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

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ClinicalTrials.gov Identifier: NCT03743649
Recruitment Status : Recruiting
First Posted : November 16, 2018
Last Update Posted : July 3, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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
Caregiver 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:

I. 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:

I. 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.

II. 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 as needed and placebo IV every 4 hours and as needed until discharge from palliative care unit.

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

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

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


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Study Type : Interventional  (Clinical Trial)
Estimated 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 : May 31, 2019
Estimated Primary Completion Date : May 31, 2023
Estimated Study Completion Date : May 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group I (haloperidol, placebo)
Patients receive haloperidol IV over 3-15 minutes every 4 hours and as needed and placebo IV every 4 hours and 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 Name: 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 as needed and placebo IV every 4 hours and as needed until discharge from palliative care unit.
Drug: Lorazepam
Given IV
Other Name: Ativan

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: 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 as needed and lorazepam IV over 3-15 minutes every 4 hours and 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 Name: Ativan

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Experimental: Group IV (placebo, lorazepam)
Patients receive placebo IV every 4 hours and lorazepam IV over 3-15 minutes as needed until discharge from palliative care unit.
Drug: Lorazepam
Given IV
Other Name: Ativan

Other: Placebo
Given IV
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Change in Richmond Agitation Sedation Scale (RASS) score in patients admitted to an acute palliative care unit (APCU) [ Time Frame: 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. 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 :
  1. Rescue medication use [ Time Frame: 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.

  2. 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) [ Time Frame: 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.

  3. Perceived comfort as assessed by caregivers and bedside nurses [ Time Frame: At 24 hours ]
  4. Delirium-related distress in caregivers and nurses assessed using Delirium Experience Questionnaire [ Time Frame: 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.

  5. Proxy comfort goal [ Time Frame: Up to 24 hours ]
  6. Symptom expression assessed using Edmonton Symptom Assessment Scale [ Time Frame: 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.

  7. Delirium severity assessed using Memorial Delirium Assessment Scale [ Time Frame: 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.

  8. Incidence of adverse events [ Time Frame: Up to 24 hours ]
  9. Quality of end-of-life care [ Time Frame: 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. Survival distributions will be estimated using the Kaplan-Meier method and compared across all four treatment groups using Cox proportional hazards regression analysis, including selected pairwise treatment comparisons. Survival plots, probabilities at selected times with 95% confidence intervals, and median survival times with 95% confidence intervals will be computed for each treatment arm.

  10. Novel predictive markers of response [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03743649


Contacts
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Contact: David Hui 713-792-6085 dhui@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: David Hui    713-792-6085      
Principal Investigator: David Hui         
United States, Virginia
Virginia Commonwealth University/Massey Cancer Center Not yet recruiting
Richmond, Virginia, United States, 23298
Contact: Egidio Del Fabbro    804-628-0617    Egidio.DelFabbro@vcuhealth.org   
Principal Investigator: Egidio Del Fabbro         
Brazil
Hosptial de Cancer de Barretos Not yet recruiting
Barretos, Sao Paulo, Brazil, 14784
Contact: Carlos E. Paiva    (17) 3321-660    caredupai@gmail.com   
Principal Investigator: Carlos E. Paiva         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: David Hui M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03743649     History of Changes
Other Study ID Numbers: 2018-0706
NCI-2018-02438 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0706 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
R01CA225701 ( U.S. NIH Grant/Contract )
First Posted: November 16, 2018    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Delirium
Recurrence
Neoplasms
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neurocognitive Disorders
Mental Disorders
Disease Attributes
Pathologic Processes
Lorazepam
Haloperidol
Haloperidol decanoate
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Anticonvulsants