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
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 566
Healthy volunteers: no

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.

Arms:
arm 1: Haloperidol arm 2: Ziprasidone arm 3: Placebo

Interventions: intervention 1: Haloperidol intervention 2: Ziprasidone intervention 3: Placebo
Intervention descriptions: intervention 1: 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 2: 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 3: 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.

Protocol document:
Prot_000.pdf: 
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!
 
 
 
The MIND-USA Study 
Modifying the Impact of ICU-Associated Neurological Dysfunction 
 
FDA-IND #104322 
 
E. Wesley Ely, MD, MPH 
Timothy D. Girard, MD, MSCI 
 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Center for Health Services Research 
Vanderbilt University School of Medicine 
 
Geriatric Research, Education and Clinical Center (GRECC) Service 
Department of Veterans Affairs Medical Center 
Tennessee Valley Healthcare System 
 
 
 
 
 
 
 
 
 
Contact Details 
 
Primary Investigator  
 
E. Wesley Ely, MD, MPH 
 
 
 
 
 
Phone  
(615) 936-2795 
 
 
 
 
 
Fax 
 
(615) 936-1269 
 
 
 
 
 
E-mail  
wes.ely@vanderbilt.edu 
Co-Investigator 
 
 
Timothy D. Girard, MD, MSCI 
 
 
 
 
 
Phone  
(615) 936-5069 
 
 
 
 
 
Fax 
 
(615) 936-1269 
 
 
 
 
 
E-mail  
timothy.girard@vanderbilt.edu 
 
 


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Table of Contents: 
 
1.0 
Introduction and Specific Aims 
2.0 
Background 
3.0 
Preliminary Studies 
4.0 
Study Objectives and Endpoints 
5.0 
Inclusion/Exclusion Criteria 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Risks of Investigational Agents/Devices (side effects) 
9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 
 


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1.0 
Introduction 
 
Intensive care will soon represent 2% of the United States’ gross domestic product,1 and nearly 
two-thirds of intensive care unit (ICU) days are accounted for by people over 65 years old.2 The 
population of aging Americans filling our ICUs is especially vulnerable to the development and 
persistence of delirium.3-6 We and others have shown ICU delirium to independently predict a 3-
fold higher mortality within a year,7-9 longer hospital stays,10,11 much higher costs of care,12 and 
long-term cognitive impairment.13,14 Delirium, a form of acute brain dysfunction, develops in 7 
out of 10 mechanically ventilated patients in general medical and surgical ICUs.7,15-18 Delirium’s 
high prevalence and independent relationship with poor outcomes in critically ill patients have 
led to numerous recommendations that delirium monitoring be part of the standard daily 
assessment in all ICU patients.19-21 Delirium is usually multifactorial,22,23 and treatment of 
underlying disturbances represents first-line management. Even after addressing modifiable risk 
factors for ICU patients, however, delirium often persists from a few days to months. 
Antipsychotics are recommended as the medication class of choice for delirium by all major 
clinical guidelines,19-21,24 yet very little evidence exists to support this internationally recognized 
and adopted treatment.25-28 Because the vast population of older ICU patients are at very high 
risk for delirium, millions of older patients around the world receive significant amounts of 
intravenous antipsychotic medications for delirium despite the fact that no placebo-controlled 
trial has definitively demonstrated efficacy or safety of these medications for ICU delirium. Tens 
of thousands of ICU patients receive antipsychotics for delirium every day with limited evidence 
to establish best practice for effective pharmacologic management of this debilitating syndrome. 
Haloperidol, a “typical” antipsychotic, is the most commonly chosen, used by 86% of ICU 
practitioners.29,30 Atypical antipsychotics, of which there are currently eight available in the U.S., 
are the next most commonly utilized drug for delirium in ICUs; 38% of practitioners use 
atypicals.29,30 Despite their popularity, the use of antipsychotics for delirium remains 
controversial. Concerns about the safety of these drugs are fueled by well-known toxicities, 
including lethal cardiac arrhythmias and extrapyramidal symptoms, as well as reports of 
increased death rates associated with antipsychotic use in ambulatory geriatric populations.31-37 
The MIND-USA study is a multicenter, double-blind, randomized, placebo-controlled trial 
investigating the effects of intravenously (IV) administered typical and atypical 
antipsychotics (haloperidol and ziprasidone) on delirium in critically ill patients, many of 
whom are older than 70 years. This study will have adequate (> 80%) power to detect a 
therapeutic difference between haloperidol and an atypical antipsychotic (ziprasidone) versus 
placebo in a broad adult ICU population and within important subgroups such as severely ill 
older patients with significant comorbidities. In the burgeoning field of aging brain research—
which involves the disciplines of medicine, surgery, geriatrics, psychiatry, critical care, 
neuroscience, nursing, and clinical pharmacology—this timely interdisciplinary investigation of 
a common, expensive, deadly condition without known effective therapy will both direct clinical 
practice and shape future work. 
 


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Hypothesis: The administration of typical (haloperidol) and atypical (ziprasidone) antipsychotics 
to critically ill patients with delirium will improve short- and long-term clinical outcomes. 
 
Specific Aims 
Aim 1: To determine whether haloperidol or ziprasidone administered to delirious 
medical/surgical ICU patients will increase days alive without delirium (measured as 
delirium/coma-free days [DCFDs]) over a 14-day study period compared with placebo 
and compared with one another. 
Aim 2: To determine whether haloperidol or ziprasidone will improve 30-day, 90-day, and 1-
year survival compared with placebo and compared with one another. 
Aim 3: To determine whether haloperidol or ziprasidone will reduce ICU length of stay (LOS) 
(i.e., time to ICU discharge) compared with placebo and compared with one another. 
Aim 4: To determine whether haloperidol or ziprasidone will improve long-term 
neuropsychological outcomes, functional independence, quality of life, and 
posttraumatic stress disorder symptoms at 3-month and 1-year follow-up compared 
with placebo and compared with one another. 
 
To complete these Aims, we will consent adult medical and surgical ICU patients (a) on 
mechanical ventilation or non-invasive positive pressure ventilation, and/or (b) in shock 
requiring vasopressors. Once delirium occurs, we will randomize a total of 561 delirious patients 
(187 to the haloperidol group, 187 to the ziprasidone group, and 187 to the placebo group) and 
follow them for 1 year. In the absence of an indication requiring hold of study drug, patients will 
receive study drug until delirium has resolved for two days or ICU discharge or 14 days after the 
day of randomization, whichever occurs first. While tracking primary (delirium duration, Aim 
1) and secondary outcomes (mortality, ICU LOS, and long-term neuropsychological function; 
Aims 2-4), we will closely monitor safety parameters, including arrhythmias, extrapyramidal 
symptoms (EPS), neuroleptic malignant syndrome (NMS), and posttraumatic stress disorder 
(PTSD). The study sample size was explicitly chosen to ensure adequate power (≥ 80%) to 
detect the effect of antipsychotics in four important subgroups: age ≥ 70 years, high severity 
of illness (APACHE II ≥ 25), presence of severe sepsis at enrollment, and medical vs. surgical 
ICU patients. We will also conduct hypothesis-generating subgroup analyses of the effect of 
antipsychotics on delirium in patients with pre-existing cognitive impairment. 
 
2.0 
Background 
 
“For many aging people in good physical condition, who succumb to an acute illness, 
cognitive decline [e.g., delirium followed by an acquired post-ICU long-term cognitive 
impairment] is the main threat to their ability to recover and enjoy their favorite 
activities; for those whose physical activities were already limited, cognitive decline is a 
major additional threat to quality of life.” 
-National Research Council38  
“In patient populations for whom the evidence of the efficacy of antipsychotic 
medications is limited…prudence would suggest that the use of these drugs should be 
reduced sharply.” 
-January 2009 NEJM39 (yet data show sharp increases in ICU use recently)29,40 
 


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Figure 1. Defining Delirium and Coma 
 
2.1 
The Magnitude of the Problem of Delirium in Critically Ill Patients. Delirium is a 
syndrome of acute organ dysfunction occurring in 50% to 80% of ICU patients.11,15,16,18,41-45 The 
DSM IV-TR46 and the CAM-ICU define delirium as an acute form of brain dysfunction 
characterized by a change in baseline mental status and inattention, plus disorganized thinking or 
an altered level of consciousness as noted in 
Figure 1,47 which distinguishes delirium 
from coma, and highlights the cardinal 
symptoms of delirium. A dashed line 
encircles optional symptoms of delirium (i.e., 
those sometimes present but not mandatory 
for 
a diagnosis of delirium). Whereas 
“respiratory failure” is the most common 
reason for ICU admission across ages, 
delirium (i.e., brain “failure”) is the classic 
geriatric syndrome serving as the strongest 
determinant of hospitalized patients’ length 
of 
stay and disposition.10 Delirium in ICU 
patients carries enormous financial and societal burdens due to its association with increased 
morbidity, mortality,7 and prolonged hospital stays,10 as well as its relationship to long-term 
neuropsychological deficits among ICU survivors.48-50 In fact, the occurrence of ICU delirium 
predicts a 3- to 13-fold rise in the likelihood of death by 1 year after adjusting for severity of 
illness, coma, sedatives, and other relevant covariates.7,8 In addition, each additional day of 
delirium independently increases the risk of death by 10% (p=0.03),7,9 strongly supporting 
Aims 1 and 2 of the MIND-USA study. It is estimated that ICU delirium is associated with 
costs ranging from $4 to $16 billion annually in the U.S. alone,12 not including added cost of lost 
workdays, caregiver burden, or cognitive rehabilitation for the 66% of patients with ongoing 
neuropsychological deficits at 6 months and the 50% with ongoing deficits at 24 months 
following their ICU stay.13,48,51,52 Due to the increased utilization of intensive care and our aging 
population, who have multiple medical problems, pre-existing cognitive impairment, and 
increased risk of functional decline,53 the toll of ICU delirium is likely to grow exponentially in 
upcoming decades.54 This toll is not merely measured in lives lost. Links are increasingly well 
established between delirium and long-term morbidities, including impaired quality of life, 
frailty, depression, anxiety, PTSD, and persistent cognitive dysfunction akin to dementia 
(supporting Aim 4 of MIND-USA).55 An intervention to reduce delirium may allow more 
patients not only to survive but also to live more meaningfully. 
As a result of the above-mentioned facts, the Society of Critical Care Medicine (SCCM) 
and numerous others internationally have recommended routine monitoring for delirium in all 
ICU patients.19-21 Monitoring increases detection and has resulted in earlier and widespread 
increases in treatment with typical and atypical antipsychotics29,30,56-58 despite cautionary 
studies.37,39,59,60 The majority of health care professionals in a national survey conducted in 
200240 believed that delirium was a vital yet inadequately addressed problem in critically ill 
patients and that there were few data directing appropriate therapy for this condition. 
Unfortunately, only a few randomized trials of any pharmacological interventions in ICU 
patients have improved our knowledge base,18,45,61,62 though we are poised to correct this deficit 
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Other approaches to managing delirium, such as multicomponent prevention protocols, 
have been shown in non-ICU populations to improve the incidence and duration of delirium but 
not mortality.63-68 Unfortunately, none of these studies have included ICU patients and the 
marked clinical differences of the ICU population (higher number of risk factors for delirium, 
difficulty with communication due to intubation, and omnipresent use of sedatives) limit the 
utilization of these protocols in the ever-expanding population of ICU patients. 
 
2.2 
Aligning Proposed Mechanisms of Delirium with Recommended Therapy. Delirium 
is thought to result from imbalances in neurotransmitters within the brain.69-73 These imbalances 
form the fundamental scientific rationale and biological plausibility for our investigation. It is 
not the purpose of this research, nor would it be possible within such a large trial, to measure or 
document correction of neurotransmitter imbalances. This section provides a basic introduction 
to the concepts underlying this study proposal. It is hypothesized that delirium treatment may be 
achieved by partial correction of neurotransmitter imbalances via haloperidol or ziprasidone, 
with the secondary aim of minimizing adverse effects. This last point is important because drugs 
that help correct a neurotransmitter at one site might improve delirium yet cause an adverse 
event via the same neurotransmitter at another site or via downstream effects on alternative 
neurotransmitters.74,75 In general, neurotransmitter imbalances that have received the most 
attention in literature are dopamine excess, acetylcholine deficiency, and interactions 
between the serotonergic and dopaminergic systems.73 Importantly, there appears to be a 
link between dopaminergic and acetylcholine hypotheses for delirium that support a 
biological rationale for the MIND-USA study.76-82 These references and others indicate 
pharmacological and neuroanatomical evidence that acetylcholine and dopamine appear to be 
inversely related in delirium pathogenesis. Anatomically, dopaminergic and cholinergic 
pathways overlap in the brain: D2 receptors for dopamine, which inhibit acetylcholine synthesis, 
coincide with cholinergic fibers in layer V of the prefrontal cortex. Common events in the ICU, 
such as hypoxia or hypotension (to be tracked objectively in MIND-USA), can result in surges of 
dopamine that decrease acetylcholine and precipitate or exacerbate delirium. Neurotransmitter 
derangements may also be secondary to causal factors that ICU patients frequently possess 
including severe sepsis, multiple organ dysfunction syndrome, hypoxemia, metabolic 
disturbances, sleep deprivation, exogenous toxic agents, withdrawal from substances of abuse, 
and exposure to psychoactive medications, such as narcotics and benzodiazepines, which are 
indicated but often given in much higher doses and for longer durations than required. Indeed, 
ICU patients often have greater than 10 risk factors for delirium.10,16,43,83-86 Critically ill patients 
experiencing these problems are hypothesized to develop acute brain dysfunction/delirium due to 
the deranged neurotransmitter levels noted above, a concept that forms the basis of current 
worldwide (though controversial) practice of treating delirium with typical and atypical 
antipsychotics, the efficacy and safety of which will be tested in the MIND-USA trial. 
 
2.3 
State of the Evidence Regarding Haloperidol and Atypical Antipsychotics in 
Treatment of ICU Delirium. Haloperidol (used by 75-80% of intensivists) and more recently 
atypical antipsychotics (used by 35-40%) have emerged as the standard pharmacological 
treatments for delirium in the ICU.29 In the Society of Critical Care Medicine (SCCM)19 and 
other societal guidelines87,88 for the management of pain, anxiety, and delirium in the ICU, 
haloperidol is recommended as the drug of choice for delirium, though this is based on sparse 
outcomes data from nonrandomized case series and anecdotal reports. The dearth of data in this 


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area was emphasized in recent systematic reviews25,27,28,89 that concluded as follows: (1) “To 
date, there are no published double-blind, randomized, placebo-controlled trials to establish 
efficacy or safety of any antipsychotic medication in the management of delirium. There is 
limited evidence from uncontrolled studies that supports the use of low-dose, short-term 
treatment of delirium with some antipsychotics. Further study with well-designed clinical trials 
is required in this area,”89 (2) “Better designed and larger studies evaluating the addition of 
antipsychotic agents to nonpharmacologic treatments are needed to measure the true effect of 
pharmacologic treatment,”25 (3) “Small studies of limited scope require further corroborating 
evidence before translation into specific recommendations for delirium treatment.”27 Consistent 
with these conclusions, in their newly drafted guideline on the diagnosis, prevention and 
management of delirium, the National Institute for Health and Clinical Excellence (NICE) 
has explicitly called for a large, randomized placebo-controlled trial of haloperidol and 
atypical antipsychotics.21  
Haloperidol has been touted for over 15 years as a preferred delirium treatment.90-94 In a 
2002 survey40 of 638 professionals who reported treating delirium with haloperidol or atypical 
antipsychotics, the top reasons they used these agents were few side effects and satisfactory 
anecdotal efficacy. Still, over half of the respondents reported witnessing adverse reactions 
associated with haloperidol. A double-blind, randomized investigation of delirium in AIDS 
patients found that haloperidol was equal to chlorpromazine regarding delirium outcomes, and 
both were superior to lorazepam, which exacerbated delirium95 (a characteristic of 
benzodiazepines now shown consistently in ICU patients).6,16,18,45,86 More recently, a large, 
placebo-controlled prophylaxis study in elderly hip fracture patients (n=430) showed reductions 
in the severity (p<0.001) and duration (p<0.001) of delirium, but without lowering incidence 
(~16% in both groups).96 A retrospective cohort study concluded that haloperidol in ventilated 
patients was associated with lower mortality.97 Atypical antipsychotics—clozapine, ziprasidone, 
olanzapine, risperidone, aripiprazole, and quetiapine—are used at varying rates anecdotally 
throughout the world, though very sparse supportive data exist in non-ICU98-103 and ICU patient 
populations.62,104 Risperidone (in non-ICU patients)99,103 and olanzapine (in ICU patients)62 have 
been randomized against haloperidol, and in both studies there was a temporalreduction in 
delirium without differences between groups. The olanzapine vs. haloperidol study was an 
unblinded, non-placebo-controlled trial of 73 low severity and largely non-ventilated ICU 
patients that concluded olanzapine was a safe alternative to haloperidol.62 Most recently, in a 
prospective trial105 of 36 patients randomized to either quetiapine or placebo (n=18 per group) 
after having received ~3 to 5 mg of haloperidol, it was found that the haloperidol plus quetiapine 
treated patients experienced faster resolution of their delirium by 3.5 days as compared with the 
group receiving haloperidol plus placebo. In addition, the quetiapine-treated patients were over 
30% more likely to be discharged home or to rehabilitation than the placebo-treated patients. The 
lack of a true placebo group in any of these trials precludes any firm conclusions about the role 
of antipsychotics in ICU delirium. 
Regarding survival, however, 5 retrospective studies and 1 prospective placebo-
controlled study in non-ICU, non-delirium patients (i.e., predominantly demented elderly 
cohorts)31-37 have reported an association between long-term use (e.g., 2 to 3 months or longer) 
of both typical and atypical antipsychotics and increased mortality rates (prompting an FDA 
warning). Whereas both the duration of use and the patient population will be much 
different in the MIND-USA trial, these reports of increased mortality with antipsychotic 
use coupled with our data showing rising rates of use of antipsychotics in ICU patients for 


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delirium mandate that the medical community confirm the safety of short-term use in ICU 
patients.29,40 ICU patients’ vulnerability to adverse effects may be favorably balanced by 
their short term (days rather than months) exposure meeting the acute need for delirium 
treatment in a very well-monitored setting, especially in light of alternatives otherwise used 
such as benzodiazepines. 
 
2.4 
Mechanism and Safety Profile of Antipsychotics. The mechanism of action of 
haloperidol is believed primarily to be antagonism at dopamine (D2)106-109 and 5HT2A
74 receptors. 
In addition, its anti-inflammatory effects97,110 may help mitigate organ dysfunction in critical 
illness. Dopamine blockade in the cerebral cortex could improve cognition and reduce delirium. 
The potent affinity of haloperidol for D2 receptors extends beyond the cortex. Haloperidol also 
causes concomitant nigrostriatal pathway D2 blockade, disinhibition of acetylcholine (i.e., 
acetylcholine excess), and a risk for developing EPS acutely and dystonia when used 
chronically.109,111 In the 2002 survey,40 the most frequently mentioned adverse effects of 
haloperidol were oversedation, EPS, NMS, QT interval prolongation and torsades de pointes, 
respiratory complications, dystonia, and worsening delirium. Initially, potential adverse effects 
of haloperidol appeared to exceed those of atypical antipsychotics,112,113 but recent data on 
adverse events such as EPS, NMS, tardive dyskinesia, glucose and cholesterol abnormalities, 
cardiac dysrhythmias, and venous thromboembolism appear largely to counter-balance one 
another between typical and atypical agents37,114-122 and have called into question the safety 
profile of both typical and atypical antipsychotics in older patients (especially the demented 
elderly).32-36,36,122-124  
Atypical antipsychotic agents, compared with haloperidol, have a wider variety of 
reported affinities for CNS receptors, including dopamine, serotonin, adrenergic, and muscarinic 
receptors.107,125 Ziprasidoneis an antagonist at D2, H1, α1, 5-HT2A, 5-HT2C, and 5-HT1D receptors 
and an agonist at 5-HT1A receptors.125,126 Like other successful antipsychotic medications, it has 
high affinity for the D2 receptor, though this is not the majority of its receptor activity (as seen 
with haloperidol). It is distinguished from other atypicals by blocking reuptake of norepinephrine 
and 5-HT.126 As stated above, atypical antipsychotics typically have a lower incidence of EPS 
versus haloperidol.112,127 A high 5HT2A/D2 receptor affinity ratio, which is a particularly strong 
characteristic of ziprasidone, has been correlated with lower propensity for EPS and may be 
advantageous in treating negative symptoms126 so prevalent in hypoactive delirium. The α1 
receptor affinity of ziprasidone is reduced in comparison to other atypical antipsychotic 
medications, which may translate into less orthostatic hypotension. It increases central nervous 
system acetylcholine and through agonism at the 5HT1A receptor (as seen with the antidepressant 
and anxiolytic buspirone) can increase dopamine in the cortex, both of which theoretically would 
be helpful for delirium. 
The strikingly divergent receptor affinities of these two classes of antipsychotics adds to 
the clinical conundrum surrounding the fact that they are both used anecdotally in widely varying 
rates across the country for treatment of delirium. Thus, in addition to being the first ever 
adequately powered trial to compare antipsychotics vs. placebo for ICU delirium, MIND-USA 
will also be a major step toward making evidence-based decisions about which class of 
antipsychotics is most effective for critically ill delirious patients. Lastly, the trial may begin to 
shed light on the complex and poorly understood neurophysiologic derangements underlying 
delirium in critically ill patients.128  
 


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2.5 
QT Prolongation and Haloperidol and Ziprasidone. Antipsychotic medications as a 
class pose a risk of cardiac conduction disturbance and sudden death.6,37,59,59,129-134 The risk of 
QT prolongation and torsades de pointes appears to be cross-class.135 In fact, haloperidol had the 
lowest rate ratio for cardiac death among typical and atypical agents in a recent NEJM report.37 It 
has been noted that haloperidol’s average QTc prolongation at 15 mg/d is 7.1 milliseconds. This 
modest increase in QTc has rarely been associated with significant arrhythmia risk as long as 
baseline and “on-treatment” QTc are < 500 ms, which is easy to detect on continuous ECG 
monitoring as will be used in all ICU patients for MIND-USA.132,136 The risk is dose-related130 
and greater for haloperidol when > 35mg per day, nearly double the maximum dose to be used in 
this trial.131 The incidence of QT prolongation varies with the specific type of atypical 
antipsychotic. It is considered rare with ziprasidone137 at 0.06% QTc ≥ 500 msec (data from 
2004 Up-To-Date report on ziprasidone), and one study found that ziprasidone and haloperidol 
have equivalent effects on the QTc interval.138 The clinical significance of this associated QT 
prolongation is not known, yet the occurrence of arrhythmias (including torsades de pointes) has 
been reported as rare. In a study using a total of 50mg of IM ziprasidone and 17.5mg of IM 
haloperidol over 4 hours, the average increase in QTc from baseline in the ziprasidone group was 
12.8 msec at Cmax and in the haloperidol group it was 14.7 msec at Cmax. In this study no 
patient had a QTc interval exceeding 500 msec (data from package insert for ziprasidone). 
 
2.6 
Route of Administration, Pharmacokinetics, and Drug Interactions of Haloperidol 
and Ziprasidone. We have an FDA IND for the MIND-USA investigation (IND #104322) that 
includes three treatment groups (haloperidol, ziprasidone, and placebo). Both study drugs, 
haloperidol and ziprasidone, may be delivered reliably and with rapid onset via the PO and IM 
routes, though the IV route is preferable in an ICU setting, where patients frequently do not have 
enteral access and coagulopathy precludes IM injections. Whereas haloperidol has routinely 
been administered IV for decades (despite the absence of FDA approval for this route), the 
IV use of atypical antipsychotics is less common but is reported in case reports139-141 and in 
one phase I study of healthy volunteers (N=12 received IV ziprasidone with no ill effects).142 
For example, a 47-yr-old mechanically ventilated ICU patient experiencing profound delirium 
despite multiple doses of haloperidol and sedatives received a 20mg IV bolus of ziprasidone with 
“dramatic” improvement in restlessness and delirium and no extrapyramidal or cardiac side 
effects.139 In the only report of extrapyramidal side effects due to IV ziprasidone, symptoms 
completely resolved after treatment with single doses of diphenhydramine and benztropine.143 
Both haloperidol and ziprasidone are greater than 90% protein bound. The mean half-life of 
haloperidol is 21 hours with N-dealkylation being the predominant pathway of metabolism; all of 
the metabolites are inactive with the possible exception of an active hydroxyl metabolite. The 
mean half-life of ziprasidone is 7 to 10 hours, with CYP 3A4 being the predominant isoenzyme 
involved in metabolism. The IM formulation of ziprasidone contains a solubilizing agent called 
β-cyclodextrin (in this case, specifically SBE-β-CD) that has been safely used in other IV 
medications (e.g., itraconazole and voriconazole) at much higher concentrations.144,145 In fact, in 
this investigation our dosing range will have around 3% of what is given routinely with 
voriconazole, and even in study patients with renal impairment, they will only receive around 15-
18% of what is given to humans currently with FDA-approved use of IV voriconazole. 
Haloperidol is extensively metabolized by the liver’s CYP2D6, CYP3A4, and CYP1A1 
enzymes,74,146-150 leaving 1% of administered dose excreted unchanged in urine. Haloperidol has 
metabolic interactions with ~20 drugs,148,150 but those of considerable hazard are infrequently 


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used in ICU patients. Some important candidates to consider include carbamazepine and 
phenytoin, which can cause increased haloperidol metabolism and lower its levels. Others with 
the opposite effect, thereby possibly causing increased concentrations of haloperidol, include 
buspirone, fluoxetine, and itraconazole. When given concomitantly with lithium, CNS toxicity 
can result. Rather than exclude patients on these agents and thereby lose the ability to advance 
our understanding through the context of a controlled trial, methods have been designed to 
collect haloperidol plasma concentrations and to monitor safety parameters, including continuous 
cardiac monitoring. Ziprasidone is unlikely to cause significant interactions with drugs 
metabolized by the cytochrome P450 system. There are no clinically significant interactions with 
lorazepam or other benzodiazepines, narcotics, H2 blockers, propranolol, or lithium. 
 
2.7 
Placebo “Treatment” of Delirium as the Comparator for the MIND-USA Trial. 
Justification for a placebo treatment group as the primary comparator for this trial rests on four 
distinct and firm issues. First, though many delirious ICU patients receive antipsychotics, the 
majority of delirious patients actually receive no specific treatment, largely due to the fact that 
delirium, especially hypoactive delirium,151-153 remains unrecognized over 66% of the time in 
clinical practice.152-160 Of note, < 5% of ICU delirium is pure hyperactive, with the vast majority 
being hypoactive or mixed type.153 While delirium monitoring is now available, data from the 
2002 survey indicated that fewer than 5% of practicing ICU healthcare professionals used a 
specific delirium monitoring instrument.40 Even though this rate is now up to 33% and rising, 
most delirium in the ICU is not recognized or treated, which serves as the first major rationale 
for this placebo-controlled investigation. Second, there are no FDA-approved medications for 
treatment of delirium. Outside of the pilot studies, there are no placebo-controlled trials of any 
medications to treat delirium in the highest risk patients, namely older medical and surgical ICU 
patients. Third, it is possible that typical and atypical antipsychotics could induce harmful 
effects unrelated to delirium or even via adverse effects on delirium itself.161 As will be 
presented below, haloperidol could actually precipitate or worsen delirium in ICU patients, and 
the placebo group of our pilot MIND study experienced no apparent harm. Fourth, and perhaps 
most importantly, the definitive study must include a placebo comparison to account for 
spontaneous improvements in delirium. Such equipoise regarding efficacy and safety of any 
therapy, especially one as routinely yet erratically prescribed as antipsychotics in the care of 
fragile, delirious ICU patients, presents a solid rationale for the conduct of a landmark, 
randomized, placebo-controlled clinical investigation that will be accomplished via this MIND-
USA trial. 
 
2.8 
Conclusions on Background Evidence in Support of MIND-USA Trial. Taken 
together, this background section highlights two main points: (1) There has been an accelerated 
path of medical research in the area of delirium, especially among the fastest growing segment of 
the ICU population—older patients with acute potentially life-threatening illnesses—which 
happens to have the highest rates of delirium. (2) A dilemma in medicine is clinicians who 
monitor critically ill patients for brain organ dysfunction are posing the same question that 
geriatricians, psychiatrists, and neurologists have been for 20 years: “If I prescribe the 
recommended antipsychotics (haloperidol or an atypical antipsychotic) for my delirious 
patients, will it help them or hurt them?” In addition, many physicians not monitoring 
objectively for delirium are waiting for level I evidence from a placebo-controlled multi-center 
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what reasons. The MIND-USA Trial has been designed to address this dilemma. Whether 
positive or negative, this trial will shape practice due to the driving unmet need for hard data to 
direct delirium management at a time when practice remains random from hospital to hospital, 
doctor to doctor, and patient to patient. In 2010, equipoise remains regarding efficacy and safety 
of routinely prescribed typical and atypical antipsychotics in the care of fragile, delirious ICU 
patients.30  
 
3.0 
Preliminary Studies 
 
3.1 
Haloperidol is a Possible Precipitant of Delirium. Dr. Margaret Pisani, a MIND-USA 
co-investigator and the site PI at Yale, conducted a prospective observational cohort study 
enrolling 309 patients aged 60 and older from 2002 to 2004.6 This study was designed to 
examine risk factors for ICU delirium, specifically psychoactive drug use. Detailed medication, 
physiologic, and delirium data (using the CAM-ICU) were collected daily. Median duration of 
delirium was 3 days. In a multivariable model, receipt of haloperidol (analyzed as a time-varying 
covariate) was associated with increased delirium duration [OR=1.35 (1.21-1.50), p<0.001], as 
were benzodiazepine and opioid use [1.64 (1.27-2.10), p<0.001], dementia [1.19 (1.07-1.33), 
p=.002], and APACHE II score [1.01 (1.00-1.02), p=0.02]. Risk factors for persistent delirium, 
defined as a continuous episode of ICU delirium that continued to the ward, were examined. Of 
173/309 (56%) patients with ICU delirium, 100 (58%) had persistent delirium. Multivariable 
regression using time-varying covariates showed haloperidol to be a predictor of persistent 
delirium [2.88 (1.38-6.02), p=0.005], as was age > 75 (2.52, p=0.01) and high dose opioids (2.9, 
p=0.02). While not conclusive, these data establish equipoise to consider that haloperidol might 
cause harm. 
 
3.2 
Pilot Investigation of IV Haloperidol in Titratable Dose Format. Dr. Ivor Douglas, a 
MIND-USA co-investigator and the site PI at University of Colorado, conducted a small pilot 
study to explore the safety profile of IV haloperidol in addition to standard sedation in delirious 
mechanically ventilated patients.162 Once patients met CAM-ICU delirium criteria, they were 
randomized to either placebo (n=9) or stepped-dose IV haloperidol (n=8) in addition to usual 
care (including low dose haloperidol) for ICU sedation. Patients in the active treatment group 
received haloperidol q6 hours with 2 to 4 mg stepped increase or decrease in dose based on 
presence or absence of delirium. The haloperidol treatment group received 13.1±10.6 mg/d and 
through open-label use the control group received 2.3 ±1.9 mg/d (p<0.001). Median duration of 
intubation was 3.5 d (control) vs. 3 d (intervention, p=0.24), and median durations for ICU stay 
were 10 d (control) and 8.3 d (intervention, p=0.50). Median Folstein Mini-Mental State 
Examination (MMSE) scores at ICU discharge were 19.5 (control) and 30 (intervention, p=0.08). 
Two patients in the control group died. Adverse events included one self-extubation in each 
group, one patient in each group developed QTc prolongation to ≥ 500 msec, one intervention 
patient experienced paradoxical increase in delirium, and one in the control group had a possible 
seizure. These preliminary data suggest that titratable dose IV haloperidol was well-
tolerated and a suitable approach to adopt for a large-scale, definitive, randomized 
controlled trial. The trend towards better MMSE scores in patients who received an average of 
13mg/d of haloperidol is consistent with the cognitive change literature recently subjected to 
meta-analysis,163 which reported that overall cognitive performance improves while on 
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although doses ≥ 25mg/d had deleterious effects. The MIND-USA investigators want to give the 
least amount of haloperidol required to balance efficacy with the need in ICU patients to provide 
some sedation so that breakthrough and potentially deliriogenic sedatives are minimized. 
 
3.3 
The MIND Pilot Feasibility Trial.44 The MIND trial was designed to test the feasibility 
of a protocol to address the hypothesis that antipsychotic medications will improve the duration 
of delirium in a safe manner. In conducting the MIND feasibility study, we included both typical 
and atypical antipsychotics. The MIND trial was double-blind and randomized placebo vs. 
haloperidol vs. ziprasidone in 103 medical and surgical ventilated ICU patients at 6 
centers.44 Study drug was administered PO or IM because the FDA would not allow IV 
administration of atypical antipsychotics at that time since they are not available in this 
formulation, though they indicated they would allow IV haloperidol. The study was exempted by 
the FDA for an IND. An atypical antipsychotic was included because this class of drugs might 
have a favorable safety profile as compared with haloperidol and because of varied affinities of 
atypical antipsychotics at dopamine, serotonin, adrenergic, and muscarinic receptors.75,107 
Ziprasidone was chosen because it is an 
antagonist at D2, H1, α1, 5-HT2A, 5-HT2C, and 5-
HT1D and a 5-HT1A agonist.126 Like other 
successful antipsychotic medications, it has high 
affinity for the D2 receptor, though this is not the 
majority of its receptor activity. Haloperidol was 
given in doses of 2.5 to 5 mg ranging from once 
per day to every 6 hours (i.e., haloperidol dose 
ranged from 2.5 to 20 mg per day). This 
moderate dose range, while higher than used by 
most geriatricians and psychiatrists yet lower 
than the range currently used in most ICUs, was 
(a) supported by psychiatric “cognitive change” literature,163 and (b) important in the ICU 
because haloperidol provides patient sedation. Because sedation is usually perceived as more 
urgent than resolution of delirium, it will never be plausible to suggest an avoidance of sedatives 
altogether, though haloperidol could provide a sedative sparing affect. The average amount of 
haloperidol administered in the MIND pilot was 17 mg/day over a median of 7 days on study 
drug, and this resulted in a median haloperidol plasma concentration of 4.5 ng/mL [IQR, 2.8-
6.0]. Notably, the median [IQR] haloperidol plasma concentration in both the placebo and 
ziprasidone group was 0 ng/mL [0-0]. The protocol for MIND was similar to that of the MIND-
USA trial. Treatment groups were balanced at enrollment by age, severity of illness, and 
admission diagnosis (#1 diagnosis being severe sepsis). The amount of sedatives given 
(benzodiazepines, propofol, and fentanyl) were balanced between groups over the course of the 
study. Figure 2 shows that there were no differences in resolution of delirium and coma; other 
outcomes, such as length of stay, cognition at discharge, and survival, were similar between the 
three groups. It is important to emphasize that this pilot feasibility study was neither intended nor 
powered to detect differences in these outcomes. We used a modified Simpson-Angus Scale164 to 
monitor objectively for EPS and checked an ECG at baseline and at 24 hours after start of study 
drug to detect QTc prolongation as well as cardiac arrhythmias. No differences in these 
anticipated study drug-related adverse events were noted between groups. 
 


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4.0 
Study Objectives and Endpoints 
 
4.1 
Study Objectives. The primary objective of the MIND-USA study is to determine the 
efficacy and safety of haloperidol and ziprasidone vs. placebo in critically ill medical and 
surgical patients with delirium. 
 
4.2 
Efficacy Endpoints 
 
4.2.1 Primary Endpoint. The primary endpoint of the trial will be delirium/coma-free days 
(DCFDs), defined as the number of days alive without delirium or coma during the 14-day 
Treatment Period (from randomization until day 14 post-randomization). This continuous 
variable represents duration of time a patient is alive and free of acute brain dysfunction and has 
been used in other high impact studies.61,165 The MIND-USA study will have tremendous 
implications for practice based on the outcome of the delirium duration (i.e., DCFD) results even 
if the secondary outcome of mortality is neutral between the two study groups. Thus, duration of 
time free of delirium and coma will be the key consideration of whether or not the study is 
considered positive or negative in the eyes of the medical community and the factor upon which 
the sample size is determined. 
The analysis of this endpoint, as well as all primary analyses, will examine the Intention-
to-Treat (ITT) population, defined as all patients who are randomized, regardless of receipt of 
study drug. Secondary analyses of patients who received at least one dose of study drug will also 
be conducted. 
 
4.2.1 Secondary Endpoints 
[1] 
30-day, 90-day, and 1-year survival (Aim 2). 
[2] 
ICU length of stay, i.e., time to ICU discharge, represented by readiness for ICU 
discharge indicated by a physician order for transfer to lower level of care even if a 
bed availability problems prevent actual discharge from the ICU (Aim 3). 
[3] 
Ventilator-free days (VFDs), i.e., days alive and free of mechanical ventilation at 28 
days. 
[4] 
Co-administration (frequency and quantity) of analgesics and sedatives will be 
closely tracked to determine whether benefits of antipsychotics, if present, are due to 
sedative-sparing effects. Our MIND pilot study reported a trend towards reduced 
benzodiazepine exposure in the antipsychotic groups (haloperidol and ziprasidone) 
vs. placebo (p=0.10). Dexmedetomidine use will also be tracked because it is known 
to be associated with more DCFDs.45  
[5] 
Neuropsychological function will be assessed using a telephone battery166 to 
determine incidence, duration, and severity of cognitive impairment at 90 days and 1 
year post-randomization (Aim 4). The battery includes tests of memory, attention, 
reasoning, and executive function. 
[6] 
Quality of life, functional status (ADLs, IADLs), and psychological outcomes 
(PTSD) at 90-days and 1-yearas determined by telephone follow-up. Follow-up 
testing will consist of ADL/IADL,167 -168 CAM,169 a neuropsychological battery,166 
EuroQOL quality of life (EQ-5D),170-172 and PTSD/PCL.173  
 


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4.3 
Safety Endpoints. Arrhythmias (including torsades de pointes), extrapyramidal 
symptoms, neuroleptic malignant syndrome, thromboembolism, and readmission (ICU and 
hospital) will be tracked.37,114-122  
 
5.0 
Inclusion/Exclusion Criteria 
 
5.1 
Inclusion Criteria. Patients will be eligible for inclusion in the Pre-Randomization Phase 
of the MIND-USA study (i.e., consented for data collection but not yet randomized because 
disease- or drug-induced coma prevents assessment for delirium or because delirium is not 
present) if they are [1] adult patients (≥ 18 years old) [2] in a medical and/or surgical ICU and 
[3] on mechanical ventilation or non-invasive positive pressure ventilation (NIPPV), and/or 
being treated for shock (e.g., with vasopressors or intra-aortic balloon pump). Only patients 
who meet inclusion criteria, have no exclusion criteria (see section 5.2), and develop 
delirium (according to the CAM-ICU)41,42 will advance to the Interventional Trial Phase 
(i.e., the randomization phase) of the MIND-USA study (see section 6.2). 
 
5.2 
Exclusion Criteria. Patients will be excluded (i.e., not consented) for any of the 
following reasons: 
[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, such that the patient will no longer meet inclusion 
criteria. 
[2] 
Pregnancy or breastfeeding (negative pregnancy test required prior to randomization 
for female patients of childbearing potential) 
[3] 
Severe dementia or other chronic neurologic disease or disorder that either makes the 
patient incapable of living independently at baseline or results in an IQCODE ≥ 4.5 
(completed by the patient or their qualified surrogate). Examples include but are not 
limited to mental illness requiring long-term institutionalization, acquired or 
congenital mental retardation, Parkinson’s disease, Huntington’s disease, Alzheimer’s 
disease, and debilitating cerebrovascular disease. Note: Subjects with mild to 
moderate dementia will be enrolled in the study. The rationale for inclusion of these 
typically elderly patients is that they represent an important, expanding group of older 
ICU patients who are very high risk for a protracted delirium course, and only very 
sparse data exist to direct treatment for this expanding group of elders. In light of the 
recent black box warning regarding longer-term use of antipsychotics in patients with 
dementia, this trial will be an ideal mechanism by which to expand knowledge of the 
safety profile for short-term use of these medications to treat delirium in patients with 
mild to moderate dementia. Acknowledging that delirium and dementia likely share 
some pathogenetic mechanisms,174,175 subgroup analyses on these patients will help 
generate hypotheses for future aging research. 
[4] 
Acute or subacute severe neurologic deficit that is expected to make the patient 
incapable of living independently after hospital discharge due to cognitive deficits. 
Examples include stroke, intracranial hemorrhage, cranial trauma, intracranial 
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[5] 
History of torsades de pointes, documented baseline QT prolongation (congenital 
long QT syndrome), or QTc ≥ 550 ms at screening due to refractory electrolyte 
abnormalities or other refractory/uncorrectable etiologies. 
[6] 
Ongoing maintenance therapy with typical or atypical antipsychotics or lithium176 , 
with plans by the ICU team to continue the medication during the current ICU stay. 
[7] 
History of neuroleptic malignant syndrome (NMS), haloperidol allergy, or 
ziprasidone allergy 
[8] 
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) 
[9] 
Inability to obtain informed consent from the patient or an authorized 
representative/surrogate for one of the following reasons: 
(a) 
Attending physician refusal 
(b) 
Patient and/or surrogate refusal 
(c) 
Patient unable to consent and no surrogate available [Note: No longer using 
this exclusion] 
(d) 
72-hour period of eligibility was exceeded before the patient was screened 
(e) 
Non-comatose patient unable to consent and no surrogate available within 72 
hours of meeting all inclusion criteria 
(f) 
Persistently comatose patient unable to consent and no surrogate available 
within 120 hours of meeting all inclusion criteria 
 
When patients are unable to consent for themselves on enrollment, a consent/re-
consent process will be used (surrogate consent at enrollment and re-consenting 
patients when competent), in keeping with recent literature on consenting delirious 
and/or ICU patients.177,178  
[10] 
Blindness, deafness, or inability to speak or understand English, the latter only if at a 
center without Spanish-speaking research staff, since Spanish-speaking patients are 
eligible at sites that have Spanish-speaking research staff, these patients will not be 
followed in the long-term follow-up phase of the trial (see section 7.4) since the 
testing materials are primarily available only in English. 
[11] 
Incarceration, since prisoners may be difficult to test during long-term follow-up 
[12] 
Current enrollment in a study that does not allow co-enrollment or an interventional 
trial that uses delirium as a primary outcome 
 
Special Note about Patients with a history of seizures. Subjects with a history of seizures on 
and off antiepileptics who meet inclusion criteria and no exclusion criteria will be eligible for 
enrollment into the MIND-USA study. These antipsychotics pose minimal risk of lowering the 
seizure threshold.179-183 The presence of a seizure disorder in patients with schizophrenia or 
bipolar disorder is not a contraindication for use of haloperidol, ziprasidone, or other 
antipsychotics. Patients with a history, who are currently on therapy specifically for this 
indication, will be continued on antiepileptic medications and have the drug levels monitored by 
the medical team as indicated within usual practice. 
 
 
 


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6.0 
Enrollment/Randomization 
 
6.1. 
Screening and Obtaining Informed Consent (Pre-Randomization Phase). Study 
personnel at each site will screen every day using the ICU census. When an eligible patient is 
identified (i.e., inclusion criteria are met and no exclusion criteria are present), informed consent 
will be pursued; when obtained, the patient will be included in the Pre-Randomization Phase of 
the study, which will include approximately 1,300 participants. Surrogate consent will be 
required for most patients because during the initial phase of their illness they will often be either 
comatose or delirious. However, all patients consented via surrogate will be re-consented for 
participation in the trial once competent.177,178  
 
6.2. 
Randomization (Interventional Trial Phase). Once informed consent is obtained, 
patients will be assessed twice daily for delirium using the CAM-ICU. When a patient becomes 
delirious (i.e., CAM-ICU positive), they will advance to the Interventional Trial Phase of the 
study and be assigned via randomization to one of the three treatment groups. Based on the most 
recent screening data from participating sites, we estimate 50%-60% of approximately 1,100 
patients included in the pre-randomization phase will develop delirium, often after a short period 
of coma. We will thus be able to randomize 561 or more patients to participate in the 
Interventional Trial Phase, meeting our calculated sample size (see Section 11.1). 
Randomization will be conducted in a 1:1:1 ratio to treatment with haloperidol, 
ziprasidone, or placebo using a computer-generated randomization scheme (with permuted block 
sizes of 6 and 8) stratified by study center and age (< 70 years vs. ≥ 70 years). The 
randomization scheme will be created by the study’s primary biostatistician and will be 
distributed directly to the investigational pharmacy at each study site as a set of randomization 
lists stratified by study center and age (< 70 years vs. ≥ 70 years). Once a consented patient has 
become delirious and an order for blinded study drug is placed, the investigational pharmacist 
will refer to the appropriate randomization list (determined by the patient’s age) to establish that 
patient’s treatment assignment. The lists will only be accessible to investigational pharmacists, 
so that treatment assignment will be known only by the investigational pharmacists. 
 
6.3 
Blinding. Apart from the investigational pharmacists, all study personnel, patients, and 
clinicians will remain blinded to each patient’s treatment assignment throughout enrollment, 
follow-up, and data analysis. If an AE is considered study-drug related, unexpected and serious, 
the study drug will be immediately discontinued and the event will be reviewed via the usual 
process, which may involve unblinded evaluation by the Clinical Monitor, as outlined in the Data 
Safety Monitoring Plan (see sections 9.2 & 9.3). 
 
7.0 
Study Procedures 
 
7.1 
Enrollment. Once informed consent is obtained, baseline data will be collected from two 
sources: 
[1] 
The medical records will be used to collect demographics, preexisting conditions, 
home medications, and admission severity of illness and organ failure. If obtained as 
part of routine medical care, additional laboratory/test results will also be collected 
and may include sodium, creatinine, glucose and neuroimaging (e.g., CT and MRI). 


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[2] 
A pre-hospital function assessment via patient/surrogate interview will assess for 
tobacco and illicit drug use, an alcohol use disorder, and ascertain the patient’s 
physical and cognitive abilities prior to the current hospitalization. Rather than 
relying on a “label” of dementia in the medical record, we will use the IQCODE.184-186  
 
7.2 
Pre-Randomization Phase. After informed consent is obtained, patients will be 
considered in the Pre-Randomization Phase until they either (a) become delirious according to 
the CAM-ICU and are thus randomized and enter the Interventional Trial Phase (see section 7.3) 
or (b) do not become delirious within 5 days of consent, develop or are found to have an 
exclusion criterion* (see section 5.2), die, or are discharged from the ICU, any of which will 
disqualify them from entering the Interventional Trial Phase. Patients who have been disqualified 
from randomization (i.e., the Interventional Trial Phase) and discharged from the ICU are 
eligible to be reenrolled in the trial if they are readmitted to the ICU and meet inclusion but no 
exclusion criteria.   *Note: As an exception, patients who have resolution of organ failure criteria 
(e.g., discontinuation of mechanical ventilation, NIPPV, and/or vasopressors) during the Pre-
Randomization Phase will remain eligible for randomization if they become delirious according 
to the CAM-ICU and are still in the ICU within 5 days of consent. Patients who do not progress 
from the Pre-Randomization phase to the Interventional Trial Phase—referred to as “Non-
Randomized” patients—will not participate in the interventional trial, will not be randomized, 
and will not be included in the intention-to-treat population be categorized as Non-Interventional 
patients. In this case, the surrogate and/or patient and the medical team will be notified that the 
patient is not participating in the interventional trial. 
During the Pre-Randomization Phase, the following daily data will be collected. 
[1] 
The medical records will be used to collect vital signs and other data reflecting 
current severity of illness, recent and ongoing treatments (including medications and 
mechanical ventilator status), routine lab results, and complications, e.g., infections 
and device removals. These data will be generated as part of routine clinical care and 
will not require study-related tests. 
[2] 
Direct patient assessments will occur twice daily (except when the participant or 
their surrogate decision maker refuses the assessment or the participant is unavailable, 
e.g., in the operating room for an extended period) to assess for pain using the 
Critical-Care Pain Observation Tool (CPOT), determine the level of sedation using 
the RASS,187,188 and assess for delirium using the CAM-ICU.41,42,189 Participants at 
select sites will be also assessed twice daily for signs/symptoms of catatonia using the 
Bush Francis Catatonia Rating Scale (BFCRS), a bedside evaluation used widely by 
psychiatrists to diagnose catatonia, and for motor symptoms of delirium using the 
Delirium Motor Subtype Scale (DMSS). Together, these two assessments take 
approximately 5 minutes to perform. 
[3] 
A bedside checklist will be used to collect data regarding adherence to the 
nonpharmacologic ABCDE protocol (see section 7.2.1), which includes standardized 
components of ventilator weaning, sedation, and delirium management. Components 
of the ABCDE protocol will be marked as complete on a daily basis by ICU staff 
and/or study personnel after they are implemented. 
[4] 
Blood (not exceeding 4 mL) will be collected to evaluate for genetic predictors of 
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[5] 
Urine (10 mL) will be collected at select sites participating in an ancillary study to 
measure urinary cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) 
to evaluate whether exposure to cigarette smoke increases delirium risk. 
 
7.2.1 Nonpharmacologic (ABCDE) Protocol. Beginning in the Pre-Randomization Phase, we 
will standardize and/or track components of ICU care that may influence delirium risk via an 
evidence-based nonpharmacologic protocol referred to as the ABCDE protocol.61,192-195 All 
study personnel will be well trained in the ABCDE protocol during the MIND-USA startup 
meeting, and compliance will be emphasized and tracked throughout the study. The local ICU 
nursing staff at each study center will also receive educational materials that will vary according 
to the needs of each site (though standardized template materials, including a pocket reference 
card, will be provided by the VCC); education will focus on the ABCDE protocol as well as on 
delirium recognition, risk factors, and prevention. Once a year through year 4 of the trial, the 
nurses in participating ICUs at each study site will be asked to complete a voluntary survey 
designed to identify practice habits, behaviors, attitudes, and perceptions regarding the ABCDE 
protocol. When knowledge gaps are identified or if compliance with the ABCDE protocol drops 
below 80%, additional education will be provided by study personnel. The ABCDE protocol has 
3 components: 
[1] 
ABCDE (Awakening and Breathing Coordination). The ABC component is based 
on the Wake Up and Breathe protocol proven to improve outcomes, including one-
year survival, in the Awakening and Breathing Controlled Trial.61 The ABC 
component includes standardized spontaneous awakening trials196 (i.e., daily 
interruption of sedation) paired with spontaneous breathing trials,197 both 
administered only when specific safety criteria are met. All study centers use 
validated sedation scales to facilitate goal-directed sedation, a practice that will 
continue throughout the MIND-USA study. Ventilator management will be 
standardized according to each institution’s approved protocols, including the use of 
low tidal volume ventilation for acute lung injury.198  
[2] 
ABCDE (Delirium monitoring and management). The Delirium component of the 
ABCDE protocol includes nonpharmacologic strategies that have been shown to 
reduce delirium in non-ICU settings.68,199-208 Each day, study personnel will 
encourage members of the ICU team to perform the following tasks: 
(a) 
Reorient and cognitively stimulate patients by conveying the day, date, place, 
and reason for hospitalization, updating whiteboards with caregiver names, 
requesting placement of a clock and calendar in the room, and discussing 
current events.63,64,66,68,199-201,203,204,206  
(b) 
Determine need for hearing aids and/or eye glasses from the surrogate and 
request that the surrogate provide these to the patient when 
appropriate.63,64,68,200,201,203,204,206  
(c) 
Monitor and manage pain in all patients using the CPOT or other assessments, 
in accordance with practice guidelines and local ICU policies.19,63,209-213 
(d) 
Maintain sleep preservation using techniques including noise reduction 
strategies (e.g., minimize noise outside the room, offer white noise or 
earplugs), normalizing day-night variation in illumination, minimizing 
interruptions during normal sleeping hours via “time out” strategy, 
maintaining ventilator synchrony, and promoting comfort and relaxation (e.g., 


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back care, massage, oral care, washing face/hands, and daytime 
bath).64,200,201,203,204,214-219  
[3] 
ABCDE (Early mobility and Exercise). The Exercise component of the ABCDE 
protocol will include strategies to promote mobility and exercise in the earliest phases 
of critical illness. Early physical/occupational therapy significantly reduced delirium 
duration for mechanically ventilated ICU patients in a recent randomized controlled 
trial.192 Each day, study personnel will evaluate each patient’s readiness for mobility 
and exercise and encourage or help to coordinate the following activities with the 
bedside nurse and physical/occupational therapist as appropriate: active range of 
motion in bed, sitting on the side of the bed, sitting in a bedside chair, standing in 
place, and ambulation.63,64,66,192,200,203,220,221  
 
Barriers and Facilitators to the ABCDE bundle.  At sites wishing to participate in this survey, 
critical care providers (i.e., nurses, respiratory therapists, pharmacists, physicians, occupational 
therapists [OT], and/or physical therapists [PT]) will be asked to complete a one-time voluntary 
electronic survey (i.e., the ABCDE Bundle Provider Survey) designed to identify barriers and 
facilitators to the use of the ABCDE bundle.  This will replace the MIND-USA Nurse Survey at 
participating sites.  In addition, managers (e.g., nurse manager, respiratory therapy manager, 
and/or PT/OT manager) will be asked to provide details about key organizational structures and 
processes that may influence a provider’s ability to use the ABCDE bundle.  Lastly, units will be 
observed for accessibility of equipment useful for applying the ABCDE bundle and unit layout.  
Both the manager evaluation and the unit observation will be accomplished utilizing the ABCDE 
Unit Observation and Manager Questionnaire. When barriers and facilitators are identified, this 
information will be provided to study personnel and/or managers at each site.  
 
7.3 
Interventional Trial Phase. Once noted to be delirious on one of the study CAM-ICU 
assessments and confirmed to have a QTc < 550 ms, patients will be randomized, advancing to 
the Interventional Trial Phase of the study, which will consist of 4 study periods: Treatment 
Period, Post-Study Drug Period, Discharge Period, and Long-Term Follow-Up Period. Upon 
entering the Interventional Trial Phase, each patient will be assigned via randomization (see 
section 6.2) to one of the three treatment groups, entering the Treatment Period until hospital 
discharge, death, or day 14 post-randomization (whichever occurs first). During the Treatment 
Period, patients will receive study drug while in the ICU and delirious per Study Drug 
Administration rules (see section 7.3.1). 
 
7.3.1 Study Drug Administration. When a patient is diagnosed with delirium, randomization 
will be carried out by the investigational pharmacist at each study center according to the 
randomization scheme provided by the study’s primary biostatistician. At each study center, the 
pharmacist will prepare and deliver study drug to the bedside nurse according to orders placed by 
study personnel. Study drugs, all clear liquids that are stable in a syringe for up to 24 hr at room 
temperature, will be delivered via titrated doses throughout the trial according to the 
administration rules in the table below: 
 
Drug 
Diluent 
Equivalent Dose 
Concentration 
Haloperidol, USP 
Provided in solution 
5 mg 
5 mg / mL 
Ziprasidone 20 mg vial 
Sterile water, 2.2 mL 
10 mg 
10 mg / mL 
Placebo/Normal Saline, USP 
Provided in solution 
Placebo 
Placebo 


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[1] 
Route and Concentration. All study drug will be administered intravenously (IV) by 
bolus over up to 5 minutes at concentrations of 5 mg/mL haloperidol or 10 mg/mL 
ziprasidone. Patients will only receive study drug while in the ICU and thus will be 
monitored with continuous telemetry as per usual ICU practice. 
[2] 
Dosing Range. Study drug dose will be titrated in a double-blind manner according 
to clinical effect (see Titration section below). For patients in the haloperidol group, 
dose will range from 2.5mg (1.25 mg dose for patients ≥ 70 years old) to 10 mg of 
haloperidol IV q12 hours (maximum, 20mg/day), in keeping with numerous clinical 
practice guidelines.19-21 This upper limit dose for haloperidol is below the threshold 
for excess D2 receptor occupancy in order to avoid extrapyramidal side 
effects78,106,109,111,222 and within the pharmacokinetic range established to achieve the 
pro-cognitive effects of the drug.147 For patients in the ziprasidone group, dose will 
range from 5 mg (2.5 mg dose for patients ≥ 70 years old) to 20 mg of ziprasidone IV 
q12 hours (maximum, 40 mg/day) in keeping with the package insert for ziprasidone 
IM and recent case reports and case series of IV administration.139,142  
[3] 
Initiation. A pre-randomization 12-lead ECG will be obtained prior to study drug 
initiation to assess QTc. If this ECG shows QTc ≥ 550 ms, randomization and study 
drug initiation will be delayed until reversible causes for the QTc prolongation are 
found and treated. When the QTc becomes < 550 ms, randomization may occur and 
study drug may be started. For those patients whose ECG shows QTc < 550 ms, the 
first dose of study drug will be administered immediately after delirium diagnosis and 
randomization at a dose of 2.5 mg haloperidol IV (or 1.25 mg for patients ≥ 70yrs 
old), 5 mg ziprasidone IV (or 2.5 mg for patients ≥ 70yrs old), or 0.5 mL placebo (or 
0.25 mL for patients ≥ 70yrs old).  
[4] 
Titration. After study drug initiation, subsequent study drug doses will be titrated 
twice daily—with all doses being delivered at approximately 10AM or 10PM—by 
doubling (increasing by 100%) or halving (decreasing by 50%) the volume according 
to the following rules.  *Note: An exception to this schedule will occur if the 
initiation dose is given after 4PM, in which case the second study drug dose will be 
given approximately 6 hours after the initiation dose (rather than at 10PM). 
(a) 
Titrating Up. If study drug is not at maximum dose, the volume will be 
doubled approximately every 12 hours until the maximum dose is reached (10 
mg haloperidol/20 mg ziprasidone/2 mL placebo q12h) unless [1] the patient 
cannot be assessed with the CAM-ICU due to coma (see section 7.3.1.[4].(b) 
below) or [2] study drug has been restarted after being held for safety reasons 
(see section 7.3.1.[5] on Holding study drug). If study drug has been held and 
then restarted (see section 7.3.1.[5] on when study drug can be restarted after 
Holding), the volume will not be titrated up but will instead be maintained at 
half the dose that had been held as long as side effects do not recur. 
(b) 
Maintaining Current Dose. If a patient cannot be assessed with the CAM-ICU 
due to coma that is drug-induced (i.e., RASS -4 or -5 while receiving 
sedatives), study drug will be maintained at the current volume. Note: 
Sedative-induced coma is not considered a safety reason to hold study drug, 
whereas study drug will be held if sedatives have been held > 12 hours and the 
patient is comatose (per section 7.3.1.[5].(c) below). 


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(c) 
Titrating Down. If a patient is determined to be CAM-ICU negative (i.e., not 
delirious) on two consecutive assessments, the study drug volume will be 
halved approximately every 12 hours to a minimum volume of 0.25 mL. 
When a patient has been CAM-ICU negative for 4 consecutive study CAM-
ICU assessments, study drug will be discontinued regardless of the dose. 
(d) 
Restarting Study Drug. If at any time during the Treatment Period a patient is 
noted to develop a new episode of delirium and is in the ICU setting, study 
drug will be restarted at the dose most recently administered, as long as study 
drug was not discontinued permanently for safety reasons (see Permanent 
Discontinuation section below). If study drug is restarted after being 
temporarily held for safety reasons (as described in section 7.3.1[5]), it will be 
restarted at half the dose that was being administered when the safety concern 
was noted and prompted the study drug to be held. 
[5] 
Holding. Throughout the trial, study drug will be temporarily held for the following 
safety reasons: 
(a) 
QTc Prolongation (≥ 550 ms). If a pre-dose 12-lead ECG (obtained per 
sections 7.3.1.[5].(a).(i) or (iii) below) confirms QTc ≥ 550 ms, study drug 
will be held. If a reversible cause for the QTc prolongation is found and 
treated and QTc becomes < 550 ms, study drug may be resumed at half the 
previous dose (not less than the minimum volume of 0.25 mL) as in our 
MIND pilot study223 and other recent studies.224 During the Interventional 
Trial Phase, QTc will be measured as follows: 
(i) 
A pre-randomization 12-lead ECG will be obtained prior to study drug 
initiation. 
(ii) Subsequently, QTc will be checked and documented prior to the 
administration of each dose of study drug, either manually calculated 
from a bedside telemetry strip using the Bazett formula (QTc = QT / 
√RR interval) or via software algorithms available in some bedside 
telemetry machines. Whenever these pre-dose measurements show a 
QTc ≥ 550 ms, a 12-lead ECG will be obtained to confirm that QTc ≥ 
550 ms. 
 (b) Extrapyramidal symptoms (EPS). If the patient develops clinical EPS, 
including dystonia and/or symptoms detected by the modified Simpson-Angus 
Scale(see section 7.3.2.[2]), then the study drug will be held and the patient 
treated as clinically indicated by the ICU team, who will be notified of the 
EPS by study staff. Upon resolution of EPS, study drug will be resumed at 
half the previous dose (not less than the minimum of 0.25mL). 
(c) Oversedation. If the patient is oversedated (i.e., > 1 RASS level deeper than 
ICU team’s sedation target), two sequential steps will be taken: [1] sedatives 
(including analgesics being used for sedation) will be held or decreased for > 
12 hours per the ICU team’s standard protocol and study drug will be 
maintained at current dose or titrated per standard titration rules (see section 
7.3.1.[4]), then [2] study drug will be held if sedatives have been held > 12 
hours and the patient remains oversedated. In this case, study drug will be 
restarted at half the previous dose (not less than the minimum of 0.25 mL) 
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[6] 
Permanent Discontinuation. Study drug will be permanently discontinued at any 
time during the trial for any of the following safety reasons: 
(a) 
Neuroleptic malignant syndrome (NMS) 
(b) 
Torsades de pointes or another ventricular tachycardia (VT) that results in 
clinical sequelae (e.g., hypotension) and/or requires treatment 
(c) 
New-onset coma due to a known structural brain disease such as stroke, 
intracranial hemorrhage, cranial trauma, malignancy, anoxic brain injury, or 
cerebral edema 
(d) 
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome 
(e) 
Any other study drug-related, life-threatening, serious adverse event 
 
7.3.2 Monitoring. The risks of haloperidol and ziprasidone include tardive dyskinesia, 
neuroleptic malignant syndrome (NMS), extrapyramidal side effects (EPS), torsades de pointes 
and other arrhythmias, and hyperglycemia. Throughout the Treatment Period, study personnel 
will carefully monitor all patients daily for evidence of these potential adverse effects, determine 
study drug efficacy and safety, and monitor other factors that may influence outcomes. The 
above section describes how study drug will be titrated, held, or permanently discontinued 
should adverse effects occur. Additionally, all patients will be monitored carefully throughout 
the Post-Study Drug Period, which includes the four full calendar days after study drug is 
discontinued. Note: For patients who receive no study drug after day 10 post-randomization, 
daily monitoring will conclude at the end of the Treatment Period (i.e., at hospital discharge, 
death, or day 14 post-randomization, whichever occurs first) because the Post-Study Drug Period 
for these patients will be contained within the Treatment Period. Alternatively, patients who 
continue to receive study drug after day 10 post-randomization will be monitored through the 
end of the Post-Study Drug Period, which will extend beyond the Treatment Period. 
[1] 
Efficacy. To evaluate the efficacy of haloperidol and ziprasidone vs. placebo, and to 
guide titration of study drug dose (see section 7.3.1.[4]), all efficacy outcomes will be 
assessed during the Treatment Period or longer, depending on the outcome (see 
section 4.2). While patients are in the ICU and in the Treatment Period, study 
personnel will determine level of sedation using the RASS187,188 and assess for 
delirium using the CAM-ICU twice daily (except when the participant or their 
surrogate decision maker refuses the assessment or the participant is unavailable, e.g., 
in the operating room for an extended period).41,42,189 When patients are not in the 
ICU but still in the Treatment Period (i.e., in the hospital and prior to day 14 post-
randomization), study personnel will assess them using the RASS and CAM-ICU 
once daily. In cases where the Post-Study Drug Period extends beyond the Treatment 
Period, the RASS and CAM-ICU will be completed once daily from the time the 
Treatment Period ends until the Post-Study Drug Period ends. Time-to-event 
outcomes (e.g., ICU length of stay, survival, etc.) will be assessed from the time of 
randomization (entry into the Interventional Trial Phase) until the outcome in 
question or a censoring event occurs. 
[2] 
Safety. Patients will be monitored as part of routine ICU care for adverse reactions, 
including but not limited to NMS, acute dystonia (i.e., muscle spasms and 
contractions), pseudoparkinsonism, atrial and ventricular dysrhythmias, 
hyperglycemia, etc. Additionally, study personnel will specifically assess patients for 
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(a) 
Extrapyramidal symptoms (EPS) according to a modified Simpson-Angus 
Scale164 consisting of 5 items: elbow rigidity, wrist rigidity, glabella tap, 
tremor, and salivation 
(b) 
Akathisia according to a 10 cm visual analog scale used on days that patients 
are not comatose or delirious 
(c) 
QTc prolongation ≥ 550 ms as described in section 7.3.1.[5].(a) 
(d) 
Hyperactive (i.e., agitated) delirium according to RASS153 and Rescue 
Protocol use (see section 7.3.3) 
[3] 
Biological specimens. On three occasions—at the time of randomization (i.e., Trial 
Day 0) and on Trial Days 1 and 2—20 mL of blood will be collected (max of 65 mL 
during study), processed, and stored at −80º C prior to being shipped to the 
Vanderbilt Coordinating Center biorepository, where it will be stored for batched 
analyses of the following: 
(a) 
Haloperidol and ziprasidone plasma concentrations 10-60 minutes prior to 
morning doses of study drug on Trial Days 1 and 2 
(b) 
Inflammatory/coagulopathic biomarkers, (e.g., IL-6, CRP, sTNFR1, protein 
C, and D-dimer) since some have hypothesized that a potential beneficial 
effect of haloperidol may be its anti-inflammatory properties97,110,128  
(c) 
Exploratory biomarkers hypothesized to be associated with delirium and long-
term cognitive impairment (LTCI) (e.g., markers of inflammation, 
coagulation, oxidative stress, amyloid beta, etc.) as well as genetic risk factors 
hypothesized to be associated with delirium and LTCI (e.g., APOE, single 
nucleotide polymorphisms [SNPs] associated with dementia, SNPs associated 
with sedative metabolism, etc.).  Any additional biomarker analyses are to be 
determined by ongoing and future studies. 
[4] 
Delirium Experience and Cognitive Evaluation. After resolution of delirium and 
prior to hospital discharge, patients will be asked to recall their delirium experience 
using the Delirium Experience Questionnaire (DEQ).225,226 The DEQ assesses 
delirium recall and distress related to a delirium episode. Additionally, patients will 
complete a brief assessment of cognitive ability, the Montreal Cognitive Assessment 
(MoCA).227,228  
[5] 
Other data. As in the Pre-Randomization Phase, the medical records will be used 
during the Intervention Trial Phase to collect vital signs and other data reflecting 
current severity of illness, recent and ongoing treatments (including medications and 
mechanical ventilator status), routine lab results, and complications, e.g., infections 
and device removals. These data will be generated as part of routine care and will not 
require study-related tests. In addition, participants at select sites will continue to be 
assessed with the BFCRS and DMSS twice daily until ICU discharge, then once daily 
until hospital discharge. 
 
7.3.3 Rescue Protocol for Pain/Agitation/Delirium. Because half of delirious ICU patients 
have mixed (hypoactive with intermittent hyperactive) delirium153,229,230 and the majority of 
critically ill patients will experience agitation at some point during their ICU stay,231 a rescue 
protocol for the treatment of hyperactive delirium and/or agitation (which may be due to pain or 
anxiety as well as delirium) is an essential component of the ICU team’s armamentarium. In 
order to effectively test the hypothesis, however, that antipsychotics improve outcomes for ICU 
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limited to ensure that patients are not exposed to antipsychotics except for what is administered 
as study drug. Due to the equipoise regarding the effects of antipsychotics in the ICU (see 
sections 2.3, 2.7, 3.3, and 3.5) and the importance of maintaining separation between treatment 
groups with respect to antipsychotic use, the administration of open-label haloperidol, 
ziprasidone, or any other antipsychotic (except those prescribed specifically for nausea, 
such as compazine) will be restricted during the Treatment Period. The Rescue Protocol 
described below is a 3-part evidence-based alternative to open-label antipsychotics for the 
management of hyperactive delirium/agitation based on current practice at participating study 
centers, clinical practice guidelines,19-21 and other recent literature.18,45,223,232-235 This rescue 
protocol prioritizes analgesia first, then sedation for patients displaying agitation/unsafe 
behavior, and then delirium treatment. All medications given will be recorded and analyzed by 
study group. 
[1] 
Pain/Analgesia. Fentanyl or morphine (and, less often, hydromorphone) should be 
given as an IV bolus or a continuous infusion per the local ICU’s protocol and/or the 
ICU team’s preferences when pain is suspected or diagnosed (using the Critical-Care 
Pain Observation Tool [CPOT]212,213 or other assessments, per local ICU policies). 
Doses will be titrated to achieve adequate analgesia. 
[2] 
Agitation/Sedation. If hyperactive delirium/agitation that poses a risk to the patient 
or ICU staff persists after adequate analgesics are delivered, sedation should be 
administered in the form of propofol via continuous infusion for patients with airway 
protection (endotracheal or tracheostomy tube). An alternative drug choice for 
patients without airway protection, dexmedetomidine via continuous infusion, should 
be considered. This sedative does not cause respiratory suppression. In centers where 
dexmedetomidine is not available, patients without airway protection who are 
agitated may be treated with benzodiazepines. 
[3] 
Delirium/Antipsychotics. While in the ICU, all patients will be managed with the 
ABCDE nonpharmacologic protocol (which includes a Delirium component, see 
section 7.2.1) from the time consent is obtained until hospital discharge, death, or 
until the Treatment Period ends (whichever occurs first). If the patient is outside the 
ICU or the Treatment Period has ended, open-label antipsychotics can be 
administered for refractory delirium according to the ICU team’s preference. 
 
7.4 
Long-Term Follow-Up Period. We will evaluate long-term outcomes among survivors, 
including neuropsychological function (Aim 4), quality of life, ADL/IADLs, PTSD, and 
caregiver burden approximately 3 months and 1 year after randomization. Under the direction 
of the Vanderbilt Coordinating Center’s lead neuropsychologist, trained study personnel will 
assess patients using the following validated telephone assessments: 
[1] 
Delirium will be assessed via the “phone” Confusion Assessment Method169 
algorithm. Patients diagnosed with delirium will not be assessed further at that time, 
but contacted at weekly intervals and tested if/when delirium resolves. 
[2] 
A neuropsychological phone battery166 derived from standard cognitive tests and 
proven feasible and valid for phone use in a study of ICU survivors (with similar 
characteristics to those targeted for enrollment in the MIND-USA) will be used to 
assess memory, attention, reasoning, and executive functioning. 
[3] 
Activities of Daily Living (ADL)167 and Instrumental ADLs168  


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[4] 
Quality of Life will be assessed using the EQ-5D, a short, easy to administer, well-
validated, and widely used instrument.170-172  
[5] 
Post-Traumatic Stress Disorder (PTSD) will be assessed via the PTSD Checklist 
(PCL)173  
[6] 
Caregiver Burden will be assessed via a caregiver burden interview, the caregiver 
burden checklist236-238, and a brief caregiver employment questionnaire  
[7] 
Health care costs and health status will be assessed via Medicare files 
7.4.1 Retention of Patients for Long-Term Follow-Up. Throughout the trial, several methods 
will be employed to enhance patient retention through the end of the Long-Term Follow-Up 
Period. At enrollment and throughout the study, multiple contact addresses, phone numbers, and 
email addresses will be obtained to facilitate communication with participants during long-term 
follow-up. All phone conversations with participants will be characterized by study staff 
cheerfulness and respect for privacy, and these phone calls will be scheduled to accommodate 
participants’ schedules. During each phone call, which will begin with an introduction, study 
staff will inquire about the participant’s health, and express thanks for their willingness to 
participate. Participants will be compensated $50 after they complete the 3-month follow-up 
phone assessment and $50 after they complete the 12-month follow-up phone assessment. 
7.5 
Data Collection/Case Report Form Details. During all study phases, all data will be 
entered into electronic case report forms (eCRFs) in a secured password-protected database with 
the exception of the pre-hospital function assessment, the EQ-5D, the DEQ, the MoCA, and the 
neuropsychological phone battery, which will be collected on paper CRFs and later entered into 
the eCRFs for storage in the secured password-protected database. This study will utilize 
REDCap for data collection, transmission and storage. REDCap (Research Electronic Data 
Capture) is a secure, web-based application for building and managing online databases. 
Vanderbilt University, with collaboration from a consortium of institutional partners, including 
the Vanderbilt Institute for Clinical and Translation Research (VICTR) Informatics Core, 
developed and manages a software toolset and workflow methodology for electronic collection 
and management of research and clinical trial data. All study data will be entered via a password 
protected, study unique REDCap database website. REDCap servers are housed in a local data 
center at Vanderbilt and all web-based information transmission is encrypted. REDCap was 
developed specifically around HIPAA-Security guidelines and is recommended by both the 
Vanderbilt University Privacy Office and Institutional Review Board. REDCap has been 
disseminated for use locally at other institutions and currently supports > 140 academic/non-
profit consortium partners and 11,000 research end-users (www.project-redcap.org).  
During the Interventional Trial Phase daily data will be collected for up to 18 days or until 
hospital discharge or death, whichever occurs earlier. After study drug is discontinued, patients 
will be monitored for safety purposes during a 4-day Post-Study Drug Period; the duration of this 
period is chosen because the elimination half-life of haloperidol is such that all drug is expected 
to be eliminated within 4 days of the last dose; ziprasidone has a shorter elimination half-life 
than haloperidol. The Post-Study Drug Period may overlap with the Treatment Period, depending 
on the duration of study drug administration (which in turn depends on duration of delirium, ICU 
length of stay, side effects, etc., as described in section 7.3.1.) All patients will be monitored for 
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Trial Day 14, and those patients who receive more than 10 days of study drug will be monitored 
for up to 18 days after randomization, with monitoring occurring for 4 days after discontinuation 
of study drug. Additionally, data will be collected as it is generated, including but not limited to 
mechanical ventilation initiation and removal, ICU admissions and discharges, patient discharge 
assessments, and death will continue to be collected until hospital discharge. After hospital 
discharge patients will be evaluated at approximately 3 months and 1 year after randomization 
with the telephone neuropsychological battery described in section 7.4. In addition to the battery 
described, data will be collected regarding intervening events that happened since hospital 
discharge including, but not limited to, death and re-hospitalizations. Vital status at 12 months 
after randomization and date of death (if applicable) will be determined via medical records or 
the Social Security Death Index if not already known at hospital discharge.  All signed Informed 
Consent Documents will be uploaded to the study database.  This will allow the VCC ready 
access to review the consent forms for appropriate version use and completeness.   
 
[continued on next page] 
 
 


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7.6 
Schedule of Events 
 
*Abbreviations (alphabetical): ADL- activities of daily living, APACHE II- Acute Physiologic Chronic Health Evaluation II, APOE- 
apolipoprotein-E, AUDIT-Alcohol Use Disorders Identification Test, BFCRS- Bush Francis Catatonia Rating Scale, CPOT- Critical-
Care Pain Observation Tool, CAM- Confusion Assessment Method, CAM-ICU- Confusion Assessment Method for ICU, CRP- C-reactive 
protein, DMSS- Delirium Motor Subtype Scale, ECG- electrocardiogram, EPS- extrapyramidal symptomatology, FAQ- Functional 
Activities Questionnaire for IADLs, IADL- instrumental activities of daily living, IL-6- interleukin 6, IQCODE- Informant Questionnaire 
of Cognitive Decline in Elderly, NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, PCL- PTSD checklist, PTSD- post traumatic 
stress disorder, RASS- Richmond Agitation Sedation Scale, SOFA- Sequential Organ Failure Assessment, sTNFr1- soluble TNF receptor 1 
†Post-Study Drug Period: For patients who receive no study drug after day 10 post-randomization, daily monitoring will conclude at the end 
of the Treatment Period (i.e., at hospital discharge, death, or day 14 post-randomization, whichever occurs first) because the Post-Study 
Drug Period for these patients will be contained within the Treatment Period. Patients who continue to receive study drug after day 10 post-
randomization will be monitored through the end of the Post-Study Drug Period, which will extend beyond the Treatment Period. 
‡ABCDE Protocol: Awakening Breathing Coordination, Delirium monitoring/management, & Early mobility/Exercise; NOTE: Each 
component of this standardized approach to patient care, referred to as the “nonpharmacologic delirium protocol,” (see section 7.2.1) will be 
tracked daily in all patients once consented. 
¶Unless the participant has been discharged from the ICU; non-ICU patients will be assessed 1x daily in the Treatment Period. 
 
 
Variable* (abbreviations on next page) 
Enrollment 
Pre-
Randomization 
Phase 
Interventional Trial Phase 
Treatment 
Period 
Post-Study 
Drug Period
† 
Hospital 
Discharge 
3 & 12 
Month 
Demographics, Comorbidities,239 Neuroimaging (CT/MRI) if 
available 
X 
 
 
 
 
 
AUDIT,240 ADL,167 IADL/FAQ,168 IQCODE,184-186 APACHE 
II,241 tobacco and illicit drug use history, employment 
X 
 
 
 
 
 
SOFA242,243  
X 
Daily 
Daily 
Daily 
 
 
Pregnancy test (Beta hCG) 
X 
 
 
 
 
 
Blood draw: APOE genotyping 
X 
 
 
 
 
 
Urine collection: cotinine and NNAL 
X 
 
 
 
 
 
Blood draw: CPD, IL-6, CRP, D-Dimer, sTNFr1, protein-C 
 
 
Days 0, 
1, & 2 
 
 
 
Study drug levels: haloperidol & ziprasidone 
 
 
Days 0, 
1, & 2 
 
 
 
Hematology and Chemistry 
X 
Daily 
Daily 
Daily 
 
 
Co-administered psychoactive meds--
sedative/analgesic/antipsychotic 
 
Daily 
Daily 
Daily 
 
 
RASS (target/actual),187,188 CAM-ICU41,42 & CPOT19,63,209-213 
 
2x daily 
2x daily¶ 
Daily 
 
 
BFCRS & DMSS at select participating sites 
 
2x daily 
2x daily¶ 
Daily 
 
 
Hospital-acquired infections (in blood, urine, sputum) 
 
Daily 
Daily 
Daily 
 
 
ABCDE protocol compliance‡ 
 
Daily 
Daily 
 
 
 
12-lead ECG (baseline and subsequent ECGs) 
 
X 
See section 
7.3.1.[5].(a) 
 
 
 
Safety assessments: Modified Simpson-Angus EPS scale,164 
visual analog akathisia scale, neuroleptic malignant syndrome, 
& dysrhythmia/QTc review 
 
 
Daily 
Daily 
 
 
Delirium Experience Questionnaire (DEQ)225,226  
 
 
 
 
X 
 
Montreal Cognitive Assessment (MoCA)227,228  
 
 
 
 
X 
 
Caregiver burden interview & checklist236-238  
 
 
 
 
 
X 
Long-term telephone follow-up: CAM,169 neuro-
psychological battery,166 ADL,167 IADL/FAQ,168 EuroQOL 
quality of life (EQ-5D),170-172 PTSD/PCL173, employment 
 
 
 
 
 
X 
Health care costs and health status (via Medicare files) 
 
 
 
 
 
X 


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7.7 
The Vanderbilt Coordinating Center (VCC). The VCC has extensive experience in the 
conduct of large, phase III clinical trials over the past decade and is comprised of over 50 people 
on-site at Vanderbilt. The VCC will perform (among other functions) the following: 
communicate with the FDA using a schedule of reporting in accordance with IND policies, 
design the database and data collection tool, establish a web-based data database, conduct startup 
meetings and site-training regarding protocol implementation and delirium monitoring to 
standardize all research activities during the trial, monitor enrollment pace and quality to ensure 
patients meet the inclusion/exclusion criteria, maintain blinding, track adverse events and ensure 
safety reporting, ensure protocol compliance, store plasma, serum, and genetic samples for 
planned and future analyses, conduct follow-up phone testing of neuropsychological function 
and quality of life via neuropsychology technicians, and work with the study centers and local 
study personnel using multiple proven patient retention techniques that have consistently 
achieved over 80% follow-up during previous studies. 
 
8.0 
Risks 
 
8.1 
Side Effects of Study Drug (Haloperidol and Ziprasidone). The risks of antipsychotics 
(haloperidol and ziprasidone) include tardive dyskinesia, neuroleptic malignant syndrome, 
extrapyramidal side effects (EPS), torsades de pointes and other arrhythmias, and hyperglycemia. 
Throughout the Interventional Trial Phase, study personnel will carefully monitor all patients for 
evidence of these potential adverse effects of the study drugs. These assessments are described 
above in section 7.3.2. Adverse events will be monitored closely and reported as described below 
in Section 9.0. Should any of these occur, adverse events will be reported to the coordinating 
center, with Serious Adverse Events reported within 24 hours. In addition, study drug will be 
titrated, held, or permanently discontinued, depending on the adverse effect, according to study 
protocol (see section 7.3.1). Both haloperidol and ziprasidone are pregnancy category C 
medications, and female patients of childbearing age must have a negative pregnancy test to 
meet entry criteria. 
 
8.2 
Risks from Blood Draws. All patients will have blood drawn for research purposes. 
Having blood drawn is commonly painful, and it can rarely lead to bleeding, bruising, or 
infection at the site of the blood draw. For this reason, it will be our standard approach whenever 
possible to obtain blood for research purposes through existing intravenous peripheral, central or 
arterial catheters since patients routinely have such catheters while in the ICU. The volume of 
blood collected for research specimens represents a small percentage of the amount of blood 
taken during the course of a standard ICU stay and will not represent a significant risk to the 
patient. 
 
8.3 
Steps Taken to Reduce Risks and Increase Impact of Study. We have taken the 
following steps in designing our protocol to minimize risk for the study population and to 
maximize the ultimate impact of this investigation on the field of medicine.244  
[1] 
All interventions included in the MIND-USA study are supported by a well-grounded 
and clearly described rationale suggesting potential, though unproven, benefit for 
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[2] 
All interventions are common and with established equipoise within the context of 
usual care and considered good or competent care in light of an absence of clear proof 
in favor of one over the other. 
[3] 
Experts in the fields of critical care, geriatrics, psychiatry, neuropsychology, nursing, 
pharmacology, and clinical trial design have developed the interventions being 
studied. 
[4] 
The management of patients in all three treatment groups will be guided by explicit 
MIND-USA protocols so that the results of the trial can be clearly interpreted and 
imitated, where appropriate, in clinical practice. This will also allow for the use of the 
“superior group” as a control in future trials. 
[5] 
The MIND-USA protocol will adjust study drug dose to meet individual patient needs 
in the attempt to deliver safe and effective care to critically ill older and younger 
patients. This protocol is explicitly designed and drafted from landmark trials as 
referenced to meet patients’ needs over time and provide individualized care. 
[6] 
The titration protocol for study drug and the rescue protocol for hyperactive delirium 
are both designed to minimize risks in comparison to anticipated benefits. 
[7] 
Because no placebo-controlled trials of interventions for ICU delirium exist to direct 
our study design, we conducted the feasibility pilot studies described in sections 3.4 
and 3.5 prior to proceeding with the design of this definitive phase III trial. 
[8] 
An independent and qualified data safety monitoring board (DSMB) will be 
established (see section 9.3) to review the research protocol prior to the start of the 
study and conduct interim analyses for safety and review data on serious adverse 
events as close to real-time as possible. 
[9] 
We have worked very closely with the FDA to make certain that this proposal is safe 
and that they agree with our planned oversight and approach to due diligence in 
monitoring and reviewing all adverse events during the conduct of the trial. We have 
an active and approved FDA-IND #104322 for this 3-group study including both 
typical antipsychotic haloperidol and the atypical antipsychotic ziprasidone as well as 
placebo. 
[10] 
Rigorous monitoring and reporting of prospectively defined Adverse Events (AEs) 
Serious Adverse Events (SAEs), and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be conducted as outlined in section 9.2 to comprehensively 
monitor safety during the trial.245  
 
9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
A system has been established to report and track clinical outcomes and adverse events (AEs). 
Study personnel will monitor the safety of subjects and follow them until the event resolves or is 
explained. 
 
9.1 
Clinical Outcomes (not considered Adverse Events). In this study of critically ill 
patients who are at high risk for death or other adverse outcomes due to their underlying critical 
illness, clinical outcomes, including death and organ dysfunction, will be systematically tracked 
(collected in the CRF) and will be included as part of the safety and efficacy analyses for this 
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events unless the investigator believes the event may have been caused by study drug and  is 
more severe or prolonged than expected given the underlying critical illness (investigator’s 
discretion). This approach—considering death and organ dysfunction as outcomes rather than 
adverse events and systemically tracking expected safety outcomes for analysis rather than solely 
recording individual adverse events—is common in ICU trials because these outcomes/events 
occur commonly in the ICU and this system mandates that data regarding death, organ 
dysfunction, and expected safety outcomes be tracked systematically for all patients and 
analyzed appropriately. All clinical outcomes will be systemically tracked throughout the 
Treatment Period and the Post-Study Drug Period as described in section 7.3.2. Listed below are 
events that will be tracked as clinical outcomes and will not therefore be required to be reported 
as adverse events during this study (unless believed to be study-drug related and more severe or 
prolonged than expected given the underlying critical illness): 
[1] 
Death. All deaths occurring within the Interventional Trial Phase will be reported on 
the CRF in the death summary section. For deaths thought to be caused by study 
drug, a SUSAR (see section 9.2) will be reported along with the death summary. 
[2] 
Respiratory failure, including need for mechanical ventilation (invasive or 
noninvasive) or episodes of hypoxemia 
[3] 
Circulatory failure, including shock (whether requiring vasopressors or not) and 
cardiac arrhythmias, and hypertension 
[4] 
Hepatic failure or injury leading to increased bilirubin 
[5] 
Renal failure or injury leading to an increased creatinine or acute hemodialysis 
[6] 
Coagulation derangements leading to thrombocytopenia 
[7] 
Stroke and neuropsychological dysfunction that is believed to be newly acquired 
[8] 
Alterations in vital signs (e.g., temperature, respiratory rate, oxygen saturation) 
[9] 
Thromboembolisms 
[10] 
ICU readmissions 
[11] 
Infections 
[12] 
Self-removal of devices and invasive tubing and/or monitoring equipment 
[13] 
The following known adverse reactions to antipsychotics:  
(a) 
NMS 
(b) 
acute dystonia (i.e., muscle spasms and contractions) 
(c) 
pseudoparkinsonism 
(d) 
atrial and ventricular dysrhythmias 
(e) 
hyperglycemia 
(f) 
extrapyramidal symptoms (EPS) 
(g) 
tardive dyskinesia 
(h) 
akathisia 
(i) 
QTc prolongation ≥ 550 ms 
 
9.2 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Serious Unexpected 
Suspected Adverse Reactions (SUSARs).An Adverse Event (AE) will be any untoward 
medical occurrence for a patient enrolled in the trial that is not tracked as a clinical outcome (see 
section 9.1), regardless of whether the event is considered study drug-related or not. If a subject 
experiences an AE after informed consent is signed but before receiving study drug, the event 
will be reported as an AE not study drug related. Prior to enrollment, study site personnel will 
note the occurrence and nature of each subject’s medical condition(s). During the study, site 


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personnel will note changes in these condition(s) and/or the occurrence and nature of any AEs. 
All AEs occurring during the Treatment Period and/or the Post-Study Drug Period will be 
recorded on the CRF. This period is the window of time during which study drug-related adverse 
reactions are expected based on the duration of the study drug administration plus 4 additional 
days of Post-Study Drug Period (approximately 4-5 elimination half-lives of haloperidol, the 
longer acting of the two active study drugs). An AE that later meets criteria for an SUSAR 
between the start of study drug and hospital discharge will be reported as an SUSAR. If study 
drug is discontinued as a result of an AE, study personnel will document the circumstances 
leading to discontinuation of study drug. 
All AEs in MIND-USA will be assessed as to whether they are (1) related to study drug, 
(2) serious, and/or (3) unexpected according to the following definitions: 
 
9.2.1 Related. AEs that an investigator suspects are related to study drug receipt will be 
classified as Suspected Adverse Reactions (SARs). Certainty of relatedness is not required as 
long as a reasonable possibility exists that the AE is related to study drug receipt. 
 
9.2.2 Serious. AEs that result in any of the criteria below will be considered Serious Adverse 
Events (SAEs): 
[1] 
Death 
[2] 
A life-threatening episode requiring immediate intervention 
[3] 
Inpatient hospitalization or prolongation of existing hospitalization 
[4] 
Persistent or significant incapacitation or substantial disruption of the ability to 
conduct normal life functions 
[5] 
A congenital anomaly/birth defect 
[6] 
An episode that requires intervention to prevent the above and/or permanent 
impairment or damage 
 
9.2.3 Unexpected. AEs, including SARs, that are not listed in the investigator’s brochure or 
are listed but are more severe or prolonged than expected based on the investigator’s brochure 
will be considered Unexpected. In addition, AEs will be considered Unexpected even if they are 
mentioned in the investigator’s brochure as known to be caused by the classes of drugs being 
studied or to be anticipated based on the pharmacological properties of the study drugs but not as 
specifically known to be caused by the study drugs. 
 
As required by the FDA, all events that are related, unexpected, and serious will be 
reported as Serious Unexpected Suspected Adverse Reactions (SUSARs). The MIND-USA 
Study will monitor, track, and report all Clinical Outcomes and Adverse Events as required by 
regulatory bodies. 
 
9.3 
Communication and Reporting of Adverse Events with Coordinating Center and 
Regulatory Bodies. In order to ensure proper and timely reporting of all adverse events, there 
will be a clear communication plan for all sites to follow. Sites will be responsible for reporting 
all adverse events to the VCC; they will also follow their local IRB policies to determine when 
adverse events should be reported to the local IRB. The VCC will be responsible for reporting 
the events to the proper regulatory bodies (i.e., FDA, DSMB, and Coordinating Center IRB) in a 
timely manner and in communicating any responses from those bodies back to the sites. Site 


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IRBs will also get event reports according to site-specific IRB guidelines. Our procedures for 
reporting the various adverse events will be as follows: 
[1] 
AEs and SAEs will be recorded in the patient’s study chart in the electronic database 
and reported to the VCC within 5 days of occurrence. The VCC will provide a 
batched report of all study wide AEs annually to each regulatory body as part of the 
annual review process as required. 
[2] 
SUSARs will be recorded in the patient’s study chart in the electronic database and 
reported to the VCC within 24 hours of occurrence by telephone call. The VCC will 
report the event within 24 hours to the DSMB Chair and the Vanderbilt IRB. The 
DSMB Chair will serve as a real-time “Clinical Monitor” over all SUSARs by 
systematically reviewing SUSARs, evaluating relatedness of each event. When the 
DSMB Chair suspects an event is study-drug related, they will have the opportunity 
to access unblinded data in order to conduct appropriate safety monitoring. There 
should be no need for the site investigators to be unblinded since the study drug 
should have been stopped at the time of event occurrence per titrating rules of the 
study protocol. The DSMB Chair will work in concert with the rest of the DSMB to 
determine if any necessary actions need to occur as result of the event in order to 
increase the safety of the protocol. All SUSARs will be reported as required to the 
regulatory bodies, including the FDA and the full DSMB. 
[3] 
Per the specific request of the DSMB, all occurrences of torsades de pointes and 
neuroleptic malignant syndrome (whether meeting the criteria of SUSAR or not) will 
be reported to the VCC within 24 hours of occurrence by telephone call. The VCC 
will report the event within 24 hours to the DSMB Chair. 
 
9.4 
Data Monitoring Plan. To ensure data is accurately and completely collected during the 
MIND-USA study, the VCC will follow a specific Data Monitoring Plan modeled after the 
FDA’s guidelines for the monitoring of clinical investigations. Once each year, a VCC member 
will visit each study site to assure that the facilities continue to be acceptable for the purpose of 
the study, the study protocol is being followed, changes to the protocol have been approved by 
the local IRB, and the site investigator is carrying out the agreed-upon activities and has not 
delegated them to other unspecified staff. Also, the monitor will review randomized subject 
records to determine whether data collected is accurate, complete, and current. The monitor will 
also review disqualified subject records to determine whether the patient was accurately 
disqualified.  Per the FDA guidelines, the monitor will compare a representative number of 
subject records and other supporting documents with the investigator’s reports. Specifically, site 
visits will include the following: 
[1] 
A Technical Review will occur annually and will consist of a VCC research nurse 
examining the quality and accuracy of data, regulatory documents and drug 
accountability. Data quality and accuracy will be reviewed through a CRF data and 
source document review. The monitor will randomly select three randomized subjects 
(or 10% of the randomized subjects enrolled since the last site visit, if more than 30 
were enrolled in that time) to serve as a representative sample. In addition, the 
monitor will randomly select three disqualified subjects enrolled since the last site 
visit to confirm accuracy of disqualification.  Regulatory Document Review will 
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protocols/amendments. The Drug Accountability review will focus on the accuracy 
and consistency of the investigational pharmacy records. 
[2] 
A Scientific Review will occur at the discretion of the VCC as needed and could 
consist of presentations by the site staff on their organizational structure, patient 
recruitment, staff training, and quality control procedures. The site monitoring team 
will include a VCC research nurse as well as the MIND-USA Principal or Co-
Investigator.  
The site monitoring reports from these reviews will be submitted to the DSMB (Data and Safety 
Monitoring Board) and other regulatory bodies (IRB, FDA and NIH) as requested and/or 
required. Data accuracy reports (including site comparisons) as well as site monitoring updates 
will be presented to the VCC. This Monitoring Plan will serve as a method for identifying 
systematic problems and provide a means in which to institute resolution and follow-up and 
therefore increase data quality. 
 
9.5 
Data Safety Monitoring Board (DSMB) 
[1] 
Membership. The DSMB includes 4 independent voting members (3 members will 
constitute a quorum) who are not study investigators and have no financial, scientific, 
or other conflict of interest with the trial; written documentation attesting to absence 
of conflict of interest will be required. Members include Roy Brower, MD (Chair), 
Professor of Medicine at Johns Hopkins University in Baltimore, Gordon Rubenfeld, 
MD, MSc, Professor of Medicine at Sunnybrook Health Sciences Centre in Toronto, 
David Schoenfeld, PhD, Biostatistician and Professor of Medicine at the Harvard 
School of Public Health in Boston, and Kate Payne, RN, JD, Director of Ethics & 
Palliative Care at Saint Thomas Hospital in Nashville. These members were 
recommended by the MIND-USA study PI and approved by the NIA. Also, Molly 
Wagster, PhD, Chief of the Behavioral & Systems Neuroscience Branch at the NIA 
will serve as an ex officio nonvoting member. Collectively, the DSMB has expertise 
in the following fields: clinical geriatrics, critical care medicine, psychiatry, 
clinical trial methodology, and biostatistics. Dr. Brower has agreed to serve as the 
Chair and will be responsible for overseeing meetings, developing agendas in 
consultation with the NIA and PI, and being the contact person for the DSMB. 
[2] 
Initial Meeting. Prior to the initiation of the trial, the DSMB will meet and review 
the entire IRB-approved study protocol with regard to subject safety, recruitment, 
randomization, intervention, data management, quality control and analysis. If the 
protocol and other study documents are deemed satisfactory by the DSMB, they will 
recommend to the VCC that subject recruitment begin. If, alternatively, modifications 
to the protocol or other study documents are needed, the DSMB will recommend such 
modifications and postpone its recommendation to begin recruitment. This initial 
meeting may occur via conference call or in person and will begin with an 
introduction by the PI and VCC Co-Investigator, then continue as a closed session, 
including only DSMB members and (if available) NIA program staff. 
[3] 
Additional Meetings. Throughout the study period, the DSMB will meet in person or 
by teleconference at least twice (at N=100 and N=300 patients randomized; see 11.5 
for detailed description), with additional meetings when needed to review blinded or 
unblinded data as needed and appropriate, including data on recruitment, 
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completion, intervention effects, gender and minority inclusion, and subject safety. 
The DSMB is responsible for identifying problems related to safety (including all 
SUSARs), requesting additional data relevant to safety (including all SUSARs), 
proposing analyses of safety endpoints as needed, and considering the rationale for 
continuation of the study in light of safety data, progress of randomization, retention, 
protocol adherence, and data management. Reports of AEs and SUSARs for the two 
interim looks at the data (at N=100 and N=300 patients randomized; see 11.5 for 
detailed description) will initially be provided to the DSMB in a blinded fashion (i.e., 
treatment group assignment will not be revealed), but the DSMB will retain the right 
to request an unblinded report. Only DSMB members will have access to unblinded 
data in order to preserve the integrity of data and minimize potential for bias while 
maintaining appropriate safety monitoring. After each DSMB meeting, the Chair will 
provide a written report to the VCC and the NIA program official. In addition, the 
VCC, in turn, will provide the reports to the Vanderbilt University IRB and to all sites 
for submission to their local IRBs. 
 
10.0 
Study Withdrawal/Discontinuation 
 
Subjects may be withdrawn from study participation at the discretion of the investigator or if the 
patient/surrogate or attending physician requests that the subject be withdrawn. The reason and 
date of every withdrawal will be recorded. The Informed Consent Document will notify 
participants that their participation is voluntary, and they can tell the study staff at any time if 
they decide to stop participating. In addition, if they choose to withdraw their authorization for 
study staff to access protected health information (PHI) in the medical record, they may do so by 
notifying study staff in writing (the address is provided). If a participant chooses to no longer 
participate but does not notify study staff that they withdraw authorization for access to PHI, 
their medical record may be accessed to obtain outcomes and safety data. Follow-up will be 
performed for all discontinuations due to an AE or other safety concern until resolution, until 
deemed chronic and stable, or as long as clinically appropriate. 
 
11.0 
Statistical Considerations 
 
11.1 
Power Analyses and Sample Size Calculations for Delirium (Aim 1). Based on data 
collected during our BRAIN-ICU Study, we anticipate that patients in the control (placebo) 
group in MIND-USA will have a mean ± SD of 6.8±5.2 delirium/coma-free days during the 14-
day Treatment Period. At a 2-sided significance level of 2.50%, after Bonferonni adjustment for 
2 pairwise comparisons (each active treatment will be compared to placebo), a trial of 187 
patients per treatment group (total N=561) will have 92% analytical power to detect a 2-day 
improvement in delirium/coma-free days. Importantly, this sample size will also provide 80% 
power to detect a 2.5-day improvement in DCFDs within 4 subgroups expected to be ~45% 
(N=252) of the study population: severe sepsis, age ≥ 65 years, high illness severity (APACHE II 
≥ 25), and medical vs. surgical patients. We will also conduct a hypothesis-generating subgroup 
analysis for patients enrolled with preexisting cognitive impairment (~25% of study population, 
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11.2 
Power analyses for Mortality and ICU LOS (Aims 2 and 3). Assuming 40% one-year 
mortality in the control (placebo) group, this study will have 80% power to detect a 14% 
absolute difference in one-year mortality at a 2-sided significance level of 2.50% (if control 
mortality is 50%, study has 80% power to detect 15% difference). For ICU length of stay (LOS), 
this study will have 80% power to detect a 2.43-day (29%) difference at a 2-sided significance 
level of 2.50% assuming an 8.2±7.6 day ICU LOS in controls. 
 
11.3 
Power Analyses for Long-Term Cognitive Impairment (Aim 4). We expect to follow 
≥ 80% of survivors for evaluation of LTCI. Based on the expected mortality rates (see above), 
we expect an overall 31% mortality across all 3 groups and plan to test 310 (=561x0.69x0.80) 
patients for LTCI at 12 months. Analysis for this aim will use multivariable linear regression to 
account for potential confounders introduced by imbalances in groups created by death and loss 
to follow-up. With 310 patients, we will able to include independent variables with up to 21 
degrees of freedom. The proposed study will have adequate—indeed abundant—ability to assess 
the independent effect of the intervention on cognitive impairment while controlling for 
confounders. 
 
11.4 
Data Analysis Plan. To assess success of randomization, the distribution of baseline 
factors, such as age, sex, race, severity of illness, and sepsis, will be assessed by comparing 
summary measures between patients randomized into the 3 groups to identify clinically 
meaningful differences rather than relying on statistical testing.246 The primary outcome of the 
Aim 1 analysis is delirium/coma-free days, which we will examine using both unadjusted and 
adjusted analyses. To determine the unadjusted effect of antipsychotic administration on this and 
other continuous outcomes, we will utilize the Kruskal-Wallis test to compare delirium/coma-
free days between the three treatment groups. If the test is significant, we will use pairwise 
Wilcoxon rank-sum tests to compare each of the two antipsychotics groups directly to the 
placebo group. To determine the unadjusted effect of antipsychotic administration on ICU length 
of stay, survival, and other time-to-event outcomes, the cumulative incidence probability of these 
outcomes will be estimated via Kaplan-Meier product limit method, and the log-rank test will be 
used to compare the three groups. 
In addition to unadjusted analyses, we will also perform multiple regression to adjust for 
a priori-selected risk factors for outcomes, including age, severity of illness, admission diagnosis 
of sepsis, and duration of coma prior to randomization. Adjusting for strong risk factors of 
outcome variables is known to reduce measurement error, which may increase statistical 
power.247 We will carefully assess differential effects of antipsychotic treatment by study sites by 
examining site-specific effects as well as by a formal interaction analysis using multiple 
regression. We will include study site as a random effect. For the analysis of delirium/coma-free 
days and other continuous outcomes, we will choose the type of multiple regression by carefully 
examining the distribution of the data. Cox proportional hazards regression248 will be used to 
analyze the adjusted effect of antipsychotic treatment on time-to-event outcomes (including one-
year survival), with censoring as appropriate. The proportionality assumption for Cox regression 
will be assessed graphically, using log-minus-log survival plot, and by adding interaction terms 
between each covariate and time in the model. The number of variables to be included in each 
regression analysis will be based on the rule of thumb that a multivariable regression model must 
include no more than m/10 parameters for it to be reliable on future similar patients, where m is 
the effective samples size (e.g., number events for Cox regression or number of patients for 


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proportional odds logistic regression).249,250 This approach avoids overfitting and ensures 
robustness of regression parameters. 
In addition to assessing whether study site modifies the effects of antipsychotic treatment 
on outcomes, as described above, we will also assess whether patient characteristics modify the 
effects of the interventions on outcomes to identify a subcategory of patients who may benefit 
more than others. For these analyses, we will develop multiple regression models that include 
interaction terms between study group and clinical characteristics, such as age, sepsis, and 
duration of coma prior to randomization. Nonlinearity of the association between continuous 
variables and outcomes will be assessed by inclusion of restricted cubic splines. 
Regarding the analyses of all a priori-defined secondary outcomes described herein, no 
adjustments will be made for multiple comparisons in keeping with authoritative 
recommendations on this topic251-253 and standard practice when analyzing multiple, 
prospectively defined outcomes in a clinical trial. As described in our proposal, each comparison 
made will be hypothesis-driven and based upon biological plausibility rather than exploratory in 
nature. 
 
11.5 
Interim Analysis. To ensure protocol compliance and safety within the MIND-USA 
study, we will conduct interim analyses that will allow early presentation of outcomes to the 
DSMB (see section 9.3). In addition to the final analysis of 561 patients, two interim analyses are 
planned at 100 patients and 300 patients randomized; these interim analyses will compare 90-day 
survival in the blinded treatment groups. 
Using a modified Haybittle-Peto method, the MIND-USA Study should be terminated or 
modified (e.g., one group dropped) if the p value for the global test, which simultaneously 
compares the three treatment groups, is less than 0.0001 at any of the two interim analyses. If the 
trial continues to completion (N=561 randomized), a p value <0.0498 for the global test will be 
considered statistically significant to account for the two planned interim analyses. The DSMB 
will be provided data showing the effect size (relative risk) in order to put the p-values into 
clinical perspective. 
 
11.6 
Intention-to-Treat (ITT) Principle and Handling Missing Data. For all primary 
analyses, we will employ the intention-to-treat (ITT) principle (as defined in section 4.2.1). A 
secondary set of analyses will be conducted involving only patients who received at least one 
dose of study drug. One would expect that results of the primary and secondary would be nearly 
identical, yet in an ICU population, trials can sometimes experience an unexpected number of 
early and unexpected deaths. For outcome variables of Aims 1 through 3, missing data will be 
very low because the majority of data are collected during ICU stay. When missing data occur 
due to patient withdrawal, we will continue to follow patients in an observational setting to 
minimize missing outcome variables. When data cannot be collected, however, we will impute 
missing variables via multiple imputation methods, and the imputed variables will be included in 
the ITT analyses.255 For Aim 4 (long-term cognitive impairment), our pilot work indicates that 
we can complete testing on 91% of survivors, yet we are powering the study conservatively for a 
lower follow-up rate in case we achieve 80% follow-up testing. Loss of survivors to follow-up is 
not random and may be associated with more severe cognitive or functional status deficits among 
those not tested. Losing these patients will, if anything, lead to underestimation of the overall 
degree of LTCI and likely bias towards the null. We will analyze whether particular baseline 
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with long-term cognitive testing. We will also conduct analyses using data from deceased and 
untested patients due to illness along observed LTCI scores with proportional odds logistic 
regression using previously developed256 composite outcome as follows: 1 point: cognitively 
normal, 2 points: cognitively impaired, 3 points: un-able to test due to illness, 4 points: unable to 
test due to death. This method is popularly used in a research of long-term brain deficits to avoid 
survivor bias.256  
 
12.0 
Privacy/Confidentiality Issues 
 
At no time will we reveal subject identities in any manner, whether in presentation, description 
or publication of the research for scientific purposes. All data obtained with subject or provider 
identifiers will be kept in locked file cabinets to ensure confidentiality, and all paper file contents 
will be shredded before disposal. All subjects will be assigned a unique study number for use in 
the computer database, and all electronic data will be kept in password-protected computer files 
to ensure confidentiality. All biological specimens (serum, plasma, and DNA samples), maintain 
for batched assay after trial completion, will be stored in a locked –80 °C freezer and labeled 
with study ID# only, without any patient identifiers. These samples will be accessible only to 
designated co-investigators. Results of the specified laboratory tests will be maintained in a 
password-protected database to be accessed only by designated co-investigators. 
 
13.0 
Follow-up and Record Retention 
 
13.1 
Duration of Record Retention. Information stored in the database will be stored for an 
indefinite period of time for future reference, including for use in subsequent data analyses. 
Throughout the study, all collected data will be entered directly in to the secure password-
protected web-based database. 
 
13.2 
Method for Destruction or Indefinite Archival of Information. Biological specimens 
will be stored for an indefinite period of time for use in future studies (as described in the 
informed consent document). Because genetic markers of risk for delirium and other study 
outcomes are not currently known, storage of specimens for later research use is required to 
advance this knowledge of ICU delirium. It is our hope that polymorphisms will eventually be 
identified that will help us better understand the pathogenesis of delirium and patients’ response 
(or lack thereof) to therapy. When such information is available, it would be invaluable to have a 
bank of genetic samples available for testing that can be coupled with a comprehensive set of 
clinical data such as the database being collected in this investigation.  Consent for use of genetic 
samples will be obtained from patients and/or surrogates at the local sites.  In the event that the 
permission to use the genetic sample is incomplete and the patient has already been discharged 
from the hospital, study coordinators from the VCC will pursue this permission from study 
participants.  This contact may occur outside of the 12 month follow-up study period. 
 
As stated in the informed consent document, participants’ consent to use or share PHI 
does not expire unless study staff are explicitly notified of this decision in writing from the 
participant (even in the event that a subject withdraws from further participation). If a subject 
chooses to withdraw their authorization for study staff to access PHI and/or to have stored 
data/specimens destroyed, they may do so by notifying study staff in writing (the address is 


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provided). In this case, actions will be taken to ensure that the data is properly destroyed and that 
the appropriate documentation is maintained as outlined in standard operating procedures. 
 
13.3 
Duration of Study. This study is planned to last a total of 5 years. Patient recruitment 
and follow-up will take place over 4 years and 3 months. Throughout the recruitment and testing 
phases, we will diligently monitor data collection, perform data cleaning, and hold conference 
calls and in-person meetings with study personnel to ensure protocol compliance and overall 
efficiency of study implementation. We will also work regularly with our statisticians to execute 
the planned analyses. The final analyses will occur during the last 6 months of the study period, 
when monitoring, quality checks, archiving and manuscript preparation will take place. 
 
 
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SAP_001.pdf: 
1.
Administrative Information 
 
Title 
The Modifying the Impact of ICU-Associated Neurological 
Dysfunction-USA (MIND-USA) Study 
Trial Registration 
https://clinicaltrials.gov/ct2/show/NCT01211522 
Principal 
Investigators 
E. Wesley Ely, MD 
Timothy Girard, MD 
Biostatistics 
Rameela Chandrasekhar, PhD 
Jennifer Thompson, MPH 
Date 
May 7, 2018 
SAP Version 
1.0 
 
2.
Introduction 
This serves as the formal Statistical Analysis Plan (SAP) for The Modifying the Impact of 
ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study, finalized before unblinding 
of the treatment groups. The trial is registered at ​clinicaltrials.gov/ct2/show/NCT01211522​. This 
SAP is written based on guidelines in ​Gamble et al, JAMA 2017​. 
2.1
Background and Rationale 
Antipsychotics are the first-line pharmacological agents recommended to treat delirium, and 
over the past 30 years they have 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 long-term objective of the study is to define 
the role of antipsychotics in the management of delirium in vulnerable critically ill patients, 
specifically as they relate to 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. 


2.2
Objectives 
The MIND-USA study is a multicenter, double-blind, randomized, placebo-controlled trial 
investigating the effects of intravenously (IV) administered typical and atypical antipsychotics 
(haloperidol and ziprasidone) on delirium in critically ill patients. The study evaluates the 
following aims: 
●
Aim 1:​ To determine whether haloperidol or ziprasidone administered to delirious 
medical/surgical ICU patients will increase days alive without delirium and coma 
(measured as delirium/coma-free days [DCFDs]) over a 14-day study period compared 
with placebo. 
●
Aim 2:​ To determine whether haloperidol or ziprasidone will improve 30-day, 90-day, 
and 1-year survival compared with placebo. 
●
Aim 3:​ To determine whether haloperidol or ziprasidone will reduce ICU length of stay 
(LOS) (i.e., time to ICU discharge) compared with placebo. 
●
Aim 4:​ To determine whether haloperidol or ziprasidone will improve long-term 
neuropsychological outcomes, functional independence, quality of life, and 
post-traumatic stress disorder symptoms at 3-month and 1-year follow-up compared with 
placebo. 
 
 


3.
Study Methods 
3.1
Trial Design 
This is a multicenter, double-blind, randomized, placebo-controlled trial. The two treatment arms 
comprise a typical antipsychotic (haloperidol) and an atypical antipsychotic (ziprasidone). 
Patients were consented and enrolled upon meeting inclusion and exclusion criteria; patients 
were then randomized to receive study drug if and when they became delirious, per research 
coordinator CAM and RASS assessment. 
3.2
Randomization 
Randomization to haloperidol, ziprasidone, or placebo was conducted in a 1:1:1 ratio using a 
computer-generated permuted-block randomization scheme stratified by study center and age 
(<70 years vs. ≥70 years). The randomization scheme was created by a biostatistician external 
to the study and distributed directly to the investigational pharmacy at each study site. 
Unblinding of the treatment groups (and subsequent data lock) will be performed after data 
cleaning and will be documented. Any unlock of the database will be performed only to correct 
serious data entry errors and will be documented in a detailed manner.  
3.3
Power and Sample Size​ (as was written in the grant) 
Power Analyses and Sample Size Calculations for Delirium (Aim 1).​ ​Based on data 
collected during our BRAIN-ICU Study, we anticipate that patients in the control (placebo) group 
in MIND-USA will have a mean ± SD of 6.8±5.2 delirium/coma-free days during the 14-day 
Treatment Period. At a 2-sided significance level of 2.50%, after Bonferroni adjustment for 2 
pairwise comparisons (each active treatment will be compared to placebo), a trial of 187 
patients per treatment group (total N=561) will have 92% analytical power to detect a 2-day 
improvement in delirium/coma-free days. Importantly, this sample size will also provide 80% 
power to detect a 2.5-day improvement in DCFDs within 4 subgroups expected to be ~45% 
(N=252) of the study population: severe sepsis, age ≥65 years, high illness severity (APACHE II 
≥25), and medical vs. surgical patients. We will also conduct a hypothesis-generating subgroup 
analysis for patients enrolled with preexisting cognitive impairment (~25% of study population, 
N=140). 
 
Power Analyses for Mortality and ICU LOS (Aims 2 and 3)​. Assuming 40% one-year 
mortality in the control (placebo) group, this study will have 80% power to detect a 13% absolute 
difference in one-year mortality at a 2-sided significance level of 1.67% (if control mortality is 
50%, study has 80% power to detect 14% difference). For ICU length of stay (LOS), this study 
will have 80% power to detect a 2-day (24%) difference at a 2-sided significance level of 1.67% 
assuming an 8.2±7.6 day ICU LOS in controls. 


Timing of Final Analysis 
In-Hospital Database Cleaning & Lock Procedures 
MIND-USA uses the ​REDCap​ electronic data capture platform for data collection. Upon 
completion of the in-hospital portion of the MIND-USA study, the following procedures will be 
followed and documented within the ​Database Cleaning & Lock SOP​: 
1.
VCC will work with site coordinators to address all data issues revealed by ongoing data 
cleaning. This process will continue until all issues have been addressed. 
2.
Upon completion of in-hospital data cleaning, the REDCap database ​MIND-USA Study: 
Exclusion Log​ will be locked in the following way: 
a.
Initially all users with current “view and edit” user privileges will be moved to 
“read only” user privileges.  
b.
After the window closes for sites to export their data the database will be 
permanently moved to inactive status (meaning that no data can be changed). 
3.
Upon completion of in-hospital data cleaning, the REDCap database ​MIND-USA Study: 
In-Hospital Database ​will be locked in the following way: 
a.
Initially all study site personnel will be restricted to “read-only” user access for the 
entire database. VCC Project Managers and the Follow-Up Team will be 
restricted to read-only access for all fields except those needed for patient 
contact, reconsenting, DNA permissions, notes to file and event reporting, and 
tracking dates of death and study withdrawal. All fields not needed by these 
teams will be restricted to read only by use of the @readonly action tags. The 
follow-up team will continue to be blinded (via restricted access) to all information 
about the hospital course, as has been the case throughout the study. 
  
  
VCC Project Managers 
Follow-Up Team 
Dates Tracking Form - all variables made 
read-only (using action tag @readonly) 
to all users except variables pertaining to 
consenting, death and study withdrawal 
View and Edit 
View and Edit 
Contact Form - all fields 
Read Only 
View and Edit 
NTF - all fields 
View and Edit 
View and Edit 
Adverse Events - all fields 
View and Edit 
View and Edit 
DNA Log - all fields 
View and Edit 
No Access 
All other forms/fields 
Read Only 
No Access 


  
b.
During the remaining Follow-Up period, the sites will be given a window for 
downloading their data for local storage.  
c.
Once 12-month follow-up is completed, we will conduct final data cleans on the 
updated information and then permanently move the entire database to inactive 
status, meaning that no data can be changed unless serious errors are noted. 
 
A log of all steps in this process will be maintained in the ​Database Cleaning & Lock SOP​. 
 


4.
Statistical Principles 
Statistical analysis will be conducted in accordance to the plan outlined in this SAP. Statistical 
analysis will abide by these general statistical principles below. 
Confidence Intervals and P-Values 
Level of statistical significance will be set at 5% (with multiple comparisons adjustments for the 
primary outcome, as noted below). All tests will be two-sided. 95% confidence intervals will be 
reported along with all effect estimates. Presentation of r​esults will emphasize clinical 
significance, effect sizes and confidence intervals, over statistical significance. 
Modeling Principles 
Whenever possible (based on variable distribution), we will not assume linear associations 
between covariates and outcomes; rather, n​onlinear associations between continuous variables 
and outcomes will be permitted by inclusion of restricted cubic splines with 3 knots. To ​account 
for correlation among patients within a given site, we will adjust standard errors using 
Huber-White sandwich estimation. 
Multiple Comparisons 
For the primary outcome (DCFDs), multiple comparisons will be conducted at a 2.5% level if the 
overall test of association is significant at a 5% level. Regarding the analyses of all ​a 
priori​-defined secondary outcomes described herein, no adjustments will be made for multiple 
comparisons, in keeping with authoritative recommendations on this topic and standard practice 
when analyzing multiple, prospectively defined outcomes in a clinical trial. As described in our 
proposal, each comparison made will be hypothesis-driven and based upon biological 
plausibility rather than hypothesis-generating in nature. 
Missing Data 
Individual Variables 
Missing data for individual variables will be imputed using clinical imputation rules when 
appropriate; details on these rules are noted in the Definitions and Derived Variables section. 
This section also describes the imputation process for summary variables for mental status (eg, 
days alive and free of delirium and coma), which may involve ​partially​ missing data. 


Missingness when Modeling 
In adjusted analyses, model-based multiple imputation strategies will be used (using R’s ​mice 
library) if >5% of any covariates are missing. In all cases, decisions and processes will be 
documented both in data management and analysis code and in statistical reports.  
Adherence to the Intervention and Protocol Noncompliance 
Definition & assessment of adherence to the intervention 
All analysis will be conducted based on the intention to treat principle. Subjects will be 
considered to have the treatment they were randomized to regardless of withdrawal from 
treatment or extent of exposure. 
Presentation of adherence to intervention 
We will describe, within each treatment group, the following: 
●
Patient level: 
○
How many randomized patients received >=1 dose of study treatment 
○
Days each randomized patient received study treatment 
○
Doses of study treatment each randomized patient received, along with average 
daily dose 
○
Whether study treatment was ever held or permanently discontinued, and 
reasons for hold/discontinuation 
●
Dose level: 
○
Proportion of opportunities to receive study treatment which were given, 
temporarily held, or permanently discontinued 
○
Amount (mL) of each dose given 
○
Whether dose amount was maintained, increased, or decreased 
○
Reasons for hold or discontinuation 
Definition and description of protocol noncompliance 
Any noncompliance that increased safety risk to the patient was considered protocol 
noncompliance. These events will be captured for a variety of causes considered related to 
patient safety and will be described in the final study report, broken down according to a simple 
categorization scheme followed prospectively during the conduct of the MIND-USA 
investigation. 


Analysis Populations 
All analysis will be conducted on the randomized, intent-to-treat population. We will also 
compare demographic and admission characteristics of patients who were enrolled but not 
randomized to those who were randomized. 
 
Analysis for all ​in-hospital​ outcomes will include all randomized patients in an intent-to-treat 
manner, with the following exceptions: 
1.
Liberation from mechanical ventilation will include only patients who were on mechanical 
ventilation (invasive or noninvasive) at or within 24 hours following the time of 
randomization. 
2.
ICU readmission will include only patients who survived and remained in the study with 
access to medical data throughout their first ICU admission. 
 
Analysis for ​long-term​ outcomes will include all patients who survive and remain in the study at 
the specified time point (3 or 12 months after randomization), and who have data for the 
outcome in question. We will describe the general cohort of patients who are included in any 
long-term outcome models at each time point. 
5.
Trial Population 
The study inclusion and exclusion criteria can be obtained from ​clinicaltrials.gov​. Patient flow 
information as recommended by CONSORT guidelines will be presented for both enrolled and 
randomized patients, including screening, exclusions, refusal of consent, enrollment, 
randomization, withdrawals, and hospital discharge status. We will describe, by treatment group 
and overall, baseline characteristics of randomized patients including demographics (age, race, 
ethnicity, gender, insurance status, education, BMI); baseline clinical status (comorbidities, 
home antipsychotic use, frailty, disability, cognition); and ICU admission characteristics 
(admission reason, severity of illness). 
 


6.
Statistical Analysis 
Outcome Definitions 
Primary outcome (PO) 
The primary outcome is delirium/coma-free days (DCFDs) over a 14-day study period, 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. 
Secondary outcomes (SO) 
Time frames, as noted in parentheses, all begin on the day of randomization to study treatment, 
with the exception of ICU readmission. 
SO1.
Survival 
○
Description: Time to death 
○
Time frame: 30 days, 90 days, 1 year 
SO2.
Delirium duration 
○
Description: Duration of delirium during the intervention period 
○
Time frame: 14 days 
SO3.
Time to final ICU discharge 
○
Description: 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. 
○
Time frame: 90 days 
SO4.
Time to hospital discharge 
○
Description: Days from randomization to successful hospital discharge, where 
“successful” indicates that discharge was followed by at least 48 hours alive. 
○
Time frame: 90 days 
SO5.
Time to liberation from mechanical ventilation 
○
Description: 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. 
○
Time frame: 30 days 
SO6.
Time to ICU readmission 
○
Description: Days from first ICU discharge to next ICU readmission within the 
index hospitalization. 
○
Time frame: 90 days after first ICU discharge 


SO7.
Hospital readmission 
○
Description: Readmission to the hospital after index hospital discharge 
determined by self-report during follow-up interviews. 
○
Time frame: 365 days 
SO8.
Neuropsychological dysfunction 
○
Description: Assessed using Telephone Interview for Cognitive Status (TICS), 
Digit Span and Similarities from the WAIS-III, Confusion Assessment Method 
(CAM) Telephone version, Paragraph Recall (both immediate and delayed 
portions) from the WMS-III, Controlled Oral Word Association Test (COWA), and 
the Hayling Test.  These assessments will be scored in standard fashion and will 
allow us to characterize cognitive impairment across patients. 
○
Time frame: 3 and 12 months post-randomization 
SO9.
Quality of life 
○
Description: Assessed using the Katz ADL, Employment Questionnaire, 
Functional Activities Questionnaire (FAQ), EQ-5D-3L and a Healthcare Utilization 
Survey. 
○
Time frame: 3 and 12 months post-randomization 
SO10. Post-traumatic stress disorder 
○
Description: Assessed using the PTSD Checklist (PCL-S, event specific version) 
with respondents instructed to answer questions in reference to the ICU 
experience. 
○
Time frame: 3 and 12 months post-randomization 
SO11. Torsades de pointes 
○
Description: Incidence of tachyarrhythmias determined to be torsades de pointes 
after review by the site primary investigator, DSMB, and coordinating center. 
○
Time frame: 14 days plus 4-day post-study drug period (if longer than 14 days) 
SO12. Extrapyramidal symptoms 
○
Description: Occurrence and severity of extrapyramidal symptoms as measured 
by a modified Simpson-Angus Scale, Akathisia Visual Analogue Scale, and a 
standardized definition of dystonia 
○
Time frame: 14 days plus 4-day post-study drug period (if longer than 14 days) 
SO13. Neuroleptic malignant syndrome 
○
Description: Incidence of neuroleptic malignant syndrome identified by the clinical 
team and confirmed by the site primary investigator and coordinating center 
○
Time frame: 14 days plus 4-day post-study drug period (if longer than 14 days) 
 
 
 


7.
Analysis Methods 
All in-hospital outcomes will be analyzed using both univariate methods and multivariable 
regression, adjusting for covariates noted below. Though patient characteristics should 
theoretically be balanced between treatment groups due to randomization, adjustment 
increases our power and precision. Though we will perform both types of analyses for each 
outcome, ​adjusted analyses will be considered the primary analysis. 
Unadjusted Analyses 
In-Hospital Continuous Outcomes 
We will analyze continuous outcomes (delirium/coma-free days [​PO​]; delirium duration [total, 
SO2​; hyperactive and hypoactive delirium separately; coma duration; mean CV SOFA and 
lowest mean arterial pressure]) using the Kruskal-Wallis test. These outcomes are typically not 
normally distributed; therefore, the assumptions for a parametric ANOVA would be violated, and 
results would be unreliable. The nonparametric Kruskal-Wallis test does not assume that the 
outcome has a normal distribution, and thus provides more power and reliability in the case of a 
non-normal distribution. 
If the unadjusted test for the primary outcome (DCFDs) only is statistically significant, we will 
use Dunn’s test for pairwise differences between treatment groups, using a Bonferroni 
correction for multiple comparisons at a 2.5% alpha level. 
Time to Event Outcomes 
We will describe and test for differences in time to death (​SO1​) using Kaplan-Meier curves and 
the log-rank test, respectively. ICU and hospital discharge, liberation from mechanical 
ventilation, and ICU readmission all have a competing risk of death (​SO3​, ​SO4​, ​SO5​, and ​SO6​, 
respectively). (For ICU readmission and liberation from mechanical ventilation, hospital 
discharge without experiencing the outcome will be treated as an additional competing risk.) 
Therefore, we will describe the cumulative incidences of both the outcome of interest and each 
competing risk, along with a modified chi-squared test for the difference between groups in the 
subdistribution of interest (​Gray 1988​). Patients who withdrew in the hospital with no discharge 
or death information available are censored at the time of withdrawal; we censor at x.01 days 
anyone who has experienced neither death nor the outcome of interest by x days (where x is 
the end of the time frame specified above for each outcome). We will detail how many and when 
patients were censored for each analysis. 
“Time 0” will be the time of randomization for each of these outcomes, with the exception of ICU 
readmission; for this outcome, “time 0” will be the time of the first ICU discharge, and only 
patients who survived their first ICU admission will be included. 


Long-Term Outcomes 
We will use multivariable regression to analyze the relationship between treatment group and 
scores measuring long-term neuropsychological, quality of life, and PTSD outcomes as outlined 
in the Outcomes section above. Depending on the distribution of each outcome, we will use 
linear regression, negative binomial regression, or proportional odds logistic regression, as 
appropriate. These models will not include covariates other than treatment. 
 
For each outcome, we will have separate models for 3- and 12-month scores. At each time 
point, we include all patients with available outcome data, using inverse probability weighting to 
account for patient death and attrition. To decrease reliance on a few highly influential 
observations, we will truncate weights at the top 1 percentile. 
 
As a sensitivity analysis, we will also define long-term outcomes using the unadjusted 
composite endpoint approach (reference: ​Lachin​) to deal with outcomes truncated due to death 
or loss to follow up. The composite endpoint will be defined as: 
 
-
If the patient dies prior to assessment: days between randomization and death 
-
If the patient survives and is successfully assessed: days between randomization and 
planned assessment (constant) + assessment score 
 
For example, if we are analyzing a 3-month outcome, the constant would be 90. Differences 
between the composite end point distribution amongst groups will be assessed using the 
Kruskal-Wallis test.  
Adjusted Analyses 
We will adjust all coefficient variances using Huber-White sandwich estimation, clustered by 
study site. This will help account for unmeasured variability and correlation among patients 
within a given site. 
In-Hospital Continuous Outcomes 
We will use proportional odds logistic regression for continuous outcomes (delirium/coma-free 
days; delirium duration [any, hyperactive, and hypoactive]; coma duration; mean CV SOFA and 
lowest mean arterial pressure); this method assumes an ordinal outcome but does not assume 
that it follows a specific statistical distribution. 
If the overall test for treatment vs our primary outcome (DCFDs) is significant at the 5% level, 
we will report individual treatment tests vs placebo at the 2.5% level. 
Time to Event Outcomes 


We will use Cox proportional hazards regression for mortality. For all other time to event 
outcomes (ICU and hospital discharge, ICU readmission, and liberation from mechanical 
ventilation), we use Fine-Gray competing risks regression, treating death as our competing risk. 
(For ICU readmission and liberation from mechanical ventilation, hospital discharge without 
experiencing the outcome will be treated as an additional competing risk.) Patients who 
withdrew in the hospital with no discharge or death information available will be censored at the 
time of withdrawal; we will censor at x.01 days anyone who has experienced neither death nor 
the outcome of interest by x days, where x is the end of the time frame specified above for each 
outcome. Details on censoring will be provided with each analysis. 
“Time 0” will be the time of randomization for each of these outcomes, with the exception of ICU 
readmission; for this outcome, “time 0” will be the time of the first ICU discharge, and only 
patients who survived their first ICU admission will be included. 
Long-Term Outcomes 
We will use the same modeling techniques as described in “Unadjusted Analyses” above; 
however, here, we will adjust for the covariates listed below. 
Model Assumptions 
Model assumptions will be evaluated graphically. Proportional odds assumptions will be 
checked using logistic regression with multiple cutoffs for proportional odds assumption (see 
Harrell’s ​Regression Modeling Strategies​, section 13.3.3) and Schoenfeld residuals will be used 
for proportional hazards. If linear regression is used for long-term outcomes, we check residual 
vs fitted plots and quantile-quantile plots to ensure assumptions are met. For negative binomial 
models, we will check goodness-of-fit measures. 
Covariates 
Covariates for all multivariable regression models include (all demographic or ICU admission 
characteristics): 
●
Age at study consent 
●
Preexisting CI, via the IQCODE (performed via patient or surrogate questionnaire) 
●
Preexisting frailty, via the CSHA Clinical Frailty Score 
●
Preexisting comorbidities, via the Charlson Comorbidities Index 
●
SOFA on the day of randomization, excluding the CNS component 
●
Level of arousal at randomization, via the RASS closest to the time of randomization 
 
Prior to modeling, we perform redundancy analyses to ensure that no covariates completely 
explain any of the others (resulting in multicollinearity). 


Exploratory Analysis 
In addition to the primary and secondary outcomes listed on clinicaltrials.gov, the following 
additional analyses will be used to inform specific decisions on missing data and modeling, to 
elucidate findings from primary outcomes, and more fully describe the course of the 
intervention: 
●
Exploration and description of outcome and covariate missingness 
●
Distribution of all continuous covariates, to determine ability to use restricted cubic 
splines and knot placement 
●
Coma duration as an additional outcome, to aid in elucidating relationship between 
treatment and primary outcome of DCFDs; will be analyzed in the same manner as 
delirium duration (Kruskal-Wallis for unadjusted analysis, and proportional odds logistic 
regression for adjusted analysis, with the same covariates) 
●
Durations of a) hypoactive and b) hyperactive delirium as additional outcomes, to 
describe any relationship between treatment and specific types of delirium. These will be 
defined as follows: 
○
Hypoactive: CAM positive and RASS -3, -2, -1, or 0 
○
Hyperactive: CAM positive and RASS +1, +2, +3, or +4 
●
Daily compliance on the first five elements (A-E) of the ​ICU Liberation ABCDEF Bundle 
during the intervention period (number and % of eligible days compliant; descriptive 
statistics only). 
●
Description of incidents of Torsades de pointes, to accompany other secondary 
outcomes related to safety. 
●
Severity of Shock 
○
Description: 
■
Mean CV SOFA per day 
■
Mean lowest MAP per day  
○
Time Frame: 14 days plus 4-day post-study drug period (if longer than 14 days) 
Subgroup/Effect Modification Analysis 
We will assess whether patient characteristics modify the effects of the interventions on 
outcomes to identify a subcategory of patients who may benefit more than others. For these 
analyses, we will develop separate multivariable regression models that include interaction 
terms between study group and the following clinical characteristics: 
●
Age at consent (continuous) 
●
Presence of severe sepsis at ICU admission (yes/no) 
●
Preexisting cognitive impairment (measured by the IQCODE; continuous covariate) 
●
Medical vs surgical patients 
Surgical patients are those who have a recorded primary ICU admission reason involving 
surgery; had emergency or elective surgery between hospital admission and ICU admission; 
and/or went to the operating room between ICU admission and study enrollment. All other 
patients will be considered medical patients. 
 


8.
Definitions and Derived Variables 
Severity of Illness 
Due to the nature of clinical data collection, we have some missing values for APACHE II and 
SOFA components despite our coordinators’ best efforts. We handled these missing values in 
the following ways: 
APACHE II (ICU admission only) 
●
Oxygenation: If no arterial blood gas was done, we converted the lowest O2 saturation 
to PaO2 per the​ ​EPIC II conversions​ and assigned points based on PaO2 alone. O2 
saturations below the lowest level included in the conversion table were assigned the 
lowest PaO2; O2 saturations of 100 were assigned the highest PaO2. 
●
pH: If no arterial blood gas was done, we used the serum HCO3 conversions noted in 
the original reference. 
●
Glasgow Coma Score: If no GCS was available, we assigned points for the APACHE 
using the lowest RASS on the day of ICU admission using ​Vasilevskis et al’s​ point 
values for the SOFA. 
●
All other components: If no values were available on a given day, we looked for a value 
on the closest day within the three full days after ICU admission. If none was available, 
we assumed that no measurement implied no clinical reason to suspect dysfunction, and 
assigned a normal value (0 points). 
SOFA (ICU admission + daily throughout intervention period) 
●
Substitutions for specific components: 
○
Respiratory: If P/F ratio was not available, we used the lowest S/F ratio, per 
Pandharipande et al​. 
○
Central nervous system: If no GCS was available, we used the lowest RASS 
available that day, per​ ​Vasilevskis et al​, method C. 
●
Missing data at ICU admission: Using only data from ICU admission, there are 28 
consented patients and 7 randomized patients missing at least one SOFA component 
score. For these patients’ missing components, we imputed the next available value 
within the following two calendar days. If none was available, we assumed a normal 
value (0 points). (This could happen either because there was no clinical reason to order 
labs, or because the patient was not consented within three days of ICU admission and 
thus no study data was collected in that period.) 
●
Missing data during the intervention period: 
○
We were unable to calculate SOFA scores using raw data on 3 patient-days 
during the study period (randomization + 13 days). ​(Missingness is much higher 
after the official intervention/post-intervention periods, when patients were no 
longer being actively followed for daily data collection.) 


○
If the data required to calculate a given component was unavailable, we imputed 
the closest non-missing component score before ​or​ after the missing day, up to 
two full days away (missing day +/-2 days). If data was available X days both 
before ​and​ after the missing day, we prioritized past over future values. 
○
If, after this imputation, values are still missing, we assume that no available data 
indicates no clinical reason to suspect organ dysfunction and therefore impute a 
normal value for that component. Again, this applies to 3 patient-days during the 
study period. 
Medications 
●
Benzodiazepines include midazolam, lorazepam, and/or diazepam. Doses are 
expressed in midazolam equivalents. 
●
Opioids include fentanyl, morphine, and/or hydromorphone. Doses are expressed in 
fentanyl equivalents. 
●
Antipsychotics include open-label haloperidol, open-label ziprasidone, quetiapine, 
aripiprazole, olanzapine (including in combination with fluoxetine), and/or risperidone. 
Doses are expressed in haloperidol equivalents. 
●
All conversion formulas can be found in​ ​this spreadsheet​. 
Mechanical Ventilation 
During the course of the study, patients could be on invasive mechanical ventilation (MV), 
noninvasive positive pressure support (NIPPV), both, or neither. For our purposes, “time on MV” 
describes the number of days each patient was on ​either​ type of MV beginning at the time of 
randomization, including time between discontinuation of MV and reinitiation or death, if that 
time is less than 48 hours. (In other words, if a patient was extubated at 12pm and died at 3pm, 
those final three hours are included in the total time on MV.) 
 
“Liberation from mechanical ventilation” indicates the first discontinuation of either type of MV 
which was followed by at least 48 hours alive without reinitiation of MV. 
Delirium/Coma-Free Days 
This primary outcome variable is calculated over the 14 days including and immediately 
following randomization. It is defined as days alive and without brain dysfunction. 
Mental Status (Delirium and Coma) 
Determining Mental Status Using CAM and RASS 
We determined mental status for a given ​assessment​ using the following criteria: 
1.
Comatose: RASS -4 or -5, or RASS missing and CAM Unable to Assess 
2.
Delirious: RASS missing or >= -3, and CAM Positive 


3.
Normal: RASS missing or >= -3, and CAM Negative 
 
Patients could have multiple assessments on a given study day. On a given ​day​, a patient was 
considered delirious if any assessment was considered delirious; comatose if no assessments 
met criteria for delirium and at least one was considered comatose; and normal if no 
assessments met criteria for delirium or coma, and at least one was considered normal. 
Handling Missing Data 
Prior to unblinding, the data shows that among all consented patients, 401 (4%) in-hospital 
patient-days have insufficient information to determine mental status (due to missing data or 
study withdrawal). Among randomized patients during the intervention period, 251 (4%) of 
patient-days have missing mental status, again due either to missing data or study withdrawal. 
Mental status can change quickly; therefore, simple imputation methods like last observation 
carried forward could be inaccurate. Since we have strong covariate data, we performed single 
imputation using polytomous logistic regression, including the following variables as covariates 
in the imputation. 
●
Baseline: age at consent; gender; BMI; education; level of proficiency in English; 
insurance; home antipsychotic use; Charlson comorbidities index; CSHA Clinical Frailty 
Score; APACHE II Acute Physiology Score 
●
Daily: 
○
Medications (clonazepam, dexmedetomidine, propofol, remifentanil, 
antipsychotics, benzodiazepines, opioids [IV and PO], antibiotics, anxiolytics, 
statins) 
○
Variables indicating severity of illness (CV SOFA, creatinine, urine output, 
platelets, lowest recorded RASS, Glasgow Coma Scale, P/F ratio, S/F ratio, 
bilirubin) 
○
Any mental status data available the day of, the day before, and the day after the 
missing day 
All summary variables (delirium/coma-free days, delirium duration, and coma duration) are 
presented using imputed mental status. 
9.
Software Details 
R version 3.4.4 (2018-03-15) or above will be used for all analyses. Versions of specific 
packages used for analysis will be noted in the analysis report. The ​checkpoint package​ will be 
used to preserve R package versions throughout the manuscript submission and review 
process. 


10. References 
1.
Gamble C, Krishan A, Stocken D, et al. Guidelines for the content of statistical analysis 
plans in clinical trials. JAMA. ​doi: 10.1001/jama.2017.18556 
2.
R. Gray. ​A class of k-sample tests for comparing the cumulative incidence of a 
competing risk​. Ann Stat, 16:1141-1154, 1988. 
3.
Fine, J., & Gray, R. (1999). A Proportional Hazards Model for the Subdistribution of a 
Competing Risk. ​Journal of the American Statistical Association,​ ​94​(446), 496-509. 
doi:10.2307/2670170 
4.
Harrell. ​Regression Modeling Strategies with Applications to Linear Models, Logistic 
Regression, and Survival Analysis 2001, Springer-Verlag. ​link 
5.
Pandharipande P, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, 
Ware LB, Bernard GR, Ely EW. Derivation and validation of Spo2/FiO2 ratio to impute 
for PaO2/FiO2 ratio in the respiratory component of the Sequential Organ Failure 
Assessment Score. Crit Care Med, 2009 Apr; 37(4): 1317-21. ​doi: 
10.1097/CCM.0b013e31819cefa9 
6.
Vasilevskis EE, Pandharipande PP, Graves AJ, Shintani A, Tsuruta R, Ely EW, Girard 
TD. Validity of a Modified Sequential Organ Failure Assessment Score Using the 
Richmond Agitation-Sedation Scale. Crit Care Med 2016 Jan; 44(1): 138-146. doi: 
10.1097/CCM.0000000000001375 
7.
Lachin JM. Worst-rank score analysis with informatively missing observations in clinical 
trials. Control Clin Trials 1999 Oct; 20(5):408-22. ​PMID: 10503801​.