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

Delirium Clinical Trial

— MIND-USA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01211522
• Other study ID #: AG035117-01A1
• Secondary ID: 101082
• Status: Completed
• Phase: Phase 3
• Start date: December 14, 2011
• Est. completion date: July 19, 2018

Study information

• Verified date: October 2019
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 566
• Est. completion date: July 19, 2018
• Est. primary completion date: August 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Albert Einstein Medical College-Montefiore Medical Center	Bronx	New York
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	The Ohio State Medical Center	Columbus	Ohio
United States	Baylor Health Care System	Dallas	Texas
United States	Denver Health/University of Colorado Health Sciences Center	Denver	Colorado
United States	Moses Cone Health System	Greensboro	North Carolina
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University Medical Center	New Haven	Connecticut
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Washington	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

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