E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012224 |
E.1.2 | Term | Delirium toxic |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000702 |
E.1.2 | Term | Acute delirium |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042275 |
E.1.2 | Term | Subacute delirium |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012220 |
E.1.2 | Term | Delirium due to a general medical condition |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012226 |
E.1.2 | Term | Delirium, cause unknown |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071313 |
E.1.2 | Term | Hypoactive delirium |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071314 |
E.1.2 | Term | Hyperactive delirium |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071315 |
E.1.2 | Term | Mixed delirium |
E.1.2 | System Organ Class | 100000004873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of haloperidol to resolve delirium in adult critically ill patients and thereby render the patient awake and non-delirious. |
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E.2.2 | Secondary objectives of the trial |
To study the efficacy of haloperidol to reduce ICU-delirium associated short- and long-term burdens (up to one-year), consisting of: 1) mortality; 2) cognitive and functional impairment; 3) patient- and family experiences and psychological sequelae during and after ICU stay; 4) safety concerns associated with haloperidol use. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for eligibility: 1. Age ≥ 18 years 2. Admitted to one of six participating ICUs of the EuRIDICE trial.
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 |
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E.4 | Principal exclusion criteria |
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 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. 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Delirium- and coma free days at ICU |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 14 days after randomisation |
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E.5.2 | Secondary end point(s) |
• Time from randomisation to resolution of delirium into a wakeful, non-delirious state. • Cognitive outcomes in ICU survivors at 3 and 12 months after ICU admission (assessment by trained research nurses or MSc students neuropsychology is feasible) with a brief cognitive assessment battery of validated and repeatable measures of general cognition, memory, language, processing speed, attention and executive functioning and mood (Montreal Cognitive Assessment [MOCA], Rey Auditory Verbal Learning Test, Semantic fluency, Digit Span [WAIS-IV], Trailmaking tests A and B, Boston naming Test [short version], Hospital Anxiety and Depression Scale [HADS]). • Functional outcomes and quality of life in survivors at 3 and 12 months after admission (Short Form-36 [SF-36]). • Mortality rate at 28 days and one year after randomisation. • Time to “readiness for discharge from the ICU”, as is being recorded routinely by all participating hospitals by the treating physicians on a daily basis, as an alternative to length-of-ICU stay which may be determined by other factors (e.g. capacity at the ward) than clinical condition. • Adverse drug associated events (prolonged QTc by EKG, muscle rigidity and other associated movements disorders [Simpson Angus Scale] and ventricular arrhythmia’s including torsade de pointes). • Patient and family-member well-being and experiences associated with delirium during and after ICU stay, assessed after hospital discharge and at 3 months after randomisation. We have chosen the most appropriate tool after consultation of our patient perspective representatives and the Steering Committee associated with this trial. The tools for this category of secondary outcomes are added to Appendix 2 (including a Table with overview of timing of assessments), and include the ICU Memory Tool (ICU-MT [21]), Delirium Experience Questionnaire (DEQ [22]), Caregiver Strain Index (CSI [23]). • Posttraumatic stress syndrome (PTSS) in participants and family-members at 3 months after admission with the Impact of Event Scale – Revisited (IES-R). • Maximum ICU Mobility Scale (IMS [24]) during ICU stay (and day of max IMS). • Quality of sleep (Richards-Campbell Sleep Questionnaire [RCSQ] [25]) • Workload experienced by ICU nurses while caring for delirious patients (based on Delirium Experience Questionnaire (DEQ [22]). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During ICU admission, at discharge from hospital, after 28 days, 1 month, 3 months, 6 months and 12 months. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |