Trial Outcomes & Findings for The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study (NCT NCT01211522)

NCT ID: NCT01211522

Last Updated: 2019-11-18

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 566 participants
• Primary outcome timeframe: 14 days
• Results posted on: 2019-11-18

Participant Flow

Participant milestones

Measure	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.	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.	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.
Overall Study STARTED	192	190	184
Overall Study COMPLETED	189	183	179
Overall Study NOT COMPLETED	3	7	5

Reasons for withdrawal

Measure	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.	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.	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.
Overall Study Withdrawal by Subject	3	7	5

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.	Total n=566 Participants Total of all reporting groups
Age, Continuous	61 years n=93 Participants	61 years n=4 Participants	59 years n=27 Participants	60 years n=483 Participants
Sex: Female, Male Female	84 Participants n=93 Participants	82 Participants n=4 Participants	77 Participants n=27 Participants	243 Participants n=483 Participants
Sex: Female, Male Male	108 Participants n=93 Participants	108 Participants n=4 Participants	107 Participants n=27 Participants	323 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	23 Participants n=93 Participants	27 Participants n=4 Participants	26 Participants n=27 Participants	76 Participants n=483 Participants
Race (NIH/OMB) White	163 Participants n=93 Participants	151 Participants n=4 Participants	153 Participants n=27 Participants	467 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	6 Participants n=93 Participants	12 Participants n=4 Participants	5 Participants n=27 Participants	23 Participants n=483 Participants
Region of Enrollment United States	192 participants n=93 Participants	190 participants n=4 Participants	184 participants n=27 Participants	566 participants n=483 Participants
Admission diagnosis ARDS	44 Participants n=93 Participants	35 Participants n=4 Participants	39 Participants n=27 Participants	118 Participants n=483 Participants
Admission diagnosis Sepsis	43 Participants n=93 Participants	33 Participants n=4 Participants	35 Participants n=27 Participants	111 Participants n=483 Participants
Admission diagnosis Airway protection	46 Participants n=93 Participants	44 Participants n=4 Participants	53 Participants n=27 Participants	143 Participants n=483 Participants
Admission diagnosis COPD/asthma/other pulmonary	20 Participants n=93 Participants	28 Participants n=4 Participants	23 Participants n=27 Participants	71 Participants n=483 Participants
Admission diagnosis Surgery	13 Participants n=93 Participants	23 Participants n=4 Participants	13 Participants n=27 Participants	49 Participants n=483 Participants
Admission diagnosis CHF/MI/arrhythmia	6 Participants n=93 Participants	6 Participants n=4 Participants	6 Participants n=27 Participants	18 Participants n=483 Participants
Admission diagnosis Cirrhosis/liver failure	3 Participants n=93 Participants	3 Participants n=4 Participants	6 Participants n=27 Participants	12 Participants n=483 Participants
Admission diagnosis Seizures/neurologic disease	4 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants	6 Participants n=483 Participants
Admission diagnosis Other	13 Participants n=93 Participants	17 Participants n=4 Participants	8 Participants n=27 Participants	38 Participants n=483 Participants

PRIMARY outcome

Timeframe: 14 days

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.

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Delirium/Coma-free Days (DCFDs)	8 days Interval 0.0 to 11.0	8 days Interval 2.0 to 11.0	7 days Interval 0.0 to 11.0

SECONDARY outcome

Timeframe: 30-day and 90-day

Deaths within the specified timeframe

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Mortality 30-day mortality	50 Participants	53 Participants	50 Participants
Mortality 90-day mortality	73 Participants	65 Participants	63 Participants

SECONDARY outcome

Timeframe: 14 days

Duration of delirium during the intervention period

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Delirium Duration	4 days Interval 2.0 to 7.0	4 days Interval 2.0 to 6.0	4 days Interval 2.0 to 8.0

SECONDARY outcome

Timeframe: 14 days plus 4-day post-study drug period (if longer than 14 days)

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Number of Participants With Torsades de Pointes	2 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 14 days plus 4-day post-study drug period (if longer than 14 days)

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Number of Participants With Extrapyramidal Symptoms	1 Participants	1 Participants	1 Participants

SECONDARY outcome

Timeframe: 14 days plus 4-day post-study drug period (if longer than 14 days)

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Number of Participants With Neuroleptic Malignant Syndrome	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 30 days

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.

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Time to Liberation From Mechanical Ventilation	2 days Interval 1.0 to 6.0	3 days Interval 2.0 to 5.0	3 days Interval 1.0 to 5.0

SECONDARY outcome

Timeframe: 90 days

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.

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Time to Final ICU Discharge	5 days Interval 3.0 to 13.0	6 days Interval 3.0 to 10.0	5 days Interval 3.0 to 14.0

SECONDARY outcome

Timeframe: 90 days after first ICU discharge

Population: Time to ICU readmission reported among those who were readmitted to the ICU

Days from first ICU discharge to next ICU readmission.

Outcome measures

Measure	Haloperidol n=27 Participants 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.	Ziprasidone n=18 Participants 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.	Placebo n=23 Participants 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.
Time to ICU Readmission	5 days Interval 2.0 to 9.0	5 days Interval 2.0 to 9.0	4 days Interval 1.0 to 8.0

SECONDARY outcome

Timeframe: 90 days

Days from randomization to successful hospital discharge, where "successful" indicates that discharge was followed by at least 48 hours alive.

Outcome measures

Measure	Haloperidol n=192 Participants 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.	Ziprasidone n=190 Participants 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.	Placebo n=184 Participants 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.
Time to Hospital Discharge	13 days Interval 8.0 to 22.0	12 days Interval 8.0 to 21.0	13 days Interval 8.0 to 23.0

Adverse Events

Haloperidol

Serious events: 3 serious events

Other events: 55 other events

Deaths: 73 deaths

Ziprasidone

Serious events: 1 serious events

Other events: 70 other events

Deaths: 65 deaths

Placebo

Serious events: 1 serious events

Other events: 56 other events

Deaths: 63 deaths

Serious adverse events

Measure	Haloperidol n=192 participants at risk 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.	Ziprasidone n=190 participants at risk 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.	Placebo n=184 participants at risk 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.
Cardiac disorders Torsades de pointes	1.0% 2/192 • 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.	0.53% 1/190 • 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.	0.54% 1/184 • 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.
Nervous system disorders Neuroleptic malignant syndrome	0.00% 0/192 • 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.	0.00% 0/190 • 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.	0.00% 0/184 • 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.
Nervous system disorders Extrapyramidal symptoms	0.52% 1/192 • 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.	0.53% 1/190 • 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.	0.54% 1/184 • 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.

Other adverse events

Measure	Haloperidol n=192 participants at risk 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.	Ziprasidone n=190 participants at risk 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.	Placebo n=184 participants at risk 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.
Nervous system disorders Oversedation	21.9% 42/192 • 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.	26.3% 50/190 • 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.	25.0% 46/184 • 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.
Cardiac disorders Prolonged QTc	6.8% 13/192 • 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.	10.5% 20/190 • 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.	5.4% 10/184 • 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.

Additional Information

E Wesley Ely

Vanderbilt University Medical Center

Phone: ‭(615) 936-3395‬

Email: wes.ely@vumc.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place