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    Clinical Trial Results:
    Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU)

    Summary
    EudraCT number
    		 2017-003829-15
    Trial protocol
    		 DK   FI   ES   IT  
    Global end of trial date
    31 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Nov 2024
    First version publication date
    13 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AID-ICU
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov: NCT03392376
    Sponsors
    Sponsor organisation name
    Zealand University Hospital
    Sponsor organisation address
    Lykkebækvej 1, Copenhagen, Denmark, 4600
    Public contact
    Lone Musaeus Poulsen, Department of Anaesthesia and intensive Care Medicine, Zealand University Hospital, Koege, +45 47326451, lmp@regionsjaelland.dk
    Scientific contact
    Lone Musaeus Poulsen, Department of Anaesthesia and intensive Care Medicine, Zealand University Hospital, Koege, +45 47326451, lmp@regionsjaelland.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
    31 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess benefits and harms of haloperidol in adult, critically ill patients with delirium in the ICU. The primary objective is to determine, if haloperidol treatment in ICU patients with delirium will increase the number of days alive out of the hospital within 90 days. This primary objective includes 90 days mortality and length of hospital stay within 90 days after randomisation.
    Protection of trial subjects
    The enrollment of patients was predominantly allowed as an emergency procedure because all the patients lacked the capacity to provide consent owing to delirium. Consent or assent was obtained from a physician independent of the trial (who represented the patient as a legal guardian) before enrollment of the patient, after which oral and written informed consent to continue participation was obtained from a relative or an authorized representative of the patient and later from the patient after the capacity to provide informed consent had returned. If consent was withdrawn, the assigned haloperidol or placebo was discontinued, and permission was sought to continue collection of trial data for analysis in accordance with national regulations. An independent data and safety monitoring committee assessed safety in an interim analysis, which was performed when 500 patients had been followed for 90 days. The trial was approved by ethic committees, national health authoritees and dataprotection agencies in particip
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Denmark: 964
    Country: Number of subjects enrolled
    Finland: 28
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    1000
    EEA total number of subjects
    993
    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)
    302
    From 65 to 84 years
    652
    85 years and over
    46

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients 18 years of age or older who had been admitted to an ICU for an acute condition and had received a positive result on a screening test for delirium according to either the Confusion Assessment Method for the ICU (CAM-ICU)12 or the Intensive Care Delirium Screening Checklist (ICDSC) were assessed for eligibility.13

    Pre-assignment
    Screening details
    		 Exclusion criteria - Contraindications to haloperidol - Habitual treatment with antipsychotics - Permanently incompetent - Delirium assessment non-applicable - Withdrawal from active therapy - Fertile women with a positive urin hCG - Patient under coercive measures - Patients suffering from delirium tremens. - Consent according to natio

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Clinicians, patients, investigators, outcome assessors, statisticians, and members of the data and safety monitoring committee were unaware of the trial-group assignments. Haloperidol and placebo were contained in identical ampules with identical labeling. The solutions were colorless and indistinguishable from each other

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Haloperidol
    Arm description
    		 2,5mg haloperidol x 3 daily with as needed dosing up to a maximum of 20 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Haloperidol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2,5mg haloperidol x 3 daily with possibility of as needed doses up to a maximum of 20mg daily.

    Arm title
    		 Placebo
    Arm description
    		 Normal saline
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    Corresponding to active drug

    Number of subjects in period 1
    		Haloperidol Placebo
    Started
    510
    490
    Completed
    501
    486
    Not completed
    9
    4
         did not receive the intervention
    9
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Haloperidol
    Reporting group description
    		 2,5mg haloperidol x 3 daily with as needed dosing up to a maximum of 20 mg.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal saline

    Reporting group values
    		 Haloperidol Placebo Total
    Number of subjects
    		 510 490 1000
    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)
    		 164 138 302
        From 65-84 years
    		 327 325 652
        85 years and over
    		 19 27 46
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 70 (62 to 76) 71 (63 to 76) -
    Gender categorical
    No. of females
    Units: Subjects
        Female
    		 182 162 344
        Male
    		 328 328 656

    End points

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    End points reporting groups
    Reporting group title
    Haloperidol
    Reporting group description
    		 2,5mg haloperidol x 3 daily with as needed dosing up to a maximum of 20 mg.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal saline

    Primary: Days alive and out of hospital to day 90

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    End point title
    		 Days alive and out of hospital to day 90
    End point description
    End point type
    Primary
    End point timeframe
    90 days
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    491
    472
    Units: days
        arithmetic mean (confidence interval 95%)
    35.8 (32.9 to 38.6)
    32.9 (29.9 to 35.8)
    Statistical analysis title
    		 Intention to treat
    Statistical analysis description
    All analyses were adjusted for stratification variables (trial site and delirium motor subtype). In the primary analysis, we used a linear-regression model to estimate the adjusted mean difference between the groups. Because of the nonnormal distribution, we bootstrapped 95% confidence intervals; 50,000 resampling iterations were used in the bootstrap.
    Comparison groups
    Haloperidol v Placebo
    Number of subjects included in analysis
    963
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22 [1]
    Method
    		 see comment
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 7
    Notes
    [1] - The Kryger Jensen and Lange16 test was used to estimate the P value because this test was designed for distributions of outcome results that show many patients with a value of zero.

    Primary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Primary
    End point timeframe
    90
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    501
    486
    Units: Number
    182
    210
    Statistical analysis title
    		 Intention to treat
    Comparison groups
    Haloperidol v Placebo
    Number of subjects included in analysis
    987
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    -6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 -0.6

    Primary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    End point type
    Primary
    End point timeframe
    90
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    491
    472
    Units: days
        arithmetic mean (confidence interval 95%)
    28.8 (26.7 to 30.8)
    26.4 (24.4 to 28.5)
    Statistical analysis title
    		 Intention to treat
    Comparison groups
    Haloperidol v Placebo
    Number of subjects included in analysis
    963
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Kryger-Lange test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 5.1

    Secondary: Days alive without delirium or coma

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    End point title
    		 Days alive without delirium or coma
    End point description
    Number of days a patient is alive and CAM-ICU negative
    End point type
    Secondary
    End point timeframe
    90 days post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    490 [2]
    466 [3]
    Units: days
        number (confidence interval 99%)
    57.7 (53.4 to 62.2)
    52.6 (48.0 to 57.1)
    Notes
    [2] - 20 had incomplete delirium screenings
    [3] - 24 had incomplete CAM-ICU screenings
    No statistical analyses for this end point

    Secondary: Days alive without mechanical ventilation

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    End point title
    		 Days alive without mechanical ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    90 days post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    500
    476
    Units: days
        number (confidence interval 99%)
    57.9 (53.7 to 62.2)
    53.9 (49.5 to 58.3)
    No statistical analyses for this end point

    Secondary: Serious Adverse Reactions in ICU

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    End point title
    		 Serious Adverse Reactions in ICU
    End point description
    End point type
    Secondary
    End point timeframe
    90 days post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    501
    486
    Units: patients
    11
    9
    No statistical analyses for this end point

    Secondary: Use of rescue medication

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    End point title
    		 Use of rescue medication
    End point description
    End point type
    Secondary
    End point timeframe
    90 days post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    501
    486
    Units: patients
    288
    302
    No statistical analyses for this end point

    Secondary: Days with rescue medication

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    End point title
    		 Days with rescue medication
    End point description
    End point type
    Secondary
    End point timeframe
    90 days post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    501
    486
    Units: days
        number (confidence interval 99%)
    2.9 (2.3 to 3.5)
    2.9 (2.3 to 3.4)
    No statistical analyses for this end point

    Secondary: One-year mortality

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    End point title
    		 One-year mortality
    End point description
    End point type
    Secondary
    End point timeframe
    1 year post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    491
    471
    Units: patients
    214
    236
    No statistical analyses for this end point

    Secondary: EQ-VAS (health-related quality of life)

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    End point title
    		 EQ-VAS (health-related quality of life)
    End point description
    End point type
    Secondary
    End point timeframe
    1 year post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    501 [4]
    486 [5]
    Units: points
        number (confidence interval 95%)
    25 (0.0 to 75)
    3.3 (0.0 to 75)
    Notes
    [4] - Multiply imputed data was used and deceased patients was assigned wirst possible value
    [5] - Multiply imputed data was used and deceased patients was assigned wirst possible value
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Index values

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    End point title
    		 EQ-5D-5L Index values
    End point description
    End point type
    Secondary
    End point timeframe
    1 year post-randomization
    End point values
    		 Haloperidol Placebo
    Number of subjects analysed
    501 [6]
    486
    Units: points
        number (confidence interval 95%)
    0.3 (0.0 to 0.88)
    0 (0.0 to 0.83)
    Notes
    [6] - Multiply imputed data was used and deceased patients was assigned wirst possible value
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    90 days post-randomisation
    Adverse event reporting additional description
    Serious Adverse Reactions to haloperidol
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Serious Adverse Reactions Haloperidol
    Reporting group description
    		 -

    Reporting group title
    Serious Adverse Reaction Placebo
    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: Justification: The trial did not record non-serious adverse event in accordance with and justified in the protocol.
    Serious adverse events
    		 Serious Adverse Reactions Haloperidol Serious Adverse Reaction Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 501 (2.20%)
    9 / 486 (1.85%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Arytmia
    Additional description: Occurence of VT or VF
         subjects affected / exposed
    5 / 501 (1.00%)
    4 / 486 (0.82%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Tardive dyskinesia
         subjects affected / exposed
    1 / 501 (0.20%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    3 / 501 (0.60%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroleptic malignant syndrome
         subjects affected / exposed
    0 / 501 (0.00%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Anaphylaxia
         subjects affected / exposed
    1 / 501 (0.20%)
    0 / 486 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 501 (0.00%)
    2 / 486 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 501 (0.20%)
    1 / 486 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.1%
    Non-serious adverse events
    		 Serious Adverse Reactions Haloperidol Serious Adverse Reaction Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 501 (0.00%)
    0 / 486 (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 reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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