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

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ClinicalTrials.gov Identifier: NCT01211522
Recruitment Status : Recruiting
First Posted : September 29, 2010
Last Update Posted : June 5, 2017
Information provided by (Responsible Party):
Wes Ely, Vanderbilt University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Delirium Impaired Cognition Long Term Psychologic Disorders Drug: Haloperidol Drug: Ziprasidone Drug: Placebo Phase 3

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). In the latter third of the study, as a result of a paper by Patel S et al AJRCCM 2014 about rapidly reversible delirium (RRD), we considered modifying delirium assessments to detect those who might convert from CAM-ICU positive to negative following SATs, but we estimated that only 5 patients per arm would be in this category (and indeed <20 per arm in the entire study using the 10% rate published by Patel). With such low numbers and the assurance that through randomization we would have all groups analyzed similarly according to the study drug assignment, we elected not to alter the protocol and not to conduct subgroup analyses according to RRD status.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 561 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: MIND-USA Study: Modifying the Impact of ICU-Associated Neurological Dysfunction
Study Start Date : December 2011
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Haloperidol
Drug: Haloperidol
Haloperidol, up to 10mg q12 hours, will be administered intravenously (IV) by bolus over up to 5 minutes at concentrations of 5mg/mL. Patient will only receive IV while in the ICU.
Other Name: Haldol
Experimental: Ziprasidone
Drug: Ziprasidone
Ziprasidone, up to 20mg q12 hours, will be administered intravenously (IV) by bolus over up to 5 minutes at concentrations of 10mg/mL. Patient will only receive IV while in the ICU.
Other Name: Geodon
Placebo Comparator: Placebo
Drug: Placebo
Placebo, up to 10mL q12 hours, will be administered intravenously (IV) by bolus over up to 5 minutes. Patient will only receive IV while in the ICU.

Primary Outcome Measures :
  1. Delirium/coma-free days [ Time Frame: 14 days ]

Secondary Outcome Measures :
  1. Survival [ Time Frame: 30-day, 90-day, and 1-year ]
  2. Delirium duration [ Time Frame: 14 days ]
  3. ICU length of stay [ Time Frame: 1 to 90 days ]
    Time to ICU discharge, represented by readiness for ICU discharge indicated by a physician order for transfer to a lower level of care even if a bed availability problems prevent actual discharge from the ICU.

  4. Hospital length of stay [ Time Frame: 1 to 90 days ]
  5. Ventilator-free days [ Time Frame: 14 days ]
  6. ICU readmission [ Time Frame: 1 to 90 days ]
  7. Hospital readmission [ Time Frame: 1 to 365 days ]
  8. Neuropsychological dysfunction [ Time Frame: 3-month, 12-month ]
    Assessed using a battery of cognitive tests.

  9. Quality of life [ Time Frame: 3-month, 12-month ]
  10. Posttraumatic stress disorder [ Time Frame: 3-month, 12-month ]
  11. QTc prolongation [ Time Frame: 14 days ]
  12. Extrapyramidal symptoms [ Time Frame: 14 days ]
  13. Neuroleptic malignant syndrome [ Time Frame: 14 days ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01211522

Contact: E. Wesley Ely, MD, MPH 615-936-3395 wes.ely@vanderbilt.edu
Contact: Timothy D Girard, MD, MSCI 615-936-1010 timothy.girard@vanderbilt.edu

United States, Colorado
Denver Health/University of Colorado Health Sciences Center Recruiting
Denver, Colorado, United States, 80204-4507
Contact: Ivor S Douglas, MD    303-436-5905    idouglas@dhha.org   
Principal Investigator: Ivor S Douglas, MD         
United States, Connecticut
Yale University Medical Center Recruiting
New Haven, Connecticut, United States, 06520-8057
Contact: Margaret A Pisani, MD    203-785-3627    margaret.pisani@yale.edu   
Principal Investigator: Margaret A Pisani, MD         
United States, Indiana
Indiana University Active, not recruiting
Indianapolis, Indiana, United States, 46202-2915
United States, Iowa
University of Iowa Active, not recruiting
Iowa City, Iowa, United States, 52242
United States, Maryland
University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Peter Rock, MD, MBA    410-328-8919    prock@anes.umm.edu   
Principal Investigator: Peter Rock, MD, MBA         
United States, Massachusetts
Massachusetts General Hospital Active, not recruiting
Boston, Massachusetts, United States, 02114-2696
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Robert L Owens, MD    617-983-7489    rowens@partners.org   
Principal Investigator: Robert L Owens, MD         
United States, Michigan
University of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109-5360
Contact: Robert C Hyzy, MD    734-936-5201    rhyzy@med.umich.edu   
Principal Investigator: Robert C Hyzy, MD         
United States, New York
Albert Einstein Medical College-Montefiore Medical Center Recruiting
The Bronx, New York, United States, 10461
Contact: Michelle Ng Gong, MD, MS    718-430-3712    mgong@montefiore.org   
Principal Investigator: Michelle Ng Gong, MD, MS         
United States, North Carolina
University of North Carolina - Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599-7248
Contact: Shannon S Carson, MD    919-966-2531    shannon_carson@med.unc.edu   
Principal Investigator: Shannon S Carson, MD         
Moses Cone Health System Recruiting
Greensboro, North Carolina, United States, 27410
Contact: Daniel J Feinstein, MD    336-832-2432    daniel.feinstein@mosescone.com   
Principal Investigator: Daniel J Feinstein, MD         
Wake Forest University Withdrawn
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
The Ohio State Medical Center Recruiting
Columbus, Ohio, United States, 43210-1228
Contact: Matthew C. Exline, MD, MPH    614-293-4925    matthew.exline@osumc.edu   
Principal Investigator: Matthew C. Exline, MD, MPH         
United States, Pennsylvania
University of Pennsylvania Active, not recruiting
Philadelphia, Pennsylvania, United States, 19104-6205
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232-8300
Contact: Wes E. Ely, MD, MPH    615-936-3702    wes.ely@vanderbilt.edu   
Contact: Tim Girard, MD, MPH    1-615-936-3702    timothy.girard@vanderbilt.edu   
United States, Texas
Baylor Health Care System Active, not recruiting
Dallas, Texas, United States, 75206
United States, Washington
University of Washington Recruiting
Seattle, Washington, United States, 98195-9472
Contact: Catherine Hough, MD    206-744-3356    cterrlee@uw.edu   
Principal Investigator: Catherine Hough, MD         
Sponsors and Collaborators
Vanderbilt University
Principal Investigator: E. Wesley Ely, MD, MPH Vanderbilt University Medical Center

Responsible Party: Wes Ely, Professor of Medicine, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01211522     History of Changes
Other Study ID Numbers: AG035117-01A1
101082 ( Other Identifier: Vanderbilt University Institutional Review Board )
First Posted: September 29, 2010    Key Record Dates
Last Update Posted: June 5, 2017
Last Verified: June 2017

Keywords provided by Wes Ely, Vanderbilt University:
Intensive care
Mechanical ventilation
Long-term cognitive impairment

Additional relevant MeSH terms:
Antipsychotic Agents
Cognitive Dysfunction
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Haloperidol decanoate
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Serotonin Antagonists
Serotonin Agents