Back to resultsHaloperidol for Delirium in Adult Critically Ill Patients (EuRIDICE)
Primary Purpose
Delirium, Critical Illness, Intensive Care Psychosis
Status
Terminated
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Haloperidol
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Delirium focused on measuring delirium, intensive care unit, critical illness, cognitive impairment
Eligibility Criteria
Inclusion Criteria for randomisation:
- Delirium, as assessed with the Intensive Care Delirium Screening Checklist - ICDSC: ≥4 or Confusion Assessment Method for the ICU - CAM-ICU: positive). NB Delirium can occur in the course of ICU admission or be present at admission.
- Written Informed Consent is obtained from patient or legal representative
- Complies with inclusion criteria but NOT exclusion criteria for eligibility:
Eligibility
Inclusion criteria for eligibility
- Age ≥ 18 years
- Admitted to ICU.
Exclusion criteria for eligibility
- Admitted to ICU with a neurological diagnosis (such as acute stroke, traumatic brain injury, intracranial malignancy, anoxic coma). Previous non-acute stroke or other previous neurological condition without cognitive deterioration is not an exclusion criterion.
- Pregnancy (to be excluded by pregnancy test in women of child baring age)
- History of ventricular arrhythmia including "torsade de pointes" (TdP)
- Known allergy to haloperidol
- History of dementia or an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score ≥ 4
- History of malignant neuroleptic syndrome or parkinsonism (either Parkinson's disease or another hypokinetic rigid syndrome)
- Schizophrenia or other psychotic disorder
- Inability to conduct valid delirium screening assessment (e.g. coma, deaf, blind) or inability to speak Dutch
- The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours after evaluation (may be reassessed daily)
Exclusion Criteria for randomisation:
- Prolonged QT-interval (QTc > 500ms)
- (recent) "torsade de pointes" (TdP)
- (recent) malignant neuroleptic syndrome or parkinsonism
- Evidence of acute alcohol (or substance) withdrawal requiring pharmacological intervention (e.g. benzodiazepines or alfa-2 agonist) to treat
- IQCODE not assessed
- The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours.
- No (previously) signed informed consent by patient or representative
- Current participation in another intervention trial that is evaluating a medication, device or behavioural intervention
Sites / Locations
- Jeroen Bosch ziekenhuis
- IJsselland Hospital
- Albert Schweitzer Hospital
- Radboudumc
- ErasmusMC
- Franciscus Gasthuis (Hospital)
- Ikazia Hospital
- Maasstad Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
haloperidol
placebo
Arm Description
study drug will be titrated based on delirium, diagnosed with a validated screening instrument (CAM-ICU or ICDSC), starting with 2.5mg IV q8h and titrated to a maximum of 5mg IV q8h. Agitation and hallucinations will be managed according to a pre-specified protocol in both treatment arms. First the study drug will be increased when agitation or delirium remain present. Further options include mainly the use of alfa-2 agonists (agitation) or atypical antipsychotic drugs (hallucinations).
study drug will be titrated based on delirium, diagnosed with a validated screening instrument (CAM-ICU or ICDSC), starting with 2.5mg IV q8h and titrated to a maximum of 5mg IV q8h. Agitation and hallucinations will be managed according to a pre-specified protocol in both treatment arms. First the study drug will be increased when agitation or delirium remain present. Further options include mainly the use of alfa-2 agonists (agitation) or atypical antipsychotic drugs (hallucinations).
Outcomes
Primary Outcome Measures
delirium- and coma-free days
days without brain dysfunction (=delirium OR coma) while at the ICU
Secondary Outcome Measures
Cognitive deterioration: Global cognitive functioning
Global cognitive functioning as assessed with the Montreal Cognitive Assessment (MOCA). Total score will be reported, with a range of 0-30 (higher values representing better cognitive functioning).
Cognitive deterioration: Verbal learning and memory
Auditory-verbal learning and memory will be assessed with the Rey Auditory Verbal Learning Test. Three subscores will be reported: total correct words in 5 trials (range: 0 -75), total correct words after delay (range: 0-15) and total correct words at recognition (range: 0-30).
Cognitive deterioration: Semantic fluency
Semantic fluency will be tested with the Semantic Category Fluency Test. The amount of animals given within a time of 60 seconds will represent the score.
Cognitive deterioration: Working memory
Working memory will be assessed using the Wechsler Adult Intelligence Scale - Third Edition (WAIS-III). Subscales will be reported for both digit span under forward and backward recall conditions. In addition, a total score will be reported, which equals the sum of both separate digit spans.
Cognitive deterioration: Cognitive flexibility
Cognitive flexibility, one of the executive funcions, will be assessed with the Trialmaking tests A and B. The total amount of seconds needed to finish each test will be reported, with less seconds needed representing better cognitive flexibility.
Cognitive deterioration: Word retrieval
Word retrieval is tested with the Boston Naming Test (30-item version). The total score (range: 0-30) represents the amount of correct answered drawings.
Anxiety and depression
Anxiety and depression will be assessed with the Hospital Anxiety and Depression Scale (HADS). Two subscales will be reported, one for anxiety symptoms (range: 0-21) and one for depression symptoms (range: 0-21). Higher values represent a worse outcome. A subscore >8 indicates anxiety or depression, respectively.
Functional outcome
Health-related quality of life will be assessed with the Short Form-35 (SF-36). Nine subscales will be reported on a 0 - 100 scale: physical functioning, role functioning - physical, bodily pain, general health, vitality, social functioning, role functioning - emotional, mental health and reported health transition. Higher values represent a better health-related quality of life.
mortality
mortality
length of stay at ICU
length of stay at ICU (days)
Adverse drug associated events: prolonged QTc by EKG
prolonged QTc by EKG (ms)
Adverse drug associated events: muscle rigidity and other associated movements disorders
muscle rigidity and other associated movements disorders [measured with the Simpson Angus Scale]
Adverse drug associated events: ventricular arrhythmia's
ventricular arrhythmia's including torsade de pointes
Patients' memories related to their ICU stay
Patients' memories for their ICU stay will be evaluated with the ICU Memory Tool (ICU-MT). Subscores will be reported for factual memories (range: 0-11), delusion memories (range: 0-6) and memories of feelings (range: 0-4).
Patients' and family-members' experiences related to delirium
Delirium recall and distress related to the delirium episode will be assessed with the Delirium Experience Questionnaire (DEQ). Scores will represent whether patients remember their delirium episode. In addition, a score representing delirium-related distress levels (range: 0-4, with higher values representing more distress) will be reported for both patients and family-members.
Caregiver Strain
The strain experienced by family-members or relatives will be assessed with the Caregiver Strain Index. A total score (range: 0-13) will be reported, with higher values representing higher experienced strain.
Posttraumatic stress syndrome
Posttraumatic stress symptoms in patients and families will be assessed with the Impact of Event Scale - Revised (IES-R). A mean total IES-R score will be reported (range: 0-4), with posttraumatic stress disorder defined as a mean IES-R score ≥ 1.6. In addition, subscores will be reported for intrusion, avoidance and hyperarousal (range: 0-4).
Full Information
NCT ID
NCT03628391
First Posted
October 9, 2017
Last Updated
May 6, 2022
Sponsor
Erasmus Medical Center
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
1. Study Identification
Unique Protocol Identification Number
NCT03628391
Brief Title
Haloperidol for Delirium in Adult Critically Ill Patients
Acronym
EuRIDICE
Official Title
Efficacy of Haloperidol to Decrease the Burden of Delirium in Adult Critically Ill Patients (EuRIDICE): a Prospective Randomised Multi-center Double-blind Placebo-controlled Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
The study was stopped because of futility of being able to reach a one-day difference between treatment groups in the primary outcome of DCFD in the intended sample size.
Study Start Date
February 22, 2018 (Actual)
Primary Completion Date
February 3, 2020 (Actual)
Study Completion Date
January 23, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Erasmus Medical Center
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The EuRIDICE trial will study whether haloperidol as a first line treatment for ICU delirium reduces delirium duration (and severity). Adverse outcomes typically associated with delirium will also be studied and include long term cognition, functional outcome and quality of life. Further, patient and family experiences and cost-effectiveness will be assessed. Finally, safety concerns associated with the use of haloperidol in this vulnerable population will be studied.
Detailed Description
BACKGROUND. Although widely used, the efficacy and safety of haloperidol for delirium in critically ill adults remain unclear. A randomised controlled trial is warranted to study the effect of haloperidol on delirium or coma, long-term outcomes, safety concerns, and cost-effectiveness.
SUMMARY.
The investigators will perform a multi-center, randomised, double-blind, placebo-controlled clinical trial to evaluate the use of haloperidol for delirium treatment in 742 critically ill adults with delirium. Days spent without delirium- or coma in the first 14 days after randomisation is the primary outcome. Study drug will be initiated at 2.5mg IV q8h and increased after 24 hours to 5mg IV q8h if delirium persists. Study drug dose will be tapered when delirium has resolved during 24 hours. All patients will be managed with a standardized pain, agitation and delirium protocol. Standard operating procedures for agitation (analgesia titration, alpha2 agonists) and hallucination management (atypical antipsychotics) will be implemented to accommodate possible imbalances of these symptoms in both treatment arms. Open-label haloperidol administration is discouraged during the trial. The sample size provides a power of 90% to detect statistically significant results (p<.05) and a true treatment difference of one day for the primary outcome between trial arms.
This trial is expected to answer the clinically relevant question whether haloperidol still deserves a place in ICU delirium management. The primary outcome (delirium- and coma-free days) will be related to the secondary outcomes cognitive dysfunction, functional and psychological outcomes and patient- and family experiences. An extensive cost-effectiveness analysis will be done. Mortality at one year and safety concerns of haloperidol (QTc prolongation on EKG and rigidity) will be assessed as secondary endpoints. In conclusion, this large multicentre trial will assess efficacy and safety of haloperidol for ICU delirium.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Delirium, Critical Illness, Intensive Care Psychosis, Cognitive Impairment, Cognitive Decline
Keywords
delirium, intensive care unit, critical illness, cognitive impairment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Randomised controlled double-blind placebo controlled clinical trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
placebo and haloperidol (verum) will have the same appearance
Allocation
Randomized
Enrollment
142 (Actual)
8. Arms, Groups, and Interventions
Arm Title
haloperidol
Arm Type
Active Comparator
Arm Description
study drug will be titrated based on delirium, diagnosed with a validated screening instrument (CAM-ICU or ICDSC), starting with 2.5mg IV q8h and titrated to a maximum of 5mg IV q8h.
Agitation and hallucinations will be managed according to a pre-specified protocol in both treatment arms. First the study drug will be increased when agitation or delirium remain present. Further options include mainly the use of alfa-2 agonists (agitation) or atypical antipsychotic drugs (hallucinations).
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
study drug will be titrated based on delirium, diagnosed with a validated screening instrument (CAM-ICU or ICDSC), starting with 2.5mg IV q8h and titrated to a maximum of 5mg IV q8h.
Agitation and hallucinations will be managed according to a pre-specified protocol in both treatment arms. First the study drug will be increased when agitation or delirium remain present. Further options include mainly the use of alfa-2 agonists (agitation) or atypical antipsychotic drugs (hallucinations).
Intervention Type
Drug
Intervention Name(s)
Haloperidol
Other Intervention Name(s)
not any
Intervention Description
haloperidol for ICU delirium, titrated on validated screening tool-based diagnosis
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo for ICU delirium, titrated on validated screening tool-based diagnosis
Primary Outcome Measure Information:
Title
delirium- and coma-free days
Description
days without brain dysfunction (=delirium OR coma) while at the ICU
Time Frame
within the first 14 days after randomisation
Secondary Outcome Measure Information:
Title
Cognitive deterioration: Global cognitive functioning
Description
Global cognitive functioning as assessed with the Montreal Cognitive Assessment (MOCA). Total score will be reported, with a range of 0-30 (higher values representing better cognitive functioning).
Time Frame
3 and 12 months
Title
Cognitive deterioration: Verbal learning and memory
Description
Auditory-verbal learning and memory will be assessed with the Rey Auditory Verbal Learning Test. Three subscores will be reported: total correct words in 5 trials (range: 0 -75), total correct words after delay (range: 0-15) and total correct words at recognition (range: 0-30).
Time Frame
3 and 12 months
Title
Cognitive deterioration: Semantic fluency
Description
Semantic fluency will be tested with the Semantic Category Fluency Test. The amount of animals given within a time of 60 seconds will represent the score.
Time Frame
3 and 12 months
Title
Cognitive deterioration: Working memory
Description
Working memory will be assessed using the Wechsler Adult Intelligence Scale - Third Edition (WAIS-III). Subscales will be reported for both digit span under forward and backward recall conditions. In addition, a total score will be reported, which equals the sum of both separate digit spans.
Time Frame
3 and 12 months
Title
Cognitive deterioration: Cognitive flexibility
Description
Cognitive flexibility, one of the executive funcions, will be assessed with the Trialmaking tests A and B. The total amount of seconds needed to finish each test will be reported, with less seconds needed representing better cognitive flexibility.
Time Frame
3 and 12 months
Title
Cognitive deterioration: Word retrieval
Description
Word retrieval is tested with the Boston Naming Test (30-item version). The total score (range: 0-30) represents the amount of correct answered drawings.
Time Frame
3 and 12 months
Title
Anxiety and depression
Description
Anxiety and depression will be assessed with the Hospital Anxiety and Depression Scale (HADS). Two subscales will be reported, one for anxiety symptoms (range: 0-21) and one for depression symptoms (range: 0-21). Higher values represent a worse outcome. A subscore >8 indicates anxiety or depression, respectively.
Time Frame
3 and 12 months
Title
Functional outcome
Description
Health-related quality of life will be assessed with the Short Form-35 (SF-36). Nine subscales will be reported on a 0 - 100 scale: physical functioning, role functioning - physical, bodily pain, general health, vitality, social functioning, role functioning - emotional, mental health and reported health transition. Higher values represent a better health-related quality of life.
Time Frame
3 and 12 months
Title
mortality
Description
mortality
Time Frame
28 days and 1 year
Title
length of stay at ICU
Description
length of stay at ICU (days)
Time Frame
days of ICU stay (time in days from ICU admission until ICU discharge). Assessed up to a maximum of 12 months after randomisation (end of follow-up period).
Title
Adverse drug associated events: prolonged QTc by EKG
Description
prolonged QTc by EKG (ms)
Time Frame
while on study drug treatment during study period at ICU (up to 14 days after randomisation)
Title
Adverse drug associated events: muscle rigidity and other associated movements disorders
Description
muscle rigidity and other associated movements disorders [measured with the Simpson Angus Scale]
Time Frame
while on study drug treatment during study period at ICU (up to 14 days after randomisation)
Title
Adverse drug associated events: ventricular arrhythmia's
Description
ventricular arrhythmia's including torsade de pointes
Time Frame
during study period at ICU (up to 14 days after randomisation)
Title
Patients' memories related to their ICU stay
Description
Patients' memories for their ICU stay will be evaluated with the ICU Memory Tool (ICU-MT). Subscores will be reported for factual memories (range: 0-11), delusion memories (range: 0-6) and memories of feelings (range: 0-4).
Time Frame
at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation
Title
Patients' and family-members' experiences related to delirium
Description
Delirium recall and distress related to the delirium episode will be assessed with the Delirium Experience Questionnaire (DEQ). Scores will represent whether patients remember their delirium episode. In addition, a score representing delirium-related distress levels (range: 0-4, with higher values representing more distress) will be reported for both patients and family-members.
Time Frame
at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation
Title
Caregiver Strain
Description
The strain experienced by family-members or relatives will be assessed with the Caregiver Strain Index. A total score (range: 0-13) will be reported, with higher values representing higher experienced strain.
Time Frame
at 3 months after randomisation
Title
Posttraumatic stress syndrome
Description
Posttraumatic stress symptoms in patients and families will be assessed with the Impact of Event Scale - Revised (IES-R). A mean total IES-R score will be reported (range: 0-4), with posttraumatic stress disorder defined as a mean IES-R score ≥ 1.6. In addition, subscores will be reported for intrusion, avoidance and hyperarousal (range: 0-4).
Time Frame
at 3 months after randomisation
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for randomisation:
Delirium, as assessed with the Intensive Care Delirium Screening Checklist - ICDSC: ≥4 or Confusion Assessment Method for the ICU - CAM-ICU: positive). NB Delirium can occur in the course of ICU admission or be present at admission.
Written Informed Consent is obtained from patient or legal representative
Complies with inclusion criteria but NOT exclusion criteria for eligibility:
Eligibility
Inclusion criteria for eligibility
Age ≥ 18 years
Admitted to ICU.
Exclusion criteria for eligibility
Admitted to ICU with a neurological diagnosis (such as acute stroke, traumatic brain injury, intracranial malignancy, anoxic coma). Previous non-acute stroke or other previous neurological condition without cognitive deterioration is not an exclusion criterion.
Pregnancy (to be excluded by pregnancy test in women of child baring age)
History of ventricular arrhythmia including "torsade de pointes" (TdP)
Known allergy to haloperidol
History of dementia or an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score ≥ 4
History of malignant neuroleptic syndrome or parkinsonism (either Parkinson's disease or another hypokinetic rigid syndrome)
Schizophrenia or other psychotic disorder
Inability to conduct valid delirium screening assessment (e.g. coma, deaf, blind) or inability to speak Dutch
The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours after evaluation (may be reassessed daily)
Exclusion Criteria for randomisation:
Prolonged QT-interval (QTc > 500ms)
(recent) "torsade de pointes" (TdP)
(recent) malignant neuroleptic syndrome or parkinsonism
Evidence of acute alcohol (or substance) withdrawal requiring pharmacological intervention (e.g. benzodiazepines or alfa-2 agonist) to treat
IQCODE not assessed
The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours.
No (previously) signed informed consent by patient or representative
Current participation in another intervention trial that is evaluating a medication, device or behavioural intervention
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mathieu van der Jagt, MD PhD
Organizational Affiliation
Erasmus University Medical Center Rotterdam, The Netherlands
Official's Role
Principal Investigator
Facility Information:
Facility Name
Jeroen Bosch ziekenhuis
City
's-Hertogenbosch
Country
Netherlands
Facility Name
IJsselland Hospital
City
Capelle aan den IJssel
Country
Netherlands
Facility Name
Albert Schweitzer Hospital
City
Dordrecht
Country
Netherlands
Facility Name
Radboudumc
City
Nijmegen
Country
Netherlands
Facility Name
ErasmusMC
City
Rotterdam
Country
Netherlands
Facility Name
Franciscus Gasthuis (Hospital)
City
Rotterdam
Country
Netherlands
Facility Name
Ikazia Hospital
City
Rotterdam
Country
Netherlands
Facility Name
Maasstad Hospital
City
Rotterdam
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Can be retrieved after contacting the principal investigator
Citations:
PubMed Identifier
32967873
Citation
Smit L, Trogrlic Z, Devlin JW, Osse RJ, Ponssen HH, Slooter AJC, Hunfeld NGM, Rietdijk WJR, Gommers D, van der Jagt M; EuRIDICE study group. Efficacy of halopeRIdol to decrease the burden of Delirium In adult Critically ill patiEnts (EuRIDICE): study protocol for a prospective randomised multi-centre double-blind placebo-controlled clinical trial in the Netherlands. BMJ Open. 2020 Sep 23;10(9):e036735. doi: 10.1136/bmjopen-2019-036735.
Results Reference
derived
Learn more about this trial
Haloperidol for Delirium in Adult Critically Ill Patients
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