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

NCT01211522 | Completed Phase 3 Results DMC

• 2 other identifiers: AG035117-01A1101082
• Study Type: interventional
• Target: 566
• Locations: 1 country
• Sites: 16

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.

Conditions

Delirium; Impaired Cognition; Long Term Psychologic Disorders

Keywords

Delirium; Intensive care; Mechanical ventilation; Antipsychotic; Haloperidol; Ziprasidone; Randomized; Placebo; Sepsis; Sedation; Long-term cognitive impairment

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Mortality

  30-day and 90-day

• Delirium Duration

  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)

Study Arms (3)

Haloperidol

EXPERIMENTAL

Haloperidol

Drug: Haloperidol

Ziprasidone

EXPERIMENTAL

Ziprasidone

Drug: Ziprasidone

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Haloperidol DRUG

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.

Also known as: Haldol

Haloperidol

Ziprasidone DRUG

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.

Also known as: Geodon

Ziprasidone

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (16)

Denver Health/University of Colorado Health Sciences Center

Denver, Colorado, 80204-4507, United States

Location

Yale University Medical Center

New Haven, Connecticut, 06520-8057, United States

Location

Indiana University

Indianapolis, Indiana, 46202-2915, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114-2696, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109-5360, United States

Location

Albert Einstein Medical College-Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, 27599-7248, United States

Location

Moses Cone Health System

Greensboro, North Carolina, 27410, United States

Location

The Ohio State Medical Center

Columbus, Ohio, 43210-1228, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104-6205, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232-8300, United States

Location

Baylor Health Care System

Dallas, Texas, 75206, United States

Location

University of Washington

Seattle, Washington, 98195-9472, United States

Location

Related Publications (4)

• Ahn S, LaNoue M, Su H, Moale AC, Scheunemann LP, Kiehl AL, Douglas IS, Exline MC, Gong MN, Khan BA, Owens RL, Pisani MA, Rock P, Jackson JC, Ely EW, Girard TD, Boehm LM. Post-Intensive Care Syndrome and Caregiver Burden: A Post Hoc Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2025 Apr 1;8(4):e253443. doi: 10.1001/jamanetworkopen.2025.3443.

  PMID: 40198074 DERIVED

• Mart MF, Boehm LM, Kiehl AL, Gong MN, Malhotra A, Owens RL, Khan BA, Pisani MA, Schmidt GA, Hite RD, Exline MC, Carson SS, Hough CL, Rock P, Douglas IS, Feinstein DJ, Hyzy RC, Schweickert WD, Bowton DL, Masica A, Orun OM, Raman R, Pun BT, Strength C, Rolfsen ML, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Ely EW, Jackson JC, Girard TD. Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2024 Aug;12(8):599-607. doi: 10.1016/S2213-2600(24)00077-8. Epub 2024 Apr 30.

  PMID: 38701817 DERIVED

• Stollings JL, Boncyk CS, Birdrow CI, Chen W, Raman R, Gupta DK, Roden DM, Rivera EL, Maiga AW, Rakhit S, Pandharipande PP, Ely EW, Girard TD, Patel MB. Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024 Jan 2;7(1):e2352034. doi: 10.1001/jamanetworkopen.2023.52034.

  PMID: 38252439 DERIVED

• 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.

  PMID: 30346242 DERIVED

MeSH Terms

Conditions

Delirium; Cognition Disorders; Sepsis

Interventions

Haloperidol; ziprasidone

Condition Hierarchy (Ancestors)

Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes

Intervention Hierarchy (Ancestors)

Butyrophenones; Ketones; Organic Chemicals

Results Point of Contact

• Title: E Wesley Ely
• Organization: Vanderbilt University Medical Center

wes.ely@vumc.org

‭(615) 936-3395‬

Study Officials

• E. Wesley Ely, MD, MPH

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind, placebo controlled
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: September 28, 2010
• First Posted: September 29, 2010
• Study Start: December 14, 2011
• Primary Completion: August 28, 2017
• Study Completion: July 19, 2018
• Last Updated: November 18, 2019
• Results First Posted: August 20, 2019

Record last verified: 2019-10

Locations

US (16)