The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study

Condition(s) targeted: Delirium; Impaired Cognition; Long Term Psychologic Disorders

Intervention: Haloperidol (Drug); Ziprasidone (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Vanderbilt University

Official(s) and/or principal investigator(s):
E. Wesley Ely, MD, MPH, Principal Investigator, Affiliation: Vanderbilt University

Overall contact:
E. Wesley Ely, MD, MPH, Phone: 615-936-3395, Email: wes.ely@vanderbilt.edu

The long-term objective of the MIND-USA (Modifying the Impact of ICU-Induced Neurological Dysfunction-USA) Study is to define the role of antipsychotics in the management of delirium in vulnerable critically ill patients. We and others have shown that delirium is an independent predictor of more death, longer stay, higher cost, and long-term cognitive impairment often commensurate with moderate dementia. The rapidly expanding aging ICU population is especially vulnerable to develop delirium, with 7 of 10 medical and surgical ICU patients developing this organ dysfunction. Antipsychotics are the first-line pharmacological agents recommended to treat delirium, and over the past 30 years they gained widespread use in hospitalized patients globally prior to adequate testing of efficacy and safety for this indication. Haloperidol, the most commonly chosen antipsychotic, is used by over 80% of ICU doctors for delirium, while atypical antipsychotics are prescribed by 40%. Antipsychotics safety concerns include lethal cardiac arrhythmias, extrapyramidal symptoms, and the highly publicized increased mortality associated with their use in non-ICU geriatric populations. The overarching hypothesis is that administration of typical and atypical antipsychotics—haloperidol and ziprasidone, in this case—to critically ill patients with delirium will improve short- and long-term clinical outcomes, including days alive without acute brain dysfunction (referred to as delirium/coma-free days or DCFDs) over a 14-day period; 30-day, 90-day, and 1-year survival; ICU length of stay; incidence, severity, and/or duration of long-term neuropsychological dysfunction; and quality of life at 90-day and 1-year. To test these hypotheses, the MIND-USA Study will be a multi-center, double-blind, randomized, placebo-controlled investigation in 561 critically ill, delirious medical/surgical ICU patients who are (a) on mechanical ventilation or non-invasive positive pressure ventilation or (b) in shock on vasopressors. In each group (haloperidol, ziprasidone, and placebo), 187 patients will be enrolled and treated until delirium has resolved for 48 hours or to 14 days (whichever occurs first) and followed for 1 year.

Official title: The MIND-USA Study: Modifying the Impact of ICU-Associated Neurological Dysfunction

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Delirium/coma-free days

Secondary outcome:

Survival

Delirium duration

ICU length of stay

Hospital length of stay

Ventilator-free days

ICU readmission

Hospital readmission

Neuropsychological dysfunction

Quality of life

Posttraumatic stress disorder

QTc prolongation

Extrapyramidal symptoms

Neuroleptic malignant syndrome

Detailed description: The primary and secondary outcomes of the MIND-USA investigation will be analyzed both according to the individual comparisons by group of "haloperidol treated" vs. "placebo treated" and "ziprasidone treated" vs. "placebo treated" and also the combined grouping of both antipsychotics ("haloperidol plus ziprasidone treated" patients vs. "placebo treated" patients).

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. adult patients (≥18 years old) 2. in a medical and/or surgical ICU 3. on mechanical ventilation or non-invasive positive pressure ventilation (NIPPV), and/or requiring vasopressors due to shock 4. delirious (according to the CAM-ICU) Exclusion Criteria: 1. Rapidly resolving organ failure criteria, indicated by planned immediate discontinuation of mechanical ventilation, NIPPV, and/or vasopressors at the time of screening for study enrollment 2. Pregnancy or breastfeeding (negative pregnancy test required prior to enrollment of female patients of childbearing age) 3. Severe dementia or neurodegenerative disease, defined as either impairment that prevents the patient from living independently at baseline or IQCODE >4. 5, measured using a patient's qualified surrogate, mental illness requiring long-term institutionalization, acquired or congenital mental retardation, Parkinson's disease, Huntington's disease, and/or coma or another severe deficit due to structural brain disease such as stroke, intracranial hemorrhage, cranial trauma, intracranial malignancy, anoxic brain injury, or cerebral edema. 4. History of torsades de pointes, documented baseline QT prolongation (congenital long QT syndrome), or QTc >500 ms at screening due to refractory electrolyte abnormalities, other drugs, or thyroid disease 5. Ongoing maintenance therapy with typical or atypical antipsychotics 6. History of neuroleptic malignant syndrome (NMS), haloperidol allergy, or ziprasidone allergy 7. Expected death within 24 hours of enrollment or lack of commitment to aggressive treatment by family or the medical team (e. g., likely withdrawal of life support measures within 24 hours of screening) 8. Inability to obtain informed consent from an authorized representative within 72 hours of meeting all inclusion criteria, i. e., developing qualifying organ dysfunction criteria.

E. Wesley Ely, MD, MPH, Phone: 615-936-3395, Email: wes.ely@vanderbilt.edu

Denver Health/University of Colorado Health Sciences Center, Denver, Colorado 80204-4507, United States; Recruiting
Ivor S Douglas, MD, Phone: 303-436-5905, Email: idouglas@dhha.org
Ivor S Douglas, MD, Principal Investigator

Yale University Medical Center, New Haven, Connecticut 06520-8057, United States; Recruiting
Margaret A Pisani, MD, Phone: 203-785-3627, Email: margaret.pisani@yale.edu
Margaret A Pisani, MD, Principal Investigator

Indiana University, Indianapolis, Indiana 46202-2915, United States; Recruiting
Babar A. Khan, MD, Phone: 317-423-5674, Email: bakhan@indiana.edu
Malaz A. Boustani, MD, Phone: 317-423-5633, Email: mboustan@iupui.edu
Babar A. Khan, MD, Principal Investigator
Malaz A. Boustani, MD, Principal Investigator

University of Iowa, Iowa City, Iowa 52242, United States; Withdrawn

University of Maryland Medical Center, Baltimore, Maryland 21201, United States; Recruiting
Peter Rock, MD, MBA, Phone: 410-328-8919, Email: prock@anes.umm.edu
Peter Rock, MD, MBA, Principal Investigator

Brigham and Women's Hospital, Boston, Massachusetts 02115, United States; Recruiting
Robert L Owens, MD, Phone: 617-983-7489, Email: rowens@partners.org
Robert L Owens, MD, Principal Investigator

Massachusetts General Hospital, Boston, Massachusetts 02114-2696, United States; Withdrawn

University of Michigan Health System, Ann Arbor, Michigan 48109-5360, United States; Recruiting
Robert C Hyzy, MD, Phone: 734-936-5201, Email: rhyzy@med.umich.edu
Robert C Hyzy, MD, Principal Investigator

Albert Einstein Medical College-Montefiore Medical Center, Bronx, New York 10461, United States; Recruiting
Michelle Ng Gong, MD, MS, Phone: 718-430-3712, Email: mgong@montefiore.org
Michelle Ng Gong, MD, MS, Principal Investigator

University of North Carolina - Chapel Hill, Chapel Hill, North Carolina 27599-7248, United States; Recruiting
Shannon S Carson, MD, Phone: 919-966-2531, Email: shannon_carson@med.unc.edu
Shannon S Carson, MD, Principal Investigator

Moses Cone Health System, Greensboro, North Carolina 27410, United States; Recruiting
Daniel J Feinstein, MD, Phone: 336-832-2432, Email: daniel.feinstein@mosescone.com
Daniel J Feinstein, MD, Principal Investigator

Wake Forest University, Winston-Salem, North Carolina 27157, United States; Withdrawn

The Ohio State Medical Center, Columbus, Ohio 43210-1228, United States; Recruiting
Matthew C. Exline, MD, MPH, Phone: 614-293-4925, Email: matthew.exline@osumc.edu
Matthew C. Exline, MD, MPH, Principal Investigator

University of Pennsylvania, Philadelphia, Pennsylvania 19104-6205, United States; Withdrawn

Vanderbilt University Medical Center, Nashville, Tennessee 37232-8300, United States; Recruiting
Wes E. Ely, MD, MPH, Phone: 615-936-3702, Email: wes.ely@vanderbilt.edu
Tim Girard, MD, MPH, Phone: 1-615-936-3702, Email: timothy.girard@vanderbilt.edu

Baylor Health Care System, Dallas, Texas 75206, United States; Withdrawn

University of Washington, Seattle, Washington 98195-9472, United States; Recruiting
Catherine Hough, MD, Phone: 206-744-3356, Email: cterrlee@uw.edu
Catherine Hough, MD, Principal Investigator

Starting date: December 2011
Last updated: June 19, 2014