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

1. 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.

2. 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.

3. 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.

4. 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.

Study Overview

• Status: Recruiting
• Conditions: Advanced Cancer; Hyperactive Delirium; Olanzapine; Haloperidol; End-stage Organ Disease
• Intervention / Treatment: Drug: Haldol 2mg/ml oral solution; Drug: Olanzapine Actavis 5mg orodispersible tablet

Detailed Description

(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.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mervyn Koh; Phone Number: +6597678996; Email: mervyn_koh@ttsh.com.sg
• Study Contact Backup: Name: Allyn Hum; Phone Number: +6581263205; Email: allyn_hum@ttsh.com.sg

Study Locations

• Singapore
  • Singapore, Singapore, 308433
    • Recruiting
    • Tan Tock Seng Hospital
    • Contact: Mervyn Koh; Phone Number: +6597678996; Email: mervyn_koh@ttsh.com.sg
  • Singapore, Singapore, 308436
    • Recruiting
    • Dover Park Hospice
    • Contact: Mervyn Koh; Phone Number: +6597678996; Email: mervyn_koh@ttsh.com.sg
  • Singapore, Singapore, 529895
    • Recruiting
    • St. Andrew's Community Hospital
    • Contact: Siew Chin Chia; Email: siew_chin_chia@ttsh.com.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with advanced cancer or end-stage organ disease
2. Age ≥ 21 years old

3. 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
4. Able to consume medications orally
5. Prognosis > 48 hrs (Clinician Estimate)

Exclusion Criteria:

1. Parkinson's Disease or Vascular Parkinsonism
2. Patient with dementia
3. Chronic Schizophrenia on regular Anti-psychotic medications
4. Taking any regular Benzodiazepines* or any Anti-psychotic** medications
5. Known allergy to Haloperidol or Olanzapine
6. History of Substance Abuse
7. Known Prolonged corrected QT interval (QTc) Syndrome (In Patient's Medical History)
8. Prognosis < 48 hours (Clinician's Estimate)
9. Unable to consume oral medications
10. Richmond Agitation and Sedation Scale (RASS) Score +4 (Too agitated and will require Parenteral Anti-psychotics and/or Benzodiazepines)
11. Pregnancy * e.g. Lorazepam, Alprazolam, Clonazepam, Midazolam **e.g. Haloperidol, Risperidone, Quetiapine, Olanzapine

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Haloperidol Arm; Haldol 2mg/ml oral solution	Drug: Haldol 2mg/ml oral solution; 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).
Active Comparator: Olanzapine Arm; Olanzapine Actavis 5mg orodispersible tablet	Drug: Olanzapine Actavis 5mg orodispersible tablet; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Tan Tock Seng Hospital
• Investigators: Principal Investigator: Mervyn Koh, Tan Tock Seng Hospital

Publications and helpful links

General Publications

• Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16;354(11):1157-65. doi: 10.1056/NEJMra052321. No abstract available. Erratum In: N Engl J Med. 2006 Apr 13;354(15):1655.
• Boettger S, Friedlander M, Breitbart W, Passik S. Aripiprazole and haloperidol in the treatment of delirium. Aust N Z J Psychiatry. 2011 Jun;45(6):477-82. doi: 10.3109/00048674.2011.543411.
• Zipser CM, Knoepfel S, Hayoz P, Schubert M, Ernst J, von Kanel R, Boettger S. Clinical management of delirium: The response depends on the subtypes. An observational cohort study in 602 patients. Palliat Support Care. 2020 Feb;18(1):4-11. doi: 10.1017/S1478951519000609.
• Hosie A, Davidson PM, Agar M, Sanderson CR, Phillips J. Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: a systematic review. Palliat Med. 2013 Jun;27(6):486-98. doi: 10.1177/0269216312457214. Epub 2012 Sep 17.
• Watt CL, Momoli F, Ansari MT, Sikora L, Bush SH, Hosie A, Kabir M, Rosenberg E, Kanji S, Lawlor PG. The incidence and prevalence of delirium across palliative care settings: A systematic review. Palliat Med. 2019 Sep;33(8):865-877. doi: 10.1177/0269216319854944. Epub 2019 Jun 11.
• Hui D. Delirium in the palliative care setting: "Sorting" out the confusion. Palliat Med. 2019 Sep;33(8):863-864. doi: 10.1177/0269216319861896. No abstract available.
• Skelton L, Guo P. Evaluating the effects of the pharmacological and nonpharmacological interventions to manage delirium symptoms in palliative care patients: systematic review. Curr Opin Support Palliat Care. 2019 Dec;13(4):384-391. doi: 10.1097/SPC.0000000000000458.
• Hui D, Frisbee-Hume S, Wilson A, Dibaj SS, Nguyen T, De La Cruz M, Walker P, Zhukovsky DS, Delgado-Guay M, Vidal M, Epner D, Reddy A, Tanco K, Williams J, Hall S, Liu D, Hess K, Amin S, Breitbart W, Bruera E. Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. JAMA. 2017 Sep 19;318(11):1047-1056. doi: 10.1001/jama.2017.11468.
• Breitbart W, Alici Y. Agitation and delirium at the end of life: "We couldn't manage him". JAMA. 2008 Dec 24;300(24):2898-910, E1. doi: 10.1001/jama.2008.885.
• Agar MR, Lawlor PG, Quinn S, Draper B, Caplan GA, Rowett D, Sanderson C, Hardy J, Le B, Eckermann S, McCaffrey N, Devilee L, Fazekas B, Hill M, Currow DC. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial. JAMA Intern Med. 2017 Jan 1;177(1):34-42. doi: 10.1001/jamainternmed.2016.7491. Erratum In: JAMA Intern Med. 2017 Feb 1;177(2):293.
• Lin CJ, Sun FJ, Fang CK. An open trial comparing haloperidol with olanzapine for the treatment of delirium in palliative and hospice center cancer patients. J Internal Med Taiwan 2008; 19:346-354.
• Bush SH, Grassau PA, Yarmo MN, Zhang T, Zinkie SJ, Pereira JL. The Richmond Agitation-Sedation Scale modified for palliative care inpatients (RASS-PAL): a pilot study exploring validity and feasibility in clinical practice. BMC Palliat Care. 2014 Mar 31;13(1):17. doi: 10.1186/1472-684X-13-17.

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 30, 2021
• First Submitted That Met QC Criteria: April 5, 2021
• First Posted (Actual): April 6, 2021

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Dyskinesias; Psychomotor Disorders; Aberrant Motor Behavior in Dementia; Delirium; Psychomotor Agitation; Hyperkinesis; 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; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Olanzapine
• Other Study ID Numbers: PalC-RG-20/P001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There are no plans to make individual participant data available to other researchers.

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