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| ID | Type | Description | Link |
|---|---|---|---|
| 101082 | Other Identifier | Vanderbilt University Institutional Review Board |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Haloperidol | Experimental | Haloperidol |
|
| Ziprasidone | Experimental | Ziprasidone |
|
| Placebo | Placebo Comparator | Placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Mortality | Deaths within the specified timeframe | 30-day and 90-day |
| Delirium Duration | Duration of delirium during the intervention period |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| E. Wesley Ely, MD, MPH | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Denver Health/University of Colorado Health Sciences Center | Denver | Colorado | 80204-4507 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41739187 | Derived | Boehm LM, Mart MF, LaNoue M, Siao SF, Pun BT, Bowton DL, Exline MC, Gong MN, Hite RD, Hough CL, Hyzy RC, Khan BA, Owens RL, Pisani MA, Rock P, Schmidt GA, Jackson JC, Ely EW, Girard TD, Brummel NE. Association between ABCDE bundle compliance and long-term outcomes: a secondary longitudinal analysis. Intensive Care Med. 2026 Mar;52(3):466-475. doi: 10.1007/s00134-026-08346-0. Epub 2026 Feb 25. | |
| 40198074 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Haloperidol | Haloperidol 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. |
| FG001 | Ziprasidone |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 22, 2016 | Jul 16, 2019 |
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Double blind, placebo controlled
|
| 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. |
|
|
| 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. |
|
| 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 |
| Yale University Medical Center |
| New Haven |
| Connecticut |
| 06520-8057 |
| United States |
| Indiana University | Indianapolis | Indiana | 46202-2915 | United States |
| University of Iowa | Iowa City | Iowa | 52242 | United States |
| University of Maryland Medical Center | Baltimore | Maryland | 21201 | United States |
| Massachusetts General Hospital | Boston | Massachusetts | 02114-2696 | United States |
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| University of Michigan Health System | Ann Arbor | Michigan | 48109-5360 | United States |
| Albert Einstein Medical College-Montefiore Medical Center | The Bronx | New York | 10461 | United States |
| University of North Carolina - Chapel Hill | Chapel Hill | North Carolina | 27599-7248 | United States |
| Moses Cone Health System | Greensboro | North Carolina | 27410 | United States |
| The Ohio State Medical Center | Columbus | Ohio | 43210-1228 | United States |
| University of Pennsylvania | Philadelphia | Pennsylvania | 19104-6205 | United States |
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232-8300 | United States |
| Baylor Health Care System | Dallas | Texas | 75206 | United States |
| University of Washington | Seattle | Washington | 98195-9472 | United States |
| Derived |
| 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. |
| 38701817 | 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. |
| 38252439 | 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. |
| 30346242 | 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. |
Ziprasidone 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. |
| FG002 | Placebo | Placebo 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. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Haloperidol | Haloperidol 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. |
| BG001 | Ziprasidone | Ziprasidone 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. |
| BG002 | Placebo | Placebo 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. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||
| Admission diagnosis | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Median | Inter-Quartile Range | days | 14 days |
|
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| Secondary | Mortality | Deaths within the specified timeframe | Posted | Count of Participants | Participants | 30-day and 90-day |
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| ||||||||||||||||||||||||||||||||||
| Secondary | Delirium Duration | Duration of delirium during the intervention period | Posted | Median | Inter-Quartile Range | days | 14 days |
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| Secondary | Number of Participants With Torsades de Pointes | Posted | Count of Participants | Participants | 14 days plus 4-day post-study drug period (if longer than 14 days) |
|
| |||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants With Extrapyramidal Symptoms | Posted | Count of Participants | Participants | 14 days plus 4-day post-study drug period (if longer than 14 days) |
|
| |||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants With Neuroleptic Malignant Syndrome | Posted | Count of Participants | Participants | 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. | Posted | Median | Inter-Quartile Range | days | 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. | Posted | Median | Inter-Quartile Range | days | 90 days |
| ||||||||||||||||||||||||||||||||||
| Secondary | Time to ICU Readmission | Days from first ICU discharge to next ICU readmission. | Time to ICU readmission reported among those who were readmitted to the ICU | Posted | Median | Inter-Quartile Range | days | 90 days after first ICU discharge |
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| ||||||||||||||||||||||||||||||||
| 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. | Posted | Median | Inter-Quartile Range | days | 90 days |
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|
During the period when the patients were receiving a trial drug or placebo and for 4 days after discontinuation, we assessed the patients for side effects. We also collected clinical outcomes data until hospital discharge or up to 90 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Haloperidol | Haloperidol 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. | 73 | 192 | 3 | 192 | 55 | 192 |
| EG001 | Ziprasidone | Ziprasidone 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. | 65 | 190 | 1 | 190 | 70 | 190 |
| EG002 | Placebo | Placebo 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. | 63 | 184 | 1 | 184 | 56 | 184 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Torsades de pointes | Cardiac disorders | Systematic Assessment |
| ||
| Neuroleptic malignant syndrome | Nervous system disorders | Systematic Assessment |
| ||
| Extrapyramidal symptoms | Nervous system disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Oversedation | Nervous system disorders | Systematic Assessment |
| ||
| Prolonged QTc | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| E Wesley Ely | Vanderbilt University Medical Center | â€(615) 936-3395‬ | wes.ely@vumc.org |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 7, 2018 | Jul 16, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D003693 | Delirium |
| D003072 | Cognition Disorders |
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D006220 | Haloperidol |
| C092292 | ziprasidone |
| ID | Term |
|---|---|
| D002090 | Butyrophenones |
| D007659 | Ketones |
| D009930 | Organic Chemicals |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Sepsis |
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| Airway protection |
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| COPD/asthma/other pulmonary |
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| Surgery |
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| CHF/MI/arrhythmia |
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| Cirrhosis/liver failure |
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| Seizures/neurologic disease |
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| Other |
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