Trial Comparing Haloperidol, Quetiapine and Placebo in the Pharmacological Treatment of Delirium

Delirium Clinical Trial

— Haloquet  

Official title:

Randomized Controlled Trial Comparing Haloperidol, Quetiapine and Placebo in the Pharmacological Treatment of Delirium : The Haloquet Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01811459
• Other study ID #: CE12.189
• Status: Completed
• Phase: Phase 3
• First received: March 12, 2013
• Last updated: February 7, 2018
• Start date: February 2013
• Est. completion date: September 2016

Study information

• Verified date: July 2016
• Source: Centre hospitalier de l'Université de Montréal (CHUM)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Delirium is an important problem in critical care. Its prevalence often reaches 75% in intensive care patients. Its occurrence is associated with numerous complications and deleterious consequences such as death, longer stay, higher cost, and long-term cognitive impairment. Delirium treatment entails correcting its underlying causes and usually initiating a pharmacological intervention with an antipsychotic. Typical antipsychotics, particularly haloperidol, are commonly used to treat delirium although few placebo-controlled trials of pharmacological treatments for delirium have been conducted. Furthermore, appropriate doses for delirium treatment have yet to be established. In critical care, two pilot studies provided the first randomized, placebo-controlled evidence for the pharmacologic treatment of ICU delirium. One found that neither haloperidol nor ziprasidone significantly reduced the incidence or duration of delirium compared with placebo whereas the other one found that quetiapine added to as-needed haloperidol resulted in faster delirium resolution.

Objective:

The goal of this study is to determine the effectiveness of antipsychotics in regular dosage regimen (quetiapine group and haloperidol group) compared to as-needed haloperidol (placebo group) in the pharmacological treatment of delirium. We will conduct a three-arm randomized controlled trial to achieve this goal.

Materials and Methods:

During one year, 45 delirious patients from three intensive care units will be recruited and randomized into one of three groups. Randomization will be performed in blocks of 9 by the pharmacy department, using a random numbers table.

Patients will be continuously screened for delirium using the Intensive Care Delirium Screening Checklist (ICDSC) as part of routine care. A positive screening score (≥4) will warrant confirmation of delirium diagnosis by the treating physician. Treatment will begin according to randomization group, provided that informed consent has been obtained. Delirium status will be monitored during the episode using the Nursing Delirium Screening Scale (Nu-DESC). When the Nu-DESC monitoring will become negative for delirium (total score below 2), the resolution of the episode will be confirmed by the treating physician. A clinical evaluation by a psychiatrist will be performed within 24-48 hours of each of the two evaluations made by the treating physician (beginning and end of the delirium episode).

The treating physician will initiate twice-daily treatment at the first of five levels for each of the three groups: 1) 1 mg of intravenous (IV) haloperidol + oral (PO) placebo, 2) 50 mg of PO quetiapine + IV placebo, or 3) IV + PO placebo. Therapy will be titrated upwards on a daily basis by increments of 1) 1 mg of IV haloperidol or 2) 50 mg of PO quetiapine, or 3) IV + PO placebo every 12 hrs, respectively, if the subject received at least two doses of as-needed haloperidol in the previous 24 hrs. As-needed (PRN) doses of 2 mg of IV haloperidol q 30 minutes will be available to patients from all three groups and administered by nurses until symptoms associated with delirium resolve. In case of unsuccessful as-needed treatment, rescue (STAT) doses of 5 mg of IV haloperidol q 30 minutes will be available to patients from all three groups and will be administered by nurses if agreement is reached with the treating physician that the situation indeed calls for it. The treatment level of patients requiring a STAT dose will immediately be raised to the above level. The treatment will stop when one of the following occurs: (1) the subject is deemed by the treating physicians, based on their clinical judgment, to no longer demonstrate signs of delirium and, therefore, to no longer require scheduled therapy with an antipsychotic agent; (2) 21 days of therapy has elapsed; (3) ICU discharge occurred; or (4) a life-threatening adverse event potentially attributable to the study drug occurred that warranted discontinuation of the study drug.

Adverse effects will be closely monitored: extrapyramidal reactions, neuroleptic malignant syndrome, drowsiness, hypotension, QTc prolongation. The treatment level of patients presenting a non life-threatening adverse event will immediately be lowered to the level directly below.

The sample size was calculated for a 2-tailed test with an alpha of .05 and a power of .80.

The primary statistical analysis will involve Cox proportional time to event analysis comparing the three groups. Secondary analysis will use T-test comparisons for continuous variables and chi square for proportional analysis.

Description:

Primary Outcome Measures:

•Time to first resolution of delirium.

Secondary Outcome Measures:

• Days in delirium during the study

• Duration of delirium

• Severity of delirium (highest Nu-DESC score, mean episode Nu-DESC score)

• ICU and hospital mortality

• ICU and hospital length of stay

• Length of mechanical ventilation

• Time spent deeply sedated (RASS <3)

• Episodes of subject-initiated device removal

• Use of haloperidol therapy (including total dose in haloperidol equivalents during the study, number of doses, number of days of therapy, use of rescue IV haloperidol)

• Average daily and maximum total antipsychotic drug dose in haloperidol equivalents

• Duration of study drug administration

• Use of benzodiazepines (converted to lorazepam equivalents)

• Use of opioids (converted to morphine equivalents)

• QTc prolongation

• Extrapyramidal symptoms

• Neuroleptic malignant syndrome

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: September 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients aged 18 years or older.

• Patients with a diagnosis of delirium made by a psychiatrist.

Exclusion Criteria:

• Patients with active schizophrenia or bipolar disorder.

• Patients with Parkinson disease.

• Patients with severe liver failure.

• Patients with alcohol or sedative/hypnotics dependence.

• Patients with QTc interval above 500 msec.

• Pregnant patients.

Related Conditions & MeSH terms

• Delirium

Intervention

Drug:
• Quetiapine
PO
• Haloperidol
IV
• Placebo
PO or IV

Locations

Country	Name	City	State
Canada	Centre hospitalier de l'Université de Montréal (CHUM)	Montreal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Centre hospitalier de l'Université de Montréal (CHUM)	Fondation des pompiers du Québec pour les grands brûlés

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to first resolution of delirium	Confirmed by clinical evaluation of a psychiatrist	21 days
Secondary	Days in delirium during the study	From log	21 days
Secondary	Duration of delirium	From log	21 days
Secondary	Severity of delirium (highest Nu-DESC score, mean episode Nu-DESC score)	Nursing evaluation every 8 hours- shift	21 days
Secondary	ICU and hospital mortality	From the chart	21 days
Secondary	ICU and hospital length of stay	From the chart	21 days
Secondary	Length of mechanical ventilation	From daily clinical évaluation	21 days
Secondary	Time spent deeply sedated (RASS <3)	From chart	21 days
Secondary	Episodes of subject-initiated device removal	From daily clinical évaluation	21 days
Secondary	Use of haloperidol therapy (including total dose in haloperidol equivalents during the study, number of doses, number of days of therapy, use of rescue IV haloperidol)	From long	21 days
Secondary	Average daily and maximum total antipsychotic drug dose in haloperidol equivalents	From long	21 days
Secondary	Duration of study drug administration	From log	21 days
Secondary	Use of benzodiazepines	All benzodiazepines received in lorazepam equivalent	21 days
Secondary	Use of opioids	All opioids received in morphine équivalent	21 days
Secondary	QTc prolongation	From EKG recording	21 days
Secondary	Extrapyramidal symptoms	Daily clinical evaluation	21 days
Secondary	Neuroleptic malignant syndrome	Daily clinical evaluation	21 days