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The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study
Phase 3 trial testing Haloperidol in Delirium in 566 participants. Completed in 19 July 2018.
| Lead sponsor | Vanderbilt University Medical Center |
|---|---|
| Phase | Phase 3 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | quadruple |
| Primary purpose | treatment |
| Enrollment | 566 |
| Start date | 14 December 2011 |
| Primary completion | 28 August 2017 |
| Estimated completion | 19 July 2018 |
| Sites | 16 locations across United States |
Vanderbilt University Medical Center
18 and older, any sex, with Delirium or Impaired Cognition. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
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.
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 8 | 0 – 11 |
| Ziprasidone | 8 | 2 – 11 |
| Placebo | 7 | 0 – 11 |
Deaths within the specified timeframe
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 50 | |
| Ziprasidone | 53 | |
| Placebo | 50 |
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 73 | |
| Ziprasidone | 65 | |
| Placebo | 63 |
Duration of delirium during the intervention period
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 4 | 2 – 7 |
| Ziprasidone | 4 | 2 – 6 |
| Placebo | 4 | 2 – 8 |
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 2 | |
| Ziprasidone | 0 | |
| Placebo | 0 |
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 1 | |
| Ziprasidone | 1 | |
| Placebo | 1 |
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 0 | |
| Ziprasidone | 0 | |
| Placebo | 0 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 2 | 1 – 6 |
| Ziprasidone | 3 | 2 – 5 |
| Placebo | 3 | 1 – 5 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 5 | 3 – 13 |
| Ziprasidone | 6 | 3 – 10 |
| Placebo | 5 | 3 – 14 |
Days from first ICU discharge to next ICU readmission.
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 5 | 2 – 9 |
| Ziprasidone | 5 | 2 – 9 |
| Placebo | 4 | 1 – 8 |
Days from randomization to successful hospital discharge, where "successful" indicates that discharge was followed by at least 48 hours alive.
| Group | Value | 95% CI |
|---|---|---|
| Haloperidol | 13 | 8 – 22 |
| Ziprasidone | 12 | 8 – 21 |
| Placebo | 13 | 8 – 23 |
Time frame: 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.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Haloperidol | Ziprasidone | Placebo |
|---|---|---|---|---|
| Torsades de pointes | Cardiac disorders | — | — | — |
| Extrapyramidal symptoms | Nervous system disorders | — | — | — |
| Neuroleptic malignant syndrome | Nervous system disorders | — | — | — |
| Reaction | System | Haloperidol | Ziprasidone | Placebo |
|---|---|---|---|---|
| Oversedation | Nervous system disorders | — | — | — |
| Prolonged QTc | Cardiac disorders | — | — | — |
Most-reported serious reactions: Torsades de pointes, Extrapyramidal symptoms, Neuroleptic malignant syndrome.
Data from ClinicalTrials.gov NCT01211522 adverse events section.
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.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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