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

Phase 3

Completed

• Conditions: Long Term Psychologic Disorders; Delirium; Impaired Cognition
• Interventions: Drug: Placebo; Drug: Haloperidol; Drug: Ziprasidone

• Registration Number: NCT01211522
• Lead Sponsor: Vanderbilt University Medical Center

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 Timeline

• Study First Submitted: 2010-09-28
• Study First Submitted QC: 2010-09-28
• Study First Posted: 2010-09-29
• Study Start: 2011-12-14
• Primary Completion: 2017-08-28
• Study Completion: 2018-07-19
• Results First Submitted: 2019-07-16
• Results First Submitted QC: 2019-08-19
• Results First Posted: 2019-08-20
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-31
• Last Update Posted: 2019-11-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 566

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo
Haloperidol	Haloperidol	Haloperidol
Ziprasidone	Ziprasidone	Ziprasidone

Primary Outcome Measures

Name	Time	Method
Delirium/Coma-free Days (DCFDs)	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

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

Trial Locations

Locations (16)

University of Michigan Health System; 🇺🇸 Ann Arbor, Michigan, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

Denver Health/University of Colorado Health Sciences Center; 🇺🇸 Denver, Colorado, United States

Yale University Medical Center; 🇺🇸 New Haven, Connecticut, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

University of Maryland Medical Center; 🇺🇸 Baltimore, Maryland, United States

Albert Einstein Medical College-Montefiore Medical Center; 🇺🇸 Bronx, New York, United States

The Ohio State Medical Center; 🇺🇸 Columbus, Ohio, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Baylor Health Care System; 🇺🇸 Dallas, Texas, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

University of North Carolina - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Moses Cone Health System; 🇺🇸 Greensboro, North Carolina, United States