Haloperidol and Lorazepam for Delirium in Patients With Advanced Cancer

Phase 2

Active, not recruiting

Conditions: Advanced Cancers

Interventions: Drug: Placebo
Drug: Lorazepam
Drug: Haloperidol decanoate
Behavioral: Questionnaires

Registration Number: NCT01949662

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 93

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + Haloperidol	Haloperidol decanoate	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
Placebo + Haloperidol	Placebo	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
Placebo + Haloperidol	Questionnaires	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
Lorazepam + Haloperidol	Haloperidol decanoate	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
Lorazepam + Haloperidol	Questionnaires	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
Lorazepam + Haloperidol	Lorazepam	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

Primary Outcome Measures

Name	Time	Method
Change in Richmond Agitation-Sedation Scale Score (Baseline to 8 hr), Points	Baseline to 8 hours	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.
Absolute Richmond Agitation-Sedation Scale Score at 8 Hour, Points	8 hours	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.

Secondary Outcome Measures

Name	Time	Method
Change in Richmond Agitation-Sedation Scale Score From Baseline to 30 Min	Baseline to 30 minutes	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.
Number of Participants With Richmond Agitation-Sedation Scale Score >=1 Within 8 hr	Baseline to 8 hours	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.