HALO Trial: Haloperidol vs Olanzapine in Hyperactive Delirium in Palliative Care Patients; A Multi-Centre, Randomised-Controlled Trial

Study Overview
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Brief Summary
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Background and Clinical Need: Delirium is common at the end of life and is challenging to control. There is a clinical need to study the benefits of commonly used drugs like Haloperidol and Olanzapine in the management of hyperactive delirium in advanced cancer or end-stage organ disease patients in a scientifically robust manner. Aims/Hypotheses: The investigators aim to study the effectiveness of Haloperidol compared with Olanzapine in the management of hyperactive delirium in advanced cancer or end-stage organ disease patients receiving palliative care. The investigators hypothesise that Olanzapine is as effective as Haloperidol in the control of hyperactive delirium. Methods: The investigators will conduct a pragmatic, multi-centre, (hospital, inpatient hospice, community hospital) open-label randomised-controlled trial comparing the use of Haloperidol versus Olanzapine in advanced cancer or end-stage organ disease patients with hyperactive delirium. The primary outcome is the change in Richmond Agitation and Sedation Scale (RASS) scores among patients in each treatment group at 8 hours post-drug administration. The secondary outcome is the control of hyperactive delirium at 24, 48 and 72 hours using either Haloperidol or Olanzapine. The mean doses of Haloperidol and Olanzapine used as well as the volume of rescue Midazolam required as well as side-effects of the study medications, survival after enrolment into study will also be studied. Significance to palliative care The results of this study will advance the knowledge of delirium management worldwide with regards to the efficacy of Haloperidol and Olanzapine in managing hyperactive delirium in patients with advanced cancer or end-stage organ disease. Haloperidol is used traditionally in palliative care for managing delirium. However, as a conventional anti-psychotic, it does cause extra-pyramidal side-effects. Olanzapine, a newer atypical anti-psychotic with a more favourable side-effect profile is being used increasingly in the control of delirium. These 2 commonly used drugs have never been compared head to head in a randomised-controlled, multi-centre study.

Detailed Description
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(A) Background & Clinical Need Delirium is commonly encountered in palliative care with a prevalence of between 26-74% and rising to as high as 88% nearer the end of life (2). It negatively impacts patient care and leads to greater morbidity and mortality (3). There are 3 sub-types of delirium - hyperactive, mixed and hypoactive (4) with majority of well-designed studies in palliative care focusing on the management of delirium as a whole (5). However, recently published literature suggests that these delirium subtypes appear to have different trajectories and are also generally treated differently (6). Overall, the management of delirium in palliative care remains controversial. Agar had shown in a randomised controlled trial that supportive care may be superior to the use of anti-psychotics, even though the patients in Agar's study were only 'mildly' delirious and the overall doses of anti-psychotics used was lower than compared to common practice (9). Other studies have shown the benefits of anti-psychotics like haloperidol, olanzapine and aripiprazole in the management of delirium (10,11). Hui et al was the only study which looked at the management of hyperactive delirium in the palliative care setting (7). Patients with hyperactive delirium exhibit restlessness, agitation and even aggression towards their loved ones and to healthcare providers caring for them (8). To date, there have not been any multi-centre, randomised-controlled trial which has addressed the effectiveness of oral Haloperidol vs Olanzapine in the management of hyperactive delirium in the palliative care setting. (B) Specific Aims The investigators aim to study the effectiveness of Olanzapine vs Haloperidol in the management of hyperactive delirium in patients with advanced cancer or end-stage organ disease in 3 different settings. The primary outcome is the change in Richmond Agitation and Sedation Scale (RASS) scores among patients in each treatment group at 8 hours after the administration of Haloperidol or Olanzapine as measured using the Richmond Agitation and Sedation Scale (RASS). The secondary outcome is the change in Richmond Agitation and Sedation Scale (RASS) score at 24, 48 and 72 hours with the use of either Haloperidol or Olanzapine required. The mean doses of Haloperidol and Olanzapine used as well as the doses of rescue Midazolam required as well as side-effects of the study medications, survival after enrolment into study will also be studied. (C) Methods Study Design The investigators aim to conduct a multi-centre, randomised-controlled, open-label trial (Acute Hospital Palliative Care Unit, Palliative Care Unit in Community Hospital and Inpatient Hospice) comparing the use of haloperidol vs olanzapine in a 1:1 ratio in advanced cancer or end-stage organ disease patients with hyperactive delirium. Patients will be followed up for 3 days (72 hours) with regards to the response to study medications as well as other factors and outcomes as described below. Mortality data will also be collected. The study will be conducted in 3 different Palliative Care Centres in Singapore - 1. Tan Tock Seng Hospital Acute Palliative Care Unit, 2. Palliative Care Unit in St Andrews' Community Hospital and 3. Dover Park Hospice. This is to increase the pragmatic applicability and external validity in this study to different palliative care units in Singapore and internationally. Informed consent will be taken from the patient's legal representative according to the HBR Act as the patients recruited will be delirious and therefore will not able to provide informed consent adequately.

Official Title
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HALO Trial: Haloperidol vs Olanzapine in Hyperactive Delirium in Palliative Care Patients; A Multi-Centre, Randomised-Controlled Trial

Conditions
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Haloperidol, Advanced Cancer, Hyperactive Delirium, Olanzapine, End-stage Organ Disease

Intervention / Treatment
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* Drug: Haldol 2mg/ml oral solution
* Drug: Olanzapine Actavis 5mg orodispersible tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with advanced cancer or end-stage organ disease Age ≥ 21 years old Fulfil All Three Diagnosis of Delirium: Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for delirium Memorial Delirium Assessment Scale (MDAS)©1996 >/= 13 Richmond Agitation-Sedation Scale (RASS) Score +1 to +3 Able to consume medications orally Prognosis > 48 hrs (Clinician Estimate) Exclusion Criteria: Parkinson's Disease or Vascular Parkinsonism Patient with dementia Chronic Schizophrenia on regular Anti-psychotic medications Taking any regular Benzodiazepines* or any Anti-psychotic** medications Known allergy to Haloperidol or Olanzapine History of Substance Abuse Known Prolonged corrected QT interval (QTc) Syndrome (In Patient's Medical History) Prognosis < 48 hours (Clinician's Estimate) Unable to consume oral medications Richmond Agitation and Sedation Scale (RASS) Score +4 (Too agitated and will require Parenteral Anti-psychotics and/or Benzodiazepines) Pregnancy * e.g. Lorazepam, Alprazolam, Clonazepam, Midazolam **e.g. Haloperidol, Risperidone, Quetiapine, Olanzapine

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Haloperidol Arm<br>Haldol 2mg/ml oral solution | Drug: Haldol 2mg/ml oral solution<br>* Starting dose: 1mg Maximum Dose within 24 hours: 6mg Doses can be escalated every 2 hourly to the maximum doses allowed within 24 hours. If maximum dose of Haloperidol has been reached for the day (within 24 hours), rescue dose of Midazolam 2mg can be used (2mg Q2H PRN).<br>|
| Active Comparator: Olanzapine Arm<br>Olanzapine Actavis 5mg orodispersible tablet | Drug: Olanzapine Actavis 5mg orodispersible tablet<br>* Starting dose: 2.5mg Maximum Dose within 24 hours: 15mg Doses can be escalated every 2 hourly to the maximum doses allowed within 24 hours. If maximum dose of Olanzapine has been reached for the day (within 24 hours), rescue dose of Midazolam 2mg can be used (2mg Q2H PRN).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Richmond Agitation and Sedation Scale (RASS) score | The change in Richmond Agitation and Sedation Scale (RASS) score 8 hours after administration of either Haloperidol and Olanzapine. Minimum value is -5 which represents that the patient is in hypoactive delirium and is unarousable and maximum value is +4 with the higher score representing that the patient is in hyperactive delirium and is combative. The aim of the study is to reduce the hyperactive delirium to a score of 0 which represents patient is alert and calm. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparing Patient and Family's concurrence on state of delirium with of the Diagnosis of Delirium from Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for delirium. | There have not been any studies that looked at interviewing patients who are delirious about their acknowledgement and concurrence of their state of delirium. The investigators aim to interview patients by asking the patient 'Did you feel confused' and caregivers similarly by asking 'Do you feel that your loved one is Confused' as shown as an example below and compare this to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for delirium. Please ask the Patient the following question Do you feel that you are confused? Yes/Sometimes No Not Sure/ Unable to answer Please ask the Family member or Caregiver the following question Do you think the patient is confused? 1) Yes/Sometimes 2) No 3) Not sure/ Unable to answer | 72 hours | 
| Mean dose used of Haloperidol and Olanzapine | Mean doses of Haloperidol and Olanzapine used at 8hours / D1 / D2 / D3 from the first time-point that the study medication is administered to the patients | 72 hours | 
| Mean Time to control of Hyperactive Delirium | Mean Time to control of Hyperactive Delirium | 72 hours | 
| Rescue Psychotropic (Mean Doses): Midazolam | Rescue Psychotropic (Mean Doses): Midazolam | 72 hours | 
| Side-effects of Study Medications | Side-effects of Study Medications | 72 hours | 
| Survival time in days | Survival time in days | 72 hours | 
| Edmonton Symptom Assessment Score revised (ESAS-r) | Edmonton Symptom Assessment Score revised (ESAS-r) - At the point of recruitment Minimum value for the scale is 0 and maximum value for the scale is 10 with the higher value representing worse outcome. | 1 hour | 
| Memorial Delirium Assessment Score (MDAS) | Memorial Delirium Assessment Score (MDAS) - At the point of recruitment and after 72 hours It is a scale comprising of 10 items with scores of 0-3 for each question. Add up the score for all 10 questions and scores with more than or equal to 13 point indicates delirium. | 72 hours | 
| Richmond Agitation and Sedation Scale (RASS) score | Richmond Agitation and Sedation Scale (RASS) score: 8hours / 24hours (Day 1) / 48 hours (Day 2) / 72 hours (Day 3) Minimum value is -5 which represents that the patient is in hypoactive delirium and is unarousable and maximum value is +4 with the higher score representing that the patient is in hyperactive delirium and is combative. The aim of the study is to reduce the hyperactive delirium to a score of 0 which represents patient is alert and calm. | 72 hours | 
| Caregiver and Nurses Perception on the control of hyperactive delirium | Caregiver and Nurses Perception on the control of hyperactive delirium (5-point Likert Scale). Kindly refer to the example of the question below. The patient is less agitated as compared to 72 hours ago? (Clinician/Nurse): - Strongly Disagree - Disagree - Neutral - Agree - Strongly Agree The patient is less agitated as compared to 72 hours ago? (Family/Caregiver): - Strongly Disagree - Disagree - Neutral - Agree - Strongly Agree | 72 hours |