Clinical trial NCT03628391: Haloperidol for Delirium in Adult Critically Ill Patients
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
Overall status: TERMINATED
Phase: PHASE3
Conditions: Delirium
Critical Illness
Intensive Care Psychosis
Cognitive Impairment
Cognitive Decline
Keywords: delirium
intensive care unit
critical illness
cognitive impairment
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2018-08-14
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised controlled double-blind placebo controlled clinical trial
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria for randomisation:

1. 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.
2. Written Informed Consent is obtained from patient or legal representative
3. Complies with inclusion criteria but NOT exclusion criteria for eligibility:

Eligibility

Inclusion criteria for eligibility

1. Age ≥ 18 years
2. Admitted to ICU.

Exclusion criteria for eligibility

1. 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.
2. Pregnancy (to be excluded by pregnancy test in women of child baring age)
3. History of ventricular arrhythmia including "torsade de pointes" (TdP)
4. Known allergy to haloperidol
5. History of dementia or an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score ≥ 4
6. History of malignant neuroleptic syndrome or parkinsonism (either Parkinson's disease or another hypokinetic rigid syndrome)
7. Schizophrenia or other psychotic disorder
8. Inability to conduct valid delirium screening assessment (e.g. coma, deaf, blind) or inability to speak Dutch
9. 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:

1. Prolonged QT-interval (QTc \> 500ms)
2. (recent) "torsade de pointes" (TdP)
3. (recent) malignant neuroleptic syndrome or parkinsonism
4. Evidence of acute alcohol (or substance) withdrawal requiring pharmacological intervention (e.g. benzodiazepines or alfa-2 agonist) to treat
5. IQCODE not assessed
6. The patient is expected to die within 24 hours, or is expected to leave the ICU within 24 hours.
7. No (previously) signed informed consent by patient or representative
8. Current participation in another intervention trial that is evaluating a medication, device or behavioural intervention

Primary outcomes:
measure: delirium- and coma-free days
timeFrame: within the first 14 days after randomisation
Secondary outcomes:
measure: Cognitive deterioration: Global cognitive functioning
timeFrame: 3 and 12 months
measure: Cognitive deterioration: Verbal learning and memory
timeFrame: 3 and 12 months
measure: Cognitive deterioration: Semantic fluency
timeFrame: 3 and 12 months
measure: Cognitive deterioration: Working memory
timeFrame: 3 and 12 months
measure: Cognitive deterioration: Cognitive flexibility
timeFrame: 3 and 12 months
measure: Cognitive deterioration: Word retrieval
timeFrame: 3 and 12 months
measure: Anxiety and depression
timeFrame: 3 and 12 months
measure: Functional outcome
timeFrame: 3 and 12 months
measure: mortality
timeFrame: 28 days and 1 year
measure: length of stay at ICU
timeFrame: 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).
measure: Adverse drug associated events: prolonged QTc by EKG
timeFrame: while on study drug treatment during study period at ICU (up to 14 days after randomisation)
measure: Adverse drug associated events: muscle rigidity and other associated movements disorders
timeFrame: while on study drug treatment during study period at ICU (up to 14 days after randomisation)
measure: Adverse drug associated events: ventricular arrhythmia's
timeFrame: during study period at ICU (up to 14 days after randomisation)
measure: Patients' memories related to their ICU stay
timeFrame: at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation
measure: Patients' and family-members' experiences related to delirium
timeFrame: at discharge from hospital (up to a maximum of 12 months after randomisation = end of follow-up period) and 3 months after randomisation
measure: Caregiver Strain
timeFrame: at 3 months after randomisation
measure: Posttraumatic stress syndrome
timeFrame: at 3 months after randomisation
Other outcomes:
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch ziekenhuis
city: Capelle aan den IJssel
country: Netherlands
facility: IJsselland Hospital
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Hospital
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Rotterdam
country: Netherlands
facility: ErasmusMC
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis (Hospital)
city: Rotterdam
country: Netherlands
facility: Ikazia Hospital
city: Rotterdam
country: Netherlands
facility: Maasstad Hospital
Study officials:
affiliation: Erasmus University Medical Center Rotterdam, The Netherlands
name: Mathieu van der Jagt, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.