Agents Intervening Against Delirium in Intensive Care Unit (AID-ICU)

Agents Intervening Against Delirium in Intensive Care Unit (AID-ICU) A Randomized, Blinded, Placebo-controlled Trial

Delirium is a frequent condition in the Intensive Care Unit (ICU) with no existing evidence-based treatment. The aim of the AID-ICU study is to assess the benefits and harms of haloperidol treatment for the management of ICU acquired delirium.

Study Overview

• Status: Active, not recruiting
• Conditions: Delirium
• Intervention / Treatment: Drug: Haloperidol Injection; Other: Saline (0,9%)

Detailed Description

Delirium among critically ill patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. No evidence-based treatment exist of this condition. Haloperidol is the most frequently used agent to treat ICU-related delirium, but according to the available literature there is no firm evidence of efficacy and safety of this intervention. AID-ICU aims to assess the benefits and harms of haloperidol in adult, critically ill patients with delirium in the ICU.

• Study Type: Interventional
• Enrollment (Anticipated): 1000
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Aabenraa, Denmark, 6200
    • Dept. Intensive Care, Aabenraa Hospital
  • Aalborg, Denmark, 9000
    • Dept. of Intensive Care, Aalborg University Hospital
  • Copenhagen, Denmark, 2100
    • Dept. of Intensive Care 4131, Copenhagen University Hospital, Rigshospitalet
  • Herlev, Denmark, 2730
    • Dept. of Intensive Care, Herlev Hospital
  • Herning, Denmark, 7400
    • Dept. of Intensive Care, Herning Hospital
  • Hillerød, Denmark, 3400
    • Dept. of Intensive Care, Nordsjaelland Hospital
  • Hjørring, Denmark, 9800
    • Regionshospitalet Nordjylland, Hjørring
  • Holstebro, Denmark, 7500
    • Dept. of Intensive Care, Holstebro Hospital
  • Køge, Denmark, 4600
    • Dept. of Intensive Care, Zealand University Hospital, Køge
  • Nykøbing Falster, Denmark, 4800
    • Dept. of Intensive Care, Nykøbing Falster Hospital
  • Odense, Denmark, 5000
    • Dept of intensive care, Odense University Hospital
  • Roskilde, Denmark, 4000
    • Dept. of Intensive Care, Zealand University Hospital Roskilde
  • Sønderborg, Denmark, 6400
    • Dept. of Intensive Care, Sønderborg Hospital
• Finland
  • Helsinki, Finland, 00120
    • Dept. of Intensive Care, Helsinki University Central Hospital
• Italy
  • Monza, Italy
    • Dept. of Neurosurgical Intensive Care, San Gerardo Hospital, Monza.
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • UHW Adult Critical Care Cardiff

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Acute admission to the ICU AND
• Age ≥ 18 years AND
• Diagnosed delirium with validated screening Tool as either CAM-ICU or ICDSC

Exclusion Criteria:

• Contraindications to haloperidol
• Habitual treatment with any antipsychotic medication or treatment with antipsychotics in the ICU prior to inclusion
• Permanently incompetent (e.g. dementia, mental retardation)
• Delirium assessment non-applicable (coma or language barriers)
• Withdrawal from active therapy
• Fertile women (women < 50) with positive urine human chorionic gonadotropin (hCG) or plasma hCG.
• Consent according to national regulations not obtainable
• Patients under coercive measures by regulatory authorities
• Patients with alcohol-induced delirium (Delirium Tremens)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Haloperidol injection; Haloperidol 2,5mg x 3 daily, with additional as needed doses to a maximum of 20mg/daily. Other name: Serenase	Drug: Haloperidol Injection; ICU patients with diagnosed delirium are treated with 2,5mg haloperidol x 3 daily intravenously with additional as needed doses to a maximum of 20mg/daily.; Other Names: Serenase
Placebo Comparator: Normal Saline; Saline (0,9%)	Other: Saline (0,9%); ICU patients with diagnosed delirium are treated with 0,5ml isotonic saline x 3 daily and as needed doses to a maximum of 4ml/daily, corresponding to the algorithm in the experimental arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive out of the hospital within 90 days post-randomization	Number of days alive and out of hospital	90 days
90-day mortality	Death from any cause within 90 days post-randomization	90 days
Hospital Length of Stay	Total number of days the patient is admitted to any hospital within the 90-day intervention period	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days alive without delirium or coma in the ICU	Number of days where patients are both alive and free of delirium and coma	Until ICU discharge, maximum 90 days
Number of patients with one or more serious adverse reactions to haloperidol and the total number of serious adverse reactions to haloperidol compared with placebo	Serious adverse reactions are: Anaphylactic reactions, Agranulocytosis, Pancytopenia, Ventricular arrhythmia, Extrapyramidal symptoms, Tardive dyskinesia, Malignant Neuroleptic Syndrome, Acute hepatic failure	Measured every day from inclusion until ICU discharge, maximum 90 days
Usage of escape medicine	Number of patients receiving escape medicine and number of days with escape medicine per patients	Measured every day from inclusion until ICU discharge, maximum 90 days
Number of days alive without mechanical ventilation within 90 days postrandomisation	Number of days where patients are both alive and free of mechanical ventilation	Measured every day from inclusion until ICU discharge, maximum 90 days
Mortality	Landmark mortality 1 year post-randomisation	1 year
Quality of life (five level)	EQ-5D-5L total score 1 year post-randomisation (1-5 of each of the five domains)	1 year
Quality of life (overall self assessment)	EQ-Visual Analogue Scale 1 year post-randomisation (0-100)	1 year
Cognitive function 1 year after randomisation at selected sites	Repeated Battery for the Assesment of Neuropsychological Status score 1 year post-randomisation at selected sites (40-150)	1 year
Executive function 1 year after randomisation at selected sites	Trail Making Test 1 year post-randomisation at selected sites (40-150)	1 year
A health economic analysis	The analytic details will be based on the primary results of the trial (cost-benefit or cost-minimisation analyses)	90 days
Cognitive function at admission	Informant Questionnaire on Cognitive Decline in the Elderly at ICU admission at selected sites (40-150)	At inclusion (within the first week)

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Collaborators: Copenhagen Trial Unit, Center for Clinical Intervention Research; Scandinavian Critical Care Trials Group; Centre for Research in Intensive Care (CRIC); The Danish Centre of Applied Social Science (VIVE)
• Investigators: Study Chair: Jørn Wetterslev, MD, PhD, Copenhagen Trial Unit, Center for Clinical Intervention Research; Study Chair: OIe Mathiesen, MD, PhD, Zealand University Hospital; Study Chair: Anders Perner, MD,PhD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Andersen-Ranberg NC, Poulsen LM, Perner A, Wetterslev J, Estrup S, Hastbacka J, Morgan M, Citerio G, Caballero J, Lange T, Kjaer MN, Ebdrup BH, Engstrom J, Olsen MH, Oxenboll Collet M, Mortensen CB, Weber SO, Andreasen AS, Bestle MH, Uslu B, Scharling Pedersen H, Gramstrup Nielsen L, Toft Boesen HC, Jensen JV, Nebrich L, La Cour K, Laigaard J, Haurum C, Olesen MW, Overgaard-Steensen C, Westergaard B, Brand B, Kingo Vesterlund G, Thornberg Kyhnauv P, Mikkelsen VS, Hyttel-Sorensen S, de Haas I, Aagaard SR, Nielsen LO, Eriksen AS, Rasmussen BS, Brix H, Hildebrandt T, Schonemann-Lund M, Fjeldsoe-Nielsen H, Kuivalainen AM, Mathiesen O; AID-ICU Trial Group. Haloperidol for the Treatment of Delirium in ICU Patients. N Engl J Med. 2022 Dec 29;387(26):2425-2435. doi: 10.1056/NEJMoa2211868. Epub 2022 Oct 26.

Helpful Links

• LINK to the AID-ICU webpage

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2018
• Primary Completion (Actual): July 9, 2022
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: November 30, 2017
• First Submitted That Met QC Criteria: December 30, 2017
• First Posted (Actual): January 8, 2018

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Haloperidol; ICU Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agents; Dopamine Antagonists; Anti-Dyskinesia Agents; Haloperidol; Haloperidol decanoate
• Other Study ID Numbers: REG-169-2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Study Data/Documents

1. Statistical Analysis Plan
   Information identifier: DOI: 10.1111/aas.13661
   Information comments: Published Statistical Analysis Plan for the AID-ICU trial
2. Study Protocol
   Information identifier: DOI: 10.1111/aas.13453
   Information comments: Published Study Protocol for the AID-ICU trial

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No