Wearable Eye-Tracking Device as Means of Communication in the Critically Ill and Mechanically Ventilated Patient
Phase: NA
Conditions: Acute Respiratory Failure Requiring Mechanical Ventilation
Sponsor: Emory University

Study Protocol 
 
Title: Eye-Control Trial: Wearable Eye-Tracking Device as Means of 
CommunicaƟon in the CriƟcally Ill and Mechanically VenƟlated PaƟent 
 
NCT Number: NCT04582149 
 
Protocol date: October 18, 2021 

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Eye-Control Trial:
Wearable Eye-Tracking Device as Means of 
Communication in the Critically Ill and 
Mechanically Ventilated Patient
STUDY PROTOCOL
Principal Investigator:
Ofer Sadan, MD, PhD
Assistant Professor, 
Department of Neurology and Neurosurgery,
Division of Neurocritical Care
Emory University School of Medicine
Sponsor: 
EyeFree Assisting Communication Ltd., Tel Aviv, Israel
Protocol version: 
1.2           
Protocol date: 
18OCT2021

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SYNOPSIS
Title
Wearable eye-tracking device as means of communication in the critically ill, 
and mechanically ventilated patient
Short Title
Eye-Control Trial
Principal 
Investigator
Ofer Sadan, MD, PhD
Assistant Professor, Department of Neurology and Neurosurgery, 
Division of Neurocritical Care
Emory University School of Medicine
Study 
Description
The study will have two steps: (1) safety and efficacy phase, in which we will 
enroll up to 60 patients, with main goal to experience the use of the device in 
critical care settings, and better prepare for the second part (burn-in period); 
(2) a randomized controlled trial that will treat eligible and consented patients 
with either EyeControl or the current standard of care from a communication 
stand point. On a daily basis, all patients admitted will be screened according to 
the predefined inclusion/exclusion criteria. Eligible patients (or their LARs) will 
be approached by the study team to obtain consent. Once enrolled, and 
randomized to the intervention arm, the patients will be instructed how to use 
the EyeControl device and will keep the device on for as long as they would like. 
While on, the device will collect data as a potential monitor, such as time of 
wakefulness, and will screen for delirium by CAM-ICU questionnaire. At six 
months, we will contact the patient to assess his functional and cognitive 
performance using standardized questioners. Following this interview, the 
patient will end the participation in the trial. 
Purpose
To determine the safety, tolerability, and ease of use of the EyeControl device 
and determine impact on communication and delirium in critically ill, ventilated 
patients in the intensive care unit.
Design
This is a single-center, Phase 1/2, two-step prospective, open-label, blinded-
endpoint (PROBE) study evaluating the tolerability and efficacy of the 
EyeControl device.
Objectives 
To evaluate the efficacy of a wearable communication device in preventing and 
treating ICU-delirium in critically ill patients who are admitted to the intensive 
care unit (ICU) and mechanically ventilated. The study will assess the safety, 
tolerability, and ease of use of the EyeControl device; examine its potential 
monitoring capabilities; determine the change in level of frustration and 
discomfort following use of the device; and measure long-term outcome of these 
critically ill patients.
Study 
Population
Critically ill patients who are admitted to the ICU at Emory University Hospital 
(EUH) who require mechanical ventilation for at least two days and are awake 
enough and cooperative to attempt working with the communication device 
(defined as Richmond Agitation Sedation Scale (RASS) score of -1 to 1).
Enrollment / 
Duration
Step 1: 60 Patients, approximately 8 months – No Long-Term Outcomes
Step 2: 244 Patients, approximately 12 months – With LTO extending to 6 
months
Subject 
Inclusion

Intensive Care Unit (ICU) Admission

Mechanically ventilated for at least 24 hours

RASS between -1 to 1 at the time of screening (Note: minimal sedation is 
allowed including low-dose Fentanyl, Dexmedetomidine, Ketamine, 
Propofol, etc.)

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Subject 
Exclusion

< 18 years of age

Not admitted to the ICU

Inability to follow commands during screening

Known cerebral injury (acute or chronic) in the dominant hemisphere 
concerning for aphasia on clinical assessment

Significant pre-existing neurologic (i.e., dementia and/or cognitive 
deficiencies), psychologic, or baseline communication challenges that 
would confound outcomes assessments (including hearing loss)

Inability to blink or move eyes for any reason

Prisoner or incarceration

Inability or unwillingness to provide informed consent

Unwillingness to be contacted for follow-up
Outcome 
Measures
For the burn-in phase, the primary outcome will be time to successful 
operation of the device (see below for definition), and secondary outcomes 
include length, type and intensity of use (e.g. use for communication, 
entertainment, call for help etc), safety, and proof of concept of non-
communication features of the device such as wakefulness time monitoring 
and CAM-ICU capturing. 
The primary end point of the second step will be number of alive and delirium 
days while in the ICU and on the ventilator up to 14 days from randomization, 
or to extubation or ICU discharge, the earliest. Secondary endpoints will 
include: proportion of patients who were able to operate and use EyeControl, 
the specific parameters of successful patients compared to those who were 
unable to operate it; the length and intensity of use; the correlation between 
the monitoring data and clinical data; and the cognitive and functional long 
term outcomes as assessed by telephone by the Critical care, Brain Dysfunction 
and Survivorship (CIBS Center from Vanderbilt University).

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SCHEDULE OF EVENTS
SCHEDULE OF EVENTS
SCREEN
ENROLL
(DAY 0)
ICU 
admission
DAY 
180
Procedure
Eligibility Verification
X
Informed Consent
X
Lead diagnosis for ICU admission
X
Physiologic Data (Vitals, GCS, etc)
X
X
Neuroimaging (if available)
X
X
Demographics
X
Medical History
X
Laboratory Results
X
X
CAM-ICU q12h
X
X
Discharge Data
X
Clinical Endpoint Monitoring
X
X
X
General Questionnaire re: communication in ICU
X
X
Follow-up Assessments
Neurocognitive Battery
X

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TABLE OF CONTENTS
SYNOPSIS...............................................................................................................................................................................................................................................2
SCHEDULE OF EVENTS....................................................................................................................................................................................................................4
TABLE OF CONTENTS......................................................................................................................................................................................................................5
TABLE OF ABBREVATIONS ...........................................................................................................................................................................................................7
BACKGROUND AND SIGNIFICANCE...........................................................................................................................................................................................8
Study Rationale..............................................................................................................................................................................................................................8
Communication in the Critically Ill...................................................................................................................................................................................8
Delirium in the ICU..................................................................................................................................................................................................................8
How Many Patients Would Benefit from a Communication Device?.................................................................................................................8
Eye-Control Device ...............................................................................................................................................................................................................10
STUDY PURPOSE .............................................................................................................................................................................................................................12
Step 1:..............................................................................................................................................................................................................................................12
Step 2:..............................................................................................................................................................................................................................................12
STUDY DESIGN OVERVIEW ........................................................................................................................................................................................................13
Study Hypothesis and Rationale..........................................................................................................................................................................................13
Study Design and Methods.....................................................................................................................................................................................................13
Step 1: Assess the safety, tolerability, and ease of use of the EyeControl device ......................................................................................13
Step 2: Measure reduction in delirium-free and alive days in the ICU with EyeControl-based communication compared 
with the standard of care. ..................................................................................................................................................................................................14
Subject Flow Schema ................................................................................................................................................................................................................15
STUDY POPULATION AND SUBJECT SELECTION .............................................................................................................................................................16
Participant Selection and Sample Size ..............................................................................................................................................................................16
Inclusion Criteria...................................................................................................................................................................................................................16
Exclusion Criteria ..................................................................................................................................................................................................................16
SUBJECT PROCEDURES AND GUIDELINES..........................................................................................................................................................................18
DATA COLLECTION........................................................................................................................................................................................................................19
Subject Hospital Data...........................................................................................................................................................................................................19
Long-Term Outcomes (LTO) Battery............................................................................................................................................................................19
Electronic and Paper Data Collection Systems..............................................................................................................................................................19
STATISTICAL ANALYSIS PLAN..................................................................................................................................................................................................21
HUMAN SUBJECTS ..........................................................................................................................................................................................................................22
Ethical Conduct of Study .........................................................................................................................................................................................................22
Institutional Review Board (IRB)........................................................................................................................................................................................22
Informed Consent.......................................................................................................................................................................................................................22
Subject Confidentiality.............................................................................................................................................................................................................22
Subject Withdrawal...................................................................................................................................................................................................................23
Safety Monitoring Plan.............................................................................................................................................................................................................23
Compensation for time and effort.......................................................................................................................................................................................23
References..........................................................................................................................................................................................................................................24

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TABLE OF ABBREVATIONS
AE
Adverse Event
APP
Advanced Practice Provider 
ARICU
Acute Respiratory Intensive Care Unit
CAM-ICU
Confusion Assessment Method in Intensive Care Unit
CCU
Cardiac Intensive Care Unit
CRF
Case Report Form
CTS-ICU
Cardiothoracic surgery Intensive Care Unit
EMR
Electronic medical record
ICU
Intensive Care Unit
IRB
Institutional Review Board
LAR
Legally Authorized Representative
LOC
Level of Consciousness
LOS
Length of Stay
MD
Medical Doctor
MICU
Medical Intensive Care Unit
NeuroICU
Neuroscience Intensive Care Unit
RASS
Richmond Agitation Sedation Score
RN
Registered Nurse
SICU
Surgical Intensive Care Unit

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BACKGROUND AND SIGNIFICANCE
Critically ill patients, who are mechanically ventilated, suffer not only from their acute, potentially devastating 
illness, but also from the lack of ability to communicate in an effective manner. On top of the mechanical change in 
air flow, communication challenges result from sedation, neurological injuries (primary brain injury or secondary 
encephalopathy), and delirium. Lack of communication can lead to increased frustration, anxiety, confusion and 
delirium and overall psychological stress, and could continue to the development of post- traumatic stress disorder 
(PTSD). On top of the subjective discomfort, the inability to communicate in an effective manner may impair medical 
care—for example, by failure to assess symptoms such as pain or breathing discomfort. In order to solve these 
difficulties, a new, wearable, eye-tracking communication device was developed (EyeContol). 
STUDY RATIONALE
COMMUNICATION IN THE CRITICALLY ILL
Critically ill patients, who are mechanically ventilated, suffer not only from their acute, potentially devastating 
illness, but also from the lack of ability to communicate in an effective manner. This is the direct result of the 
orotracheal tube or tracheostomy required for the mechanical ventilation, which does not allow speech to be 
produced. On top of the mechanical change in air flow, communication challenges result from sedation, neurological 
injuries (primary brain injury or secondary encephalopathy), and delirium. 
Lack of communication can lead to increased frustration (Guttormson et al., 2014), anxiety, and overall psychological 
stress (Carruthers et al., 2017) and could continue to the development of post-traumatic stress disorder (PTSD) 
(Wade et al., 2012). On top of the subjective discomfort, the inability to communicate in an effective manner may 
impair medical care—for example, by failure to assess symptoms such as pain (Chanques et al., 2014) or breathing 
discomfort (Binks et al., 2017) by behavioral cues only.
DELIRIUM IN THE ICU
One of the dreaded complications in critically ill patients is delirium. Delirium is an acute form of encephalopathy, 
or brain dysfunction, that is manifested by waxing and waning changes in cognitive abilities during acute illness. 
Delirium is diagnosed in 48-83% of critically ill patients (Girard et al., 2018, Ely et al. 2001), and is linked to increased 
mortality (Ely et al., 2004). Several risk factors associated with delirium include older age, prior neurological injuries 
or neurodegenerative disorders, as well as the acuity of illness and admission in the ICU (Ely et al., 2001; Oldham et 
al., 2018). Disorganized sleep is also linked to higher risk of delirium (Dres et al., 2019; Marra et al., 2019a). Delirium 
is strongly correlated with worse outcomes, including longer length of stay in the ICU and the hospital, and increased 
mortality (Marra et al., 2019b). Treatment for delirium includes pharmacological (mostly anti-psychotic 
medications) and non-pharmacological interventions (Marra et al., 2019). Non-pharmacological interventions to 
prevent and treat delirium include early mobilization, frequent reorientation, etc. (Martínez et al., 2017). Recently, 
a large randomized controlled trial failed to show benefit for pharmacological interventions to treat and prevent 
delirium, leaving non-pharmacological interventions as the main treatment option for now (Girard et al., 2018). Lack 
of effective communication not only could impair such non-pharmacological interventions but limit the diagnosis of 
delirium in the first place (Rowley-Conwy, 2018). However, from a diagnostic stand point, others have shown a valid 
method to diagnose delirium even in mechanically ventilated patients (Ely et al., 2001). 

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HOW MANY PATIENTS WOULD BENEFIT FROM A COMMUNICATION DEVICE?
On average, across the U.S., 39.5% of patients in the ICU at any given hour require mechanical ventilation (Wunsch 
et al., 2013). Estimating the number of patients who have an unmet communication need is difficult. Not all patients 
who are mechanically ventilated could communicate, even with assistance. For example, a patient who suffered a 
large stroke in the dominant hemisphere will suffer from aphasia and may not be able to communicate efficiently, 
with or without being ventilated. Similarly, in many critically ill patients, there is a need for continuous sedation, 
which limits the patient’s ability to communicate. 
Happ et al. (2015) estimated the number of patients who are mechanically ventilated and potentially could 
communicate. They found that 53.9% of patients who were mechanically ventilated for at least 48 hours were awake 
and following commands for at least 12 hours (one nursing shift). 
Analyzing the data from the years 2016 to 2018 at EUH, there are, on average, 469±37 admissions to all ICUs per 
month. In order to identify the potential study population, we examined what proportion of patients were ventilated 
for at least two, three, or five days. We further calculated the duration of ventilator days for these patients, rate of 
tracheostomy, and the proportion of patients who had at least two days in which their RASS was documented as -1 
to 1, suggesting that they were awake and cooperative enough to engage with a communication device. 
We found that 27.8% of admissions to the ICU were intubated for at least 48 hours, while 18.9% were intubated for 
at least three days and 12.6% were intubated for at least five days. The mean number of ventilator days for patients 
ventilated for at least two days was 8.6, and 11.6 and 16.2 for patients ventilated for at least three and five days, 
respectively. Given the high mean number of ventilation days for the patients who are ventilated for at least two 
days, it seemed reasonable to further analyze this group as a the inclusion criterion. We further found that nearly 
25% of the patients ventilated for at least two days had recorded RASS of -1 to 1 for at least two days, suggesting a 
window in which these patients could potentially communicate (see Figure 1A for breakdown by units). It was also 
found that 17.9% of patients ventilated for at least two days ended up being ventilated long- term, requiring a 
tracheostomy (see Figure 1B for breakdown by units). We hypothesize that this group, those who will need to be on 
the ventilator for a long period of time, will be the patient population that will mostly benefit from a wearable, eye-
tracking-based communication device. At Emory, by this retrospective analysis of the past three years, we are 
estimated to screen about 130 patients per month who are ventilated for at least two days. 
NeuroICU 
(2D/2G)
CT-S ICU (5E) SICU (5T-S)
MICU (5T-N) CCU (3G/4G)
ARICU (5G)
All
0%
5%
10%
15%
20%
25%
30%
Proportion of Patients with RASS (-1 to 1) for at least two days

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Figure 1: Breakdown of patients by units who are ventilated for at least two days and have RASS between -1 to 1 for 
at least two days (A) and patients who ended up requiring tracheostomy (B). 
EYE-CONTROL DEVICE
Currently, the solutions for communication deficits in mechanically ventilated patients are mainly using yes/no 
communication, attempting to write, and communication boards that allow people to point at defined pictures or 
letters (Khalaila et al., 2011). Recently, technological advancements led to incorporation of more sophisticated 
communication devices, proving the feasibility of an eye-tracking approach, for example (Carruthers et al., 2017).
The EyeControl is a new, wearable, eye-tracking device (Figure 2) that facilitates communication by means of 
internal feedback to the patients with a bone-conducting speaker. In this way, the device can ask the patient what he 
or she wants to say, and the patient replies by eye gestures such as blinking or moving the eyes in a certain direction. 
This approach eliminates the need for calibration, as most eye-tracking devices that use a screen require, and is 
relatively easy to operate. It is currently being tested in general ICU-based settings in Tel Aviv, Israel, where the 
company reports nearly 100% success in teaching patients to use the device within minutes. 
Figure 2: The EyeControl device.
NeuroICU 
(2D/2G)
CT-S ICU (5E) SICU (5T-S)
MICU (5T-N) CCU (3G/4G)
ARICU (5G)
All
0%
10%
20%
30%
40%
Percentage of Patients with Trach
Proportion of Patients requiring trach

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This device has other potential advantages that could be utilized in the critical care settings. It could be used as a 
monitor; for example, it could record times that the patient has her or his eyes open as a marker for wakefulness (it 
could be an important indirect marker for quality and length of sleep); it could use its communication with the 
patient to assess for delirium (using known basic questionnaires such as the CAM-ICU); it could assess, to some 
extent, the ability to follow commands with blinking and eye movements. The device could be part of the non-
pharmacological interventions to prevent and treat delirium. For example, it could state the day, time, and location 
to the patients every few hours. 
The risk associated with the device seems very low. It is external, wearable, and could be easily removed with any 
signs of discomfort. No significant side effect was recorded from using this device according to the manufacturer. 

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STUDY PURPOSE
To determine the safety, tolerability, and ease of use of the EyeControl device and determine impact on 
communication and delirium in critically ill, ventilated patients in the intensive care unit.
STEP 1:
Primary Goal: Assess the safety, tolerability, and ease of use of the EyeControl device. The outcome measure for this 
goal will be the time of training required for a patients to successfully execute two tasks using the device: call for 
help and choose a predefined sentence for the device to say three times straight.
Secondary Goals: 
1.
Assess the proportion of mechanically ventilated, critically ill patients, with or without primary neurological 
injury, who could benefit and operate an eye-movement-tracking device as a means of communication.
2.
Assess the type and length of the use done by the patient. For example, we will monitor how long a patient 
wears the device, uses it, and for what purpose (communication, call for help or entertainment).
3.
Assess the EyeControl device as a diagnostic/monitoring tool for delirium in comparison to the bedside nurse 
assessment. Specifically, the device will record times of wakefulness for each 24h period of time, and will test 
for delirium using CAM-ICU. The later will be correlated with a live, verbal assessment done by a study team 
member.
4.
Assess patient proficiency in device operation through daily orientation questionnaire. 
5.
Assess the change in level of frustration and discomfort patients and families feel in relation to 
communication with and without the device. These will be assessed by a questionnaire given to patients and 
families near their discharge.
6.
Explore possible correlation between eye movements and clinical events by evaluating photographs of the 
eyes at the times of these events.
STEP 2:
Primary goal: Measure the time spent alive and non-delirious in the ICU up to 14 days from randomization with 
EyeControl-based communication compared with the standard of care, in a randomized-controlled fashion.
Secondary goals: 
1.
Assess the safety, tolerability, and ease of use of the EyeControl device; Specifically, we will assess on a daily 
basis for any adverse events related to the device. We will also document need for re-training on the device 
as a marker for ease of use.
2.
Measure the length and intensity of use for communication and call for help; Intensity will be measured by 
the number of times the device is used and for which purpose as a categorical measure (eg, call for help, talk 
using predefined sentences, communicate using letter by letter dictation etc). 
3.
Correlate between the monitoring data and clinical data: the device will assess CAM-ICU independently, and 
a study team member will repeat this analysis and the documented results will be documented. We will also 
track any clinical decision making based on wakefulness time information (for example a decision to add 
melatonin agonist to promote sleep) ; 
4.
Measure the cognitive and functional long-term outcomes, by phone questioners, to be done in a blinded 
fashion at 6 months from ICU discharge. 

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STUDY DESIGN OVERVIEW
STUDY HYPOTHESIS AND RATIONALE
The study hypothesizes that effective communication could be part of prevention and treatment for ICU-delirium in 
critically ill, mechanically ventilated patients. 
Lack of communication is a common, unmet need for these patients. It is believed that effective communication 
deprivation could be a contributing factor to the development of ICU delirium. It is further hypothesized that this 
communication gap could be matched by a wearable, eye-tracking-based communication device. 
EyeControl is a wearable, easy-to-use device that could supplement current communication methods between the 
patient and the treating team (and family). Current standard of communication for the critically ill mechanically 
ventilated patients is limited to nodding, writing, and pointing at communication boards. The wearable device could 
potentially allow broader and more effective communication. It may have secondary benefits as well, as a monitoring 
device, an emergency-call device, and to improve patients’ orientation. 
STUDY DESIGN AND METHODS
This is a two-step trial, that will first have a “burn-in” phase to gain real-life experience with the device in critical 
care settings, and later in the second step transition into a randomized controlled study that measure the efficacy of 
the communication intervention on prevention and treatment of ICU-delirium. The study will be run across all ICUs 
at Emory University Hospital, a large, tertiary referral center. The different ICUs are detailed in Table 1. 
STEP 1: ASSESS THE SAFETY, TOLERABILITY, AND EASE OF USE OF THE EYECONTROL DEVICE
On a daily basis all patients admitted to any of the ICUs at EUH will be screened for participating in the trial. Since 
during admission the patient could be first excluded and later meet inclusion criteria, the screening will continue for 
all patients on a daily basis (for inclusion/exclusion criteria, see below).
During screening, the patients’ EMR will be accessed and/or their clinical status will be discussed with the treating 
team (RN, APP, MD) by a member of the study team in order to identify whether they meet inclusion/exclusion 
criteria. For example, the study-team personnel will identify if the patient is ventilated, for how long, and what is the 
patient’s wakefulness and cooperation by nursing charting (e.g., RASS scale, nursing neurological and clinical 
assessment). 
Of note, due to the different nature of neurologically injured patients in these settings (primary organ effected is the 
brain), we will enroll about 33-50% of the patients in this step from the neuroscience ICU. This approach will allow 
us to consider re-defining our parameters in the second step of the trial and design a pre-defied subgroup analysis.
Upon meeting inclusion criteria, patients and/or their LARs will be approached for consent (see below for consent 
process details). Consented patients will be instructed how to use and operate the EyeControl device. The primary 
outcome of this part of the study will be time to operate the device. Successful operation will be defined as the ability 
to use the device to call for help, and produce one predefined sentence out of several options, three different times. 

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Once the patient is able to operate the device, it will stay on the patient for as long as she or he would like it on, or 
until the patient is successfully extubated or discharged from the ICU, whichever is earliest. During the time the 
patient is wearing the device, apart from its original intention to serve as a communication device, the following 
features will be activated and tested:
a.
Emergency call—if the patient is in distress, she or he could call for help by simply blinking three times. This 
will initiate a call for help from the device. We will monitor the use of this emergency call, its frequency, and 
causes for calling.
b.
Wakefulness monitoring—the device will record the times in which the patient is awake by monitoring when 
the patient’s eyes are open. This data will later be correlated with outcome measures such as delirium, LOS, 
and functional outcome.  Changes in wakefulness time will also be correlated with ICU interventions such as 
adding a melatonin-agonist to promote sleep. 
c.
CAM-ICU validation—every shift, after the nurse and/or study team member assesses CAM-ICU, the device 
will repeat the test by using multiple-choice questions and ask the patient to choose the correct answers by 
blinking. We will later correlate the device’s results with the nursing/study team ones.
d.
Reorientation – at a defined time interval, if the patient’s eyes will be open, the device will read the patient 
the current date/time/location.
e.
Entertainment – patients will have the option to listen to music. 
f.
Family communication – Families will be supplied with a patient-unique link to record audio messages which 
the patient will be able to listen to through the device. 
To address the secondary goal of proficiency with device operation, we will administer a daily orientation 
questionnaire via the device. If a patient fails this proficiency check,  study staff will perform a device re-training 
module. The frequency and amount of necessary re-training will be captured as another data parameter.
During the study, we will collect clinical information from the patient’s chart including: demographics, diagnoses, 
use of sedatives or medications that could change cognitive function, nursing charting (including neurological 
assessment), laboratory results, days on the ventilator, procedures, discharge destination, mortality, and 
functional outcome. All of these will be taken into account for the final analysis of the study. For example, this 
data could help us better identify which patients used the device more than others and which could benefit from 
its monitoring properties apart from its communication function. 
As part of its operation, the device captures photographs and video of the patient’s eyes (figure 3). In addressing 
the secondary goal of  potential correlation between eye behavior and clinical events, we will explore this 
possibility by evaluating photographs of the eyes at the times of clinical events (i.e. hypoxia, new onset shock, or 
new onset sepsis). The device will activate the image data collection only after 50 consecutive frames of eye-in-
the-image. This should be a safety index to verify that the device is only recording the eye. It will stop recording 
immediately when non-eye-in-the-image occurs. Data processing to decide if an eye is in the image is done locally 
on the device, so eventually only images of eyes should be collected. All external image data processing will be 
done following deidentification of the data, using the patient code only as an identifier. 

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Figure 3. Example photographs captured by the EyeControl device.
No randomization or blinding is planned for this step of the study, and no samples are planned to be collected. 
STEP 2: MEASURE REDUCTION IN DELIRIUM-FREE AND ALIVE DAYS IN THE ICU WITH 
EYECONTROL-BASED COMMUNICATION COMPARED WITH THE STANDARD OF CARE.
The second step will be similar to the operation of the first one, in terms of patient screening and enrolling. The main 
difference will be the randomization process. Patients will be randomized to use EyeControl for as much as they 
wish, versus the standard of care. Randomization will be done centrally, and will be stratified to the specific unit, 
gender and age, race and ethnicity. 
The primary goal of the second step will be to measure the time spent alive and non-delirious in the ICU with 
EyeControl-based communication compared with the standard of care. Delirium will be defined as CAM-ICU positive, 
starting at day 1 of use (following the day of training), up to 14 days from randomization or ICU discharge, the 
earliest. However, patients could require moderate to deep sedation following randomization, for example due to 
new or evolving medical complication. Whenever the RASS is below (-1), CAM-ICU will not be measured, and will be 
charted as undetermined. Therefore, only days in which the patient will be CAM-ICU positive, will be counted 
towards the primary outcome. CAM-ICU positive days prior to randomization will not be counted towards the 
primary outcome.
The secondary outcomes will include the following: 
1.
Assess the safety, tolerability, and ease of use of the EyeControl device. This will be achieved by daily review 
of advance events, and ask patients, families and clinical team regarding challenges of use. 
2.
Measure the length and intensity of use; We will measure time to first activation, as detailed under the 
primary goal of the first step, and on a daily basis we will collect data from the device including the number 
of hours a day the device was worn, how many times it was used for communication, and the type of 
communication (eg use of predefined sentences, call for help, using new sentences by dictation, 
entertainment listening etc). 
3.
Correlate between the monitoring data and clinical data, specifically validate CAM-ICU with nursing and/or 
study team independent assessment; and correlating wakefulness time with ICU interventions; We will 
collect from the device on a daily basis the times when the patient has his or hers eyes open, as a marker of 
wakefulness. We will also record interventions related to sleep and wake cycles, such as administration of 
 
  

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Melatonin or Melatonin agonists, night time antipsychotics, benzodiazepines etc. We will also perform a 
correlation between the device independent assessment of CAM-ICU, and the clinical team assessment.  
4.
Measure the cognitive and functional long-term outcomes, by phone questioners, to be done in a blinded 
fashion at 6 months from ICU discharge. This will include a pre-defined battery of tests, as detailed under  
the Long-Term Outcomes (LTO) Battery section below. 
SUBJECT FLOW SCHEMA (STEP 2)

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STUDY POPULATION AND SUBJECT SELECTION
Potential study population includes any patients admitted to the ICU. At Emory University Hospital, there are 121 
active ICU beds as described in table 1. 
Table 1: Intensive care units (ICUs) at Emory University Hospital
ICU
No. of Beds
Medical ICU (MICU, 5T-N)
17
Surgical ICU (SICU, 5T-S)
23
Neuroscience ICU (2D/2G)
40
Cardiothoracic surgery ICU (5E)
20
Cardiac ICU (CCU, 3G/4G)
14
Respiratory ICU (4A, 6A, 5G, 6G)
28
Total
142
PARTICIPANT SELECTION AND SAMPLE SIZE
According to our retrospective analysis, we intend to screen all admissions to all the ICUs at EUH on a daily basis and 
identify patients who were ventilated for at least two days as the initial screening. For those who meet these criteria, 
a further investigation into the patients’ chart will occur by the study team to identify the inclusion/exclusion 
criteria. We will obtain a de-identified list of screen failures and the reason for the failure. 
INCLUSION CRITERIA
-
Intensive Care Unit (ICU) Admission
-
Mechanically ventilated for at least 24 hours
-
RASS between -1 to 1 at the time of screening (Note: minimal sedation is allowed including low-dose 
Fentanyl, Dexmedetomidine, Ketamine, Propofol, etc., as long as the RASS is in the predefined range).
EXCLUSION CRITERIA
-
< 18 years of age
-
Not admitted to the ICU
-
Inability to follow commands during screening (at a minimum: open and close eyes, move eyes to one side 
or the other).
-
Known cerebral injury (acute or chronic) in the dominant hemisphere concerning for aphasia on clinical 
assessment
-
Significant pre-existing neurologic (i.e., dementia and/or cognitive deficiencies), hearing loss (with inability 
to hear through a bone-conduction speaker), psychiatric, or baseline communication challenges that would 
confound outcomes assessments
-
Inability to blink or move eyes for any reason
-
Prisoner or incarceration
-
Inability or unwillingness to provide informed consent
-
Unwillingness to be contacted for follow-up
Patients who meet the inclusion and do not meet any exclusion criteria will be approached for consent, as will be 
described below. 

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SAMPLE SIZE
From our retrospective analysis (described in the introduction), we expect about 130 patients per month for the 
initial screening (ventilated for at least two days). The same patient could be ineligible on a certain day, but become 
eligible later in the admission (e.g., due to the severity of the illness, the patient is deeply sedated for the first few 
days, and later sedation is weaned). This will allow us to recruit more patients, at different time points of their 
admission. Even with this in mind, it would be reasonable to assume that about half of these initially screened 
patients will not be eligible at any point of their admission due to any one of the exclusion criteria. Of those who will 
be eligible, we expect a high rate of consent, due to the low risk and the potential benefit of using the device while in 
the ICU. We therefore expect a rate of about 30 patients a month to be enrolled. 
For the first step, we will plan to enroll up to 60 patients, and at least a third of the sample will be from the 
neuroscience ICU, and specifically patients with an acute brain injury
Given that there are no prior data, there is no clear criteria that would justify a specific number. We believe that 
having 40 to 60 patients work with this new device would be sufficient to draw initial conclusions about its use and 
specific indications according to the study aims as stated above. 
For the second part of the trial, power calculations are based on previously published BRAIN-ICU trial. In that 
observational trial patients had 6.8±5.2 delirium/coma-free days within the first 14 days of admission, with an 
overall rate of about 50% rate of delirium. For the present trial, we considered a 2 day reduction in the time spect 
delirious as clinically significant. Given these parameters, the present trial will require 248 patients (N = 124 per 
arm) to achieve sufficient power (80%, α = .05) to detect a 2 day difference. In general, a sample size of 248 will 
provide sufficient power to detect a standardized mean difference of 0.38 (assuming minimal asymptotic relative 
efficiency of Mann-Whitney U test), an odds ratio of 2.14 for binary variables (assuming maximal variance for a 
binomial distribution), and a Cohen’s ƒ of 0.18.

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SUBJECT PROCEDURES AND GUIDELINES
Please See Schedule of Events on Page 4 of this protocol.
DATA COLLECTION
As mentioned above, we will collect clinical data from the chart, as well as data from the device per patients. Data 
could be, for example, what type of use did the patient practice with the device (call for help? communicate? listen 
to music or e-books?), for how long was the device worn, wakefulness timing and CAM-ICU results. 
We will also collect the long-term results from the phone-based questioners. 
Clinical data, as well as device-originating data, will be coded to allow de-identification during analysis, and stored 
in a HIPPA-compliant database (e.g., RedCAP). 
SUBJECT HOSPITAL DATA 
a) Consent material (study files)
b) EyeControl measurement session data
c)
Demographic information: age, weight, height, gender, ethnicity
d) Clinical status on admission (main diagnosis, procedures, or operations done)
e) CAM-ICU
f)
Lab results, imaging, vitals, and charting during the ICU stay
g) List of current medications, dose, and route of administration
h) Medical history
i)
Previous and current head and brain imaging
j)
Previous and current EEG, if available
k) Outcome measures: modified Rankin scale on discharge, discharge disposition, modified Rankin scale on 
follow-up clinic visits
l)
Responses of the patient and family members to a structured questionnaire regarding communication 
and use of the device
m) Device training success and frequency for proficient utilization
n) Eye photographs/video to explore possible relation to clinical events
Every study file will contain a fully signed consent form. The study files will be stored in a locked cabinet in a locked 
office. 
LONG-TERM OUTCOMES (LTO) BATTERY
Evaluations will be done using a specially-designed battery of tests that evaluates key aspects of functioning and 
behavior. This battery, which takes ~40 minutes to complete, will assess cognition, mental health (depression and 
PTSD), quality of life, and employment - all of which have been shown to be adversely affected in between 1/3 and 
2/3rds of survivors of sepsis. The questioners will be executed by the Critical care, Brain Dysfunction and 
Survivorship (CIBS Center from Vanderbilt University). This battery has been successfully used by researchers in 
multiple studies at Vanderbilt Medical Center and elsewhere - it is well tolerated by patients, easy to administer and 

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to understand, and is very sensitive to the detection of even minor difficulties.  Tests comprising the battery (by 
domain and name) are as follows:  Cognition -Attention (Digit Span), Delirium (Telephone Confusion Assessment 
Method), Executive Functioning (Hayling Test), Language (Controlled Oral Word Association Test or COWA), 
Memory (Paragraph Recall from the Wechsler Memory Scale IV), Orientation (Telephone Interview for Cognitive 
Status), Reasoning (WAIS-IV Similarities); Functioning – Activities of Daily Living (Katz ADL), Employment 
(Employment Questionnaire), Instrumental Activities of Daily Living (Functional Activities Questionnaire); Mental 
Health - Depression (Beck Depression Inventory-II), PTSD (Post Traumatic Stress Disorder Checklist for the DSM V); 
Quality of Life – EQ5D.
ELECTRONIC AND PAPER DATA COLLECTION SYSTEMS
REDCap is a secure online database for building and managing research data supported by Emory. All data collection 
will be input into the electronic data capture system. When subjects are enrolled, they will be sequentially assigned 
a unique subject code. This unique code will be used in the REDCap database. A centralized subject key that links 
subject identification with the unique subject code will be maintained in a secured and password protected 
electronic format. 
Data Handling – For the duration of the study, the Investigator will maintain complete and accurate documentation 
including but not limited to medical records, study progress records, laboratory reports, case report forms, signed 
informed consent forms, correspondence with the IRB and adverse event reports, and information regarding subject 
discontinuation or completion of the study.
Source Documentation – Source documents are defined as original documents, data and records. Investigator will 
maintain source documents in the subject’s medical records and/or subject binders, which confirm the data entered 
on the electronic case report forms.
CRF Completion – Data collection based on source-documented hospital and/or chart reviews will be performed 
accurately on the eCRFs by research personnel. 
Retention of Study Records – Study records will be retained at all sites for a minimum of 3 years following the end 
of subject recruitment and follow-up activities. 
Data Quality – Routine regulatory monitoring of regulatory compliance will be conducted by the Departmental 
Clinical Trials Regulatory Specialist. 

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STATISTICAL ANALYSIS PLAN 
Step 1: Step 1 of the present trial focuses on describing device usage and acceptability. Continuous data will be 
described using medians and interquartile ranges. Categorical variables will be described using frequencies, 
percentages, and 95% confidence intervals. No statistical hypothesis testing will be conducted.
Step 2:
Primary Outcome: The time spent alive and non-delirious in the ICU
Covariates/Confounders: age, gender, race, baseline education level, unit to which the patient was admitted to, need 
for tracheostomy, severity of illness by SOFA or APACHI score on admission and randomization day, categorical 
reason for admission (e.g. sepsis, ARDS, elective surgery, stroke etc), diagnosis of delirium prior to randomization 
and the presence of an acute central neurological injury.
Unadjusted Analyses: The time spent alive and non-delirious in the ICU will be evaluated using the stratified variant 
of the Mann-Whitney U test. In this analysis, patients will be stratified by ICU setting. For other variables, the 
unadjusted comparison will depend on the type of variable. In general, continuous variables will be compared using 
a Mann-Whitney U test and categorical variables will be compared using the χ2 test.
Adjusted Analyses: The time spent alive and non-delirious in the ICU will be evaluated using a multi-level/mixed-
effects quantile regression (median/50th percentile) while controlling for the previously listed covariates. The multi-
level/mixed-effects model will be used to account for clustering within ICU setting. In the event that the regression 
fails to estimate properly, the covariates will be used to generate propensity scores and patients will be stratified 
into ≥5 propensity score strata. The time spent alive and non-delirious in the ICU will then be analyzed using the 
stratified variant of the Mann-Whitney U test. Analyses of the secondary outcomes will depend on the type of 
variable. Continuous variables will be analyzed using multi-level/mixed-effects quantile regressions (median/50th 
percentile), binary variable will be analyzed using multi-level/mixed-effects binary logistic regressions, ordinal 
scales will be analyzed using multi-level/mixed-effects ordinal (cumulative logit) logistic regressions. 
Missing Data: In the event of substantial missing data, data will be imputed using a multiple imputation procedure. 
The type of procedure (e.g. fully conditional specification, hot decks etc.) and the number of imputed data sets will 
be determined by the amount of missing data and the pattern of missingness.

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HUMAN SUBJECTS
ETHICAL CONDUCT OF STUDY
The study will be conducted in accordance with the current guidelines and in accordance with local applicable laws 
and regulations.  All investigators and research personnel will have appropriate human subjects training (i.e., CITI). 
INSTITUTIONAL REVIEW BOARD (IRB)
The IRB will review all appropriate study documentation to safeguard the rights, safety, and well-being of the 
subjects. The study will only be conducted after IRB approval has been obtained. The protocol, sample ICF, 
advertisements (if applicable), written information given to the subjects, safety reports, progress reports, and any 
revisions to these documents will be provided to the IRB by the investigator.
INFORMED CONSENT
A written or electronic consent form that complies with the policies of local IRB will be utilized. The informed consent 
form should include the following elements and be in compliance with 21CFR Part 50: 

Title of the protocol

Name of the investigator

Study objectives and purpose

Detailed description of the procedures

Explanation of the responsibilities of the subject during follow-up interviews

Any foreseeable risks, anticipated benefits, available alternatives

An explicit statement of confidentiality

Non-compensation for participation

Right to withdraw at any time

Signature section

Number to contact the site investigator or a member of the study team with any questions. 
Informed Consent will be obtained by the site investigator or designee prior to any research activities. The informed 
consent form should be the IRB approved version corresponding to the version of the IRB approved protocol, and 
may occur through and electronic informed consent form approved by Emory IRB. There is no activity required in 
the screening process that is not typically considered standard of care evaluation for mild traumatic brain injury. A 
partial-HIPAA wavier will be sought for screening purposes to ensure eligibility prior to being approached for 
informed consent.
As part of the informed consent process, the patient will be informed of the ability to withdraw participation from 
the study at any time, without penalty or change in their ongoing healthcare. The study team should discuss any 
concerns about the study with the patient. 
In case of an eConsent process, the patient and/or LAR will be supplied with a link to a HIPPA-approved cloud-based 
service (RedCAP), in which there will be a copy of the latest version of the IRB-approved consent. The patient and/or 
LAR will have the ability to sign the consent electronically as an alternative to the written (paper) one.

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SUBJECT CONFIDENTIALITY
All data (case report forms, laboratory specimens, imaging, and other records) kept at the site will be physically and 
electronically secured to maintain subject confidentiality. Paper records and computers with subject data will be 
stored in locked office or cabinet. Computer records will always be password protected, and encrypted when 
possible. The study database is maintained behind a secure firewall, access is password protected for all data entry 
and access. Clinical information will not be released without written permission of the subject, except as necessary 
for monitoring by the IRB or other regulatory agencies. 
SUBJECT WITHDRAWAL
In those who wish to discontinue participation, no further data will be collected. Data collected prior to withdrawal 
will remain in the study database. Those wishing to discontinue participation will also have the informed consent 
document explained to them, will have any questions answered and will be asked to review and sign an informed 
withdrawal from the study, however, subjects are not required to complete this document to withdraw. Standard 
consent procedures will be used.  If subjects withdrawal prior to reaching the 30 day outcome visit they will not be 
counted toward the subject totals in their respective cohort. These subjects will be considered ‘incomplete’ and 
coded separately in the electronic database. 
SAFETY MONITORING PLAN
No Data and Safety Monitoring Board is necessary for this prospective trial. No untoward medical occurrence is 
expected due to subjects’ participation in this research. Adverse events In the event subjects report medical illness 
during follow-up phone calls they will be advised to seek medical evaluation (i.e., emergency department, primary 
care, etc). During the course of this study, if the principal investigator and/or research personnel believe there are 
unseen clinically relevant adverse events [related to wearing Eye Control Device], all events will be reviewed by the 
PI with the clinical team and relevant information reported to the local IRB as unanticipated problems. If an 
immediate safety concern is discovered by the clinical team, this will be addressed immediately by the study PI and 
may require no further wearing of the headset. 
COMPENSATION FOR TIME AND EFFORT
There will be no compensation for time or effort. The study will occur while the patient is in the ICU, and no travel 
will occur. 

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