Managing Agitated Delirium With Neuroleptics and Anti-Epileptics as a Neuroleptic Sparing Strategy

To examine the effects of haloperidol, chlorpromazine, valproic acid and placebo, in conjunction with standardized non-pharmacologic interventions, in the first line treatment of agitated delirium in hospitalized patients with cancer. This double-blind, randomized clinical trial aims to provide evidence on various therapeutic options for palliating delirium, thereby reducing delirium-related distress and ultimately alleviating suffering.

Study Overview

• Status: Recruiting
• Conditions: Delirium; Epileptics; Neuroleptics
• Intervention / Treatment: Drug: Haloperidol; Drug: Chlorpromazine; Drug: Valproate; Drug: Placebo

Detailed Description

Objectives:

Primary objective:

Compare the effect of scheduled haloperidol, chlorpromazine, valproate and placebo (non-pharmacological interventions alone) on the frequency of breakthrough restlessness over 72 hours in patients with agitated delirium seen by the palliative care consultation team. Our working hypothesis is that haloperidol, chlorpromazine, and valproate will lead to fewer episodes of breakthrough restlessness than placebo.

Secondary Objective #1:

Compare the effects of scheduled haloperidol, chlorpromazine, valproate and placebo on (1) RASS-PAL, (2) need for dose escalation, (3) perceived comfort by caregivers and bedside nurses, (4) delirium severity (Memorial Delirium Assessment Scale), (5) delirium-related distress in caregivers and nurses (Delirium Experience Questionnaire), (6) delirium recall in patients (Delirium Recall Questionnaire), (7) symptom expression (Edmonton Symptom Assessment Scale), (8) adverse effects, and (9) survival. Our working hypothesis is that haloperidol, chlorpromazine, and valproate are superior to placebo (non-pharmacologic interventions alone) in improving delirium-related outcomes.

Secondary Objective #2:

Estimate the efficacy of non-pharmacologic interventions alone on breakthrough restlessness. Our working hypothesis is that patients in the placebo group will require fewer breakthrough doses in the 72 hours after implementation of non-pharmacological interventions

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: David Hui, MD; Phone Number: (713) 792-6258; Email: dhui@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: David Hui, MD; Phone Number: 713-792-6258; Email: dhui@mdanderson.org
      • Principal Investigator: David Hui, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. [Patients] Diagnosis of advanced cancer (defined as locally advanced, metastatic recurrent, or incurable disease)
2. [Patients] Seen by palliative care inpatient consultation team
3. [Patients] Delirium as per DSM-5 criteria
4. [Patients] Hyperactive or mixed delirium with either a rescue medication order or any non-pharmacologic measures (e.g. sitter, restraints) for agitation, restlessness, or delirium
5. [Patients] Age 18 years or older
6. [Patients] Permission from clinician from primary team to enroll
7. [Family Caregivers] Patient's spouse, adult child, sibling, parent, other relative, or significant other (defined by the patient as a partner)
8. [Family Caregivers] Age 18 years or older

Exclusion Criteria:

1. [Patients] On scheduled haloperidol >4 mg/d, chlorpromazine >100 mg/d, or valproate >750 mg/d
2. [Patients] History of myasthenia gravis, acute narrow-angle glaucoma, or hepatic encephalopathy as documented in chart
3. [Patients] Hepatic dysfunction (unresolved AST or ALT >2.5x ULN, bilirubin >1.5x ULN or INR >1.5 within past month)
4. [Patients] History of neuroleptic malignant syndrome as documented in chart
5. [Patients] Active seizure disorder within past month as documented in chart
6. [Patients] History of Parkinson's disease or dementia as documented in chart
7. [Patients] History of prolonged QTc interval (>500 ms) if documented by most recent ECG within the past month
8. [Patients] Hypersensitivity to haloperidol, chlorpromazine, or valproate as documented in chart
9. [Patients] Pancreatitis within past month as documented in chart
10. [Patients] Currently on lamotrigine, phenobarbital, or carbamazepine
11. [Patients] Physical signs of impending death such as respiration with mandibular movement and death rattle
12. [Patients] Pregnancy as documented in chart
13. [Patients] Active COVID-19 infection as documented in chart

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Participants will receive haloperidol by vein every 12 hours (or more often, as needed).	Drug: Haloperidol; Given by Vein (IV)
Experimental: Group 2; Participants will receive chlorpromazine by vein every 12 hours (or more often, as needed).	Drug: Chlorpromazine; Given by Vein (IV); Other Names: Chlorpromazine hydrochloride, Thorazine®
Experimental: Group 3; Participants will receive valproate by vein every 12 hours.	Drug: Valproate; Given by Vein (IV); Other Names: Depakene; Valproate Acid
Experimental: Group 4; Participants will receive placebo every by vein every 12 hours.	Drug: Placebo; Given by Vein (IV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Edmonton Symptom Assessment Scale Questionnaire	Edmonton Symptom Assessment Scale (ESAS)-score scale ranges from (0-10) No pain-0/Worse Possible Pain 10 (0-10)	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Cancer Prevention Research Institute of Texas
• Investigators: Principal Investigator: David Hui, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2022
• Primary Completion (Estimated): February 2, 2027
• Study Completion (Estimated): February 2, 2027

Study Registration Dates

• First Submitted: June 20, 2022
• First Submitted That Met QC Criteria: June 20, 2022
• First Posted (Actual): June 24, 2022

Study Record Updates

• Last Update Posted (Estimated): November 18, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Delirium; Epilepsy; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Pentanoic Acids; Valerates; Fatty Acids, Volatile; Heterocyclic Compounds, 3-Ring; Butyrophenones; Ketones; Phenothiazines; Valproic Acid; Chlorpromazine; Haloperidol
• Other Study ID Numbers: 2022-0172; NCI-2022-05252 (Other Identifier: NCI-CTRP Clinical Trial Reporting Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No