Haloperidol and Lorazepam in Controlling Symptoms of Persistent Agitated Delirium in Patients With Advanced Cancer Undergoing Palliative Care

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03743649

Collaborator

National Cancer Institute (NCI) (NIH)

206

Enrollment

Locations

Arms

58.5

Anticipated Duration (Months)

68.7

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II/IIII trial studies how well haloperidol and lorazepam work in controlling symptoms of persistent agitated delirium in patients with cancer that has spread to other places in the body undergoing palliative care. Haloperidol and lorazepam may help in controlling symptoms of agitated delirium in patients with cancer and may lessen any distress that their caregivers may be experiencing.

Condition or Disease	Intervention/Treatment	Phase
Delirium Locally Advanced Malignant Neoplasm Metastatic Malignant Neoplasm Recurrent Malignant Neoplasm	Drug: Haloperidol Drug: Lorazepam Other: Placebo Other: Quality-of-Life Assessment Other: Questionnaire Administration	Phase 2/Phase 3

Detailed Description

PRIMARY OBJECTIVES:

To compare the effect of neuroleptic dose escalation, benzodiazepine rotation, combination therapy, and neuroleptic withdrawal on the change in the Richmond Agitation Sedation Scale (RASS) score over 24 hours in patients admitted to an acute palliative care unit (APCU) who do not respond to low-dose haloperidol.

SECONDARY OBJECTIVES:

To compare the effects of neuroleptic dose escalation, benzodiazepine rotation, combination therapy, and neuroleptic withdrawal on (1) rescue medication use; (2) the proportion of patients in the target RASS range (defined as RASS between -2 and 0) as well as the proportion of patients achieving treatment response (defined as RASS reduction of >= 1.5 points); (3) perceived comfort as assessed by caregivers and bedside nurses; (4) delirium-related distress in caregivers and nurses (Delirium Experience Questionnaire); (5) achievement of the proxy comfort goal; (6) symptom expression (Edmonton Symptom Assessment Scale [ESAS]); (7) delirium severity (Memorial Delirium Assessment Scale [MDAS]); (8) adverse effects; and (9) quality of end-of-life care.
To identify novel predictive markers of response to haloperidol and lorazepam.

OUTLINE: Patients are randomized to 1 of 4 groups.

GROUP I: Patients receive haloperidol intravenously (IV) over 3-15 minutes every 4 hours and then every hour as needed and placebo IV every 4 hours and then every hour as needed until discharge from palliative care unit.

GROUP II: Patients receive lorazepam IV over 3-15 minutes every 4 hours and then every hour as needed and placebo IV every 4 hours and then every hour as needed until discharge from palliative care unit.

GROUP III: Patients receive haloperidol IV over 3-15 minutes every 4 hours and then every hour as needed and lorazepam IV over 3-15 minutes every 4 hours and then every hour as needed until discharge from palliative care unit.

GROUP IV: Patients receive two different placebos IV every 4 hours. Patients then receive placebo IV and lorazepam IV over 3-15 minutes every hour as needed until discharge from palliative care unit.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

206 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Supportive Care

Official Title:

Strategies for Persistent Agitated Delirium in Palliative Care

Actual Study Start Date :

Jul 17, 2019

Anticipated Primary Completion Date :

May 31, 2024

Anticipated Study Completion Date :

May 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group I (haloperidol, placebo) Patients receive haloperidol IV over 3-15 minutes every 4 hours and then every hour as needed and placebo IV every 4 hours and then every hour as needed until discharge from palliative care unit.	Drug: Haloperidol Given IV Other Names: Haldol McN-JR-1625 R 1625 R-1625 Other: Placebo Given IV Other Names: placebo therapy PLCB sham therapy Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies
Experimental: Group II (lorazepam, placebo) Patients receive lorazepam IV over 3-15 minutes every 4 hours and then every hour as needed and placebo IV every 4 hours and then every hour as needed until discharge from palliative care unit.	Drug: Lorazepam Given IV Other Names: Ativan Other: Placebo Given IV Other Names: placebo therapy PLCB sham therapy Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies
Experimental: Group III (haloperidol, lorazepam) Patients receive haloperidol IV over 3-15 minutes every 4 hours and then every hour as needed and lorazepam IV over 3-15 minutes every 4 hours and then every hour as needed until discharge from palliative care unit.	Drug: Haloperidol Given IV Other Names: Haldol McN-JR-1625 R 1625 R-1625 Drug: Lorazepam Given IV Other Names: Ativan Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies
Experimental: Group IV (placebo, lorazepam) Patients receive two different placebos IV every 4 hours. Patients then receive placebo IV and lorazepam IV over 3-15 minutes every hour as needed until discharge from palliative care unit.	Drug: Lorazepam Given IV Other Names: Ativan Other: Placebo Given IV Other Names: placebo therapy PLCB sham therapy Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies

Outcome Measures

Primary Outcome Measures

Change in Richmond Agitation Sedation Scale (RASS) score in patients admitted to an acute palliative care unit (APCU) [Baseline to 24 hours]
The effect of neuroleptic dose escalation, benzodiazepine rotation, combination therapy, and neuroleptic withdrawal will be compared on the change in the RASS score over 24 hours in patients admitted to an APCU who do not respond to low-dose haloperidol.(RASS between -2 and 0) Will use 2-sided t-tests for four pre-specified paired comparisons, if the required assumptions for this model are met. Non-parametric methods such as Wilcoxon rank-sum test may be used if any assumptions are violated.

Secondary Outcome Measures

Rescue medication use [At 24 hours]
Will conduct Bonferroni adjustment for the number of rescue doses. Will perform a comparison among the four arms using analysis of variance (ANOVA), followed by selected pairwise t-test comparisons, or the Kruskal-Wallis test followed by pairwise Wilcoxon rank-sum tests if the data violate assumptions for ANOVA. Will also compare these outcomes longitudinally using linear mixed models, with treatment as a between-patient factor and time as a within-subject factor. Appropriate transformations will be used as needed to satisfy model assumptions.
Proportion of patients in the target RASS range (defined as RASS between -2 and 0) as well as the proportion of patients achieving treatment response (defined as RASS reduction of >= 1.5 points) [At 24 hours]
Will compare the proportions across all four treatment groups using a chi-squared test, followed by selected pairwise chi-squared tests. We will also compare these outcomes longitudinally and include all data after treatment administration using generalized linear mixed models, with treatment as a between-patient factor and time as a within-subject factor.
Perceived comfort as assessed by caregivers and bedside nurses questionnaire [At 24 hours]
Will be used for patients with caregivers or nurses listing "agree" or "strongly agree" for patient comfort, proportion of patients with at least 2 on the Udvalg for Kliniske Undersogelser (UKU) scale, and proportion of patients with caregivers listing "excellent" quality of end-of-life care)
Delirium-related distress in caregivers and nurses assessed using Delirium Experience Questionnaire [At 24 hours]
Examines both the recalled frequency of 6 delirium symptoms and associated distress in the rater: disorientation to time and place, visual/tactile/auditory hallucinations, delusional thoughts, and psychomotor agitation. It will be administered to family caregivers and nurses daily. The score for recalled frequency ranges between 0 and 4, where 0=not present, 1=a little of the time, 2=some of the time, 3=good part of the time, and 4=most or all of the time. The score for distress in the rater related to each delirium symptom also ranges from 0 to 4, where 0=no distress, 1=a little, 2=a fair amount, 3=very much, and 4=extremely distressed. This assessment will be administered to the blinded caregivers and bedside nurses daily.
Proxy comfort goal level [Up to 24 hours]
The achievement of the proxy comfort goal will be assessed.
Symptom expression assessed using Edmonton Symptom Assessment Scale [At 24 hours]
Validated and widely used in different clinical settings, including the APCU. It assesses the average symptom intensity of 10 symptoms (pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and feeling of well-being) over the past 24 hours using an 11-point numeric rating scale, ranging from 0 (none) to 10 (worst). Because all patients will be delirious, caregivers will be asked to provide their proxy rating of ESAS daily.
Delirium severity assessed using Memorial Delirium Assessment Scale [At 24 hours]
Will perform a comparison among the four arms using ANOVA, followed by selected pairwise t-test comparisons, or the Kruskal-Wallis test followed by pairwise Wilcoxon rank-sum tests if the data violate assumptions for ANOVA. Will also compare these outcomes longitudinally using linear mixed models, with treatment as a between-patient factor and time as a within-subject factor. Appropriate transformations will be used as needed to satisfy model assumptions.
Incidence of adverse events [Up to 24 hours]
Quality of end-of-life care: questionnaire [4-8 weeks]
Will phone the bereaved caregivers who were most involved in the patient's care within 4-8 weeks of the patient's death to assess the patient's perceived quality of care and quality of life at the end-of-life, on the basis of questions previously used in the Coping with Cancer Study. Specifically, will ask caregivers, "Overall, how would you rate the care (the patient) received at the palliative care unit? Would you say it was excellent, very good, good, fair, or poor?" and "In your opinion, how would you rate the overall quality of (the patient)'s death or last week of life?" using a numeric rating scale from 0 (worst possible) to 10 (best possible). Will also ask them 2 questions related to control of agitation, adapted from the Quality of Death and Dying Questionnaire.
To identify novel predictive markers of response to haloperidol and lorazepam. [Up to 24 hours]
In each of the groups, will identify independent factors that are predictive of response (i.e. RASS reduction of >= 1.5 points) to treatment using multivariable logistic regression analysis. Will assess the predictive value of plasma biomarkers (i.e. IL-6, IL-8, IL-10, and S100B) in the subset of patients.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

PATIENTS: Diagnosis of advanced cancer (defined as locally advanced, metastatic recurrent, or incurable disease)
PATIENTS: Admitted to the acute palliative care unit
PATIENTS: Delirium as per Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria
PATIENTS: Hyperactive or mixed delirium with RASS >= 1 in the past 24 hours (h) despite efforts to treat potential underlying causes
PATIENTS: On scheduled haloperidol for delirium (=< 8 mg in the past 24 h) or required

=4 mg of rescue haloperidol for agitation in the past 24 h

CAREGIVERS: Patient's spouse, adult child, sibling, parent, other relative, or significant other (partner as defined by patient)

Exclusion Criteria:

PATIENTS: History of myasthenia gravis, acute narrow angle glaucoma, or hepatic encephalopathy
PATIENTS: History of neuroleptic malignant syndrome or active seizure disorder (with seizure episode within the past week)
PATIENTS: History of Parkinson's disease, Alzheimer's or Lewy body dementia
PATIENTS: History of prolonged corrected QT (QTc) or corrected QT interval by Fredericia (QTcF) interval (> 500ms) if documented by electrocardiogram (ECG) within the past month
PATIENTS: History of hypersensitivity to haloperidol or lorazepam
PATIENTS: On scheduled lorazepam within the past 48 hours

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030
2	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
3	Hosptial de Cancer de Barretos	Barretos	Sao Paulo	Brazil	14784