The MIND Study: Modifying the INcidence of Delirium

January 28, 2016 updated by: Wes Ely, Vanderbilt University

Delirium in the ICU: a Prospective, Randomized, Trial of Placebo vs. Haloperidol vs. Ziprasidone

Delirium is associated with increased risk of death, prolonged stay, higher cost of care, and likely long-term brain deficits in survivors. This form of brain dysfunction occurs in intensive care unit (ICU) patients in epidemic proportions, and the scope of this problem is likely to worsen in upcoming years due to the aging of our population and increased utilization of the ICU. Currently, delirium goes unrecognized and untreated in the vast majority of circumstances in the ICU unless the patient presents with hyperactive delirium and agitation. In the latter circumstance, a commonly used typical antipsychotic called haloperidol is considered the principal agent for treating delirium based largely on anecdotal evidence to support its usefulness, though no placebo controlled trials exist. There are no FDA approved medications for delirium. The atypical antipsychotics provide a promising alternative for the treatment of delirium due to their enhanced beneficial effects on positive (agitated) and negative (quiet) symptoms proven in mania and schizophrenia, reduced risk for side effects common to haloperidol such as extrapyramidal symptomatology, and less potentially lethal heart rhythm disturbances. It is imperative that well-designed phase II studies to determine proof of principle be conducted. A pilot study of feasibility to begin assessing the role of antipsychotics in the management of ICU delirium.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This investigation will be the first placebo controlled trial of delirium prevention/treatment, in or out of the ICU. As mentioned above, clinical practice guidelines for medical management of pain, anxiety, and delirium (major determinants of patient comfort) are endorsed by the major critical care societies. These guidelines will form the template for this investigation. Pain management is prioritized as a clinicians' first concern. The assessment and treatment algorithm in the guidelines then places anxiety and delirium, respectively, as sequential tiers of priority. While delirium monitoring is now available, recent data indicate that less than 5% of practicing ICU healthcare professionals use a specific delirium monitoring instrument. Thus, as outlined here, most delirium is not recognized or treated, which serves as the rationale for this placebo-controlled investigation. Anxiety is currently treated with drugs such as benzodiazepines. Such anxiety, however, may be due to delirium, in which case treatment with anxiolytics such as benzodiazepines might exacerbate this form of brain dysfunction. On the other hand, it is possible that treatment with antipsychotics will reduce the duration and severity of delirium, result in less breakthrough sedatives (due to the sedating effects of the antipsychotics), and improve clinical outcomes. Alternatively, treatment with antipsychotics may not alter or worsen clinical outcomes.

The specific aims of this study are as follows:

Aim 1: To determine whether antipsychotics reduce the incidence and duration of delirium in high risk mechanically ventilated patients.

Aim 2: To determine whether antipsychotics reduce the severity of neuropsychological dysfunction at hospital discharge in high risk mechanically ventilated patients.

Hypothesis 1: Our primary hypothesis is that in mechanically ventilated patients, the duration of delirium and the days alive and free of delirium - as measured using the Confusion Assessment Method for the ICU (CAM-ICU)- will be significantly improved by early treatment with antipsychotics (haloperidol or ziprasidone) as compared to placebo. Furthermore, we hypothesize that delirium duration will be comparable between the two intervention groups (haloperidol and ziprasidone). To test the primary hypothesis, we propose to perform a randomized, double-blind, placebo-controlled trial of the prevention/treatment of delirium in ICU patients using oral liquid formulations of haloperidol versus ziprasidone versus placebo. This study is powered to show a 50% improvement in the duration of delirium (CAM-ICU positive days) and will enroll 102 patients (34 in each group) over a two-year period. In addition, we will compare between groups the overall incidence of delirium and the number of delirium free days (DFDs) - defined as days alive and free of coma and delirium to day 21.

Hypothesis 2: We hypothesize that scores on a neuropsychological testing battery administered at the time of hospital discharge will be better in patients treated with antipsychotics (either haloperidol or ziprasidone) than those treated with placebo. Furthermore, we hypothesize that neuropsychological test scores will be comparable between the two intervention groups (haloperidol and ziprasidone).

Study Type

Interventional

Enrollment (Actual)

102

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina - Chapel Hill
      • Greensboro, North Carolina, United States, 27401
        • Moses Cone
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center
      • Nashville, Tennessee, United States, 37205
        • Saint Thomas Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Medical or surgical ICU patients on mechanical ventilation who are receiving sedatives or analgesics or displaying an abnormal level of consciousness (delirium or coma).

Exclusion Criteria:

  • Subjects expected to have a short time on mechanical ventilation. That is, those in whom the likelihood for the need for mechanical ventilation is less than 24 hours.
  • Subjects who have been on mechanical ventilation for more than 72 hours.
  • Subjects in whom gastric access is not available (i.e., no enteral feeding tube or NG/OG tube)and is not anticipated to be available for 48 hours.
  • Subjects younger than 18 years old.
  • Subjects who are pregnant (a pregnancy test will be performed on all women of child bearing age) or breastfeeding.
  • Inability to obtain informed consent from the subject or the subject's authorized representative.
  • Documented history of allergic reaction to ziprasidone or haloperidol.
  • Subjects admitted to the ICU for drug/alcohol overdose, suicide attempts, alcohol withdrawal/delirium tremens.
  • Subjects with active seizures or cerebrovascular accident within the last 2 weeks.
  • Subjects who are benzodiazepine dependent at the time of index hospitalization (i.e., patients on benzodiazepines as outpatient and whose attending judges it unsafe to withhold these medications due to risk for withdrawal syndrome).
  • Subjects with chronic pain syndromes or who are on maintenance narcotics.
  • Subjects with a history of torsades de pointes, known history of QT prolongation (e.g., congenital long QT syndrome), a QTc at baseline of 500 ms or over in the absence of bundle branch block, documented myocardial infarction within the previous 2 weeks, or uncompensated NYHA IV heart failure (dyspnea or anginal syndrome present at rest due to CHF). [NOTE: ICU patients who have an incidental rise in troponin in the absence of definitive ischemic ECG changes remain eligible]
  • Subjects who are on neuroleptic therapy as an outpatient maintenance drug (e.g., haloperidol, mesoridazine, thorazine, chlorpromazine, trifluoperazine, droperidol, risperidone, quetiapine, olanzapine, or ziprasidone).
  • Subjects who are receiving and will continue to receive other drugs that prolong the QT interval such as sotalol, quinidine, other Class Ia or III anti-arrhythmics, dofetilide (Tikosyn for arrhythmias), pimozide (for Tourette's), gatifloxacin, moxifloxacin (levofloxacin permissible), pentamidine, tacrolimus (Prograf), dolasetron (Anzemet). Azithromycin is an acceptable medication for study patients, and anyone slated to receive (or receiving) either clarithromycin or erythromycin can be switched to azithromycin by their primary team and be enrolled into the study the following day. Patients receiving clindamycin or clotrimazole will be excluded from the study.
  • Subjects who have a history of neuroleptic malignant syndrome.
  • Subjects with potassium levels below 3.0 mg/dl or magnesium levels below 1.8 mg/dl. NOTE: If the patient is receiving replacement of K+ or Mg+, then he/she would be eligible unless there is reason to suspect that these electrolyte abnormalities will be refractory.
  • Subjects with moderate/severe dementia (e.g., Alzheimer's type, vascular origin, or HIV-related) as documented by medical history or modified Blessed dementia rating scale (mBDRS) 4 or more or Informant Questionnaire of Cognitive Dysfunction in the Elderly (IQCODE) over 3.6.
  • Subjects who have suspected anoxic brain injury or documented cerebral edema at the time of screening.
  • Subjects who are moribund and not expected to survive 24 hours from the time of study enrollment, or who have a "Do Not Resuscitate" order, or whose family or medical team have not committed to aggressive support (e.g., not going to use vasopressors or mechanical ventilation or likely to have withdrawal of support within 24 hours).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: A - placebo
per oral pill
Other: Placebo
Other Names:
  • per oral pill
Active Comparator: B
Ziprasidone
Drug: Ziprasidone
Active Comparator: C
Haloperidol
Drug: Haloperidol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Days alive and free of delirium and coma (delirium and coma free days)
Time Frame: enrollment to day 21
enrollment to day 21

Secondary Outcome Measures

Outcome Measure
Time Frame
Severity of neuropsychological dysfunction at hospital discharge
Time Frame: 48-72 following d/c of study drug
48-72 following d/c of study drug
alive and free of delirium (delirium free days)
Time Frame: enrollment to day 21
enrollment to day 21
Length of stay on mechanical ventilation
Time Frame: enrollment to day 21
enrollment to day 21
Mechanical ventilation free days
Time Frame: enrollment to day 21
enrollment to day 21
length of stay in the ICU
Time Frame: enrollment to day 21
enrollment to day 21
Length of stay in the hospital
Time Frame: enrollment to day 21
enrollment to day 21
hospital mortality
Time Frame: enrollment to day 21
enrollment to day 21
mortality at 1 year
Time Frame: enrollment to 12 months post discharge
enrollment to 12 months post discharge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University

Investigators

  • Principal Investigator: E Wesley Ely, MD, MPH, Vanderbilt University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2004

Primary Completion (Actual)

July 1, 2007

Study Completion (Actual)

July 1, 2007

Study Registration Dates

First Submitted

November 16, 2004

First Submitted That Met QC Criteria

November 16, 2004

First Posted (Estimate)

November 17, 2004

Study Record Updates

Last Update Posted (Estimate)

January 29, 2016

Last Update Submitted That Met QC Criteria

January 28, 2016

Last Verified

January 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB # 040542

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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