Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

The MIND Study: Modifying the INcidence of Delirium

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Wes Ely, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00096863
First received: November 16, 2004
Last updated: February 5, 2013
Last verified: February 2013
  Purpose

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.


Condition Intervention Phase
Delirium
Cognition Disorders
Drug: Ziprasidone
Drug: Haloperidol
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Delirium in the ICU: a Prospective, Randomized, Trial of Placebo vs. Haloperidol vs. Ziprasidone

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Days alive and free of delirium and coma (delirium and coma free days) [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Severity of neuropsychological dysfunction at hospital discharge [ Time Frame: 48-72 following d/c of study drug ] [ Designated as safety issue: No ]
  • alive and free of delirium (delirium free days) [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
  • Length of stay on mechanical ventilation [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
  • Mechanical ventilation free days [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
  • length of stay in the ICU [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
  • Length of stay in the hospital [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
  • hospital mortality [ Time Frame: enrollment to day 21 ] [ Designated as safety issue: No ]
  • mortality at 1 year [ Time Frame: enrollment to 12 months post discharge ] [ Designated as safety issue: No ]

Enrollment: 102
Study Start Date: December 2004
Study Completion Date: July 2007
Primary Completion Date: July 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: A - placebo
per oral pill
Other: Placebo
Other Name: per oral pill
Active Comparator: B
Ziprasidone
Drug: Ziprasidone
Active Comparator: C
Haloperidol
Drug: Haloperidol

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00096863

Locations
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, North Carolina
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Moses Cone
Greensboro, North Carolina, United States, 27401
United States, Tennessee
Saint Thomas Hospital
Nashville, Tennessee, United States, 37205
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: E Wesley Ely, MD, MPH Vanderbilt University
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Wes Ely, Professor of Medicine, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00096863     History of Changes
Other Study ID Numbers: IRB # 040542
Study First Received: November 16, 2004
Last Updated: February 5, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
Delirium
Cognition Disorders
Antipsychotics
Mechanical Ventilation
Critical Illness

Additional relevant MeSH terms:
Cognition Disorders
Delirium
Confusion
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Nervous System Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Haloperidol
Haloperidol decanoate
Ziprasidone
Anti-Dyskinesia Agents
Antiemetics
Antipsychotic Agents
Autonomic Agents
Central Nervous System Agents
Central Nervous System Depressants
Dopamine Agents
Dopamine Antagonists
Gastrointestinal Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Serotonin Antagonists
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014