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

Tracking Information

• First Submitted Date: September 28, 2010
• First Posted Date: September 29, 2010
• Results First Submitted Date: July 16, 2019
• Results First Posted Date: August 20, 2019
• Last Update Posted Date: November 18, 2019
• Actual Study Start Date: December 14, 2011
• Actual Primary Completion Date: August 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 19, 2018)

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.

• Original Primary Outcome Measures (submitted: September 28, 2010): Delirium/coma-free days [ Time Frame: 14 days ]

Current Secondary Outcome Measures (submitted: October 31, 2019)

• Mortality [ Time Frame: 30-day and 90-day ]
  Deaths within the specified timeframe
• Delirium Duration [ Time Frame: 14 days ]
  Duration of delirium during the intervention period
• Number of Participants With Torsades de Pointes [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
• Number of Participants With Extrapyramidal Symptoms [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
• Number of Participants With Neuroleptic Malignant Syndrome [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
• 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.
• 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.
• Time to ICU Readmission [ Time Frame: 90 days after first ICU discharge ]
  Days from first ICU discharge to next ICU readmission.
• 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.

Original Secondary Outcome Measures (submitted: September 28, 2010)

• Survival [ Time Frame: 30-day, 90-day, and 1-year ]
• 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.
• Neuropsychological Dysfunction [ Time Frame: 3-month, 12-month ]
  Assessed using a battery of cognitive tests.
• Quality of life [ Time Frame: 3-month, 12-month ]
• Posttraumatic Stress Disorder [ Time Frame: 3-month, 12-month ]
• QTc prolongation [ Time Frame: 14 days ]
• Extrapyramidal symptoms [ Time Frame: 14 days ]
• Neuroleptic malignant syndrome [ Time Frame: 14 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study
• Official Title: MIND-USA Study: Modifying the Impact of ICU-Associated Neurological Dysfunction
• 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.
• 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
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double blind, placebo controlled

Primary Purpose: Treatment

Condition

• Delirium
• Impaired Cognition
• Long Term Psychologic Disorders

Intervention

• 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
• 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
• 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.

Study Arms

• Experimental: Haloperidol
  Haloperidol
  Intervention: Drug: Haloperidol
• Experimental: Ziprasidone
  Ziprasidone
  Intervention: Drug: Ziprasidone
• Placebo Comparator: Placebo
  Placebo
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 19, 2019): 566
• Original Estimated Enrollment (submitted: September 28, 2010): 876
• Actual Study Completion Date: July 19, 2018
• Actual Primary Completion Date: August 28, 2017 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01211522
• Other Study ID Numbers: AG035117-01A1; 101082 ( Other Identifier: Vanderbilt University Institutional Review Board )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Wes Ely, Vanderbilt University Medical Center
• Study Sponsor: Vanderbilt University Medical Center
• Collaborators: Not Provided

Investigators

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

• PRS Account: Vanderbilt University Medical Center
• Verification Date: October 2019