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Treatment of Hypoactive Delirium and Outcome Measures (THDOM)

Primary Purpose

Hypoactive Delirium

Status
Unknown status
Phase
Phase 3
Locations
Mexico
Study Type
Interventional
Intervention
Haloperidol
Placebo
non-pharmacologic measures
Sponsored by
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoactive Delirium

Eligibility Criteria

70 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients who fulfill criteria for delirium according to CAM and DOSS
  • Patients in hospitalization who are not receiving treatment for delirium
  • Patients without treatment with antipsychotics for any other reason
  • Patients whose legally proxy accepts to participate

Exclusion Criteria:

  • Patients who have received pharmacologic treatment for delirium
  • Patients with a corrected QT interval prolongation
  • Patients who receive antipsychotics for any other reason
  • Patients in another age group
  • Patients whose legally proxy does not accept to participate
  • Patients with dementia
  • Patients with Parkinson disease
  • Patients with arrythmias
  • Patients with language or hearing disorders that impede communication
  • Patients hospitalized in the Intensive Care Unit
  • Patients who are receiving benzodiazepines and anticholinergics
  • Patients with dopamine agonists or antagonists
  • Patients who develop a severe neurologic disease

Sites / Locations

  • Department of Neurology and Psychiatry. Instituto Nacional de Ciencias Médicas y NutriciónRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Haloperidol and non-pharmacologic

Placebo and non-pharmacologic

Arm Description

Haloperidol 1.25mg PO q. d. during nine days Non-pharmacologic measures: A. Reorientation (i.e., calendar, clocks, familiar objects) B. Glasses and hearing devices for the particular patients needing such aids C. Avoidance of physical restraints D. Limitation of excessive personnel shifts or hospital room E. A tranquil and comfortable environment, especially at night, to avoid interruptions (i.e., dim light, low levels of noise) F. Adequate schedules for medication administration and to take vital signs or medical procedures G. Sleep hygiene (light in the room and movement during the day) H. Avoidance of dehydration I. Avoidance of medications use which are associated with delirium (e.g., psychoactive medications)

Placebo 1.25 mg PO q.d during nine days. Non-pharmacologic measures: A. Reorientation (i.e., calendar, clocks, familiar objects) B. Glasses and hearing devices for the particular patients needing such aids C. Avoidance of physical restraints D. Limitation of excessive personnel shifts or hospital room E. A tranquil and comfortable environment, especially at night, to avoid interruptions (i.e., dim light, low levels of noise) F. Adequate schedules for medication administration and to take vital signs or medical procedures G. Sleep hygiene (light in the room and movement during the day) H. Avoidance of dehydration I. Avoidance of medications use which are associated with delirium (e.g., psychoactive medications)

Outcomes

Primary Outcome Measures

Change in delirium severity
Reduction of 50% from the basal DOSS score

Secondary Outcome Measures

Necessity of additional open label haloperidol doses to control delirium symptoms
In case the patient develops a hyperactive state will receive haloperidol in an open label dose, 1 mg that could be repeated every 4 hours in case the agitation persists, for a maximum daily dose of 6 mg. In this way, the dose will never exceed the recommended 10 mg dose per day. If the patient persists with a hypoactive state (absence of improvement on the DOSS score), we will increase the dose to 2.5 mg or half a tablet (of haloperidol or placebo q.d.) or 3.75 mg,three quarters of a tablet ( of haloperidol or placebo q.d.)
Delirium duration
Using the DOSS basal score and the CAM
Perceived stress
in patients, health staff and caregivers of both groups using the delirium experience questionnaire
Posttraumatic stress disorder
In patients of both groups using the posttraumatic stress disorder section of the Mini International Neuropsychiatry Interview
Cognitive impairment as assessed by Montreal Cognitive Assessment (MoCA) <24 points
Number of patients with <24 points in the Montreal Cognitive Assessment at 6 months after delirium remission, as compared with the number of patients with scoring >3.5 points in the Informant Questionnaire on Cognitive Decline in the Elderly, as an estimate of the baseline (pre-delirium) state
Cerebral blood flow as assessed by transcranial Doppler
in patients of both groups using a cerebral ultrasound
Side effects associated with either intervention
We will list all adverse reactions associated with haloperidol (extra pyramidal effects, arrhythmias, hypersensitivity to the drug or corrected QT interval prolongation), the medication will be stopped in case of the appearance of an life-threatening reaction. We will consider this case when a patient needs ventilator support, use of cardiac amines, hemodialysis or the use of the Intensive Care Unit. These conditions will require opening the masking and exit the patient from the study.

Full Information

First Posted
November 7, 2014
Last Updated
April 20, 2017
Sponsor
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
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1. Study Identification

Unique Protocol Identification Number
NCT02345902
Brief Title
Treatment of Hypoactive Delirium and Outcome Measures
Acronym
THDOM
Official Title
Randomized Double-Blind Clinical Trial to Compare Haloperidol and Non-Pharmacologic Treatment Versus Non-Pharmacologic Treatment and Placebo, in Elderly Hospitalized Patients With Hypoactive Delirium
Study Type
Interventional

2. Study Status

Record Verification Date
January 2016
Overall Recruitment Status
Unknown status
Study Start Date
January 2016 (undefined)
Primary Completion Date
March 2018 (Anticipated)
Study Completion Date
December 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Haloperidol and Non-Pharmacologic Treatment are recognized treatments for delirium. This study will evaluate which is the best treatment for hypoactive delirium.
Detailed Description
Background Delirium is a cognitive disorder that affects attention and other mental functions. It has an acute onset (in hours or days), a fluctuating course and has various conditioning factors such as diseases or withdrawal or intoxication syndromes. Delirium is a syndrome with multifactorial origin, it commonly presents in elderly patients, with a prevalence of 20%. Delirium develops when basal vulnerability interacts with precipitating factors. Delirium has three types according to its psychomotor presentation, hyperactive (agitated), hypoactive (tranquil) or mixed. Delirium has serious outcomes, such as prolonged hospitalization (1), cognitive decline and dementia (2,3,4,), posttraumatic stress disorder (5) and a higher mortality (1). A neurotransmitter imbalance between acetylcholine and dopamine explains delirium symptoms. A dopamine excess has various consequences: hallucinations that are present in 51 %, and delusions, present in up to 43% in hypoactive delirium. These symptoms produce acute stress in patients and caregivers. It is reported that 53.5% of patients recalled the episode of delirium and from these, 55% of them recalled it associated to hallucinations and 95% of them to delusions. Family recalled the event as stressful in 66%, nurses in 65% of those who did not have hallucinations and in 88% of those who had (6). Hallucinations and delusions are risk factors for the development of posttraumatic stress disorder, which occurs in up 22% of patients. Dopamine increase has been associated to apoptosis for its neurotoxic effects. Inflammation has a role in delirium. A study demonstrated that cortisol, Interleukin 6 ( IL-6) and protein S100 calcium binding protein B (S 100β) are all associated with delirium (7). It is important to note that antipsychotics may have a neuro-protective effect by blocking dopamine receptors, and, therefore, diminishing the potential negative outcomes associated with dopamine excess. Furthermore in an observational study using haloperidol in the intensive care unit there was a decrease in mortality, possibly by its effects on inflammation, inhibiting the release of proinflammatory cytokines (8). One of the effects of haloperidol in vitro is the induction of interleukin receptor antagonist ( IL-IRA), which has shown to have an independent role in delirium. IL-IRA blocks the actions of Interleukin 1α (IL-1α) and interleukin 1β (IL-Iβ) . IL-IRA also downregulates ischaemic and excitotoxic damage (9). Treatment of Delirium Psychiatrist, Geriatricians and Neurologists, usually, treat delirium; however treatment strategies vary widely among disciplines, due to differences in the practice guidelines and local applications of current knowledge among centers. An integration of their treatment approaches could offer important clinical advantages. To refer some differences, The American Psychiatric Association (APA) Guidelines (10) recommend treatment with antipsychotics for elderly patients. Where haloperidol is the gold standard, with a dose of 0.25 to 0.50 mg every 4 hours, although the dose may need to be increased for those patients severely agitated. There is no mention among all subtypes of delirium. This guideline recognizes the non-pharmacologic intervention as part of the treatment. On the other hand, Geriatrics Guidelines for the treatment of delirium, mention that the treatment of delirium should be mainly based on non-pharmacologic treatment. Restricting the pharmacologic treatment for those patients with severe manifestations of agitation (11). The NICE Guidelines mention that pharmacologic treatment in hypoactive delirium patients is indicated during one week to those patients with distress due to hallucinations (12). Authors have mentioned that non-pharmacologic measures have not been assessed in clinical trials, and that pharmacologic treatment has not been recommended at this time (13). Furthermore, others addressed that currently, treatment with antipsychotics are used where non-pharmacologic measures have failed to treat psychotic symptoms. Or when the safety of patients or others are compromised, and that clinical trials with antipsychotics are few (14). As it was mentioned before, there is no standardized treatment of delirium among different disciplines. Therefore, it is still on debate to determine which the best strategy in treating delirium is. As far as we know, there are no clinical trials adequately evaluating haloperidol as the cornerstone of management in hypoactive delirium. Nonetheless, those patients who were exposed to a higher dose of haloperidol improved significantly with this antipsychotic (15). Therefore, it is not known whether hypoactive delirium (the most frequent and difficult to recognize) should be treated with haloperidol at lower doses. Or if haloperidol should be used only in mixed and hyperactive types of delirium. Though despite few studies that have included patients with hypoactive delirium suggest that antipsychotics may have a role in the treatment of this delirium subtype (16). Statement of the Problem Hypoactive delirium is a common condition in hospitalized elderly patients. It is the most common type of delirium that carries more difficulty in its diagnosis. It is associated to a longer hospital stay, increased expenses associated to its diagnosis and more doubts on the most efficacious treatment strategy. Surprisingly, even when hypoactive delirium is the most frequent, it is the hyperactive type the paradigm of study, and it is the one specifically mentioned in treatment guidelines. To the best of our knowledge, there are no studies evaluating specifically haloperidol in hypoactive delirium. Some studies have excluded this type of delirium systematically or include all delirium subtypes where hypoactive delirium is poorly represented/analyzed. Significance of the Investigation There are few clinical studies correctly designed, exempt of methodological flaws and evaluating the most important clinical outcomes in delirium patients in general. There are no randomized clinical trials (RCTs) testing low-dose haloperidol against non-pharmacologic measures in the treatment of hypoactive delirium. Just few studies have included patients with hypoactive delirium with varying results, contributing to the lack of uniform recommendations (16). Currently, its treatment is based on the particular experiences of each clinical center without measuring its impact on relevant outcomes. Furthermore, there are no studies evaluating perceived stress in patients and their caregivers, as well as posttraumatic stress in hypoactive delirium patients. None has evaluated cognitive decline after a hypoactive delirium treated either with antipsychotics or non-pharmacologic measures. The purpose of the present RCT is to bring out knowledge about different treatments in elderly patients with hypoactive delirium.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoactive Delirium

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Haloperidol and non-pharmacologic
Arm Type
Experimental
Arm Description
Haloperidol 1.25mg PO q. d. during nine days Non-pharmacologic measures: A. Reorientation (i.e., calendar, clocks, familiar objects) B. Glasses and hearing devices for the particular patients needing such aids C. Avoidance of physical restraints D. Limitation of excessive personnel shifts or hospital room E. A tranquil and comfortable environment, especially at night, to avoid interruptions (i.e., dim light, low levels of noise) F. Adequate schedules for medication administration and to take vital signs or medical procedures G. Sleep hygiene (light in the room and movement during the day) H. Avoidance of dehydration I. Avoidance of medications use which are associated with delirium (e.g., psychoactive medications)
Arm Title
Placebo and non-pharmacologic
Arm Type
Active Comparator
Arm Description
Placebo 1.25 mg PO q.d during nine days. Non-pharmacologic measures: A. Reorientation (i.e., calendar, clocks, familiar objects) B. Glasses and hearing devices for the particular patients needing such aids C. Avoidance of physical restraints D. Limitation of excessive personnel shifts or hospital room E. A tranquil and comfortable environment, especially at night, to avoid interruptions (i.e., dim light, low levels of noise) F. Adequate schedules for medication administration and to take vital signs or medical procedures G. Sleep hygiene (light in the room and movement during the day) H. Avoidance of dehydration I. Avoidance of medications use which are associated with delirium (e.g., psychoactive medications)
Intervention Type
Drug
Intervention Name(s)
Haloperidol
Other Intervention Name(s)
haloperil
Intervention Description
haloperidol 1.25 mg P.O q.d
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
placebo 1.25 mg P.O q.d
Intervention Type
Other
Intervention Name(s)
non-pharmacologic measures
Intervention Description
A. Reorientation (i.e., calendar, clocks, familiar objects) B. Glasses and hearing devices for the particular patients needing such aids C. Avoidance of physical restraints D. Limitation of excessive personnel shifts or hospital room E. A tranquil and comfortable environment, especially at night, to avoid interruptions (i.e., dim light, low levels of noise) F. Adequate schedules for medication administration and to take vital signs or medical procedures G. Sleep hygiene (light in the room and movement during the day) H. Avoidance of dehydration I. Avoidance of medications use which are associated with delirium (e.g., psychoactive medications)
Primary Outcome Measure Information:
Title
Change in delirium severity
Description
Reduction of 50% from the basal DOSS score
Time Frame
Participants will be followed at an expected average of nine days
Secondary Outcome Measure Information:
Title
Necessity of additional open label haloperidol doses to control delirium symptoms
Description
In case the patient develops a hyperactive state will receive haloperidol in an open label dose, 1 mg that could be repeated every 4 hours in case the agitation persists, for a maximum daily dose of 6 mg. In this way, the dose will never exceed the recommended 10 mg dose per day. If the patient persists with a hypoactive state (absence of improvement on the DOSS score), we will increase the dose to 2.5 mg or half a tablet (of haloperidol or placebo q.d.) or 3.75 mg,three quarters of a tablet ( of haloperidol or placebo q.d.)
Time Frame
Participants will be followed at an expected average of nine days
Title
Delirium duration
Description
Using the DOSS basal score and the CAM
Time Frame
Participants will be followed at an expected average of nine days
Title
Perceived stress
Description
in patients, health staff and caregivers of both groups using the delirium experience questionnaire
Time Frame
At 24 hours after delirium remission
Title
Posttraumatic stress disorder
Description
In patients of both groups using the posttraumatic stress disorder section of the Mini International Neuropsychiatry Interview
Time Frame
At 6 months after delirium remission
Title
Cognitive impairment as assessed by Montreal Cognitive Assessment (MoCA) <24 points
Description
Number of patients with <24 points in the Montreal Cognitive Assessment at 6 months after delirium remission, as compared with the number of patients with scoring >3.5 points in the Informant Questionnaire on Cognitive Decline in the Elderly, as an estimate of the baseline (pre-delirium) state
Time Frame
At 6 months after delirium remission
Title
Cerebral blood flow as assessed by transcranial Doppler
Description
in patients of both groups using a cerebral ultrasound
Time Frame
At baseline and after 24 h of delirium remission
Title
Side effects associated with either intervention
Description
We will list all adverse reactions associated with haloperidol (extra pyramidal effects, arrhythmias, hypersensitivity to the drug or corrected QT interval prolongation), the medication will be stopped in case of the appearance of an life-threatening reaction. We will consider this case when a patient needs ventilator support, use of cardiac amines, hemodialysis or the use of the Intensive Care Unit. These conditions will require opening the masking and exit the patient from the study.
Time Frame
Participants will be followed at an expected average of nine days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients who fulfill criteria for delirium according to CAM and DOSS Patients in hospitalization who are not receiving treatment for delirium Patients without treatment with antipsychotics for any other reason Patients whose legally proxy accepts to participate Exclusion Criteria: Patients who have received pharmacologic treatment for delirium Patients with a corrected QT interval prolongation Patients who receive antipsychotics for any other reason Patients in another age group Patients whose legally proxy does not accept to participate Patients with dementia Patients with Parkinson disease Patients with arrythmias Patients with language or hearing disorders that impede communication Patients hospitalized in the Intensive Care Unit Patients who are receiving benzodiazepines and anticholinergics Patients with dopamine agonists or antagonists Patients who develop a severe neurologic disease
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Maria Carmen Flores, MD, MSc
Phone
54870900
Ext
2523
Email
mcflormir@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Sara Aguilar, MD, MSc
Phone
54870900
Ext
5701
Email
sgan30@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Erwin Chiquete, MD, PhD
Organizational Affiliation
Instituto Nacional de Ciencias Médicas y Nutrición
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Carlos Cantú, MD, PhD
Organizational Affiliation
Instituto Nacional de Ciencias Médicas y Nutrición
Official's Role
Study Director
Facility Information:
Facility Name
Department of Neurology and Psychiatry. Instituto Nacional de Ciencias Médicas y Nutrición
City
Mexico City
State/Province
DF
ZIP/Postal Code
14000
Country
Mexico
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Carmen Flores, MD, MSc
Phone
54870900
Ext
2523
Email
mcflormir@gmail.com
First Name & Middle Initial & Last Name & Degree
Sara Aguilar-Navarro, MD, MSc
Phone
54870900
Ext
5701
Email
sgan30@hotmail.com

12. IPD Sharing Statement

Plan to Share IPD
Undecided
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Citation
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Treatment of Hypoactive Delirium and Outcome Measures

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