Haloperidol and Lorazepam for Delirium in Patients With Advanced Cancer

A Preliminary Double-Blind Randomized Controlled Trial of Haloperidol and Lorazepam for Delirium in Patients With Advanced Cancer Admitted to a Palliative Care Unit

This randomized phase II trial studies how well haloperidol with or without lorazepam works in reducing confusion, disorientation, and inability to think or remember clearly (delirium) in patients with cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Palliative therapy with haloperidol and lorazepam may reduce symptoms of delirium and help patients with advanced cancer live more comfortably. It is not yet known whether lorazepam may be an effective treatment for delirium when given with haloperidol.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Cancers
• Intervention / Treatment: Drug: Lorazepam; Drug: Haloperidol decanoate; Behavioral: Questionnaires; Drug: Placebo

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the effect of single dose lorazepam and placebo as an adjuvant to haloperidol on the intensity of agitation (Richmond Agitation Sedation Scale) over 8 hours.

II. To assess the within-arm effect of single-dose lorazepam or placebo, as an adjuvant agent with haloperidol, on agitation intensity (Richmond Agitation Sedation Scale) over 8 hours in patients admitted to an acute palliative care unit.

SECONDARY OBJECTIVES:

I. To compare the effect of single dose lorazepam and placebo as an adjuvant to haloperidol on (1) delirium related distress in nurses and caregivers, (2) delirium duration, (3) need for rescue doses of neuroleptics, (4) delirium recall, (5) symptom expression (Edmonton Symptom Assessment Scale), (6) communicative capacity, (7) adverse effects, (8) discharge outcomes, and (9) survival in cancer patients.

II. To evaluate proportion of patients who consent and are randomized to study however drop out before being treated or before finishing 8-hour Richmond Agitation Sedation Scale (RASS) assessment; and the reasons of drop-outs will be documented and reported.

III. To explore the changes in biomarker levels in saliva samples (salivary cortisol, cholinesterase, C-reactive protein, interleukin-1 beta, -6, and -10) over time and in association with delirium severity.

IV. To examine the inter-rater reliability of RASS in the Acute Palliative Care Unit (APCU) setting between the bedside nurse and the research nurse at the time of study enrollment.

V. To conduct exploratory analyses on RASS as an outcome. VI. To examine the association among rescue medication use, RASS and perceived comfort by the nurses and caregivers.

VII. To examine the proportion of patients enrolled onto the delirium trial who achieved control of agitation and did not require the randomized study medication.

VIII. To identify patient factors associated with control of agitated delirium.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive lorazepam intravenously (IV) over 1-2 minutes and haloperidol IV every 6 hours or every 1 hour if needed.

ARM II: Patients receive placebo IV over 1-2 minutes and haloperidol IV every 6 hours or every 1 hour if needed.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• PATIENTS:
• Diagnosis of advanced cancer (defined as locally advanced, metastatic, recurrent, or incurable disease)
• Admitted to Acute Palliative Care Unit (APCU)
• Delirium as per the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV- TR) criteria
• Hyperactive/mixed delirium with RASS >= 2 in the last 24 hours
• On scheduled haloperidol of =< 8 mg in the last 24 hours
• Legally authorized representative consent
• FAMILY CAREGIVERS:
• Patient's spouse, adult child, sibling, parent, other relative, or significant other (defined by the patient as a partner)
• Age 18 or older
• At the patient's bedside at least 4 hours each day during patient delirium episode
• Patients and family caregivers able to communicate in English or Spanish

Exclusion Criteria:

• PATIENTS
• History of myasthenia gravis or acute narrow angle glaucoma
• History of neuroleptic malignant syndrome
• History of Parkinson's disease or dementia
• Uncontrolled seizure disorder
• History of hypersensitivity to haloperidol or benzodiazepine
• On regular doses of benzodiazepine or chlorpromazine within the past 48 hours
• Previously documented and persistent corrected QT (QTc) prolongation (> 500 ms)
• Heart failure exacerbation at the time of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lorazepam + Haloperidol; Participants given a single dose of lorazepam 3 mg by vein, in addition to a standardized dose of haloperidol 8 mg/day by vein, while in palliative care unit. Questionnaire completion at baseline, and every day while participant is in the palliative care unit. These questions will take about 20 minutes to complete	Drug: Lorazepam; 3 mg by vein one time only.; Drug: Haloperidol decanoate; 8 mg/day by vein.; Behavioral: Questionnaires; Questionnaire completion at baseline, and every day while participant is in the palliative care unit. These questions will take about 20 minutes to complete.; Other Names: Surveys
Active Comparator: Placebo + Haloperidol; Participants receive placebo, preservative free 0.9% normal saline, by vein plus a standardized dose of haloperidol 8 mg/day by vein, while in palliative care unit. Questionnaire completion at baseline, and every day while participant is in the palliative care unit. These questions will take about 20 minutes to complete	Drug: Haloperidol decanoate; 8 mg/day by vein.; Behavioral: Questionnaires; Questionnaire completion at baseline, and every day while participant is in the palliative care unit. These questions will take about 20 minutes to complete.; Other Names: Surveys; Drug: Placebo; Placebo consisting of preservative free 0.9% normal saline given one time by vein.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Richmond Agitation-Sedation Scale Score (Baseline to 8 hr), Points	The primary outcome was change in Richmond Agitation-Sedation Scale score from baseline to 8 hours after treatment administration. Richmond Agitation-Sedation Score ranged from -5 (unarousable) to +4 (very agitated) , where 0 denotes a calm and alert patient.	Baseline to 8 hours
Absolute Richmond Agitation-Sedation Scale Score at 8 Hour, Points	Absolute score of Richmond Agitation-Sedation Scale at 8 hr, points. Richmond Agitation-Sedation Score ranged from -5 (unarousable) to +4 (very agitated) , where 0 denotes a calm and alert patient.	8 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Richmond Agitation-Sedation Scale Score From Baseline to 30 Min	Change in Richmond Agitation-Sedation Scale score from baseline to 30 min. Richmond Agitation-Sedation Score ranged from -5 (unarousable) to +4 (very agitated) , where 0 denotes a calm and alert patient.	Baseline to 30 minutes
Number of Participants With Richmond Agitation-Sedation Scale Score >=1 Within 8 hr	Number of participants with Richmond Agitation-Sedation Scale score >=1 within 8 hr. Richmond Agitation-Sedation Score ranged from -5 (unarousable) to +4 (very agitated) , where 0 denotes a calm and alert patient.	Baseline to 8 hours

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: David Hui, MD, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• 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.

Helpful Links

• University of Texas MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Actual): August 26, 2016
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: September 20, 2013
• First Submitted That Met QC Criteria: September 23, 2013
• First Posted (Estimated): September 24, 2013

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Questionnaires; Surveys; Delirium; Advanced Malignant Solid Neoplasm; Hematopoietic and Lymphoid Cell Neoplasm; Locally Advanced Malignant Solid Neoplasm; Malignant Solid Neoplasm; Neurotoxicity Syndrome; Acute palliative care unit
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Neoplasms; Delirium; 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; Dopamine Agents; Dopamine Antagonists; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Anti-Dyskinesia Agents; Haloperidol; Haloperidol decanoate; Lorazepam
• Other Study ID Numbers: 2013-0345; NCI-2013-02351 (Registry Identifier: NCI CTRP); 1R21CA186000-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No