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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 : April 25, 2018
Sponsor:
Information provided by (Responsible Party):
Wes Ely, Vanderbilt University

September 28, 2010
September 29, 2010
April 25, 2018
December 2011
December 2018   (Final data collection date for primary outcome measure)
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.
Delirium/coma-free days [ Time Frame: 14 days ]
Complete list of historical versions of study NCT01211522 on ClinicalTrials.gov Archive Site
  • Survival [ Time Frame: 30-day, 90-day, and 1-year ]
    Time to death
  • Delirium duration [ Time Frame: 14 days ]
    Duration of delirium during the intervention period
  • 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 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.
  • 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 ICU readmission [ Time Frame: 90 days after first ICU discharge ]
    Days from first ICU discharge to next ICU readmission.
  • Hospital readmission [ Time Frame: 365 days ]
    Readmission to the hospital after index hospital discharge determined by self-report during follow-up interviews.
  • Neuropsychological dysfunction [ Time Frame: 3 and 12 months post-randomization ]
    Assessed using Telephone Interview for Cognitive Status (TICS), Digit Span and Similarities from the WAIS-III, Confusion Assessment Method (CAM) Telephone version, Paragraph Recall (both immediate and delayed portions) from the WMS-III, Controlled Oral Word Association Test (COWA), and the Hayling Test. These assessments will be scored in standard fashion and will allow us to characterize cognitive impairment across patients.
  • Quality of life [ Time Frame: 3 and 12 months post-randomization ]
    Assessed using the Katz ADL, Employment Questionnaire, Functional Activities Questionnaire (FAQ), EQ-5D-3L and a Healthcare Utilization Survey.
  • Posttraumatic stress disorder [ Time Frame: 3 and 12 months post-randomization ]
    Assessed using the PTSD Checklist (PCL-S, event specific version) with respondents instructed to answer questions in reference to the ICU experience.
  • Torsades de pointes [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
    Incidence of tachyarrhythmias (as documented by telemetry rhythm strip and/or 12-lead ECG) determined to be torsades de pointes by the site primary investigator and confirmed by the coordinating center.
  • Extrapyramidal symptoms [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
    Listing of any incidence of EPS, including treatment group and circumstances, during the study drug intervention period.
  • Neuroleptic malignant syndrome [ Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) ]
    Listing of any incidence of NMS, including treatment group and circumstances, during the study drug intervention period.
  • 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 ]
Not Provided
Not Provided
 
The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study
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.
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.
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Delirium
  • Impaired Cognition
  • Long Term Psychologic Disorders
  • 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.
  • Experimental: Haloperidol
    Haloperidol
    Intervention: Drug: Haloperidol
  • Experimental: Ziprasidone
    Ziprasidone
    Intervention: Drug: Ziprasidone
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
561
876
July 2019
December 2018   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
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
United States
 
 
NCT01211522
AG035117-01A1
101082 ( Other Identifier: Vanderbilt University Institutional Review Board )
Yes
Not Provided
Not Provided
Wes Ely, Vanderbilt University
Vanderbilt University
Not Provided
Principal Investigator: E. Wesley Ely, MD, MPH Vanderbilt University Medical Center
Vanderbilt University Medical Center
April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP