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

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

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.

Study Overview

• Status: Completed
• Conditions: Delirium; Impaired Cognition; Long Term Psychologic Disorders
• Intervention / Treatment: Drug: Haloperidol; Drug: Ziprasidone; Drug: Placebo

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
• Enrollment (Actual): 566
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80204-4507
      • Denver Health/University of Colorado Health Sciences Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8057
      • Yale University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-2915
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114-2696
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5360
      • University of Michigan Health System
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Medical College-Montefiore Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7248
      • University of North Carolina - Chapel Hill
    • Greensboro, North Carolina, United States, 27410
      • Moses Cone Health System
  • Ohio
    • Columbus, Ohio, United States, 43210-1228
      • The Ohio State Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-6205
      • University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37232-8300
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75206
      • Baylor Health Care System
  • Washington
    • Seattle, Washington, United States, 98195-9472
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.
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 Names: 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 Names: Geodon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delirium/Coma-free Days (DCFDs)	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.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Deaths within the specified timeframe	30-day and 90-day
Delirium Duration	Duration of delirium during the intervention period	14 days
Number of Participants With Torsades de Pointes		14 days plus 4-day post-study drug period (if longer than 14 days)
Number of Participants With Extrapyramidal Symptoms		14 days plus 4-day post-study drug period (if longer than 14 days)
Number of Participants With Neuroleptic Malignant Syndrome		14 days plus 4-day post-study drug period (if longer than 14 days)
Time to Liberation From Mechanical Ventilation	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.	30 days
Time to Final ICU Discharge	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.	90 days
Time to ICU Readmission	Days from first ICU discharge to next ICU readmission.	90 days after first ICU discharge
Time to Hospital Discharge	Days from randomization to successful hospital discharge, where "successful" indicates that discharge was followed by at least 48 hours alive.	90 days

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2011
• Primary Completion (Actual): August 28, 2017
• Study Completion (Actual): July 19, 2018

Study Registration Dates

• First Submitted: September 28, 2010
• First Submitted That Met QC Criteria: September 28, 2010
• First Posted (Estimate): September 29, 2010

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: October 31, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Randomized; Sedation; Sepsis; Placebo; Delirium; Antipsychotic; Mechanical ventilation; Intensive care; Haloperidol; Long-term cognitive impairment; Ziprasidone
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Delirium; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Anti-Dyskinesia Agents; Ziprasidone; Haloperidol; Haloperidol decanoate
• Other Study ID Numbers: AG035117-01A1; 101082 (Vanderbilt University Institutional Review Board)