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

• ClinicalTrials.gov Identifier: NCT01211522
• Recruitment Status: Completed
• First Posted: September 29, 2010
• Results First Posted: August 20, 2019
• Last Update Posted: November 18, 2019
• Sponsor: Vanderbilt University Medical Center
• Information provided by (Responsible Party): Wes Ely, Vanderbilt University Medical Center

Study Description

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 566 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blind, placebo controlled
• Primary Purpose: Treatment
• Official Title: MIND-USA Study: Modifying the Impact of ICU-Associated Neurological Dysfunction
• Actual Study Start Date: December 14, 2011
• Actual Primary Completion Date: August 28, 2017
• Actual Study Completion Date: July 19, 2018

Arms and Interventions

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

Primary Outcome Measures :

1. Delirium/Coma-free Days (DCFDs) [ Time Frame: 14 days ]
   Defined as the number of days during the 14-day intervention period (beginning on the day of randomization) that the patient was alive and experienced neither delirium nor coma.

Secondary Outcome Measures :

1. Mortality [ Time Frame: 30-day and 90-day ]
   Deaths within the specified timeframe
2. Delirium Duration [ Time Frame: 14 days ]
   Duration of delirium during the intervention period
3. Number of Participants With Torsades de Pointes [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
4. Number of Participants With Extrapyramidal Symptoms [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
5. Number of Participants With Neuroleptic Malignant Syndrome [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
6. Time to Liberation From Mechanical Ventilation [ Time Frame: 30 days ]
   Days from randomization to successful liberation from mechanical ventilation, where "successful" indicates that liberation was followed by at least 48 hours alive and without reinitiation of invasive or noninvasive ventilation.
7. Time to Final ICU Discharge [ Time Frame: 90 days ]
   Days from randomization to final, successful ICU discharge, where "successful" indicates that discharge was followed by at least 48 hours alive. "ICU discharge" is 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.
8. Time to ICU Readmission [ Time Frame: 90 days after first ICU discharge ]
   Days from first ICU discharge to next ICU readmission.
9. Time to Hospital Discharge [ Time Frame: 90 days ]
   Days from randomization to successful hospital discharge, where "successful" indicates that discharge was followed by at least 48 hours alive.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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

Locations

United States, Colorado

Denver Health/University of Colorado Health Sciences Center

Denver, Colorado, United States, 80204-4507

United States, Connecticut

Yale University Medical Center

New Haven, Connecticut, United States, 06520-8057

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202-2915

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Maryland

University of Maryland Medical Center

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114-2696

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Michigan

University of Michigan Health System

Ann Arbor, Michigan, United States, 48109-5360

United States, New York

Albert Einstein Medical College-Montefiore Medical Center

Bronx, New York, United States, 10461

United States, North Carolina

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States, 27599-7248

Moses Cone Health System

Greensboro, North Carolina, United States, 27410

United States, Ohio

The Ohio State Medical Center

Columbus, Ohio, United States, 43210-1228

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104-6205

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232-8300

United States, Texas

Baylor Health Care System

Dallas, Texas, United States, 75206

United States, Washington

University of Washington

Seattle, Washington, United States, 98195-9472

Sponsors and Collaborators

Vanderbilt University Medical Center

Investigators

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

  Study Documents (Full-Text)

Documents provided by Wes Ely, Vanderbilt University Medical Center:

Study Protocol  [PDF] June 22, 2016

Statistical Analysis Plan  [PDF] May 7, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD, Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM, Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR, Dittus RS, Ely EW; MIND-USA Investigators. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018 Dec 27;379(26):2506-2516. doi: 10.1056/NEJMoa1808217. Epub 2018 Oct 22.

• Responsible Party: Wes Ely, Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT01211522
• Other Study ID Numbers: AG035117-01A1; 101082 ( Other Identifier: Vanderbilt University Institutional Review Board )
• First Posted: September 29, 2010
• Results First Posted: August 20, 2019
• Last Update Posted: November 18, 2019
• Last Verified: October 2019

Keywords provided by Wes Ely, Vanderbilt University Medical Center:

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; 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