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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Delirium, Impaired Cognition, Long Term Psychologic Disorders

Intervention / Treatment
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* Drug: Haloperidol
* Drug: Ziprasidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients (≥18 years old) in a medical and/or surgical ICU on mechanical ventilation or non-invasive positive pressure ventilation (NIPPV), and/or requiring vasopressors due to shock delirious (according to the CAM-ICU) Exclusion Criteria: 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 Pregnancy or breastfeeding (negative pregnancy test required prior to enrollment of female patients of childbearing age) 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. 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 Ongoing maintenance therapy with typical or atypical antipsychotics History of neuroleptic malignant syndrome (NMS), haloperidol allergy, or ziprasidone allergy 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) Inability to obtain informed consent from an authorized representative within 72 hours of meeting all inclusion criteria, i.e., developing qualifying organ dysfunction criteria.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Haloperidol<br>Haloperidol | Drug: Haloperidol<br>* 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.<br>* Other names: Haldol;|
| Experimental: Ziprasidone<br>Ziprasidone | Drug: Ziprasidone<br>* 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.<br>* Other names: Geodon;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Delirium, Intensive care, Mechanical ventilation, Antipsychotic, Haloperidol, Ziprasidone, Randomized, Placebo, Sepsis, Sedation, Long-term cognitive impairment