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    Clinical Trial Results:
    Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients - a Multicenter, Randomized Clinical Feasibility Trial

    Summary
    EudraCT number
    		 2021-000224-35
    Trial protocol
    		 DK  
    Global end of trial date
    18 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2022
    First version publication date
    31 Aug 2022
    Other versions
    Summary report(s)
    		 REFACED Sepsis_AcademicEmergencyMedicine_Jessen et al_2022

    Trial information

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    Trial identification
    Sponsor protocol code
    RECEM00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05076435
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Research Center for Emergency Medicine, Department of Clinical Medicine, Aarhus University
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, J103, Aarhus N, Denmark, 8200
    Public contact
    Research Center for Emergency Medic, Research Center for Emergency Medicine, Department of Clinical Medicine, Aarhus University, 0045 7846 6660, cfa@clin.au.dk
    Scientific contact
    Research Center for Emergency Medic, Research Center for Emergency Medicine, Department of Clinical Medicine, Aarhus University, 0045 7846 6660, cfa@clin.au.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
    18 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test if an IV fluid restrictive protocol in ED patients with sepsis is feasible, i.e., if the protocol decreases the IV fluid volumes administered compared to standard care.
    Protection of trial subjects
    Generally, fluid administration is considered safe and is very commonly used in clinical practice. In the restrictive fluid group protocol violations (i.e., giving fluids although no criteria are fulfillled) will be allowed if deamed needed by the treating physician. The clinical team will document any specific adverse events suspected to be related to the intervention.
    Background therapy
    		 Standard Care fluid administration
    Evidence for comparator
    		 Fluid restriction has been suggested to be beneficial in septic shock. No evidence in sepsis patients without shock exists. Although trials are currently exploring fluid strategies in patients with hypotension and septic shock, there are no studies on fluid administration in patients with early sepsis without shock/hypotension. Research within this field has been requested by experts. As fluid administration is very frequent, but not evidence-based, and carries potential risks, we consider it to be of great interest for society and patients to perform research in this area. Fluid resuscitation is a key intervention in sepsis, but the optimal amount of fluid to be given has not been established. The present trial is a feasibility trial, i.e., a trial assessing the feasibility of the proposed protocol in a clinical setting. The aim is to investigate the ability to reduce fluid volume using the given protocol. Should the trial prove feasible with separation between the two interventions, a large-scale trial assessing patient important outcomes is intended.
    Actual start date of recruitment
    03 Nov 2021
    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: 124
    Worldwide total number of subjects
    124
    EEA total number of subjects
    124
    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)
    20
    From 65 to 84 years
    75
    85 years and over
    29

    Subject disposition

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    Recruitment
    Recruitment details
    		 Nov 3rd, 2021, to Dec 18th 2021, Participants were recruited in the EDs at Aarhus University Hospital, the Regional Hospital Randers, and the Regional Hospital Viborg

    Pre-assignment
    Screening details
    		 inclusion criteria:1) Unplanned ED admission,2) age≥18 years,3) sepsis defined as a)infection suspected,b) blood cultures drawn,c) intravenous antibiotics administered/planned, d)SOFA-score ≥ 2, and 4) expected hospital stay>24 hours, Exclusion: see protocol: DOI: 10.1186/s40814-022-01034-y / refaced-sepsis.dk

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    It was not possible to blind the intervention for neither the treating team, patients nor relatives.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care group
    Arm description
    		 Fluids were administered by clinicians’ choice
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sodium Chloride solution 0.9%
    Investigational medicinal product code
    13341
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Dose as per the treating physicians

    Investigational medicinal product name
    Sodium chloride 9mg/ml, indsusion "Fresenius Kabi"
    Investigational medicinal product code
    14043
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As per treating physician

    Investigational medicinal product name
    Ringer-acetat "Fresenius Kabi", infusion
    Investigational medicinal product code
    12624
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for injection
    Dosage and administration details
    Per treating physician

    Investigational medicinal product name
    Ringer-lactat "Fresenius Kabi", infusion
    Investigational medicinal product code
    06756
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    As per treating physician

    Arm title
    		 Restrictive fluid administration
    Arm description
    		 In the restrictive fluid group, intravenous crystalloid fluids should not be given unless one of the below mentioned hypoperfusion criteria were met. • Lactate concentration ≥ 4 mmol/l (arterial or venous) • Hypotension (systolic blood pressure < 90 mmHg) • Mottling beyond edge of kneecap (i.e., Mottling score >2)33 • Severe oliguria, i.e., diuresis < 0.1 ml/kg/h, during the first 4 hours of admission If one or more of these criteria were met, a fluid bolus of 250 ml isotonic crystalloid (isotonic saline or Ringer’s acetate/lactate) could be administered per protocol. It was not a requirement that a fluid bolus was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Chloride solution 0.9%
    Investigational medicinal product code
    13341
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Dose as per the restrictive protocol

    Investigational medicinal product name
    Sodium chloride 9mg/ml, indsusion "Fresenius Kabi"
    Investigational medicinal product code
    14043
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    As per treating physician or per trial protocol

    Investigational medicinal product name
    Ringer-acetat "Fresenius Kabi", infusion
    Investigational medicinal product code
    12624
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for injection
    Dosage and administration details
    Per treating physician or per restrictive protocol

    Investigational medicinal product name
    Ringer-lactat "Fresenius Kabi", infusion
    Investigational medicinal product code
    06756
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    As per treating physician or per restrictive protocol

    Number of subjects in period 1
    		Standard care group Restrictive fluid administration
    Started
    62
    62
    Completed
    59
    58
    Not completed
    3
    4
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    -
         Discharge within 24 hours
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard care group
    Reporting group description
    		 Fluids were administered by clinicians’ choice

    Reporting group title
    Restrictive fluid administration
    Reporting group description
    		 In the restrictive fluid group, intravenous crystalloid fluids should not be given unless one of the below mentioned hypoperfusion criteria were met. • Lactate concentration ≥ 4 mmol/l (arterial or venous) • Hypotension (systolic blood pressure < 90 mmHg) • Mottling beyond edge of kneecap (i.e., Mottling score >2)33 • Severe oliguria, i.e., diuresis < 0.1 ml/kg/h, during the first 4 hours of admission If one or more of these criteria were met, a fluid bolus of 250 ml isotonic crystalloid (isotonic saline or Ringer’s acetate/lactate) could be administered per protocol. It was not a requirement that a fluid bolus was administered.

    Reporting group values
    		 Standard care group Restrictive fluid administration Total
    Number of subjects
    		 62 62 124
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 10 10 20
        From 65-84 years
    		 39 36 75
        85 years and over
    		 13 16 29
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 76 (68 to 83) 75 (67 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 28 25 53
        Male
    		 34 37 71

    End points

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    End points reporting groups
    Reporting group title
    Standard care group
    Reporting group description
    		 Fluids were administered by clinicians’ choice

    Reporting group title
    Restrictive fluid administration
    Reporting group description
    		 In the restrictive fluid group, intravenous crystalloid fluids should not be given unless one of the below mentioned hypoperfusion criteria were met. • Lactate concentration ≥ 4 mmol/l (arterial or venous) • Hypotension (systolic blood pressure < 90 mmHg) • Mottling beyond edge of kneecap (i.e., Mottling score >2)33 • Severe oliguria, i.e., diuresis < 0.1 ml/kg/h, during the first 4 hours of admission If one or more of these criteria were met, a fluid bolus of 250 ml isotonic crystalloid (isotonic saline or Ringer’s acetate/lactate) could be administered per protocol. It was not a requirement that a fluid bolus was administered.

    Primary: Crystalloid fluid volumes (24 h)

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    End point title
    		 Crystalloid fluid volumes (24 h)
    End point description
    (NaCl and Ringers administered in 24 hours)
    End point type
    Primary
    End point timeframe
    24 hours
    End point values
    		 Standard care group Restrictive fluid administration
    Number of subjects analysed
    62
    61
    Units: ml
        median (inter-quartile range (Q1-Q3))
    1000 (80 to 2000)
    0 (0 to 600)
    Statistical analysis title
    		 Quantile regression
    Comparison groups
    Standard care group v Restrictive fluid administration
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Quantile regression (median regression)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1000
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1392
         upper limit
    		 -607
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    90 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    eddra
    Reporting groups
    Reporting group title
    Restrictive fluid administration
    Reporting group description
    		 -

    Reporting group title
    Standard Care
    Reporting group description
    		 -

    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: We experienced no adverse events as defined by the protocol
    Serious adverse events
    		 Restrictive fluid administration Standard Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 61 (27.87%)
    18 / 62 (29.03%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Acute myocardial ischemia/infarction
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure or cardiogenic shock or cardiac arrest/death
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypervolemia
         subjects affected / exposed
    4 / 61 (6.56%)
    4 / 62 (6.45%)
         occurrences causally related to treatment / all
    0 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    New onset of severe acute kidney injury
         subjects affected / exposed
    9 / 61 (14.75%)
    10 / 62 (16.13%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Restrictive fluid administration Standard Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 62 (0.00%)

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None to report
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