomization and treated as a failed inclusion. No data were collected from these patients and they were not included in baseline characteristics. To illustrate this the trial has been divided into two periods with period 2 as baseline period.
    Number of subjects in period 2 [2]
    		Forced fluid removal Standard Care
    Started
    7
    13
    Completed
    7
    13
    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: Three patients were withdrawn from the trial without receiving the allocated intervention. No data were collected from these patients and they did not contribute to baseline characteristics

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Forced fluid removal
    Reporting group description
    		 The eksperimental treatment arm. Patients were allocated to forced fluid removal targeted at a negative fluid balance of at least 1 ml/kg/h using furosemide or CRRT

    Reporting group title
    Standard Care
    Reporting group description
    		 Control group recieving standard care. Renal replacement therapy: - Supportive therapy with RRT is indicated when life-threatening complications in fluid, electrolyte and acid-base balance occur: - Hyperkalaemia (p-K+ > 6 mmol/l) - Severe metabolic acidosis attributable to AKI (pH < 7.25 and SBE < -10 mmol/l) resistant to IV bicarbonate infusion - Severe respiratory failure with PaO2/FiO2 < 13 kPa and bilateral infiltrates/oedema on the chest x-ray. - Aside from these absolute indications, RRT may be provided in case of progressive azotaemia and plasma BUN > 25 mmol/l. Fluid therapy: Fluid administration at the discretion of the treating clinicians, using hemodynamic goal of choice Fluid removal: Pharmacological fluid removal (furosemide) at the discretion of the treating clinicians.

    Reporting group values
    		 Forced fluid removal Standard Care Total
    Number of subjects
    		 7 13 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (64 to 81) 75 (70 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 2 6 8
        Male
    		 5 7 12
    Septic Shock
    Units: Subjects
        Yes
    		 6 9 15
        No
    		 1 4 5
    KDIGO grade
    Units: Subjects
        KDIGO I
    		 1 1 2
        KDIGO II
    		 2 6 8
        KDIGO III
    		 4 6 10
    Diuresis
    Units: Subjects
        > 0.5 ml/kg/hour
    		 3 3 6
        < 0.5 ml/kg/hour for 6-12 h
    		 1 1 2
        < 0.5 ml/kg/hor for > 12 h
    		 2 5 7
        < 0.3 ml/kg/h or anuria for > 12 h
    		 1 4 5
    Renal replacement therapy
    Units: Subjects
        Yes
    		 1 4 5
        No
    		 6 9 15
    Weight
    Patient weight at admission to the ICU
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 70 (60 to 91) 73 (65 to 80) -
    Ideal body weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 71 (66 to 71) 66 (59 to 75) -
    ICU stay prior to randomisation
    Units: hour
        median (inter-quartile range (Q1-Q3))
    		 35 (29 to 41) 42 (34 to 45) -
    Charlson Comorbidity Index
    Units: CCI
        median (inter-quartile range (Q1-Q3))
    		 4 (2 to 6) 4 (4 to 5) -
    SOFA score
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 8 (6 to 12) 10 (8 to 13) -
    Maximum infusion rate of noradrenaline
    Measured in the 24 hours prior to randomisation
    Units: microgram(s)/kilogram/minute
        median (inter-quartile range (Q1-Q3))
    		 0.35 (0.25 to 1.2) 0.42 (0.35 to 0.78) -
    Creatinine Increase
    Increase in creatine from premorbid values
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 230 (150 to 290) 250 (210 to 290) -
    Renal Recovery Score
    The renal recovery score predicts the chance of recovering renal function within 28 days based upon age, creatinine increase and diuresis within the first 24 hours of admission to the ICU
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 46 (37 to 49) 27 (21 to 45) -
    Cumulative fluid balance
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    		 10834 (9679 to 11703) 8978 (7220 to 11132) -
    Fluid overload
    Calculated as cumulative fluid balance/ideal bodyweight
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 15.5 (13.6 to 18.9) 13.0 (10.9 to 16.9) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Forced fluid removal
    Reporting group description
    		 The eksperimental treatment arm. Patients were allocated to forced fluid removal targeted at a negative fluid balance of at least 1 ml/kg/h using furosemide or CRRT

    Reporting group title
    Standard Care
    Reporting group description
    		 Control group recieving standard care. Renal replacement therapy: - Supportive therapy with RRT is indicated when life-threatening complications in fluid, electrolyte and acid-base balance occur: - Hyperkalaemia (p-K+ > 6 mmol/l) - Severe metabolic acidosis attributable to AKI (pH < 7.25 and SBE < -10 mmol/l) resistant to IV bicarbonate infusion - Severe respiratory failure with PaO2/FiO2 < 13 kPa and bilateral infiltrates/oedema on the chest x-ray. - Aside from these absolute indications, RRT may be provided in case of progressive azotaemia and plasma BUN > 25 mmol/l. Fluid therapy: Fluid administration at the discretion of the treating clinicians, using hemodynamic goal of choice Fluid removal: Pharmacological fluid removal (furosemide) will be done at the discretion of the treating clinicians.
    Reporting group title
    Forced fluid removal
    Reporting group description
    		 The eksperimental treatment arm. Patients were allocated to forced fluid removal targeted at a negative fluid balance of at least 1 ml/kg/h using furosemide or CRRT

    Reporting group title
    Standard Care
    Reporting group description
    		 Control group recieving standard care. Renal replacement therapy: - Supportive therapy with RRT is indicated when life-threatening complications in fluid, electrolyte and acid-base balance occur: - Hyperkalaemia (p-K+ > 6 mmol/l) - Severe metabolic acidosis attributable to AKI (pH < 7.25 and SBE < -10 mmol/l) resistant to IV bicarbonate infusion - Severe respiratory failure with PaO2/FiO2 < 13 kPa and bilateral infiltrates/oedema on the chest x-ray. - Aside from these absolute indications, RRT may be provided in case of progressive azotaemia and plasma BUN > 25 mmol/l. Fluid therapy: Fluid administration at the discretion of the treating clinicians, using hemodynamic goal of choice Fluid removal: Pharmacological fluid removal (furosemide) at the discretion of the treating clinicians.

    Primary: Cumulative fluid balance at day five

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    End point title
    		 Cumulative fluid balance at day five
    End point description
    Cumulative fluid balance was defined as the sum of daily fluid balance calculated as the difference between total fluid input and total fluid output including estimates of metabolic water (300 ml/day) and perspiration (6-800 ml/day, as estimated by the attending physician)
    End point type
    Primary
    End point timeframe
    5 days after randomisation
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    -8103 (-9570 to -5116)
    516 (-2833 to 917)
    Attachments
    		 Untitled (Filename: Fig4.tif)
    Statistical analysis title
    		 Marginal model
    Statistical analysis description
    Linear random effects model unconditional on survival status
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.01
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5814
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2063
         upper limit
    		 9565

    Secondary: Mean daily fluid balance at ICU discharge

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    End point title
    		 Mean daily fluid balance at ICU discharge
    End point description
    End point type
    Secondary
    End point timeframe
    ICU admission
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    -1269 ( 868 )
    133 ( 1131 )
    Statistical analysis title
    		 Linear regression adjusted for observation time
    Comparison groups
    Standard Care v Forced fluid removal
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.01
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1467
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 437
         upper limit
    		 2497

    Secondary: Cumulative fluid balance at ICU discharge

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    End point title
    		 Cumulative fluid balance at ICU discharge
    End point description
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    604 ( 2379 )
    3259 ( 10721 )
    Statistical analysis title
    		 Linear regression adjusted for observation time
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.16
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3541
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1566
         upper limit
    		 8648

    Secondary: Achievement of neutral fluid balance during ICU stay

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    End point title
    		 Achievement of neutral fluid balance during ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: Patients
    6
    4
    Statistical analysis title
    		 Fisher's test
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.06
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to neutral fluid balance, median (IQR), days

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    End point title
    		 Time to neutral fluid balance, median (IQR), days
    End point description
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: day
        median (inter-quartile range (Q1-Q3))
    7 (6 to 8)
    6 (6 to 13.5)
    Statistical analysis title
    		 Time to neutral fluid balance
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 1.3

    Secondary: Major protocol violations

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    End point title
    		 Major protocol violations
    End point description
    Number of major protocol violations in each arm, defined as initiation of fluid removal after 12 hours and/or cessation of fluid removal before achieving cumulative fluid balance < 1000 ml.
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: Protocol violations
    2
    0
    No statistical analyses for this end point

    Secondary: Cumulated number of SAR's to furosemide

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    End point title
    		 Cumulated number of SAR's to furosemide
    End point description
    Total number of serious adverse reactions to furosemide defined as: Severe electrolyte disturbance (p-K+ < 3.0 mmol/l, p-Na+ < 120 mmol/l, p-Cl- < 90 mmol/l); severe thrombocytopenia (thrombocyte count < 50 x 109/l); anaemia requiring transfusion of red blood cells without bleeding; agranulocytosis; pancreatitis; arrhythmia; circulatory collapse; cramps; Steven Johnsons syndrome; toxic epidermal necrolysis; hearing loss and anaphylaxis). These were registered daily regardless of the patient recieving any furosemide on the given day
    End point type
    Secondary
    End point timeframe
    ICU stay
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: SAR
    13
    15
    No statistical analyses for this end point

    Other pre-specified: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: Patients
    2
    6
    Statistical analysis title
    		 Fisher's test
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.64
    Method
    		 Fisher exact
    Confidence interval

    Other pre-specified: Days alive and out of hospital

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    End point title
    		 Days alive and out of hospital
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: day
        median (inter-quartile range (Q1-Q3))
    0 (0 to 34)
    4 (0 to 69)
    Statistical analysis title
    		 Mann-Whitney U
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.35
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Days alive and without mechanical ventilation

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    End point title
    		 Days alive and without mechanical ventilation
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: day
        median (inter-quartile range (Q1-Q3))
    85 (0 to 87)
    25 (2 to 84)
    Statistical analysis title
    		 Mann-Whitney U
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.36
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Days alive and without renal replacement therapy

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    End point title
    		 Days alive and without renal replacement therapy
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: day
        median (inter-quartile range (Q1-Q3))
    36 (0 to 76)
    42 (1 to 89)
    Statistical analysis title
    		 Mann-Whitney U
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.48
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Days alive and without vasopressors/inotropes

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    End point title
    		 Days alive and without vasopressors/inotropes
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days
    End point values
    		 Forced fluid removal Standard Care
    Number of subjects analysed
    7
    13
    Units: day
        median (inter-quartile range (Q1-Q3))
    86 (2 to 87)
    53 (2 to 88)
    Statistical analysis title
    		 Mann-Whitney U
    Comparison groups
    Forced fluid removal v Standard Care
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.82
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    ICU stay up to a maximum of 90 days
    Adverse event reporting additional description
    The presence of adverse events was assessed daily during ICU stay
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Forced fluid removal
    Reporting group description
    		 The eksperimental treatment arm. Patients were allocated to forced fluid removal targeted at a negative fluid balance of at least 1 ml/kg/h using furosemide or CRRT

    Reporting group title
    Standard Care
    Reporting group description
    		 Control group recieving standard care. Renal replacement therapy: - Supportive therapy with RRT is indicated when life-threatening complications in fluid, electrolyte and acid-base balance occur: - Hyperkalaemia (p-K+ > 6 mmol/l) - Severe metabolic acidosis attributable to AKI (pH < 7.25 and SBE < -10 mmol/l) resistant to IV bicarbonate infusion - Severe respiratory failure with PaO2/FiO2 < 13 kPa and bilateral infiltrates/oedema on the chest x-ray. - Aside from these absolute indications, RRT may be provided in case of progressive azotaemia and plasma BUN > 25 mmol/l. Fluid therapy: Fluid administration at the discretion of the treating clinicians, using hemodynamic goal of choice Fluid removal: Pharmacological fluid removal (furosemide) at the discretion of the treating clinicians.

    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: Patients in this trial were admitted to the ICU. All ICU patients experience numerous non-serious adverse events daily during their critical illness. These were not recorded as an entity, but the most important SAEs and SAE's directly related to fluid removal have been 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.
    Serious adverse events
    		 Forced fluid removal Standard Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    6 / 13 (46.15%)
         number of deaths (all causes)
    2
    6
         number of deaths resulting from adverse events
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 13 (38.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 20
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    Myocardial ischaemia
    Additional description: Verified acute myocardial infarction resulting in intervention with PCI/thrombolysis or antithrombotic treatment
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Forced fluid removal Standard Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 13 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2016
    The inclusion criterium: Renal recovery score < 50% was changed to Renal Recovery Score < 60%

    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/29664109
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