Decreasing Delirium Through Music in Critically Ill Older Adults
Phase: NA
Conditions: Intensive Care Unit Delirium, Pain, Anxiety, Intensive Care Acquired Cognitive Impairment
Sponsor: Indiana University

 
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DECREASING DELIRIUM THROUGH MUSIC  
IN CRITICALLY ILL OLDER ADULTS 
(DDM) 
PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
Babar Khan, MD, MS 
Research Scientist, IU Center for Aging Research 
Associate Professor of Medicine, IU School of Medicine 
Division of Pulmonary/Critical Care 
 
Linda L. Chlan, Ph.D., RN, ATSF, FAAN, 
Associate Dean for Nursing Research 
Professor of Nursing, Mayo Clinic College of Medicine and Science 
Mayo Clinic, Rochester, MN 55905 
 
 
 
 
 
 
 

 
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1. 
BACKGROUND: 
One million adults in the United States receive mechanical ventilation for acute respiratory failure in the 
intensive care units (ICUs) annually and up to 80% of them develop delirium during their ICU stay. 
Presence of delirium predisposes older adults to immediate in-hospital complications including a longer 
length of ICU and hospital stay, increased risk of in-patient mortality and elevated costs of care. In 
addition, ICU delirium is associated with long-term post-discharge complications such as development of 
cognitive impairment and dementia. Not only does the presence of delirium portend adverse patient-
related outcomes; both delirium duration and delirium severity have also been identified as predictors of 
mortality and other adverse consequences. Research studies to date exploring pharmacological 
strategies to manage ICU delirium have not been successful in demonstrating efficacy. Additionally, 
receipt of sedative and opioid medications to treat other commonly co-occurring symptoms of pain and 
anxiety among the critically ill predisposes patients to further delirium propagation and persistence. Early 
implementation of a non- pharmacological intervention with the ability to manage pain and anxiety 
symptoms along with a reduction in harmful medications exposure holds great potential to reduce 
downstream delirium and its sequelae. 
 
Music listening is one such intervention that holds promise for non-pharmacological management of 
delirium commonly experienced by mechanically ventilated patients. Music has been shown to break the 
harmful cycle of over-sedation in critically ill and can reduce anxiety and stress, factors that could 
predispose to ICU delirium. These findings are not surprising given that music results in a reduction in 
inflammatory cytokines, decreases cortisol production, and dampens central nervous system arousal 
through diminished norepinephrine release; pathways similar to those implicated in delirium. In a 
randomized clinical trial conducted by Dr. Chlan (MPI), a music intervention consisting of patient-directed, 
slow-tempo, relaxing music delivered during the latter portion of mechanical ventilator support was 
superior to usual ICU care in reducing anxiety and sedative exposure in critically ill patients. Even with 
such positive findings both at mechanistic and patient-outcome levels, music listening interventions are 
notably absent in routine ICU care. Further, there is a paucity of rigorous investigation of music’s impact on 
ICU delirium, a significant knowledge gap. 
 
We now propose an adequately powered randomized clinical trial to test the efficacy of a seven-day 
music intervention in reducing delirium and improving brain health among critically ill, mechanically 
ventilated older adults through the following specific aims: 
 
2. 
RATIONALE and SPECIFIC AIMS: 
 
Critically ill patients on mechanical ventilation are at high risk to develop delirium and need innovative, 
safe and scalable interventions to ameliorate it. The scientific premise of our proposal is that early slow-
tempo music listening in the ICU setting will reduce delirium among older adults, which will lead to 
downstream beneficial effects on long-term cognition. Music has been shown to be beneficial in managing 
pain and anxiety symptoms through anti-inflammatory and cortisol mediated pathways, similar pathways 
that are disrupted and implicated in delirium development. Additionally, slow-tempo music could also 
reduce exposure to opioids and sedative medications ubiquitous in the ICU setting and associated with 
delirium. Hence it stands to reason that a music intervention will be efficacious in reducing ICU delirium. 
Even with the clinical rationale and aforementioned data, a rigorous trial testing the efficacy of music 
intervention on ICU delirium is notably lacking. 
 

 
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Primary Specific Aim: Test the efficacy of music intervention in improving delirium/coma free days 
among mechanically ventilated patients as compared to attention control. Hypothesis: Patients in the 
music intervention group will have higher number of delirium/coma free days as measured by the 
Confusion Assessment Method for the ICU (CAM-ICU) at seven days post randomization. 
 
Secondary Specific Aim 1: Test the efficacy of music intervention in improving delirium severity, pain 
and anxiety among mechanically ventilated patients as compared to attention control. Hypotheses: 
Patients in the music intervention group will have lower delirium severity, pain and anxiety scores as 
measured by the CAM- ICU-7, Critical Care Pain Observation Tool (CPOT) and Visual Analogue Scale-
Anxiety (VAS-A) respectively at seven days post-randomization. 
 
Secondary Specific Aim 2: Test the efficacy of music intervention in improving the long-term neuro- 
psychological outcomes as compared to attention control. Hypotheses: Patients in the music intervention 
group will have higher cognitive scores as assessed by the Indiana University Telephone Based 
Assessment of Neuropsychological Status (IU-TBANS), and lower depression and anxiety scores on the 
Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) scales at 3 months 
post hospital discharge. 
 
3. 
STUDY DESIGN 
 
Two-arm, randomized parallel-group, clinical trial with concealment of outcomes assessment to evaluate 
the efficacy of music intervention compared to a silence-track attention control in improving delirium/coma 
free days in mechanically-ventilated critically ill older adults. The total duration of the intervention will be 7 
days from randomization unless a patient has died, discharged, or transferred out of the ICU. 
 
4.  
INCLUSION/EXCLUSION CRITERIA 
 
 
 
DDM Inclusion and Exclusion Criteria 
Inclusion Criteria 
Exclusion Criteria 
-Age 50 years or older 
-English speaking 
-Admitted to the intensive care unit (medical 
or surgical) 
-Expected mechanical ventilator support for 
≥48 hours 
-Consentable through a legally authorized 
representative 
-Have access to a telephone 
-History of dementing illnesses and other neurodegenerative diseases such as 
Alzheimer’s disease or vascular dementia 
-Psychiatric illness which is not well controlled 
-Alcohol withdrawal symptoms/concern for withdrawal 
-Suspected or confirmed drug intoxication/overdose 
-Traumatic brain injury, ischemic or hemorrhagic cerebrovascular accident, or 
undergoing neurosurgery 
-Uncorrected hearing or vision impairment including legal blindness 
-Incarcerated at the time of study enrollment 
-Enrolled in another clinical trial which does not permit co-enrollment 
-Any medical condition precluding safe use of headphones such as:  skin breakdown, 
burns, facial or skull fractures 

 
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5. ENROLLMENT and RANDOMIZATION 
 
Clinical Settings and Study Population: Patients will be recruited from two Indianapolis Hospital systems: 
Eskenazi Health and Indiana University Health. Patients will also be recruited from Mayo Clinic Rochester. 
 
Recruitment Targets: Final study sample will comprise 160 mechanically ventilated older adults ≥50 years of 
age.  
 
Screening and Enrollment: Research staff will review the electronic medical records of ICU patients daily for 
eligibility. Eligible patients’ clinical teams will be approached if necessary to confirm eligibility. Eligible 
individuals (those who meet inclusion criteria and do not meet any exclusion criteria) will be screened up to 
twice per day for delirium until approached for the study using the CAM-ICU-7. Once eligibility is confirmed, 
the research team will approach patients or their legally authorized representatives for consent depending on 
patients’ clinical status. Patients consented through their legally authorized representative will be re-
consented once clinically able.   
 
Randomization: Using a computer-generated list of random numbers created by study statistician, 
participants will be randomized by permuted block with varying block sizes. Randomization will occur after 
consent in a 1:1 manner and will be stratified based on hospital location. 
 
6. 
STUDY PROCEDURES 
 
Interventions: For up to seven days, enrolled subjects will either receive 1) one-hour music listening 
sessions twice daily through noise-cancelling headphones, or 2) one-hour sessions consisting of a silence 
track twice daily through noise-cancelling headphones.  
 
a. Music Intervention: Twice daily one-hour intervention will be delivered based on our extensive playlist 
created by our board-certified music therapist consultant and used in our previous studies. The playlist 
contains relaxing slow tempo instrumental music (60-80 beats/minute). Featured instruments in the playlist 
include piano, harp, reed, guitar and Native American flute. The mix features classical music and relaxing 
melodies and does not contain lyrics or spoken words.71 In addition to the twice daily music intervention 
sessions, patients will be encouraged to self-initiate listening to slow-tempo music from the study playlist 
whenever desired as a means to engage in quiet time or listening enjoyment. Our iPad® app will efficiently log 
all of the ‘as desired’ music listening sessions by automatically capturing frequency, length, and music 
selections for both the twice daily music intervention sessions as well as the self-directed listening sessions. 
Variability in self-directed music listening duration and frequency will be used as a covariate in subsequent 
analyses. 

 
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Randomization 
DDM Intervention 
 
Attention Control 
 
 
IUTBANS, PHQ-9, GAD-7* 
 
 
b. Attention Control: A silence only track will be added to the study iPads® and will be activated in the form 
of an app similar to the music listening tracking app. Patients randomized to this arm will receive a noise 
cancellation headphone-applied condition identical to the music intervention experimental treatment; twice 
daily one hour-sessions. Likewise, patients will have the opportunity to use the silence app with headphones 
whenever desired. As with the music intervention, the app will track each session’s length, frequency, and 
self-directed headphone application with the silence track. 
 
Delivery of the Intervention: The research manager will ensure good operating status of the iPad® music 
app, headphones and connectivity to the tracking portal prior to the initiation of the intervention. Both the 
experimental and the attention control conditions will be delivered through identical iPads® with our music 
tracking app and noise cancellation headphones to ensure blinding of group assignment when study staff 
perform assessments. All patients will receive two one-hour sessions daily between the hours of 0900 to 
1200, and from 1300 to 2000. Nurses will receive training to minimize distractions at that time, such as 
turning off televisions and avoiding non-essential patient care. Patients will receive standard ICU care per 
local practices including the ABCDEF bundle,21,22 which is part of routine care at participating ICUs. Patients 
will continue to receive clinical care for delirium based on their primary clinical team’s discretion. 
 
Blood Sample Collection 
We will collect blood samples prior to first intervention session (up to 10ml in tubes containing anticoagulant), at 
day 3, and at the end of the intervention period  (up to 10 ml in tubes containing anticoagulant). The samples will 
be transported to the CTSI lab, and will be prepared and stored using deidentified labels. Samples will be stored 
for future biomarker analysis which includes measurement of pro-inflammatory and anti-inflammatory cytokines, 
reactive oxygen species and DNA damage, proteomics, epigenetics, and protein-gene associations. 
 
Blinding: Apart from the patient and research staff member assigning the music intervention, all study 
personnel and clinical staff interacting with the patient will remain blinded to each patient’s intervention 
assignment throughout enrollment, follow-up and data analysis. 
 
Study Flow: Eligible patients or their legally authorized representatives will be approached immediately after 
fulfilling the inclusion criteria. The intervention will start immediately post-enrollment depending on the time 
of enrollment. If enrolled prior to 1100, subjects will receive both one-hour music sessions on day of 
enrollment, if enrolled after 1200; they will receive a single one-hour music session on day of enrollment. If 
enrollment occurs after 2000, sessions will be started the following day. Study staff will assess for delirium, 
pain, and anxiety for the whole duration of ICU stay or until day 28 if the patient remains in the ICU. 
Cognition, depression and anxiety measures will be collected at three months post-hospital discharge in 
both intervention and control groups. See Figure 3 for study flow and outcomes assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcomes Assessments: Trained and blinded research assistants will complete in-hospital and post- hospital 
outcomes assessments consisting of measures of delirium, cognition, pain, depression and anxiety. Data will be 

 
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collected using Research Electronic Data Capture (REDCap). We will employ multiple techniques to ensure 
concealment of outcomes assessment.73,74 Our research assistants are trained not to inquire about study 
assignments. The research randomization staff member will deliver the intervention and the research assistants 
will not be aware of the intervention assignments. Subjects and their family members will be instructed not to 
discuss their intervention with the research assistants. All research staff undergoes a comprehensive training 
program with respect to outcomes assessments that has been employed in our prior trials. We will train the 
research staff on conducting sedation, delirium, delirium severity, pain, anxiety, depression and cognition 
assessments utilizing the same teaching methods. The PIs and Co-I will oversee the relevant training. Dr. Khan 
and Dr. Chlan will do the didactics and bedside teachings and certifications of all the research staff for sedation, 
delirium, pain, anxiety, and depression assessments. Dr. Unverzagt will train and certify the research staff on 
cognition assessments. 
 
Outcomes Measures:  
In-Hospital Outcomes: 
1. 
Delirium/Coma Free Days: Delirium/coma free days will be the primary outcome for the trial. 
Delirium/coma free days are the number of days after randomization patients are alive free of delirium and not in 
coma during the seven-day study intervention phase. This outcome describes the duration of normal cognitive 
status where the patient is not comatose and does not have delirium and has been utilized in high impact 
studies.14-17 We will utilize the Confusion Assessment Method for the ICU (CAM-ICU)75 and the Richmond 
Agitation Sedation Scale (RASS)76 for assessment of delirium and coma respectively. RASS score ranges from -
5 to +4 with a score of -4 or -5 (lack of response to verbal or physical stimuli) characterized as comatose and 
ineligible for CAM-ICU assessments. RASS scores of -3 and -2 depict moderate and light sedation, -1 
drowsiness, 0 alert and calm, and +1 to +4 various degrees of agitation. Patients with a RASS score of -3 to +4 
will be considered eligible for CAM-ICU assessments. The CAM-ICU score will be determined by examining the 
patient for (a) acute or fluctuating changes in mental status, (b) inattention, (c) altered level of consciousness 
and (d) disorganized thinking. Patients will be considered delirious if they display (a), (b), plus (c) and/or (d). 
Trained research assistants will be performing CAM-ICU twice daily after the assigned intervention. Sedation 
status through RASS will be collected before and after the intervention delivery. After the 7-day study 
intervention phase, study staff will continue to assess RASS and CAM-ICU twice daily throughout the subject’s 
hospital  stay (up till day 28). 
2. Delirium Severity: Delirium severity will be assessed twice daily by trained research assistants using the 
CAM-ICU-7 developed by Dr. Khan. CAM-ICU-7 is a seven-point scale (0-7), derived from the RASS and the 
CAM-ICU. The CAM-ICU-7 score ranges from 0-7; categorized as 0-2: no delirium, 3-5: mild to moderate 
delirium, and 6-7: severe delirium.77 Trained research assistants will be performing CAM-ICU-7 twice daily after 
the assigned intervention. After the 7-day study intervention phase, study staff will continue to assess CAM- 
ICU-7 twice daily throughout the subject’s hospital stay (up till day 28). 
 3. Pain: Pain will be assessed by trained research assistants utilizing the Critical Care Pain Observation Tool 
(CPOT), a valid and reliable instrument in critically ill patients with and without delirium,78,79 recommended by the 
SCCM 2018 PADIS guidelines.21 CPOT uses observable physiological and behavioral indicators of pain to 
determine whether pain is present and can be used in nonverbal patients. It contains 4 sections, each with 
different behavioral categories, including facial expressions, body movements, muscle tension, and either 
compliance with ventilator (intubated patients) or vocalization (non-intubated patients). The score ranges from 0-
2 for each section with a total score range of 0-8 with higher scores indicating more pain. Trained research 
assistants will be performing CPOT four times daily before and after intervention delivery. We will continue to 
assess CPOT twice daily after the 7-day study intervention phase throughout the ICU stay. 
4. Anxiety: Anxiety intensity defined as a heightened state of apprehension, agitation, and arousal,80 will be 
measured four times daily before and after assigned intervention using a 100-mm Visual Analog Scale-Anxiety 
(VAS-A), which measures changing anxiety and is amenable to intervention.81,82 The VAS-A will be presented to 
all patients vertically, like a thermometer, and will be anchored on the ends by 0 = not anxious at all and 100 
= most anxious ever. The VAS-A is scored using a ruler from the 0 anchor to the mark placed by the patient, 
which yields the current level of anxiety from 0 to 100. The same ruler will be used to score all VAS-As for 
consistency. Dr. Chlan has used the VAS-A extensively in prior research studies, including a vertical orientation 
of the instrument that is sensitive and easier for critically ill patients to see, resulting in very little missing data on 
this important variable.31,81-83 We will continue to assess VAS-A twice daily after the 7-day study intervention 
phase throughout the ICU stay. 
 
 

 
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Post-Hospital Discharge Outcomes: 
1. Cognition: Cognition will be measured by 4 objective tests of memory, attention, information processing 
speed, and executive cognitive function (Auditory Verbal Learning Test [AVLT], Digit Span, and Symbol Digit 
Modalities Test [SDMT], and Controlled Oral Word Association test [COWA]) using a telephone-based 
administration format, the Indiana University Telephone-Based Assessment of Neuropsychological Status (IU- 
TBANS) at 3-months post hospital discharge. Previous research has demonstrated that these tests can be 
delivered reliably and precisely by telephone.84 The AVLT is a 5-trial 15-item word list learning task that provides 
two scores: sum recall of the five learning trials and delayed recall. Digit Span measures working memory and 
the ability to repeat short random number sequences forward and backward. We will use the oral version of the 
SDMT. Participants will be mailed the SDMT response sheet prior to the assessment and told to keep the 
envelope sealed and at hand for the day of the assessment. At the day of the assessment, the participant will be 
instructed to open the envelope and 
the SDMT practice items will be 
completed. Total score is the 
number of correct numbers-symbol 
pairings called out in 90 seconds. 
The COWA is a measure of verbal 
fluency and executive cognitive 
function in which words are 
generated orally that begins with 
specified letters of the alphabet. 
Scores derived from these tests can 
be analyzed separately and also 
combined to form a single cognitive 
composite score. We will provide 
participants with pre-assessment 
instructions to structure the 
assessment to minimize distraction 
and interruption and maximize 
reliability and precision. 
2. Depression and Anxiety: We 
will use the Patient Health 
Questionnaire–9 (PHQ-9)85,86 and 
Generalized Anxiety Disorder Scale 
(GAD-7)87,88 to determine the 
impact of the music intervention on 
ICU survivors’ mood and anxiety. 
The PHQ-9 is a nine-item 
depression scale with a total score 
from 0 to 27 and the GAD-7 is a 
seven-item anxiety scale with a total 
score from 0 to 21. Both of these 
scales are derived from the Patient 
Health Questionnaire, have good 
internal consistency, test–retest 
reliability as well as construct, criterion, procedural and factorial validity for the diagnosis of major depression 
and general anxiety disorder.85-88 Research staff will collect PHQ-9 and GAD-7 over the phone at 3 months post-
hospital discharge. 
 
Other Data Measures: The table above shows other data measures including physiologic parameters of respiratory 
rate, heart rate, blood pressure (collected four times daily before and after assigned intervention during the 7-day 
intervention phase; daily afterwards during ICU stay) and timeline of data collection. We will also collect the post-
extubation ICU Recall Prior to/around Discharge. The Intensive Care Experience (ICE) questionnaire will be 
administered to all subjects and contains 25 total questions in four main categories: awareness of surroundings, 
frightening experiences, recall of experiences, and satisfaction with care.   
 
 

 
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2. REPORTING OF ADVERSE EVENTS 
 
Safety: Patients will be monitored for adverse events on a daily basis. Adverse events will be reported to the 
Institutional Review Board (IRB), data safety officer and contact MPI Dr. Khan immediately. In our prior work, 
we have not experienced any adverse events related to the study protocols. All infection control guidelines 
will be followed based on each hospital’s policy. Patient risks will be minimized through use of quality 
electronic devices, regular cleaning and maintenance. Lastly, given the high-intensity nature of the ICU, all 
patients will receive benefit from frequent monitoring in the ICU as part of routine care. 
 
Study Withdrawal/Discontinuation: Participants who wish to withdraw from the study will notify the study team 
verbally during study interactions or via letter as outlined in the HIPAA authorization document. 
 
3. STATISTICAL CONSIDERATIONS 
 
Statistical Analyses: We will compare baseline patients’ demographic characteristics (age, gender, race 
and levels of education) between the intervention and control group using two sample t-tests for continuous 
variables and Chi-square tests for categorical variables to determine whether the two groups are balanced in 
these variables. Variables that are found to be unbalanced will be included as covariates in all models 
comparing outcomes between the two groups. Intention to treat approach will be used in all analyses. 
 
a. Primary Specific Aim: Delirium/coma free days by day 7 will be compared using analysis of covariance 
(ANCOVA) model with group (intervention versus control) as the independent variable while adjusting for the 
baseline patients’ demographic variables not balanced between the two groups. For patients discharged 
before day 7, the days from discharge to day 7 will be counted as delirium/coma free. For patients who died 
before day 7, 0 delirium/coma free days will be counted from date of death to day 7. We have used the same 
approach in our previous trials and this approach is able to appropriately handle potential missing data due to 
discharge or death of patients before day 7.17 
 
Secondary Specific Aim 1: Mixed effects models will be used to compare delirium severity (CAM-ICU-7), 
pain (CPOT) and anxiety scores (VAS-A) measured twice daily from randomization to day 7, time of death or 
discharge. In each of the models, repeated CAM-ICU-7, CPOT or VAS-A scores will be the outcome variable 
respectively. Group, time, group and time interactions will be included as independent variables while 
adjusting for potential baseline covariates. Significant group and time interactions will indicate differences in 
changes of these outcomes between the two groups. Post-hoc analyses will be conducted to determine the 
earliest times when significant differences between these outcomes can be detected. We will compare 
various variance covariance structures including autoregressive (AR) and variance components blocked by 
time of the day (am versus pm) using the likelihood ratio tests to determine the most appropriate covariance 
structure. We will also examine potential non-linear trajectories of change in these outcomes by including 
quadratic time in the models and by fitting spline models. 
 
b. Secondary Specific Aim 2: ANCOVA models will be used to compare IU-TBANS, PHQ-9, and GAD-7 
collected at three months post hospital discharge with group as the independent variable while adjusting for 
potential baseline covariates. 
 
c. Missing Data: We expect up to 20% of patients who may not complete the primary outcome at day 7 due 
to death in the ICU or discharge before day 7. We will conduct sensitivity analyses with varying assumptions 
for the patients with missing outcomes to determine the robustness of our findings. The mixed effects model 
we propose for Secondary Aim 1 is robust to the missing at random assumption and is unbiased if we 
include all relevant covariates in the model. We will also compare baseline characteristics of patients with 3-
month 
assessment and those who are lost to follow-up and adjust for the variables associated with missing data to 
ensure unbiased estimation and inference. 
 
d. Sex as a Biological Variable: Both male and female patients will be included in the trial. We do not 
anticipate treatment efficacy will differ by sex. We will include sex as a covariate in each analysis to 

 
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determine whether estimated treatment effects differ by sex. 
 
e. Sample Size and Power: Sample size estimation is based on the observed effect size from our pilot data 
where the intervention group had higher delirium/coma free days from the control group with estimated effect 
size of 0.52. Using two sample t-test, we estimate that we will need 128 total patients with complete data to 
detect an effect size of 0.5SD or higher at α=0.05. For robustness of results, we also estimated power if we 
assume Poisson distribution for mean delirium/coma free days with a total 128 patients observed at day 7, 
we will have 98.7% power to detect group difference at α=0.05 using the nonparametric Wilcoxon test. 
Allowing up to 20% attrition rate for patients dropping out before day 7, we will enroll 160 total patients for 
this trial (80 per group). 
 
For Aim 2, for anxiety measured by VAS-A, we estimated power using results published by Chlan et al31 
where the author reported (1) changes in VAS-A in both the music and control groups appear linear; and (2) 
the music group showed an average difference of 11 points (SD=6.48) in VAS-A scores between the two 
groups and the noise canceling headphones group had no-significant change over time. Assuming 128 total 
patients complete anxiety evaluation by day 7, a daily decrease of 0.03SD on VAS-A in the music group and 
no decrease in the control group, we will have 83.5% power in detecting a group and time interaction in the 
repeated measure model at α=0.05 assuming a first order autoregressive correlation structure with 0.4 for 
measurements one day apart. For pain, assuming a baseline mean of 0.54 for both groups (SD=0.63), a 
daily decrease of 0.2SD on CPOT in the music group and no decrease in the attention control group, we will 
have 80.6% power to detect a group and time interaction in a mixed effect model. We will also have 80.6% 
power to detect a significant interaction assuming similar trajectories for CAM-ICU-7 in the two groups. For 
Aim 3, we will have 80% power to detect an effect size of 0.5SD between the two groups using two sample t-
test at α=0.05. The power estimates were conducted using the Power and GLMPower procedures in SAS 
9.4. 
 
 
 

 
 
 
3. PROTECTION OF HUMAN SUBJECTS 
 
1. Risks to Human Subjects: 
1.a. Human Subjects Involvement, Characteristics, and Design: 80% of older adults develop delirium during 
their ICU stay. Presence of delirium predisposes older adults to immediate in-hospital complications including 
a longer length of ICU and hospital stay, increased risk of in-patient mortality and elevated costs of care. In 
addition, ICU delirium is associated with long-term post-discharge complications such as development of 
cognitive impairment and dementia. Our team is proposing to conduct a randomized clinical trial called 
“Decreasing Delirium through Music (DDM) in Critically Ill Older Adults” to evaluate the efficacy of a seven-
day slow-tempo music intervention on the primary outcome of delirium/coma free days among mechanically- 
ventilated older adults admitted to the ICU. 
 
The target population will be English-speaking; mechanically ventilated adults aged 50 and older who have 
been admitted to the intensive care unit in either Eskenazi Health or Methodist Hospital in Indianapolis or the 
Mayo Clinic in Rochester. The intervention comprises slow-tempo relaxing music versus a silence track 
attention control delivered twice daily for seven days. The primary outcomes will be delirium/coma free days. 
The enrolled population will also include women and minorities who meet the inclusion criteria. Subjects will 
be excluded as follows: [1] History of dementing illnesses and other neurodegenerative diseases such as 
Alzheimer’s disease or vascular dementia; [2] Psychiatric illness which is not well controlled [3] Alcohol 
withdrawal symptoms/concern for withdrawal; [4] Suspected or confirmed drug intoxication/overdose, [5] 
Traumatic brain injury, ischemic or hemorrhagic cerebrovascular accident, or undergoing neurosurgery; [6] 
Uncorrected hearing or vision impairment including legal blindness; [7] Incarcerated at the time of study 
enrollment, [8] Enrolled in another clinical trial which does not permit co-enrollment 
 
After obtaining approval from the local institutional Review Board (IRB) and the ICU leadership at each 
hospital, subjects or their legally authorized representative will be approached for participation into the study. 
After enrollment the subjects will be randomized into two groups, slow-tempo music intervention and silence 
track attention control. The interventionist research staff will initiate the study intervention. The research staff 
will perform blinded outcomes assessment including delirium/coma free days, delirium severity, pain, and 
anxiety during the ICU stay. After discharge, at 3 months, research assistants will perform cognition 
assessment, and will collect depression and anxiety measures over the phone. 
 
1.b. Sources of Materials: During the hospital stay, research assistants will review the medical records and 
conduct delirium, coma, pain, and anxiety assessments. The blinded research assistants will also be 
collecting information on physiologic status (blood pressure, height, weight, heart rate, respiratory rate). The 
assessors will also conduct a medical record review to assess subject’s chronic conditions (Charlson 
comorbidity index) and severity of medical illness (APACHE II index, SOFA). Study specific blood specimens 
will provide biomarker data. 
 
All data gathering is done initially with subjects or their legally authorized representatives in the ICU and 
afterwards at the 3 months post hospital discharge follow-up. Data will be linked to participants through the 
use of a unique identifying number. Only persons on the research team will have access to the data. All data 
are collected for research purposes only. Case Report Forms (CRFs) will be stored in locked filing cabinets 
at Regenstrief Institute or Mayo Clinic and all data will be entered into electronic case report forms (eCRFs) 
in a secured password-protected database. All study data will be entered via a password-protected, study 
specific REDCap (Research Electronic Data Capture) database website. REDCap was developed 
specifically around HIPAA- Security guidelines and has been disseminated for use locally at other institutions 
and currently supports > 140 academic/non-profit consortium partners and 11,000 research end-users 
(www.project-redcap.org). 
 
1.c. Potential Risks: 
(1) Fatigue, anxiety, stress, or embarrassment from the assessments. Emotional distress may result from 
answering health and behavior questions. Testing may also create anxiety, stress, or embarrassment at 
perceived performance. Participants may also become fatigued during the testing. 
(2) Exposure of confidential information. There is the potential for loss of privacy or confidentiality due to the 
data collection efforts of this study. 

 
 
(3) Discomfort with music delivery. There is potential for discomfort, infection, and irritation with use of the 
headphones. Another potential risk is that a subject could have an adverse emotional response to a certain 
piece of music. The potential risk for an adverse emotional response to music is thought to be low in regards 
to the music planned for our study playlist. Our music therapist consultant has extensive professional 
experience with ICU patients receiving mechanical ventilation. Depression and suicidal ideation. The duration 
of the study intervention is limited to the ICU; therefore adverse events related to the intervention occurring 
after the date of discharge are unlikely. Because research staff will continue to collect data from participants 
for 3 months after discharge, and because psychological complications have been described in ICU 
survivors, study staff will recognize worrisome conditions such as suicidal ideation or other emergent 
concerns of clinical conditions (chest pain, etc) during any study interaction. Study personnel will follow a 
scripted protocol to notify the appropriate medical personnel and the PI so that appropriate notification and 
clinical follow-up is ensured. The PI or delegated study personnel will notify the appropriate provider or 
emergency personnel depending on the severity of the presentation. Even in depression trials conducted by 
Regenstrief investigators with clinically depressed patients, this is only an occasional event, and in the 
present study we expect it to be rare. Nonetheless, we will train study personnel in the recognition and 
communication of such events to ensure prompt response to emergent reports if they occur. 
Risks related to blood sample collection will be minimized by use of clinical nurses for sample collection, use of 
existing intravascular devices for drawing blood whenever possible, and transport of the samples using lab best 
practices, and labelling the samples with deidentified labels.  
(4) Subjects may have pain, bruising or very rarely get an infection from the blood draw. To minimize these 
problems, blood will be drawn by trained staff using sterile procedures. 
 
2. Adequacy of Protection Against Risks: 
2.a. Recruitment and Informed Consent: Eligible subjects will be identified through the intensive care units 
census to which they are admitted. A waiver of consent documentation will be obtained for recruitment 
purposes only. Study personnel will consent the patient or their legally authorized representative (if the 
patient is unable to consent for themselves). 
 
2.b. Protections Against Risk: 
(1) Fatigue, anxiety, stress, or embarrassment from the training or testing sessions. All questions planned for 
this study are part of validated standardized instruments, and we are not asking any questions that do not 
directly relate to the study purpose. Research staff will be trained in their proper use and in the importance of 
privacy and sensitivity to the participant’s time. They will be trained to be alert and sensitive to signs of 
fatigue and other symptoms and to take appropriate actions when they are present. 
(2) Exposure of confidential information. Indiana University requires certification of training in protection of 
human subjects in research. The investigators, interventionist, assessors, and all key personnel have or will 
have successfully completed training and certification in these courses. All research involving the use of 
these data must be reviewed and approved by the IRB. We will assure the privacy of subjects and 
confidentiality of study data by assigning unique identifiers to track participants’ data (rather than using 
names or hospital or social security numbers) and keep all records under lock with access only by study 
personnel. These procedures have been dutifully adhered to in prior studies. The final data files for this study 
will be merged, maintained, and analyzed on servers managed by the Division of Biostatistics, Department of 
Medicine, Indiana University School of Medicine. We will also utilize these rigorous protocols to protect 
confidentiality of biomarker analyses which include genetics and epigenetics associations. Our group has 
extensive experience in the handling and security of PHI. None of the individual participant data will be 
identifiable in published reports or manuscripts and the analyzable datasets will not contain the participant’s 
unique identifier.  
(3) Discomfort with music delivery. Patients will be monitored for adverse events on a daily basis. Adverse 
events will be reported to the Institutional Review Board (IRB), data safety officer, and PIs immediately. In 
our prior work, we have not experienced any adverse events related to the study protocols. All infection 
control guidelines will be followed based on each hospital’s policy. Patient risks will be minimized through the 
use of quality electronic devices, their regular cleaning and maintenance. If patients endorse discomfort from 
headphones, they will be switched to another set. In case of an adverse emotional response to music, 
subjects will be informed that they are free to withdraw from the study at any time they so desire without 
affecting their care. In previous work by the PI in which subjects listened to music from a discrete collection, 
no adverse emotional responses to music has occurred, thus we believe our plan here will be equally 
effective. 
(4) Depression and suicidal ideation: During follow-up assessments it is possible that participants endorse 

 
 
suicidal ideation on the PHQ-9. We have handled them extensively in our prior m-CCRP and IMPROVE trials 
and have developed a suicide response protocol. A positive PHQ-9 will be followed by the Columbia Suicide 
Severity Rating Scale (C-SSRS) questions. If a participant answers yes to any C-SSRS question, the PI (Dr. 
Khan) will be notified immediately who will contact the family member to arrange transfer to the ER. If the 
participant does not answer yes to any C-SSRS question, the RA will still notify Dr. Khan who will contact the 
PCP of the patient and will arrange for an urgent follow-up. 
(5) Subjects may have pain, bruising or very rarely get an infection from the blood draw. To minimize these 
problems, blood will be drawn by trained staff using sterile procedures. Existing intravascular devices for 
drawing blood will be used whenever possible. 
 
 
3. Potential Benefits of Proposed Research to Human Subjects and Others: Participants may 
experience short-term benefits such as improve delirium/coma free days, lower delirium severity, pain, 
anxiety, depression and improved cognition. The intervention may also reduce potential harms from short-
term, and possibly long- term use of opioids and benzodiazepines, recognized as potentially inappropriate 
medications according to the American Geriatrics Society Beer’s Criteria. Discontinuation of medications with 
adverse cognitive effects may improve short- and long-term cognitive performance. The improvement in 
cognitive function may or may not be noticeable to study participants. This research could also provide a non-
pharmacological approach for delirium management in ICU patients. 
 
The intervention proposed in this study builds upon prior research and may hold promise for an effective and 
scalable recovery model for this population. This intervention does require additional resources that will cost 
additional money; however, it is possible that these short-term costs will be offset by reductions in overall 
costs to patients and the healthcare system. While risks associated with this proposed study are thought to 
be low, findings have the potential to be applied to the million patients who receive mechanical ventilatory 
support each year in the United States. If the findings from this investigation support the research hypothesis, 
mechanically ventilated patients who listen to music would experience fewer of the side effects documented 
to occur with these symptom management regimens that rely solely on potent sedative medications. This in 
turn may lead to patients being weaned quicker from mechanical ventilation, which would decrease the 
suffering and burdensome symptoms associated with mechanical ventilation such as fewer ventilator-
associated pneumonias which could lead to reduced complications and costs for ICU medical care. 
 
4. Importance of Knowledge Gained: Up to 80% of ICU patients develop delirium and currently there are no 
effective and scalable treatment modalities. Our proposed intervention may provide a conceptual and scalable 
recovery model to remediate or treat ICU delirium and its deleterious effects on cognition. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
4.  DATA AND SAFETY MONITORING PLAN 
 
The MPIs (Dr. Khan, Dr. Chlan) and a safety officer will monitor the study. 
 
1. Qualifications and responsibilities of the Safety Officer: The safety officer for this trial will be a clinical 
researcher experienced in running intervention studies. The safety officer will review the reports sent by the 
study manager to determine whether there is any corrective action, trigger of an ad hoc review, or stopping 
rule violation that should be communicated to the study primary investigator, the Indiana University IRB, and 
the NIH. In addition, the safety officer may comment on whether the study investigators need to report any 
specific out of range data to the participant and/or her physician. As with our prior trials, the safety officer will 
receive a monthly report of all events that occurred during the month. 
 
2. Monitoring and Reporting: The frequency of data reviews for this study differs according to the type of 
data and can be summarized in the following table: 
 
Data Type 
Frequency of Review 
 
Each 
Occurrence 
Q 6 months 
Annual 
Subject accrual (adherence to 
inclusion/exclusion); drop-out 
rates; randomization 
 
X 
 
Adverse event rates 
X 
X 
 
Subjects’ Complaints 
 
X 
 
Compliance to Interventions 
 
X 
 
Protocol Violation/Non-compliance 
X 
X 
 
Risk Benefit Ratio Assessment 
 
 
X 
Stopping Rules Report 
 
 
X 
 
The study coordinator and biostatistician will generate reports for PI, and safety officer that will contain: 
 
• 
Summary of adverse events and an explanation of how each event was handled, 
 
• 
Summary of complaints and how each complaint was handled, 
 
• 
Subject retention, including the number and reasons of participant withdrawals, 
 
• 
Intervention compliance (session attendance), and 
 
• 
Summary of protocol violations and how each was handled. All reports will be submitted to IU IRB at 
time of continuing review. 
 
3. Measurement and reporting of adverse events: Adverse event rates associated with music intervention 
are low. Therefore, adverse event rates are expected to vary little between the treatment and control groups. 
We will present blinded adverse event data to the statistician and PI throughout the trial. We plan to present 
unblinded adverse events data to the safety officer throughout this trial and as requested by the safety officer 
and at annual meetings. If there is evidence of elevated adverse events, the safety officer will consult with 
the statistician and PI. The study staff will use an adverse event form to report adverse events caused by the 
intervention. 
 

 
 
4. Possible Adverse Events: Adverse events will be monitored on an ongoing basis by the study coordinator. 
The PI will be notified within 24 hours of any adverse events. Serious adverse events will be reported within 5 
business days to IU IRB, Safety Officer, and NIH. Non-serious adverse events will be reported weekly to the 
safety officer and at time of continuing review to IU IRB. In cases where there is any question regarding the 
level of adverse events or attributable cause, we will consult with the safety officer. 
 
The information collected will include the following: 
• 
Description of the AE. 
• 
Time and Date of onset and eventual date of resolution or death, if available. 
• 
Frequency: intermittent, single occurrence, or continuous. 
• 
Severity of the event. 
• 
Action taken, including use of any concomitant treatment or medication. 
• 
Outcome. 
• 
Relationship to study treatment regimen or other causality. 
 
5. Stopping Rules: It is unlikely that the study would be stopped early due to important favorable differences 
in the intervention group compared to control group because of the short-term nature of the intervention. 
However, the study could be stopped early due to adverse events. The NIA will make the final decision on 
whether or not to accept the safety officer’s recommendation about discontinuation of any component of the 
study. 
 
6. Limits of Assumptions: It is possible that baseline differences between the groups, excessive study 
dropouts and/or missing data by the interim measurement time point (midway point to targeted enrollment) 
will limit the value of data analysis. Baseline differences will be evaluated after the first measurement time 
point and effects on the power to detect differences in the primary outcome will be evaluated and 
communicated to the PI, safety officer, and NIA. Given the monitoring plans outlined elsewhere in this 
document, it is exceedingly unlikely that there will be baseline differences between groups of any magnitude 
to threaten the validity of the study. 
 
Dropout rates higher than 15% would be of concern, so we propose to monitor the dropout rate quarterly. 
Alert points are set at dropout rates of 15% (low alert), 25% (mid-alert), 35% (high alert) and 45% (extreme 
alert). 
With early alerts to problems, action would be taken to avoid higher-level alerts; if a higher-level alert should 
arise, more drastic remedial action would be invoked. 
 
The actions taken at each level of alert are given below: 
 
• 
Mid-level alert = Conference call between study investigators to discuss approaches to minimize 
further losses to follow-up/dropouts. 
 
• 
High-level alert = Conference call between investigators and safety officer to determine further 
alterations of study protocol to complete the study with no further losses. 
 
• 
Extreme-level alert = In the unlikely event of a 45% dropout rate occurs prior to the six-month 
measurement time point, study investigators, the safety officer, and the NIA program official would convene 
on a conference call to discuss the usefulness of continuing the study. 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Additional Protocol Materials based on Supplemental Funding 
 
Changes added with protocol amendment 5/22/2023 
 
1. Add baseline(prior to/around hospital discharge) and longitudinal outcomes assessment 
(month 6, month 12) data collection timepoints  
 
A. Cognition: Cognition will be measured by 4 objective tests of memory, attention, 
information processing speed, and executive cognitive function (Auditory Verbal Learning 
Test [AVLT], Digit Span, and Symbol Digit Modalities Test [SDMT], and Controlled Oral 
Word Association test [COWA]) using a telephone-based administration format, the Indiana 
University Telephone-Based Assessment of Neuropsychological Status (IU- TBANS) prior 
to/around hospital discharge, at 3-months post hospital discharge, 6 months post-
hospital discharge and 12 months post-hospital discharge. 
 
Previous research has demonstrated that these tests can be delivered reliably and precisely 
in person or by telephone.84 
 
B. Depression and Anxiety: Research staff will collect PHQ-9 and GAD-7 over the phone or 
in person prior to/around hospital discharge, at 3 months post-hospital discharge, 6 
months post-hospital discharge and 12 months post-hospital discharge. 
 
 
2. Add Blood Sample Collection Time points (month 3, month 6, month 12). 
 
During hospitalization we will collect blood samples prior to first intervention session (up to 10ml 
in tubes containing anticoagulant), at day 3, and at the end of the intervention period  (up to 10 
ml in tubes containing anticoagulant). Samples will also be collected at the month 3, month 
6 and month 12 post hospital discharge visits (up to 10ml in tubes containing 
anticoagulant) in the clinic. This will be a total of up to 4 tablespoons of blood collected. 
The samples will be transported to the CTSI lab, and will be prepared and stored using 
deidentified labels.  
 
3. Exploratory Aims added (1,2): 
 
Exploratory Aim 1: Test the efficacy of the DDM treatment in slowing the rate of post-ICU cognitive 
decline in mechanically ventilated patients as compared to attention control. Hypothesis 1a: Patients 
in the DDM intervention group will have slower cognitive decline compared to the attention control 
group as measured by the IU-TBANS completed at 6- and 12-months after hospital 
discharge. Hypothesis 1b: This difference in cognitive trajectories between the DDM intervention 
group versus the attention control group will be due, in part, to the DDM treatment decreasing the 
duration and severity of ICU delirium during the index ICU stay.  
 
Exploratory Aim 2: Determine whether the DDM treatment is associated with slower progression of 
ADRD pathology in older adult ICU survivors as compared to attention control. Hypothesis 
2a: Patients in the DDM treatment group will have slower progression in measures of 
neurodegeneration (lower level of neurofilament light (NfL), phosphorylated tau-181 (p-tau 181), 
glial fibrillary acidic protein (GFAP), and S100B), AD pathology (higher levels of Aβ42/Aβ40), 
vascular pathology (lower levels of C-reactive protein (CRP))8 and inflammation (lower levels of 
interleukins (IL)-1, 6, and 8) as measured by blood-based biomarkers collected in the ICU and 3, 6 
and 12 months after hospital discharge, compared to those in the attention control 
group. Hypothesis 2b: These differences in progression of ADRD pathology between the DDM 
treatment versus control group will be due, in part, to the DDM treatment decreasing the duration 
and severity of ICU delirium during the index ICU stay. 
 
 

 
 
4.  
Exploratory Aims Statistical Considerations added (1,2)  
 
Exploratory Aim 1: Mixed effects models will be used with repeated IUTBANS scores 
(collected at baseline, 6 months and 12 months as the outcome measures), group, time, and 
a group and time interaction as independent variables while adjusting for stratification 
variables and other potential baseline covariates found to be significantly different in 
univariate comparisons. A significant interaction between group and time would indicate 
differences in changes of cognitive functions over time between the two groups.  
 
Exploratory Aim 2: Changes in the biomarkers will be calculated and used as the 
dependent variables in ANCOVA models with group as the independent variable and 
adjusting for stratification variables and baseline covariates that are found to be different 
among the groups in univariate comparisons. Mixed effects models will be used to explore 
the association between oxidative stress biomarkers at ICU admission and those collected 
at 3, 6-, and 12- months post discharge. 
 
 
 
 
5. Revised Figure 3: DDM Trial Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
6. Revised Table Time-line of Data Collection and Outcomes Assessments 
Time-line of Data Collection and Outcomes Assessments 
Variable 
Method of 
Collection 
ICU Phase 
Hospital 
Discharge 
Post Hospital Discharge 
 
 
Enrollment 
Intervention 
Phase 
Post-
intervention 
phase 
 
3 months 
6 months 
12 months 
Demographics 
(Age, race, gender, 
education, Insurance) 
EMR 
X 
 
 
 
 
 
 
Clinical Data (lab 
values) 
EMR 
X 
 
 
 
 
 
 
Comorbidities 
(Charlson)a 
EMR 
X 
 
 
 
 
 
 
Baseline Cognitive 
function 
(IQCODE)b 
Caregiver 
Interview 
X 
 
 
 
 
 
 
History of 
depression, 
Anxiety 
EMR 
X 
 
 
 
 
 
 
Diagnoses 
EMR 
X 
 
 
X 
 
 
 
Severity of Illnessc 
(APACHE II, SOFA) 
EMR 
X 
(APACHE) 
 
 
 
 
 
 
Functional Statusd 
(ADL, IADL) 
EMR 
X 
 
 
 
 
 
 
Medications 
EMR, patient, 
caregiver 
X 
Daily 
Daily 
X 
X 
X 
X 
Duration of 
Mechanical 
Ventilation, Length 
of ICU and Hospital 
stay 
EMR 
 
 
 
X 
 
 
 
Mortality 
EMR 
 
 
 
X 
 
 
 
Discharge Disposition 
EMR 
 
 
 
X 
 
 
 
ABCDEF bundle 
adherence 
EMR, Nursing 
reports 
X 
Daily 
Daily 
 
 
 
 
Intervention 
characteristics 
iPad App and 
Web portal 
X 
X 
 
 
 
 
 
Physiologic 
Parameters 
(respiratory rate, 
heart rate, blood 
pressure) 
EMR 
X 
4X Daily 
Daily 
 
 
 
 
Delirium, Pain, 
Anxietyf  (RASS, CAM-
ICU, CAM-ICU-7, 
CPOT, VAS-A) 
Direct 
Assessment 
 
2X Daily (CAM-
ICU, CAM-ICU-
7),  
4X Daily (RASS, 
CPOT, VAS-A) 
2X Daily 
 
 
 
 
Cognition (IUTBANS)g 
Direct 
Assessment 
 
 
 
X 
X 
X 
X 
Mood Symptomsh 
(GAD-7, PHQ-9) 
 
Direct 
Assessment 
 
 
 
X 
X 
X 
X 
ICU Experience, 
Music preferencej and 
k 
Direct 
Assessment 
 
 
 
X 
 
 
 
Specimen collection 
Direct 
Assessment 
X 
X 
X 
 
X 
X 
X 
Healthcare 
Utilizationi 
EMR, INPC 
 
 
 
 
 
 
X 

 
 
aChronic comorbidities measure through Charlson Comorbidity Index89,bIQCODE: Informant Questionnaire on Cognitive Decline in Elderly90,cSeverity of Illness 
measured through APACHE II91 and SOFA92, Functional Status measured through Katz and Lawton Scales93,94,cAnalgesic and sedative exposure is defined as 
aggregate measure of pain and sedation intensity and the drug frequency in a 24 hour period. We will aggregate dose frequency and dosing intensity by each 
enrollment day. A dose frequency analysis will be used 95-97. fRASS: Richmond-Agitation Sedation Scale76,CAM-ICU: Confusion Assessment Method in the 
ICU75,CPOT: Critical Care Pain Observation Tool78, VAS-A: Visual Analog Scale-Anxiety81,gIUTBANS: Indiana University Telephone-Based Assessment of 
Neuropsychological Status84,h PHQ-9: Patient Health Questionnaire85, GAD-7: Generalized Anxiety Disorder Scale87,I Captured through Indiana Network for 
Patient Care (INPC),j Intensive Care Experience Questionnaire, Music Preferences Questionnaire. kWe will obtain the Richard-Campbell Sleep Questionnaire 
around time of extubation (once patient can communicate), at hospital discharge, and at 3-, 6-, and 12-months.