Feasibility Pilot of Bright Light in the Intensive Care Unit
Phase: NA
Conditions: Circadian Rhythm Sleep Disorder, Unspecified
Sponsor: Yale University

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Protocol Title: Circadian Rhythm as a Novel Therapeutic Target in the Intensive Care Unit 
Brief Title: Feasibility Pilot of Bright Light in the Intensive Care Unit 
 
Principal Investigator: Melissa Knauert, MD, PhD 
 
 
Version Date: v8 approval date 10.20.22 
Excerpted from full IRB protocol for observational aims and described pilot study. 
 
Unique Protocol ID: 2000022284 
Clinicaltrials.gov Registration #:   Aim 3 Pilot NCT03568045 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
Statement of Purpose: Specific Aims ............................................................................................................. 3 
Background: ................................................................................................................................................... 4 
Research Plan: ................................................................................................................................................ 6 
Approach to Aims .......................................................................................................................................... 8 
Statistical Considerations ............................................................................................................................. 11 
Subject Population ....................................................................................................................................... 13 
Recruitment Procedures ............................................................................................................................... 13 
Determination of Eligibility ......................................................................................................................... 13 
Assessment of Current Health Provider Relationship for HIPAA Consideration ....................................... 13 
Request for Waiver of HIPPA Authorization for Recruitment/ Screening .................................................. 14 
Process of Consent/Assent ........................................................................................................................... 14 
Protection of Participant Privacy ................................................................................................................. 15 
Methods for security of storage and sharing materials ................................................................................ 15 
Study Risks .................................................................................................................................................. 16 
Minimizing Risks ......................................................................................................................................... 16 
Data and Safety Monitoring Plan ................................................................................................................. 17 
Potential Benefits ......................................................................................................................................... 19 
Research Alternatives and Economic Considerations ................................................................................. 19 
References .................................................................................................................................................... 21 
 
 
 
 

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STATEMENT OF PURPOSE: SPECIFIC AIMS 
 
The overall objectives of this research project are to prospectively investigate ICU day-night light 
patterns and their association with circadian abnormalities; investigate the association between 
circadian abnormalities and the duration of delirium; and evaluate the feasibility of providing 
daytime bright light to treat circadian abnormalities among critically ill patients. Our central 
hypothesis is that exposure to abnormally high overnight light and abnormally low daytime light 
(non-circadian light patterns) disrupts the circadian master clock and causes circadian abnormalities 
in ICU patients. In turn, circadian abnormalities contribute to sleep disruption and ultimately ICU 
delirium. The rationale for the proposed project is that circadian abnormalities may constitute a 
novel therapeutic target for interventions to prevent or shorten delirium and improve ICU outcomes. 
This work builds upon our own work and published studies that describe circadian abnormalities in 
critically ill patients. Prior studies are limited by small numbers of subjects or by periods of 
observation that start many days after ICU admission.17-23 We will use a melatonin metabolite, 
urinary 6-sulfatoxymelatonin (aMT6s), to measure circadian abnormalities; this measure has been 
successfully used in critically ill patients.24 We plan to accomplish our overall objectives via the 
following specific aims: 
 
Aim 1: Determine the association between ICU day-night light patterns and circadian abnormalities 
(i.e., circadian misalignment and decreased circadian amplitude). 
 
Hypothesis 1: Non-circadian ICU light patterns (i.e., abnormally low daytime light levels and 
abnormally high overnight light levels) are associated with increased circadian misalignment 
and decreased circadian amplitude as measured by urinary aMT6s. 
 
Aim 2: Determine the association between circadian abnormalities and the duration of delirium. 
 
Hypothesis 2: Increased circadian misalignment and decreased circadian amplitude are associated 
with more days of delirium. 
 
Aim 3: Evaluate the feasibility of providing daytime bright light in the ICU and examine the effect size 
of daytime bright light on circadian abnormalities in a pilot randomized controlled trial. 
 
Hypothesis 3.1: Daytime bright light is acceptable and tolerable to patients and has high fidelity and 
sustainability as an intervention.  
Hypothesis 3.2: Daytime bright light will be associated with decreased circadian misalignment and 
increased circadian amplitude (effect size). 
 
 
 
 
 

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BACKGROUND:  
 
Overall Premise: This research project addresses intensive care unit (ICU) delirium which is a 
significant, modifiable source of ICU morbidity and mortality. Delirium affects 50-80% of patients 
admitted to the medical ICU (MICU).1 Delirium is a syndrome of acute cerebral dysfunction with features 
of a change in baseline mental status, inattention and either disorganized thinking or an altered level of 
consciousness.2 Patient risk factors for ICU delirium include older age, hypertension, dementia, alcohol 
abuse, and chronic benzodiazepine use.2 Critical illness related risk factors for delirium include severity of 
illness, mechanical and non-invasive ventilation, and high doses of benzodiazepines during ICU 
admission.2, 3 ICU delirium is associated with adverse outcomes such as longer hospital stay, impaired 
cognition, and increased mortality.4-11 Additional days of delirium incrementally increase the risk of death 
and cognitive impairment at one year.3, 4 Evidence for the use of any medications to treat delirium is 
limited. Non-pharmacologic treatments such as sleep promotion have shown promise and are 
recommended by expert guidelines.12, 13 Currently sleep promotion efforts are focused on minimizing 
overnight sound, light, and care to provide patients with a sleep opportunity.14 However, there is a lack of 
attention to the potentially significant contribution of circadian abnormalities to the problem of ICU sleep 
disruption and consequent delirium. 
The circadian system is controlled by a central master clock and is a key determinant of sleep timing. 
The master clock is synchronized with the 24-hour day by external cues via a process called entrainment. 
Light is the most influential external entrainment cue. Under normal entrainment, the circadian system 
promotes arousal during the day and allows sleep during the night. Sleep quality and length are optimal 
when they occur during an 
individual’s “biologic” or 
“circadian” night. Circadian 
abnormalities contribute to 
inappropriate sleep timing, 
impaired sleep quality and 
decreased sleep quantity. 
These three elements of 
sleep disruption have been 
clearly shown in critically ill 
patients,15-17 and together with circadian abnormalities these elements form a vicious cycle. Circadian 
abnormalities are defined in this proposal as misalignment and decreased amplitude. We assert that 
optimal sleep promotion and therefore optimal treatment and prevention of delirium requires the 
promotion of normal circadian entrainment. The proposed project supports this by investigating the 
influence of ICU day-night light patterns on circadian abnormalities, examining the association between 
circadian abnormalities and duration of delirium and piloting a daytime bright light intervention (Figure 
1).  
Premise for Aims 1 and 2: ICU day-night light patterns conflict with circadian entrainment and cause 
circadian abnormalities. External cues for entrainment include light, meal schedule, and physical activity. 
As noted above, light has by far the greatest biologic influence on entrainment.18 The robustness of 
entrainment and vulnerability to disruption are determined by the timing, intensity (lux), and duration of 
a light dose.19 Normal entrainment requires bright light exposure during the day (wake) period and dim 
or no light during the night (sleep) period. Daytime bright light interventions deliver at least 1,000 lux and 
more typically deliver 2,500 to 10,000 lux over 30 minutes to several hours.20, 21 During the night, short 
bursts of bright light (e.g., 5 minutes) at relatively lower intensities (e.g., 100 or 250 lux) can cause 
circadian abnormalities.19 Interventions aimed at ICU sleep promotion have focused on lowering overnight 

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light levels,22 but have not addressed the significant problem of daytime light being too low for 
entrainment (See preliminary data). It is our premise in Aim 1 that non-circadian day-night light patterns 
in the ICU cause circadian abnormalities. Circadian abnormalities are present in critical illness, associated 
with delirium, and feasible to study. Studies of urinary 6-sulfatoxymelatonin (aMT6s), continuous heart 
rate, and actigraphic rest-activity have shown associations between critical illness and circadian 
abnormalities.23-28 In these studies, roughly 75% of ICU patients studied have evidence of circadian 
abnormalities. One small study has shown that delirium is associated with circadian misalignment in 
patients weaning from mechanical ventilation.29 These studies (Table 1) demonstrate the feasibility of 
studying circadian rhythms in the ICU but have been limited by small numbers (<30 patients), brief periods 
of observation (24 hours), or periods of observation that start days after ICU admission (>5 days post 
admission). It is our premise in Aim 2 that circadian abnormalities are common in ICU patients and likely 
to be associated with duration of delirium. Delirium is at least partially mediated by sleep disruption, which 
is a proposed factor on the causal pathway between circadian abnormality and delirium. 
 
 
Premise for Aim 3: Daytime bright light therapy in acute medical settings and nursing homes 
improves patient outcomes. Small studies of post-operative patients exposed to a bright light dose in the 
morning showed 40 to 42% reductions in delirium.33-35 Increased exposure to sunlight in hospital rooms is 
associated with shorter lengths of stay and lower mortality (cardiac ICU).36 The provision of daytime bright 
light to nursing home patients improves the circadian amplitude and reduces depression, cognitive 
decline, agitation, confusion, and anxiety.37 To leverage the most influential circadian entrainment cue 
(light) and to take the first step towards a multi-modality entrainment intervention, the proposed project 
will investigate the feasibility and effect size (on circadian abnormalities) of a daytime bright light 
intervention. It is our premise in Aim 3 that an intervention that improves circadian function via exposure 
to daytime bright light will improve circadian abnormalities and ultimately delirium. 
Significance of research contribution: We expect that the results of this study will improve 
understanding of circadian abnormalities in the ICU. We expect that pilot data from Aim 3 will inform the 
development of a large-scale entrainment intervention for the treatment of delirium. This contribution is 
expected to be significant because it is likely to provide evidence for a therapeutic target and intervention 
to shorten or prevent delirium. Prior work has established that additional days of delirium have a 
significant impact on mortality and cognition. Though the proposed project will focus on ICU light 
exposure, this line of investigation will also lead to a multi-modality intervention using multiple 
entrainment cues: (1) daytime bright light, (2) intermittent daytime feeding (e.g., meals or bolus enteral 
feeding), and (3) promotion of physical activity.  
 
Table 1: Circadian Rhythm Measurements and Related ICU Studies 
Variable 
Strengths 
ICU Studies Using this Variable 
Urinary 6-aMT6s Gold Standard 
Septic patients (n=17) v. non-septic ICU (n=7) and healthy controls (n=21); 
enrollment 11 days post ICU admission; abnormal aMT6s patterns in 
septic patients but not controls.27 Additional References: Gehlbach,30 
Frisk24 Verceles28 
Heart rate 
Recorded as part of usual 
care; starts at ICU admission 
Medical ICU sedated patients (N=11); time post ICU admission not listed; 
heart rate with circadian variability but misaligned.31 
Actigraphy 
Low cost for long-term 
monitoring; non-invasive 
Neurologic ICU with traumatic brain injury patients (N=16); enrollment 18 
days post injury; rest-activity consolidation associated with better 
recovery.32 

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RESEARCH PLAN:  
 
Overall Project Rationale  
Optimal sleep promotion and therefore optimal treatment and prevention of delirium requires the 
promotion of normal circadian entrainment. The project supports this by investigating the influence of 
ICU light patterns on circadian abnormalities, examining the association between circadian abnormalities 
and delirium, and piloting a daytime bright light intervention. To study the most relevant patients, our 
inclusion/exclusion criteria will select patients at increased risk for delirium. 
 
Project Overview 
a. Setting: The study site is the medical intensive care unit (MICU) at Yale-New Haven Hospital (YNHH), 
York Street Campus and St. Raphael’s Campus. Median ICU stay is 3 days. Predominant reasons for 
admission are sepsis and acute respiratory failure. MICU rooms are private. There is currently a unit-
wide sleep promotion protocol which limits care activities from 00:00 to 04:00. 
b. Design: Aim 1 and 2, prospective cohort study; Aim 3 pilot randomized controlled trial (RCT). Aim 3 
which is not dependent on Aims 1 and 2 will be conducted first. 
c. Cohort: We will enroll 100 subjects at risk for ICU delirium. In addition, we will enroll 16 subjects into 
the pilot randomize control trial. 
d. Inclusion and exclusion criteria: This study will focus on adults at an increased risk for ICU delirium. 
We have selected age ≥50 years as an inclusion criteria to study middle-aged to older adults who are 
at increasing risk for delirium while not overly restricting our sample. We will not restrict patients 
based on admission severity of illness (APACHE II) because we think this is a critically important 
confounder and would like to study the effect of the full spectrum of severity of illness on our 
outcomes. We will exclude patients at significant risk for pre-existing circadian abnormalities (e.g. shift 
work). We will also exclude patients with co-morbid disease or medication use that makes 
measurement of urinary aMT6s or actigraphy unreliable. Table 2 lists inclusion and exclusion criteria.  
 
Table 2: Inclusion Criteria 
Exclusion Criteria 
1. Hospital admission less 
than 30 hours as of noon 
on day of enrollment 
2. Expected to say in the 
MICU ≥24 hours after 
enrollment  
3. Expected to produce ≥250 
mL urine / day 
4. Age ≥50 years 
5. Able to understand 
English. 
At significant risk for pre-existing circadian abnormalities:  
− 
Severe chronic brain injury (Injury greater than 30 days ago resulting in the inability 
to live independently) OR Acute brain injury of any severity (Injury less than 30 
days ago including acute intracranial bleed, traumatic brain injury, central nervous 
system infection, tumor, hepatic encephalopathy) 
− 
Documented circadian disorder (<1% population) or blind/disease of the optic 
nerve 
− 
Current history of substance abuse including alcohol (use in last 30 days) 
− 
Transferred from an outside hospital  
− 
Homeless 
 
Unable to participate in study activities: 
− 
History of bipolar disease (Bright light therapy possibly unsafe in this population). 
− 
Paralyzed (due to injury, disease or medications) 
 
e. Recruitment: Patient recruitment will follow Yale University consent procedures, and we will obtain 
HIC approval before starting study activities. MICU admissions will be screened daily via the EMR. 
Eligible patients will be approached within 30 hours of hospital admission. Before consent, the patient 
will be assessed for delirium via the Confusion Assessment Method for the ICU (CAM-ICU). If not 
delirious and able to communicate, the patient can provide consent; otherwise, a legally authorized 

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representative (LAR) as delineated by Connecticut State Law can provide consent. 
a. In cases which the LAR provides consent, assent from the patient will be attempted daily and 
obtained whenever possible via simple verbal explanation of the purpose, activities, risks and 
benefits of the study. 
b. In the event a patient originally enrolled via LAR were to regain their capacity to consent 
themselves, trained study staff will follow the below protocol for re-consent. 
i. Study staff will introduce identify themselves as a member of the research team and 
clarify that they are not part of the primary ICU team.  
ii. The protocol will be described to the patient; this description will include an overview 
of student events they already completed, cover in detail the study intervention and 
any remaining/future study procedures/events, and cover the risks associated with 
participation.  
iii. We will assure study subjects that participation is voluntary and that the decision to 
continue their participation will have no impact on their current or future care.  
iv. A copy of the consent document will be provided to the patient. 
 
f. Timeline of Study Activities (Fig 2): Patients will be enrolled within 30 hours of hospital admission and 
before 12:00 on the day of enrollment which is designated “Study Day 1 (D1).” Actigraphy, delirium 
monitoring, and light measurement (part of feasibility) will start no later than 12:00 on D1. Actigraphy 
and light measurement will continue until D5 or MICU discharge whichever is longer. If the patient is 
discharged from the hospital prior to day 5, all study activities stop upon hospital discharge. Study 
activities will continue if/when the patient is transferred to the general medical floor if the patient 
completes at least D2 (13:00) in the MICU. Delirium monitoring will occur until D30 or hospital 
discharge.  
 
Figure 2: Study activities timeline. 
 

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APPROACH TO AIMS 
 
Aim 1: Determine the association between ICU day-night light patterns and circadian abnormalities (i.e., 
circadian misalignment and decreased circadian amplitude). 
 
Rationale: Aim 1 will test our hypothesis that non-circadian ICU light patterns are associated with 
increased circadian abnormalities as measured by urinary aMT6s. Our approach is to measure light levels 
(10-second intervals) and aMT6s (1-hour intervals, gold standard) for 72 hours following study enrollment; 
we will also collect exploratory measures of circadian rhythm, namely, actigraphy and heart rate. We will 
collect descriptive patient data to allow model adjustment during analysis. We define non-circadian ICU 
light patterns as abnormally low daytime light levels and abnormally high overnight light levels. We define 
circadian abnormalities as circadian misalignment and decreased circadian amplitude. The absence of 
circadian rhythm is an extreme decrease in amplitude (i.e., 100%). This work will establish if non-circadian 
ICU light patterns are associated with the development of circadian abnormalities.  
 
Research Design: We will enroll 100 subjects at increased risk for ICU delirium; subjects will be screened 
and consented as above. We will collect the following measures:  
a. Room light levels will be monitored from enrollment until Study D5 or until MICU discharge. We will 
set the light meter (HD450, Extech Instruments, New Hampshire) to read levels in lux at 10-second 
intervals. Meters will be placed in a standard location on the wall above the head of the bed as close 
as possible to eye level. Additional light measures will be taken adjacent to the patient’s face (by 
holding the light meter next to their face for several seconds); these measures will be taken several 
times per day to assess light levels at or close to the eye. 
b. Urinary aMT6s (1-hour intervals) is the primary circadian measure for this aim. Melatonin is normally 
released just before habitual sleep time, and peak levels occur during sleep midpoint; urinary aMT6s 
peaks 2 hours after sleep midpoint.38 For the proposed study, urinary aMT6s will 
be collected for 72 hours or until MICU discharge whichever occurs first. Urinary 
aMT6s will not be collected after MICU discharge. A 10mL aliquot of pooled urine 
sample collected every 1 hour will be used for analysis; total volume of urine will 
be recorded to allow for calculation of total aMT6s excreted. Total aMT6s 
excreted can be measured and is valid in patients with acute kidney injury, 
patients receiving diuretics,39 and patients with decompensated cirrhosis.40 We 
have the support of MICU nurse champions and the agreement of nursing 
leadership for the bedside nurse to collect these samples. Samples are stable at 
room temperature for 24 hours, will be transported to the lab daily, and stored 
at -80°C in the Translational Research Core. Samples will be batched and 
subsequently analyzed using a highly sensitive, competitive ELISA kit (IBL Laboratories, Germany).  
c. Secondary measures of actigraphy, surface body temperature, and continuous heart rate monitoring 
will be used in an exploratory manner. We plan to examine correlation with urinary aMT6s for use in 
future studies.  
i. Actigraphy (Fig 3) via the Actiwatch Spectrum (Philips Healthcare, Netherlands) set at 15-second 
epochs and placed on the patient’s wrist will be used to measure rest-activity from enrollment until 
Study Day 5 or until MICU discharge. Actigraphy uses accelerometer technology mounted on a 
wristwatch-like device to characterizes rest versus activity of the wearer. This data device allows 
time series monitoring with a high sampling frequency and has been successfully used in the ICU 
Figure 1: Actiwatch 

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setting.41, 42  
ii. Heart rate varies around the clock with peaks in the late morning and early evening and a nadir 
during the sleep midpoint in normal patients.43 Heart rate (5-second intervals) will be recorded per 
MICU standard of care from MICU admission until MICU discharge; this extended period of 
monitoring will provide insight into circadian abnormalities before study enrollment and after 
melatonin monitoring has been completed.  
 
d. Patient characteristics for calculation of sleep midpoint, confounders, and effect modifiers will include 
collection of age, gender, sleep habits and timing, medical history (including hypertension and risk of 
obstructive sleep apnea (OSA) based on STOP-Bang Score46), home medications, MICU admission 
diagnosis, sepsis presence and severity (as defined by the sepsis-3 criteria47), illness severity (APACHE 
II score elements), ventilator support, and MICU medication use (including sedative-hypnotic 
medications). This data will be obtained via the EMR and via patient/surrogate interviews. Though the 
study is observational, melatonin, melatonin agonists, and non-benzodiazepine sleep aids (zolpidem, 
zopiclone, zaleplon) will not be given to study subjects while in the MICU. These agents are not part 
of usual care, and MICU leadership is agreeable to this restriction. ICU care events including 
phlebotomy, medication administration, transfusion, radiology studies, and procedures (e.g., line 
placement, intubation, endoscopy, catheterization, etc.) will be tracked by time of occurrence for the 
entire MICU admission. This process of obtaining timestamped care events has been automated via a 
collaboration with Yale ITS and requires minimal person-time.  
 
Expected Outcomes: We expect that a low day/night dose ratio will be associated with increased 
misalignment and decreased amplitude of urinary aMT6s. We expect that this relationship will remain 
after controlling for listed confounders. We anticipate that we will see effect modification by sepsis and 
by OSA risk.  
 
 
Aim 2: Determine the association between circadian abnormalities and the duration of delirium.   
 
Rationale: Aim 2 will test our hypothesis that increased circadian misalignment and decreased amplitude 
are associated with more days of delirium. Our approach is to measure days of delirium in the same cohort 
of 100 patients that have been evaluated for circadian abnormalities in Aim 1. After enrollment, we will 
check patients twice daily for delirium until hospital discharge. We have selected days of delirium as our 
metric of delirium severity because it is standard in the field and because studies have shown that 
additional days of delirium convey additional risk for mortality and cognitive impairment.4, 5 We will 
measure (and control for) total amount of sleep (sleep quantity) and overnight sleep efficiency (sleep 
quality) via actigraphy. We propose that these metrics of sleep disruption act as potential confounders 
and/or effect modifiers of the association between circadian abnormalities and delirium. For this project 
focused upon circadian patterns and sleep disruption rather than detailed sleep architecture (e.g., sleep 
stages), actigraphy, rather than polysomnography, is the sleep measure of choice. It is our expectation 
that circadian abnormalities will be associated with increased days of delirium. This aim will be the basis 
for investigation of circadian entrainment as a means of treating ICU delirium.  
 
Research Design: The 100 subjects enrolled in Aim 1 will be examined for the outcome of days of delirium 
in Aim 2. We will collect the following measures: Circadian measures, actigraphy, and patient 
characteristics will be collected as described in Aim 1. Delirium: Research staff blinded to patient circadian 

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status and trained in the CAM-ICU will assess patients for delirium once daily from the time of MICU 
admission until hospital discharge or hospital day 30.48 The CAM-ICU is a guideline recommended, 
validated delirium detection tool with a sensitivity >93% and a specificity >98%.2, 48, 49 We are increasing 
sensitivity in our study by adding validated daily chart review for delirium.50 
 
Expected Outcomes: For patients with circadian abnormalities, we predict more days of delirium. We 
expect this relationship will remain after controlling for age, gender, severity of illness and ventilator-free 
days. We expect that age, sedative-hypnotic medication dose and measures of sleep disruption will act as 
effect modifiers.  
 
Aim 3: Evaluate the feasibility of providing daytime bright light in the ICU and examine the effect size 
of daytime bright light on circadian abnormalities in a pilot randomized controlled trial. 
 
Rationale: Aim 3 will test our hypothesis that daytime bright light (hereafter bright light) is acceptable and 
tolerable to patients and has high fidelity and sustainability. Our approach to testing this hypothesis is a 
pilot RCT. We will randomize patients to usual care or to bright light daily while in the MICU. We will collect 
metrics of acceptability, tolerability, fidelity, and sustainability. The rationale for selecting bright light for 
this pilot intervention is that light is by far the dominant circadian entrainment cue.51 The proposed 
method delivers light to the patient and does not require the patient to have their eyes open or look 
directly into the light.52 In addition, brief light delivery early in the morning (e.g., 30 minutes of 10,000 lux 
directed at the patient), could cause undesirable circadian phase shifts in patient population who have 
circadian misalignment of the delayed type30 It is our expectation that this intervention with be feasible 
to deliver in MICU patients. We will use this Aim to calculate effect size for use in the anticipated large-
scale circadian intervention to follow this pilot RCT.  
 
Research Design: For Aim 3, we will screen and enroll 16 patients using the same inclusion/exclusion 
criteria as Aims 1 and 2. We will collect room light levels, circadian measurements, patient characteristics, 
and ICU care events as before. Patients will be randomized via simple randomization with assignment via 
random number generator to either usual care (n=5 patients) or to bright light for 4 hours daily (n=5 
patients) or to bright light for 8 hours daily (n=5 patients). The bright light intervention will be delivered 
from 09:00 to 13:00 daily (4 hour group) or 09:00 to 17:00 daily (8 hour group).  The bright light will be 
delivered from study day 2 until study day 5. The bright light will continue if the patient is transferred to 
the floor. Bright light will be delivered by a free-standing apparatus that delivers 10,000 lux at a 
temperature 5000K. The device will be placed at the bedside within 36 inches of the patient’s head and is 
expected to provide at least 1,250 lux at the angle of gaze.  
To remain in the study, the patient must be in the ICU through D2 (e.g., the first day of potential 
intervention and the night following). After D2, bright light and other study activities will continue if the 
patient is transferred out of the ICU to the general medical floor. To maintain as much control of the 
environment as possible, study patients will be booked only to private rooms on the general medical floor.  
If symptoms of eye strain, visual disturbance or headache occur, patients will not continue bright 
light exposure. These reversible symptoms of direct bright light therapy are unlikely, but they will be 
tracked as a metric of feasibility under the category of patient tolerance. Feasibility Metrics will include 
patient acceptance (percent of patients/surrogates who agree to bright light when described to them); 
patient tolerance (percent of days that patients continue with additional treatments once exposed to 
bright light); intervention fidelity (percent of time per day that device delivers the planned dose of light); 
and intervention sustainability (percent of intended intervention days that device is used).  

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Expected Outcomes: We expect that bright light exposure is feasible, will decrease circadian 
misalignment, and will increase circadian amplitude. 
 
 
STATISTICAL CONSIDERATIONS 
 
Aim 1 Analytical Approach: Individual sleep midpoint will be calculated as halfway between habitual 
bedtime and habitual waketime as indicated during patient/surrogate interview questionnaires. Light 
dose will be calculated as the sum of mean lux per hour for each hour between 08:00 and 17:00 (day dose) 
and 22:00 and 06:00 (overnight dose). A day/night dose ratio will then be calculated by dividing the 
daytime light dose by the overnight light dose. Light dose ratio will be treated as continuous exposure 
variables, with higher numbers indicating a more favorable (circadian) exposure and lower numbers 
indicating a less favorable (non-circadian) exposure. Circadian alignment and amplitude will be calculated 
using time series analysis of urinary aMT6s using smoothing techniques to examine characteristics of 
circadian rhythm: acrophase (maxima) and nadir (minima). Statistical measures will evaluate for serial 
correlation, seasonality (periodicity), and trend. Longitudinal cosinor techniques will be used to test for 
alignment of nadir and acrophase with normal circadian phase and amplitude (e.g., individual sleep 
midpoint and estimated normal peak aMT6s).55 The degree of misalignment versus normal will be 
recorded in minutes. The amplitude of the cycle will be defined as one-half of the difference between the 
acrophase and nadir and will be recorded in nanograms (ng) per hour.30 Normal values have been 
identified for aMT6s.30, 56 The assessment of circadian abnormalities for association with light patterns will 
be solely based on aMT6s analysis. Heart rate, iButton gradient readings, and actigraphy activity counts 
will be evaluated via cosinor techniques analogous to the aMT6s analysis described above. Actigraphy 
activity counts will also be evaluated by visual inspection of normalized mean activity per hour (Fig 3) and 
as described by Duclos et al.32 Confounder and effect modifier variables: Severity of illness will be 
calculated according to the APACHE II algorithm57 and expressed as a continuous variable. Sepsis will be 
expressed as a categorical variable (absent, septic, septic shock) based on the sepsis-3 criteria.47 The risk 
of OSA will be expressed as a categorical variable (low risk, high risk) based on the STOP-BANG 
algorithm.46, 58 Overnight ICU care events per the timestamp data described above will be calculated as 
the number of ICU care events per hour between 22:00 and 06:00. Average daytime and overnight room 
temperature will be calculated as a continuous variable. 
Testing for Associations: Because both measures of circadian abnormality (misalignment and decreased 
amplitude) are continuous and normally distributed, multivariable linear regression models will test for 
associations, with light dose ratio serving as the exposure. Linearity of the associations will be examined 
graphically, and higher order terms will be considered as necessary. Models will be adjusted for age, 
gender, severity of illness, sepsis, risk of OSA, ICU care events per hour, and room temperature variables. 
We will test for modification of the association between light dose ratio and the outcomes by sepsis and 
risk of OSA. Because of the non-trivial intra-correlation coefficient expected from the serial correlation of 
the repeated outcome measures over time, models will employ generalized estimating equations with an 
auto-regressive correlation structure. Model fit will be evaluated with residual analysis, and significance 
will be defined as a two-sided p-value ≤ 0.05. Power Calculations. For both continuous, normally 
distributed outcomes, power calculations assume a two-sided alpha of 0.05, power of 90%, a sample size 
of 100, and prevalence of covariates ranging from 20% to 50%. For minutes of misalignment, we further 
assume a mean of 180 minutes with a standard deviation of 95 and for amplitude a mean of 450 ng with 
standard deviation of 180.30 Under these assumptions, our sample of 100 is sufficient to detect a range of 
minimal average shifts between 52-65 minutes of misalignment, and 98-123 ng of urinary aMT6 per 

Page 12 of 25 
incremental change in the explanatory variables.  
 
Aim 2 Analytic Approach: Circadian measures will be analyzed as in Aim 1. Sleep disruption will include 
two measures: (1) total amount of sleep, a continuous variable calculated as the number of sleep epochs 
in a 24 hour period and (2) overnight sleep efficiency, a continuous variable calculated as the percent of 
epochs scored as sleep between 22:00 and 06:00. Sleep will be based on standard Philips Actiwatch 
Software algorithms. Days of Delirium will be calculated as the sum of days on which the patient is 
delirious. Delirium will be considered present if either the CAM-ICU or the chart abstraction is positive for 
a given calendar day. Patients will be censored at day 30 or at hospital discharge.59, 60 Confounder and 
effect mediator variables: Severity of illness, age, and gender will be treated as in Aim 1. Ventilator use 
will include invasive and noninvasive positive pressure ventilation and will be quantified as ventilator-free 
days based on published algorithms.61 For sedative-hypnotic medications, equivalent daily doses of 
benzodiazepines and narcotics will be calculated using published algorithms.62, 63 Propofol and 
dexmedetomidine total daily dose will be recorded and included in the models.  
Testing for Associations: Multivariable Poisson models will assess the associations between circadian 
misalignment and amplitude and days of delirium. Models will be adjusted for age, severity of illness, 
ventilator-free days, dose of sedative medication, and measures of sleep disruption. We will test for 
modification of the associations between misalignment and amplitude and days of delirium by age, 
sedative-hypnotic medication dose and measures of sleep disruption. Linearity, serial correlation, and 
model fit will be addressed as in Aim 1. Power Calculation: Patients with delirium on the day of enrollment 
will be excluded, our effective sample size will be reduced by 20% to 80 participants. Assuming two-sided 
alpha of 0.05, 90% power, overdispersion of 20%, and a mean of 3 days of delirium,4 our sample of 80 
allows the detection of a minimal risk ratio of 1.12 for each 60 minutes of misalignment. Under the same 
assumptions, our sample of 80 will detect a minimal risk ratio of 1.08 for each change of 100ng of aMT6s.64 
 
Aim 3 Analytical Approach: Feasibility: Based on qualitative analysis, we will judge the intervention as 
feasible if it achieves at least 70% in each of the feasibility metrics: acceptance, tolerance, fidelity, and 
sustainability. Effect Size: Circadian abnormalities will be assessed as described under Aim 1. Using 
multivariable logistic regression, we will test for associations between bright light exposure and decreases 
in circadian misalignment and increases in circadian amplitude. The estimated association will inform the 
effect size in the design of future interventional studies. 
 
 
 
 

Page 13 of 25 
SUBJECT POPULATION 
Patients admitted to the Medical ICU and who meet inclusion / exclusion criteria will be recruited into 
this study. Decisionally impaired persons, females of childbearing potential and pregnant women who are 
admitted to the MICU and who meet inclusion / exclusion criteria might be recruited into this study; 
however, they will not be specifically recruited and subjects will be ≥ 50 years old and severe chronic brain 
injury is an exclusion criteria. 
 
Table 2 (repeated) 
Inclusion Criteria 
Exclusion Criteria 
- 
Hospital admission less 
than 30 hours as of noon 
on day of enrollment 
- 
Expected to say in the 
MICU ≥24 hours after 
enrollment  
- 
Expected to produce ≥250 
mL urine / day 
- 
Age ≥50 years 
- 
Able to understand 
English. 
At significant risk for pre-existing circadian abnormalities:  
− 
Severe chronic brain injury (Injury greater than 30 days ago resulting in the inability 
to live independently) OR Acute brain injury of any severity (Injury less than 30 
days ago including acute intracranial bleed, traumatic brain injury, central nervous 
system infection, tumor, hepatic encephalopathy) 
− 
Documented circadian disorder (<1% population) or blind/disease of the optic 
nerve 
− 
Current history of substance abuse including alcohol (use in last 30 days) 
− 
Transferred from an outside hospital  
− 
Homeless 
 
Unable to participate in study activities: 
− 
History of bipolar disease (Bright light therapy possibly unsafe in this population). 
− 
Paralyzed (due to injury, disease or medications) 
 
 
RECRUITMENT PROCEDURES 
Patients will be screened daily from an automated list generated from the YNHH EMR. Patients who opt 
out of research participation via MyChart (patient information portal) will be excluded from this list. 
Potential patients and/or their legally authorized representatives will be contacted in person or via the 
phone. Such contact will be conducted by Dr. Knauert or her trained research staff. 
 
Prior to approaching patients for study recruitment, we will obtain permission from their attending 
physician. Physicians in the Medical ICU will either sign a MD permission form which will provide 
permission to approach any of their patients or, if the physician prefers, we will request permission on a 
case-by-case basis.   
 
DETERMINATION OF ELIGIBILITY 
Eligibility will be determined by study staff via review of the electronic medical record; staff will be 
appropriately trained in HIPAA, screening and consent and enrollment procedures. Currently this will be 
PI Melissa Knauert and other staff will be added to the protocol when identified and trained.  
 
 
ASSESSMENT OF CURRENT HEALTH PROVIDER RELATIONSHIP FOR HIPAA CONSIDERATION 
It is possible that some of the research subjects may be on the MICU service for which Dr. Knauert, Dr. 
Pisani or Dr. Yaggi are the attending. This will be a relatively rare event. Participation in the study will not 
alter usual MICU care (other than possible Daytime Bright Light for Aim 3 subjects randomized to this 
intervention). 
 

Page 14 of 25 
 
REQUEST FOR WAIVER OF HIPPA AUTHORIZATION FOR RECRUITMENT/ SCREENING 
This study was granted a waiver of HIPPA Authorization for recruitment and screening procedures. 
 
 
PROCESS OF CONSENT/ASSENT 
Patient and patient surrogates will be approached about enrolling their family member into this study.  
When appropriate, both the surrogate and patient will be approached together to explain the study and 
obtain consent.  Patient’s ability to make an informed decision will be assessed by multiple methods 
including speaking with the nurse and physician caring for the patient as well as the patient’s family 
(legally authorized representative).  An assessment for delirium will be performed to determine if the 
patient is delirious (CAM-ICU).  Informed consent will be obtained from the surrogate when the patient 
is unable to provide consent and from the patient when they are deemed able to provide consent. If the 
patient is conscious and communicating with study staff, but unable to provide formal consent, we will 
ask them for assent regarding study activities. Specifically, if the patient refuses study related blood 
draws including before and during phlebotomy attempts, we will not continue. Blood draw attempts will 
be limited to two (2). Furthermore, if during the course of the study, the subject should become 
sufficiently cognitively capable of understanding the nature of his/her participation in the research study 
and is capable of communicating, consent will be obtained from the subject. If the subject does not give 
consent to continue study activities, study participation will stop.  When the surrogate is not physically 
present at the hospital (i.e., COVID-19 visitor restrictions or other reasons). They will be contacted via 
phone. We will request permission to discuss the study and, if permitted, provide a summary of study 
activities. If the surrogate is interested, we will email consent paperwork and the study information 
sheet to the surrogate. We will then review the consent paperwork and answer any questions. If the 
surrogate gives consent, we will have them sign the consent paperwork and return it to us via our lab 
email (icustudy@yale.edu). Study activities will start only after signed consent is obtained. Alternatively, 
we may use the EPIC-based consent system to transmit and receive the signed consent. Use of the EPIC-
based consent system will not alter communication over the phone with the surrogate. 
 
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Subject ability to consent will 
be assessed via standard delirium assessment (CAM-ICU) and agitation assessment (RASS).  Barriers to 
communication between the patient and study staff (visual, hearing impairment) will also be assessed.  
In the case of delirium, agitation, or communication difficulty, formal surrogate consent will be obtained 
along with informal agreement from the patient (assent) when possible. 
 
 
 

Page 15 of 25 
PROTECTION OF PARTICIPANT PRIVACY 
 
All PHI and subject data will be collected and maintained electronically. Data management procedures will 
ensure accurate and efficient data collection and analysis; confidentiality and real-time, on-demand study 
monitoring reports. All data will be maintained in accordance with HIPAA guidelines for participant 
confidentiality and privacy. All data will reside on secure, HIPAA-compliant database and file-sharing 
resources managed by the Data Management and Informatics Core (DMIC) of the POA and by Yale ITS. 
Access to data resources will be strictly limited to research staff and investigators, and all such resources 
will reside on a local network not accessible outside the secure Yale environment. All study data will be 
managed using REDCap, a secure, web-based data collection and workflow management system 
developed at Vanderbilt University and supported by the national Clinical and Translational Science Award 
(CTSA) program. REDCap's authentication, security and auditing features comply with the FDA Title 21 CFR 
Part 11 guidelines for Electronic Records and Electronic Signatures. Yale's implementation of REDCap is 
managed jointly by POA/DMIC and by Yale ITS, and has been certified by Yale's Information Compliance 
Office as meeting HIPAA privacy and security guidelines. 
 
 
METHODS FOR SECURITY OF STORAGE AND SHARING MATERIALS 
 
Outcome data will be shared, along with associated demographic and clinical data including age, gender, 
race/ethnicity, evaluation of functional status, and medical conditions. To enable the widest 
dissemination of data, while also protecting the privacy of study participants and the utility of the data, 
we will de-identify and mask potentially sensitive data elements, consistent with HIPAA considerations 
and in full compliance with the NIH public data sharing policy (for further details, see 
http://grants.nih.gov/grants/policy/data_sharing).  Data sets will be subjected to cleaning and quality 
control measures. Following these procedures, for experiment types such as RNAseq and metabolomics, 
the data will be deposited in relevant public databases (e.g., the Gene Expression Omnibus (GEO), the 
Sequence Read Archive (SRA), the database of Genotypes and Phenotypes (dbGaP) and the 
Metabolomics Workbench) as required by the NIH and by journals.  We will comply with NIH expectations 
for data release specified in the Supplemental Information to the GDS Policy (as outlined at 
http://gds.nih.gov/pdf/supplemental_info_GDS_Policy.pdf ). Data will be shared once the data have been 
cleaned and quality control procedures are completed. Generally speaking, these procedures should be 
completed by 3-6 months after data generation. As per the GDS policy, after submission begins, data will 
be held in an exchange area accessible only to the submitting investigators and collaborators for a six- 
month period, after which the data will be available for research access without restrictions on 
publication. Final analyses relating these data to specific biologic outcomes will be released with 
publication. The consent form provides consent for the data to be used for future research purposes and 
to be shared broadly through unrestricted-access databases. 
 
 
 

Page 16 of 25 
STUDY RISKS 
 
There is minimal risk to subjects. There are no changes to usual MICU care during the observational 
portion of this study (Aim 1 and 2). For all enrolled patients, there is minimal risk of breach of 
confidentiality. There is a risk of minor skin irritation caused by Actiwatch Spectrum device application. 
Urine collection will be from catheterized urine that would otherwise be discarded; patients will not be 
catheterized to collect urine for the study. Patients who are enrolled in Aim 3 regarding the feasibility 
and effect size of daytime bright light will also be exposed to a bright light device set to deliver 10,000 
lux at the surface of the lamp; at the planned distance of 36 inches this will degrade to <1250 lux. Direct 
bright light exposure (i.e. during treatment for outpatient circadian disorders) has minor and reversible 
side effects of eye strain, visual disturbance, and headache. If symptoms develop, light therapy will be 
discontinued, and the side effect will be tracked as a metric of feasibility. Also, hypomania and mania in 
patients with a history of bipolar disease have also been reported as uncommon but serious side effects 
of overexposure to light therapy. Patients with a history of bipolar disease will be excluded from the 
study. 
 
 
MINIMIZING RISKS 
 
The above-mentioned risks will be minimized in the following manner: Risks regarding patient 
confidentiality are minimized via data management strategies which isolate all personal identifying data 
elements. Only users having project-specific access rights can view or modify personal identifying 
information or print reports that include patient names or other identifying information. This study will 
have no paper records other than the consent forms which are stored within a locked file cabinet in the 
PI’s office. The office is locked when not occupied. All electronic data will be maintained on a secure, 
firewalled server.  
 
Skin irritation from the Actiwatch Spectrum or iButton device can be mitigated by movement of device 
to a contralateral site. If skin irritation is severe, the Actiwatch Spectrum or iButton will be removed, and 
study participation will be discontinued. If symptoms (eye strain, visual disturbance or headache) 
develop, light therapy will be discontinued, and the side effect will be tracked as a metric of feasibility. In 
addition, hypomania and mania in patients with a history of bipolar disease have also been reported as 
uncommon but serious side effects of overexposure to light therapy. Patients with a history of bipolar 
disease will be excluded from the study. 
 
 
 
 

Page 17 of 25 
DATA AND SAFETY MONITORING PLAN  
 
Data and Safety Monitoring for Clinical Trials: This protocol presents minimal risks to the subjects and 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs), including adverse events, are 
not anticipated. In the unlikely event that such events occur, the following Data and Safety Monitoring 
for Clinical Trials Plan will be followed. 
 
Main Study DSMP 
 
A medical monitor will oversee the proposed research project. Dr. Shyoko Honiden, Yale-New Haven 
Hospital MICU attending and board certified in critical care medicine, has agreed to serve as project 
medical monitor. She has no conflicts of interest with this role. Dr. Honiden will conduct interim 
monitoring of accumulated data from research activities to assure the continuing safety of participants 
and integrity of the accumulating data. The medical monitor is independent of the study investigative 
team and will report progress including safety concerns to the project principal investigator. Safety 
concerns will be also be reported to the IRB. 
 
1. Safety: Safety will be monitored at intervals related to patient enrollment. Safety and device protocols 
will be reviewed by the medical monitor every twenty patients to assure uniform and safe application 
of project devices. Research staff will report skin irritation or bright light related symptoms as they 
occur via event evaluation forms. In addition, research staff will identify and immediately report 
unanticipated problems, unexpected adverse events and serious adverse events (defined below). 
Safety concerns will be also be reported to the IRB. 
2. Protocol Compliance: The project medical monitor will check enrolled patients for compliance with IRB 
requirements, conformance with informed consent procedures, verification of source documents and 
investigator compliance. One in ten patients will be randomly selected for conformance. 
3. Event Evaluation: Adverse event or unanticipated problem occurrence will prompt an event evaluation 
and a report to the project medical monitor. The adverse event report will NOT include identifying 
patient information but will otherwise provide a clinical summary of the study patient and the 
circumstances immediately associated with the adverse event / unanticipated problem including date 
of the event, type of event and a narrative event description.  
 
Flow Diagram for Adverse Event / Unanticipated Problem Detection, Review and Reporting: 
 
 
Unanticipated Problems are defined as any incident, experience, or outcome that meets all of the 
following criteria: 1) unexpected, 2) related or possibly related to participation in the research, and 3) 
suggests that the research places subjects or others at a greater risk of harm than was previously known 
or recognized. 
Unanticipated 
Problem or
Adverse Event
• Detected by 
research staff
Event 
Evaluation
• Reported by 
research staff 
(within 24 hours)
Project Medical 
Monitor
• Reviews problem or 
event and reports to 
PI (within 3 days).
Project 
Principal 
Investigator
• Acts on 
recommendation of 
project medical 
monitor (within 3 
days).
Reporting to 
IRB and NHLBI
• Designated 
problems or events 
reported to IRB and 
NHLBI within 5 days 
of occurrence.

Page 18 of 25 
 
Adverse Events: An adverse event will be defined as any untoward or unfavorable medical occurrence in 
a human subject, including any abnormal sign, symptom, or disease, temporally associated with the 
subject’s participation in the research, whether or not considered related to the subject’s participation 
in the research (modified from the definition of adverse events in the 1996 International Conference 
on Harmonization E-6 Guidelines for Good Clinical Practice). Adverse events that occur during study 
enrollment will be reported by research staff to the project medical monitor via an event evaluation.  
 
A serious adverse event is any adverse event temporally associated with the subject’s participation in 
research that meets any of the following criteria (modified from the definition of serious adverse drug 
experience in FDA regulations at 21 CFR 312.32(a)): 
1. results in death or is life-threatening  
2. requires prolongation of existing hospitalization 
3. results in a persistent or significant disability/incapacity 
4. results in a congenital anomaly/birth defect 
5. any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition 
 
Response to Adverse Event: All study patients are (by definition) concurrently admitted to the MICU. The 
response to any adverse event will be appropriate medical care. Adverse event occurrence will prompt an 
event evaluation and report to the project medical monitor by research staff.  
 
The project medical monitor will evaluate adverse events along the parameters of relationship, severity, 
and expectedness: 
Relatedness:  
1. Unrelated: Adverse event(s) clearly not related to the project 
2. Unlikely: Adverse event(s) doubtfully related to the project 
3. Possibly: Adverse events(s) may be related to the project; known to occur, but the temporal 
relationship is unclear; other causes are possible or biologically very plausible 
4. Probably: Adverse event(s) likely associated with the project; known to occur and temporal 
relationship is appropriate; other causes are unlikely 
5. Definitely: Adverse event(s) clearly associated with the project 
 
Severity: The following scale will be used to grade the severity of adverse events noted during the 
study: 
1. Mild adverse event: Did not interfere with normal activity, minimal symptoms, no intervention 
required 
2. Moderate adverse event: Interfered with normal activity to some extent, moderate 
symptoms, minimal or local intervention required 
3. Severe adverse event: Prolonged hospitalization with need for intervention to prevent 
escalation of condition 
4. Life-threatening / disabling adverse event: Event that puts the patient at risk of death at the 
time of the event if immediate intervention is not undertaken 
5. Fatal adverse event 
 

Page 19 of 25 
Expectedness: An unexpected adverse event is any adverse event occurring in one or more 
subjects in a research protocol, the nature, severity, or frequency of which is not consistent with 
either (1) the known or foreseeable risk of adverse events associated with the procedures involved 
in the research that are described in (a) the protocol-related documents such as the IRB-approved 
research protocol and the current IRB-approved informed consent document, and (b) other 
relevant sources of information, such as product labeling and package inserts; or (2) the expected 
natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing 
the adverse event and the subject’s predisposing risk factor profile for the adverse event. 
 
The principal investigator (Knauert) will have overall responsibility for adverse event reporting to Yale 
University's IRB and NHLBI. Unanticipated problems, unexpected adverse events or serious adverse 
events will be reviewed by the medical monitor. The principal investigator will provide reporting of 
any of the following to the IRB and NHLBI within 5 days of occurrence: 
1. 
Unanticipated problems, unexpected adverse events or serious adverse events that are 
possibly, probably or definitely related to study protocols. 
2. 
IRB approved revisions to the project which change participant risk. 
3. 
Notice of any actions taken by the Yale University IRB regarding the project and any 
responses to these actions. 
 
 
 
POTENTIAL BENEFITS 
 
This research has the potential to benefit future patients admitted to the MICU via improved circadian 
entrainment. There is minimal risk involved in this study, and appropriate precautions to guard against 
risk have been taken. This protocol is intended for broad distribution following the research study. The 
findings of this research will be generalizable to a significant portion of MICU patients and thus provide 
potential future benefit to many critically ill patients, especially those at greatest risk for delirium (older 
age, history of hypertension). 
 
 
RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1. Alternatives: What other alternatives are available to the study subjects outside of the research?  
The alternative is to not participate and to receive usual care in the Medical ICU. 
 
2. Payments for Participation (Economic Considerations): 
Study subjects will receive a $100 pre-paid gift card upon completion of study day 5 as compensation 
for their time and any minor inconveniences they may have experienced while participating in the 
study. In order to be eligible for study payment, subjects must complete through day 5 of the study 
protocol unless they are discharged from hospital prior to day 5. If a subject is discharged from the 
hospital prior to study day 5 but after study day 2, they will receive payment for their participation. 
In the event a study subject wishes to discontinue study participation before the end of study day 5 
for any reason other than listed above, they will no longer be eligible for payment. 
 

Page 20 of 25 
Study payment will be given directly to the subject at the end of study day 5 in the form of a physical 
gift card. Gift cards will be provided to the patient in a marked envelope. In the event a patient lacks 
the capacity to accept study payment at the time of study day 5, payment for participation will be 
included in the patient’s secured personal belongings or provided to the patient’s surrogate contact 
to hold for the patient. 
 
3. Costs for Participation (Economic Considerations): No cost 
 

Page 21 of 25 
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