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

NCT ID: NCT01211522

Last Updated: 2019-11-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 566 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-12-14
• Study Completion Date: 2018-07-19

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.

Conditions

Delirium; Impaired Cognition; Long Term Psychologic Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Haloperidol

Haloperidol

Group Type: EXPERIMENTAL

Haloperidol

Intervention Type: 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.

Ziprasidone

Ziprasidone

Group Type: EXPERIMENTAL

Ziprasidone

Intervention Type: 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.

Placebo

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Haldol; Geodon

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Wes Ely

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

E. Wesley Ely, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

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

University of Iowa

Iowa City, Iowa, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

Albert Einstein Medical College-Montefiore Medical Center

The Bronx, New York, United States

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Moses Cone Health System

Greensboro, North Carolina, 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

University of Washington

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 40198074 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38701817 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38252439 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30346242 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

101082

Identifier Type: OTHER

Identifier Source: secondary_id

AG035117-01A1

Identifier Type: -

Identifier Source: org_study_id