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

Study Description

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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 Design

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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 2018
Estimated Study Completion Date :	July 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Haloperidol; 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; 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; 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.

Outcome Measures

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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 ]

Eligibility Criteria

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

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.

Contacts and Locations

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Contacts

Contact: E. Wesley Ely, MD, MPH	615-936-3395	wes.ely@vanderbilt.edu
Contact: Timothy D Girard, MD, MSCI	412-532-9779	timothy.girard@upmc.edu

Locations

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
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 1-412-532-9779 timothy.girard@upmc.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

Investigators

Principal Investigator:	E. Wesley Ely, MD, MPH	Vanderbilt University Medical Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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
Last Update Posted:	April 12, 2018
Last Verified:	April 2018

Keywords provided by Wes Ely, Vanderbilt University:

Delirium; Intensive care; Mechanical ventilation; Antipsychotic; Haloperidol; Ziprasidone	Randomized; Placebo; Sepsis; Sedation; Long-term cognitive impairment

Additional relevant MeSH terms:

Delirium; Cognitive Dysfunction; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Haloperidol; Haloperidol decanoate; Ziprasidone; Antiemetics; Autonomic Agents	Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Antipsychotic 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