Tart Cherry Juice for Sleep in Older Adults With Insomnia: A Pilot Study of Feasibility and Comprehensive Mechanisms
Phase: NA
Conditions: Sleep Problems, Insomnia
Sponsor: Courtney Millar

 
 
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Tart Cherry Juice for Sleep in Older Adults with 
Insomnia: A Pilot Study of Feasibility and Comprehensive 
Mechanisms (CherryZZZ) 
 
Study Protocol 
IRB# Pro00078791 
NCT #06786494 
 
 

 
 
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CHAPTER 1. INTRODUCTION 
 
Preliminary studies have shown that drinking tart cherry juice daily can help increase sleep quantity in older 
adults with insomnia. This study aims to corroborate previous findings, determine study feasibility, and 
generate preliminary data on several putative corresponding mechanisms on how tart cherry juice may impact 
sleep. It is planned as a randomized, double-blind, placebo-controlled, cross-over intervention in 20 older 
adults with self-reported insomnia. After daily consumption of tart cherry juice and placebo (each for 4 weeks), 
change in sleep quantity/quality and relevant biomarkers (e.g., melatonin, cortisol, serotonin, and inflammatory 
makers) will be measured. 
 
CHAPTER 2. BACKGROUND 
 
An alarming 40-70% of older adults are estimated to have chronic sleep problems, which consequently 
increases risk of detrimental health outcomes, including physical ailments, mental health issues, and cognitive 
decline.1 Although effective, pharmacological strategies are often paired with severe adverse effects, which 
dissuade older adults from seeking treatment and leave them suffering from poor sleep.2 Thus, there is an 
urgent need to identify safe, non-pharmacological strategies that optimize sleep to maintain healthy aging in 
older adults and avoid the adverse outcomes often resulting from poor sleep.  
 
Diet offers a safe, non-pharmacological strategy to modulate sleep. Two small pilot studies in older adults with 
insomnia (i.e., a condition marked by poor sleep) report that intake of tart cherry juice for 2 weeks increased 
sleep quantity (e.g., total sleep time), but not quality (e.g., patient-reported satisfaction with sleep).3,4 Poor 
sleep quality is associated with mortality and other diseases of aging,5-8 which underscores the importance of 
improving both sleep quantity and quality. Interventions targeting improved sleep quality typically have 
durations of at least 4 weeks as previously reviewed.9 Given that the previous studies had 2-week durations of 
tart cherry juice intake, longer studies may be required to see increases in both sleep quantity and quality. 
 
Despite 2 successful pilot studies that show tart cherry juice increases sleep quantity in older adults, the 
underlying mechanisms remain unclear. Tart cherry juice is made from a specific type of cherry variety that is 
uniquely concentrated with melatonin, an important compound involved with the initiation of sleep.10 Yet, there 
are also other factors in tart cherries that may impact sleep,11-15 including: tryptophan, a precursor to 
serotonin, a mood regulating hormone,15-18 magnesium, a micronutrient that regulates the production of 
cortisol, a stress hormone,19,20 and flavonoids, plant-based compounds that protect cells from damage and 
lower inflammation in the body (Figure 1).11,13 Cherry-derived melatonin, tryptophan, magnesium, and 

 
 
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flavonoids all have specific effects on biomarkers, which consequently have downstream effects on sleep-
associated factors (i.e., reduction in core body temperature,10,21,22 improved mood,18,23-25 reduced 
stress,26-28 and reduced pain,29-31 respectively). Clarification of the mechanisms underlying the impact of tart 
cherry juice on sleep will allow us to ultimately identify other potential foods and/or dietary patterns that provide 
similar compounds to help with sleep. 
 
CHAPTER 3: RESEARCH DESIGN  
 
3.1 Study Objectives and Aims 
The overall goal of this study is to determine feasibility of a tart cherry juice intervention in older adults, and 
generate preliminary data of outcomes and mechanisms related to sleep. We propose a 2-arm randomized, 
double-blind, cross-over study in 20 older adults with self-reported insomnia. Participants will consume 240 mL 
of tart cherry juice or placebo (calorically matched to the tart cherry juice beverage, but theoretically devoid of 
melatonin, tryptophan, magnesium and flavonoids), twice/evening for approximately 4 weeks in a randomly 
assigned order. The aims are:  
 
Aim 1: Determine the feasibility of recruiting individuals for and implementing a 4 week tart cherry juice 
intervention in older adults with self-reported insomnia. Hypothesis: Recruitment for and implementation 
of a tart cherry juice intervention in older adults with self-reported insomnia is feasible.   
Aim 2: Generate preliminary data for sleep quantity, sleep quality, and relevant biomarkers in older 
adults with self-reported insomnia enrolled in a double-blind randomized placebo controlled tart cherry 
juice intervention. Hypothesis: Intake of tart cherry juice tends to increase sleep quantity (via sleep 
monitoring device), sleep quality (via validated questionnaire, e.g., the Pittsburg Sleep Quality Index) 
urinary melatonin, and serum serotonin, as well as decrease urinary cortisol and serum inflammatory 
markers.   
Exploratory Aim: Explore the impact of tart cherry juice intake on sleep-related factors that may be 
impacted by the Aim 2 biomarkers in older adults. Hypothesis: Intake of tart cherry juice for 4 weeks 
results in changes in mood, stress, and pain. 
 
3.2 Overview 
This will be an individual-level, 2-arm, randomized, cross-over pilot in 20 older adults with self-reported 
insomnia to determine feasibility of a tart cherry juice intervention and to generate preliminary data on 
measures of sleep and related biomarkers needed to plan a future trial. Participants will complete a 1-week 
(approximately 7 nights of sleep) pre-intervention assessment of sleep quantity, since several nights of data 
are needed to reduce variation in these outcomes. They will be randomized to consume tart cherry juice or 
placebo, which is nutritionally matched to the cherry juice beverage, but without significant amounts of our 
putative active cherry compounds (e.g., melatonin, tryptophan, magnesium, or flavonoids). They will be asked 
to consume their assigned intervention in the evening: 240 mL (i.e., 8 ounces) at approximately 5 pm and 240 
mL (i.e., 8 ounces) at approximately 1 hour before bedtime for 4 weeks. After approximately 2 weeks of 
washout, they will repeat the same process with the other arm of the study (Figure 2).  
 

 
 
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3.3 Inclusion and Exclusion Criteria 
Our target population is older adults, with self-reported insomnia. Individuals expressing an interest in 
participating will be screened to confirm that they meet the following inclusion and exclusion criteria.  
 
Inclusion Criteria 
• 
Men and women aged ≥65 years 
• 
Self-reporting insomnia (e.g., trouble sleeping approximately 3 nights a week for at least 6 months 
and/or an Insomnia Severity Index score ≥ 10 points32) 
• 
Usual bed-time between 8:00 pm and 1:00 am  
 
 
Exclusion Criteria 
• 
Unwilling to follow the study protocol 
• 
Inability to properly use the wearable device, complete smartphone-based surveys, or follow the 
intervention protocol 
• 
Self-report of medically diagnosed sleep disorders except insomnia (e.g., sleep apnea) 
• 
Current and consistent use of sleep aids or hypnotic prescriptions (e.g., trazadone)* 
• 
Self-report of cognitive impairment, dementia, or other neurological disorder 
• 
Are on unstable medications (i.e., change within the last 3 months) for other conditions 
• 
Have an allergy to the intervention products 
• 
Self-report history of diabetes 
• 
Current alcohol (Alcohol Use Disorders Identification Test ≥4 points33,34) or drug use disorder (Drug 
Abuse Screening Test,35,36 DAST-10>2 points) 
• 
Are excessive caffeine drinkers (>5 cups of caffeinated beverages a day) 
• 
Any other reason/condition the PI and investigative team believe this intervention would be unsafe  
 
*If individuals currently use certain sleep aids (e.g., melatonin), but are willing and able to avoid their use 
during the study, participants will be asked to avoid the use of the sleep aid for approximately 2-3 weeks before 
continuing with the study.  
 
3.4 Number of Subjects and Study Duration 

 
 
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We aim to recruit a total of 20 individuals (both men and women) through local newspaper and internet 
advertisements, physician referrals, our registry of research volunteers, Hebrew SeniorLife (HSL) senior 
housing sites, and patient registries  (e.g., HRC or Beth Israel Deaconess Medical Center). Given that a 
primary goal of this study is to determine recruitment and attrition rate, we may not have exactly 20 individuals 
who complete the study. Participants will remain in the study for a total of approximately 12 weeks.  
 
3.5 Study Endpoints 
The primary outcome is feasibility. Secondary outcomes are sleep quantity, sleep quality, and select 
biomarkers. Exploratory outcomes include mood, stress, pain. See §6.2 for further information. 
 
3.6 Study Intervention Products  
Tart cherry juice will be purchased from a commercial supplier (e.g., Shoreline FruitTM). Shoreline Fruit will be 
responsible for preparing and bottling the tart cherry juice. Frozen or fresh tart cherries will be juiced and 
bottled according to the manufacturers normal processing. The intervention products will be prepared following 
proper food safety/handling protocols and the bottles. The bottles of tart cherry juice will be labeled with a 
letter, number or symbol, that distinguishes it from the placebo. 
 
Unsweetened black cherry powder (e.g., Kool-aidTM) will be purchased and used as the placebo. A reputable, 
established lab (e.g., Rutgers Food Innovation Center) will prepare the placebo, who will follow safe, good 
manufacturing practices. The placebo will be prepared to match the caloric/sugar content of the tart cherry 
juice. The Kool-aid has a similar taste and color, however does not contain significant amounts of our active 
ingredient (i.e., tart cherries) or active putative compounds (e.g., magnesium, melatonin, tryptophan, 
flavonoids). The placebo will be bottled in the same bottle type that the tart cherry juice is bottled in, however it 
will be marked with a letter, number, or symbol that differs from the one used to identify the tart cherry juice.  
 
The key that decodes which of the letter/number corresponds with which product will be kept secure by an 
independent party (e.g., an individual at the Biostatistics and Data Sciences Core of the Marcus Institute). 
Thus, the participants, study staff, and analyzers of the data will be blinded to the letter/number that is used to 
identify the tart cherry juice vs the placebo. At the end of the data collection and data analysis, the study team 
will be unblinded. See §5.3 for further information on dietary intervention. Individuals will be provided with an 
allotment of the intervention products and additional bottles will be delivered by our study staff as needed.  
 
CHAPTER 4 RECRUITMENT AND DATA COLLECTION  
 
4.1 Recruitment Overview  
Participants will be recruited from the Boston area community, including senior housing facilities in 
urban/suburban areas and research recruitment repositories. We will utilize a multi-pronged approach to meet 
our recruitment goals: 
• 
We will recruit from the research repository that resides at HRC 
• 
We will connect with social workers in and outside the HRC 
• 
We will perform medical record reviews to identify potentially eligible individuals at the Hebrew 
SeniorLife (HSL) geriatric medicine practices.  
• 
We will advertise through direct mailings to all residents of HRC’s seven supportive housing facilities 
(over 3,000 residents).  
• 
We will give presentations at Hebrew SeniorLife (HSL) facilities.  
• 
We will use the Harvard Catalyst (CTSA) and Shared Health Research Information Network (SHRINE) 
to identify volunteers from Harvard-affiliated hospitals and clinics. 
• 
We will advertise our study within numerous local media outlets, on HRC’s Hinda and Arthur Marcus 
Institute for Aging Research and other websites (e.g., Craig’s List and targeted web-based 
advertisements via BuildClinical), and at www.clinicaltrials.gov. 
 

 
 
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4.2 Recruitment Timeline and Randomization 
Our trial proposes to enroll 20 individuals over approximately 6-months. In an attempt to account for the impact 
of order, we will randomly assign individuals to the order in which they receive the intervention and placebo. 
For example some individuals will start with the intervention and then placebo, others will start with the placebo 
and then the intervention. This process will be carried out while maintaining participant and investigator 
blinding. Block randomization will be employed as a means to reduce the impact of season/time.  
 
4.3 Informed Consent  
All interested individuals will be asked to provide verbal consent to complete an initial eligibility screen during a 
phone conversation with study personnel. Potentially eligible participants will then schedule an in-person 
screening visit.  Potential participants may be sent by email or conventional post (per request, and according to 
their preference) a copy of the informed consent form for them to review at their own pace prior to the in-
person screening. Written informed consent will be obtained by trained study personnel at the beginning of the 
in-person screening visit.   
 
4.4 Participant Withdrawal 
Any participant who expresses a desire to discontinue participation in the study will be withdrawn at their 
request immediately. All data collected prior to withdrawal will be maintained in the study data set. 
 
Additionally, a participant may be withdrawn from the study prior to completing all of the study related 
procedures due to the following conditions: 
• Participant safety issues 
• Failure of subject to adhere to protocol requirements (including low compliance with the intervention) 
• Disease progression 
• Participant decision to withdraw from the study (withdrawal of consent) 
 
Withdrawn participants may not reenter the study unless there are extenuating circumstances (e.g. family 
emergency or required travel out of town) that interfere with the start of the study before any interventions are 
administered. In this case, they may be scheduled to start over again. If new medical conditions arise or are 
exacerbated during the study intervention, the withdrawal of a participant will be evaluated by the PI. 
 
4.5 Methods to Protect Participant Privacy 
The following are the planned procedures for effectively protecting against and minimizing loss of participant 
privacy: 
 
1. Study visits will be conducted in private rooms.  
2. Each participant will be given a unique study identification number and data will not include any of the 
participant’s PHI. 
3. All participant-identifying information will be stored and managed on a secured database server or in a 
locked cabinet.  If on a database, the information will be password protected.  
4. Participant confidentiality will be maintained in accordance with Health Insurance Portability and 
Accountability Act (HIPAA) regulations. 
5. Only the PI, study personnel, and laboratory personnel approved by the IRB and authorized to view PHI 
will have access to the information. 
6. PHI will not be used during discussion, presentation or publication of any research data. 
7. Files containing PHI data collected for recruitment and screening purposes will be kept in locked, 
secured filing cabinets accessible only to designated study personnel (research assistants and 
investigators) 
 
4.6 Minimization of Bias 
This study is designed as a double-blind intervention so neither staff nor participants are aware of their 
assigned intervention arm. Additionally, to minimize analyst bias, biomarkers will be de-identified and analyzed 
by technicians unfamiliar with the participants or study phase.  

 
 
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4.7 Maximizing Compliance and Minimizing Attrition  
At the start of an individual’s study participation, he/she may be given a schedule of their study visits if 
requested. Visits will be scheduled at a time of day that the participant determines is most convenient for them, 
and will repeated at the same time for each visit if possible. Transportation will be provided for each visit as 
needed, snacks will be available, and stipends will be provided for each study milestone. If 
necessary/requested, reminder calls will be made to participants approximately 2 days prior to study visits. 
 
Participants will be tracked throughout their enrollment. Each study visit will be documented. Some study visits 
will be followed with a brief telephone check-in to ask the participant questions about compliance, adverse 
effects, and their experience during the most recent visit. All calls to the participant and their feedback will be 
carefully tracked. Notes that may facilitate compliance, such as “call before 10 am,” etc., will be kept in 
participant files. 
 
We will employ specific strategies to maximize participation and compliance: 
• 
Positive Framing about Benefits: Information will be presented in terms of the possible gains rather 
than the avoidance of losses as this is a more effective motivational approach.  
• 
Feedback and Recognition of Progress: Participants will be acknowledged throughout their 
participation and will be recognized for their contributions to the study. We will remain in close contact 
with individuals throughout their participation with follow-up calls each month.  
• 
Incentives and Rewards: Participants may receive snacks at each visit, cards for achieving 
milestones, such as birthdays, holidays, etc.; and certificates of completion.   
 
 
CHAPTER 5. RESEARCH METHODS 
 
5.1 Participant Visit Schedule 
Study visits will take place at the Clinical Research Laboratory at HRC, Roslindale, MA, an HRC-affiliated 
housing site, or at the participants home or via telephone (if possible). This study includes up to 7 visits. 
Participant eligibility will be determined during an in-person screening. If eligible and interested, the participant 
will be asked to continue with additional study visits. The Week numbers are approximate in order to allow for 
flexibility in scheduling (e.g., one participant may be on the intervention for 28 days, while another may be on 
the intervention for 31 days). The assessments/activities for each study visit are outlined below.  
 
Visits 
Assessments at Each Visit 
Telephone Screening 
We will assess: 
1. 
Sleep Behaviors (e.g., Insomnia Severity Index) 
2. 
Medication use (e.g., sleep aids)* 
3. 
Medical History 
4. 
Other exclusion criteria 
 
*If individuals currently use certain sleep aids (e.g., melatonin), but are willing and able to avoid their use 
during the study, participants will be asked to avoid the use of the sleep aid for approximately 2-3 weeks 
before continuing with the study 
Week 0 (Visit 1) 
We will perform/assess: 
1. 
Informed Consent/Assessment of Understanding 
2. 
Medical History 
3. 
Health Behaviors 
4. 
Substance/Alcohol Use 
5. 
Social Network 
6. 
Height 
7. 
Weight 
 
If eligible, participants will be asked to: 
1. 
Fill out a 3-day dietary record in the week prior to next visit 
2. 
Avoid consumption of certain foods, beverages, and supplements/medications 
(e.g., cherries, alcohol, and sleep aids) for the entire duration of the study. 

 
 
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3. 
Wear a digital sleep sensor (e.g, Garmin Watch) every day/night for the duration of 
the study and keep a sleep diary of time they went to bed and got out of bed for 
each night. 
Week 1 and Week 8 
(Visit 2 and 5) 
    Assessments/Activities: 
1. 
Turn in Diet Records 
2. 
Symptoms 
3. 
Vitals 
4. 
Weight 
5. 
Sleep Quality 
6. 
Blood Draw and Urine Sample for Biomarker  
7. 
Depressive Symptoms 
8. 
Stress 
9. 
Pain 
10. Additional Relevant Questionnaires 
 
Participants will: 
1. 
Continue to wear the digital sleep sensor every day/night and maintain sleep diary 
2. 
Start consuming assigned intervention product 
Within the first 5 days of starting each intervention arm, participants will be called to confirm there is no impact of the 
timing of juice impact on sleep quality. If a participant discloses that they are noticing lower than usual sleep quality after 
consuming the juice, the timing of the dose will be modified to mitigate any negative effects.  
Week 3 and Week 10 
(Visit 3 and 6) 
   Assessments/Activities: 
1. 
Symptoms 
2. 
Related Sleep Factors 
3. 
Depressive Symptoms 
4. 
Stress 
5. 
Pain 
 
Participants will: 
1. 
Continue to wear the digital sleep sensor every day/night and maintain sleep diary 
2. 
Continue consuming assigned intervention product 
3. 
Fill out a 3-day dietary record in the week prior to next visit 
Week 5 and Week 12 
(Visit 4 and 7) 
    Assessments/Activities: 
1. 
Turn in Diet Records 
2. 
Symptoms 
3. 
Related Sleep Factors 
4. 
Vitals 
5. 
Weight 
6. 
Sleep Quality 
7. 
Blood Draw and Urine Sample for Biomarkers 
8. 
Depressive Symptoms 
9. 
Stress 
10. Pain 
11. Additional Relevant Questionnaires 
12. Compliance 
 
*If Week 5, participants will continue to wear the digital sleep sensor every day/night  
Week 7 (No Visit) 
 
 
Participants will be asked to: 
1. 
Continue to wear the digital sleep sensor every day/night and maintain sleep diary 
2. Fill out a 3-day dietary record in the week prior to next visit 
 
 
5.2 Study Visits and Assessments 
A summary of study visits and assessments is provided in the table below. Given that a primary goal of this 
pilot study is feasibility, we will allow for flexibility for the administration of some assessments at visits, as long 
as these changes do not impede the scientific interpretation.  
 
 
Planned Study Assessments at Each Visit 
Visit 
1 
2 
3 
4 
- 
5 
6 
7 

 
 
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Week 
0 
Week 
1 
Week 
3 
Week 
5 
Week 
7 
Week 
8 
Week 
10 
Week 
12 
Screening 
X 
 
 
 
 
 
 
 
Update Medical History 
X 
 
 
 
 
 
 
 
Health Behaviors and Social 
Network 
X 
 
 
 
 
 
 
 
Relevant Symptoms 
 
X 
X 
X 
 
X 
X 
X 
Vitals 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
Sleep Quality 
 
X 
 
X 
 
X 
 
X 
Sleep Quantity (via Garmin 
Watch) 
X 
X 
X 
X 
X 
X 
X 
X 
Related Sleep Factors 
 
 
X 
X 
 
 
X 
X 
Proposed Biomarkers 
 
X 
 
X 
 
X 
 
X 
Depressive Symptoms 
 
X 
X 
X 
 
X 
X 
X 
Stress 
 
X 
X 
X 
 
X 
X 
X 
Pain 
 
X 
X 
X 
 
X 
X 
X 
3-Day Diet Record 
X 
 
 
X 
X 
 
 
X 
Compliance 
 
 
 
X 
 
X 
 
X 
 
Eligible participants will be asked to avoid consumption of tart cherry products, as well as supplemental forms 
of flavonoids, magnesium, and tryptophan for the entire study in order to isolate the effects of our intervention 
on the proposed outcomes. They will also be advised to avoid intake of foods, beverages, and medicines that 
may impact sleep (e.g., alcohol, caffeine, sleep aids, medications that induce drowsiness).  Participants will 
undergo a 1-week (approximately 7 nights) pre-intervention assessment of sleep quantity via a digital wearable 
device that measures aspects like sleep quantity and physical activity (e.g., Garmin WatchTM), which will serve 
as the baseline assessment for these measures. Furthermore, participants will be asked to record the time 
they went to bed and the time they got out of bed (i.e., sleep diary) for the entire study. Participants will also be 
asked to complete a 3-day diet record. At the baseline visit, medical history, and basic anthropometric 
information will be collected. Participants will provide a urine sample and fasted blood samples for biomarker 
analyses, complete questionnaires (e.g., sleep quality, mood, etc.) and have their vitals measured. Blood 
samples will be collected between 8-10 am, to avoid the impact of time of day on markers. After randomization 
to one of the intervention arms, participants will be asked to consume their intervention product twice per day 
for approximately 4 weeks, while also wearing the digital sleep sensor. Half of the intervention dose is intended 
to be consumed at approximately 5 pm and the other approximately 1 hour before bedtime. Individuals may 
receive reminder messages via their digital wearable device or via email/text to remind them about their study 
responsibilities (e.g., charging their devices etc). All assessments that were performed at baseline will be 
repeated approximately 4 weeks later at follow-up (e.g., urine sample, blood draw, questionnaires). After 
approximately 2 weeks of a washout period (to reduce the impact of a carry-over effect from the intervention), 
participants will complete the same schedule with the other intervention product.  
 
Telephone Pre-screen (~30 minutes): Volunteers will be asked about demographic information, sleep 
behaviors/insomnia, medication/supplement use, any past/present medical conditions and/or treatments, as 
well as other exclusionary criteria.  
 
Medical History: Participants will be asked to disclose any existing or previous medical conditions vis 
self-report. 
 

 
 
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Insomnia Severity Index: The insomnia severity index will be administered to determine eligibility. 
Individuals scoring 10 points or higher will be eligible.  
 
Screening Visit (Week 0; ~60 minutes): Individuals deemed potentially eligible via the phone screen will 
complete an in-person screen. All screening assessments will be administered by trained research assistants. 
Eligible and interested participants will read and sign an informed consent form approved by HRC’s IRB. A 
medical history and health behaviors questionnaire will be completed which will ask about current/past 
conditions, medications, etc. Validated questionnaires that asses substance and alcohol use, as well as social 
connectedness will be administered. The participant’s height and weight will be collected. 
 
Informed Consent: In order to participate in this study, all interested and eligible participants will be 
required to provide informed consent. They will be given ample time to ask any questions about the 
study. A trained research staff will answer any questions and if the individual is interested in 
participating in the study, they will be offered to sign the informed consent form. When the staff member 
is confident that the participant is completely familiar with the document and understands all the 
aspects of the informed consent form, it will be signed by the participant in the presence of the staff 
member, and then be signed by the staff member. All consent forms will be double-checked to make 
sure they are properly signed and dated. Copies of completed consent forms will be given to the 
participant and the original signed document will be kept on file at the Hinda and Arthur Marcus Institute 
for Aging Research. As a part of the informed consent process, potential participants will be clearly 
informed that this intervention is not a treatment option for sleep, but rather studying feasibility of a 
dietary strategy for health. If seeking a treatment, they will be directed to their primary care. 
 
Medical History/Health Behaviors: Additional measures to characterize the participants will include 
existing or previous medical conditions, medication use, smoking status, use of drug, use of alcohol etc. 
 
Drug Abuse Screening Test (DAST) will evaluate drug use. DAST will be administered to participants 
and individuals who scores >2 points, will be excluded.35,36 
 
Alcohol Use Disorders Identification Test (AUDIT) will be administered to participants to evaluate 
alcohol use. For this study, we will administer a shortened version (AUDIT-Consumption) by asking 
only the first three questions from the full questionnaire.  Individuals scoring ≥4 points will be 
excluded.33,34 
 
Social Network: Subjective perception of social support and connectedness will be evaluated using a 
validated questionnaire.37 
 
Height/Weight will be measured.  
1. Height will be measured using a stadiometer.  
2. Weight will be measured using a digital Health-o-meter scale. 
 
If eligible, all participants will be asked to avoid consumption of certain foods (e.g., tart cherries) and fill out a 3-
day diet record to estimate nutrient intake in the week prior to their next visit. Participants will also be asked to 
wear the digital sleep sensor all day and night for the remainder of the study. They will also be given a log to 
record the time they go to bed and the time they get out of bed for the duration of the study.  
 
3-Day Diet Records: Diet records (consisting of 2 weekdays and 1 weekend day) will be reviewed by 
research staff for accuracy and completeness. Records will be entered into a dietary analysis program 
(e.g., Nutrition Data System for Research) to estimate dietary intake of nutrients. 
 
Sleep Quantity: Sleep quantity will be assessed subjectively and objectively. For the subjective 
measure, participants will be given a daily log or journal to document aspects of their sleep (e.g., time 
of sleep onset, time of rising, number of disturbances, self-rated satisfaction with sleep). Participants 
are asked to complete this log every day they are in the study. To objectively measure sleep quantity, 

 
 
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participants are asked to wear a digital device that measures sleep quantity. Participants will be asked 
to wear the device throughout the intervention to objectively capture quantitative aspects of sleep (e.g., 
time in bed, number of times awake). This device has the capacity will be connected to the participants 
phone via free, downloadable applications. Reminders may be sent via the device or via email during 
the study (e.g., reminder to charge device, reminder to open up app to sync data, etc). 
 
Week 1 and Week 8 Visits (~60 minutes): Participants will be asked to turn in their 3-day diet records. 
Relevant symptoms, weight, vitals, sleep quality, depressive symptoms, stress, pain and any additional 
relevant questionnaires will be evaluated. Additionally, up to 16 mL of blood will be taken to measure 
biomarkers in serum and a morning urine sample will be collected. Participants will be given their allotment of 
intervention products to consume each day and continue to wear their Garmin Watch.  
 
Vital Signs (e.g., body temperature, pulse, and seated blood pressure) will be measured. After 3-5 
minutes of rest, seated blood pressure will be measured twice with an automated cuff.  
 
Sleep Quality will be evaluated using a validated self-report questionnaire the Pittsburgh Sleep Quality 
Index (PSQI).38  
 
Relevant Symptoms including gastrointestinal distress, appetite, pain etc., will be collected by self-
report.  
 
Blood (approximately 16 mL) will be collected by a trained phlebotomist using sterile procedures. Blood 
will be processed and stored at -80 degree C for future analyses. Batch analyses of planned 
biomarkers (e.g., kynurenine/tryptophan ratio and select inflammatory markers (e.g., C-reactive protein, 
interleukin-6, etc.) will be measured by a reputable lab (e.g., Quest or collaborators at the University of 
Connecticut). 
 
Spot Urine (approximately 30 mL) will be collected, processed, and stored at -80 degree C for future 
analyses. We will aim to collect urine in the morning hours between 8-10 am to avoid the influence of 
the circadian rhythm on cortisol. Batch analyses of planned biomarkers (e.g., cortisol and melatonin.) 
will be measured by a reputable lab (e.g., Quest or collaborators at the University of Connecticut). 
 
Depressive symptoms will be evaluated using a validated self-report questionnaire (e.g., the Center for 
Epidemiological Studies Depression Scale (CES-D), 39 the CESD-revised (CESD-R)40 version, and/or 
the Patient Health Questionnaire-9 (PHQ-9) 36). 
 
Stress will be evaluated by the validated 10-item questionnaire, the Perceived Stress Scale.41  
 
Pain will be evaluated via a validated 24-item questionnaire, the Geriatric Pain Measure.42  
 
Additional Questionnaires will be administered to evaluate other aspects that are relevant to sleep to 
help characterize our study population (e.g., validated self-report questionnaires that measure anxiety, 
affect etc.)  
 
Compliance: Compliance with our dietary intervention will be evaluated throughout the study. 
Participants will be asked to log consumption of their juice and keep all of their empty bottles. 
Participants will return all remaining empty/full bottles to estimate number of intended doses that were 
consumed.  
 
Within the first 5 days of starting each intervention arm, participants will be called to confirm there is no impact 
of the timing of juice impact on sleep quality. If a participant discloses that they are noticing lower than usual 
sleep quality after consuming the juice, the timing of the dose will be modified to mitigate any negative effects.  
 

 
 
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Week 3 and Week 10 (~30 minutes): These visits may take place over the phone. They will include an 
evaluation of relevant symptoms, related sleep factors, depressive symptoms, stress, pain, and compliance. 
Participants will be asked to fill out a 3-day diet record to estimate nutrient intake in the week prior to their next 
visit. 
 
Related Sleep Factors: In addition to the assessment of sleep quality and quantity, we will also 
collected data about factors that are known to affect sleep (e.g., use of alcohol, room temperature via 
sensor given to participants), that may occur to help characterize or understand unexpected/unusual 
patterns in the data. 
 
Week 5 and Week 12 Visits (~60 minutes): Participants will be asked to turn in their 3-day diet records. 
Relevant symptoms, weight, vitals, sleep quality, related sleep factors, depressive symptoms, stress, pain and 
any additional relevant questionnaires will be evaluated. Additionally, up to 16 mL of blood will be taken to 
measure biomarkers in serum and a morning urine sample will be collected. 
 
At Week 7, participants will be asked to fill out a 3-day diet record to estimate nutrient intake in the week prior to 
their next visit. This is not an official visit.   
 
At the end of the intervention (e.g., Week 12 Visit), participants will be asked to provide feedback via open ended 
questions on their experience during the intervention. They will also be asked if they would be willing to consume 
this intervention long-term and to guess as to which arm they were on in the beginning and ending of the 
intervention. 
 
Optional Study Assessments: Participants will also have the option to partake in two optional study 
assessments as described below. These optional study assessments allow for further investigations of potential 
mechanisms relevant to sleep, including analysis of phenolic metabolites in urine and analysis of the gut 
microbiota in fecal samples.  
 
24 Hour Urine Sample: If participants are willing, they will be asked to provide a 24 hour urine collection 
instead of the planned spot urine collection. This requires individuals to collect all of their urine for the 
24 hours preceding select study visits using a provided urine container. Urine will be processed and 
frozen until analysis. Regardless of whether participants opt for the spot or the 24 hour urine sample, 
batch analyses of planned urinary biomarkers (e.g., cortisol and melatonin) will be measured by a 
reputable lab (e.g., Quest or collaborators at the University of Connecticut). The 24 hour urine sample 
will also be used to evaluate phenolic metabolites. Briefly, urine samples acidified with formic acid will 
be purified via solid phase extraction to isolate gut-microbially generated phenolic acid metabolites (and 
their subsequent phase II hepatic conjugates). Purified samples will be analyzed using LC-MS/MS with 
a triple-quad mass spectrometer to quantify metabolites by their specific parent to daughter ion mass 
transitions. Targeted metabolomics quantifies ~60 phenolics, gut microbially generated phenolic acid 
metabolites, and hepatic phase II metabolites of absorbed phenolics and phenolic acids. 
 
Fecal Sample: If participants are willing, they will be asked to collect at least 1 (no more than 3) 
separate fecal samples before select visits. Samples will be collected as is, in a sterile collection tube 
without any preservation medium that will be provided to participants. There will be a collection for 
select visits as indicated below. Participants will temporarily store the self-collected fecal samples in 
their own freezer (-17°C), and then transported to the lab at HSL for sample processing and long-term 
storage. Fecal microbiota will be analyzed using whole genome sequencing (WGS) to obtain a holistic 
representation of the microbes in the gut. WGS was chosen because it enables identification of 
microbes down to specific species or strain of bacteria whereas other methods only identify the genus 
level and avoid biases common with 16S rRNA sequencing. A reputable lab (e.g., the Microbial Omics 
Core at the Broad Institute) will perform the DNA extraction from fecal samples and WGS library 
construction and sequencing using NEBNext Ultra FS II (2x150bp sequencing chemistry to a minimum 
depth of 3 million reads per sample). Fastq sequences will be processed and analyzed by a reputable 
lab/core (e.g., the Harvard Chan Microbiome Analysis Core). 

 
 
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Optional Study Assessments  
Visit 
1 
2 
3 
4 
- 
5 
6 
7 
 
Week 
0 
Week 
1 
Week 
3 
Week 
5 
Week 
7 
Week 
8 
Week 
10 
Week 
12 
24 Hour Urine Collection 
X 
 
 
X 
X 
 
 
X 
Fecal Sample 
X 
 
 
X 
X 
 
 
X 
 
5.3 Dietary Intervention  
The duration of this study will be approximately 12 weeks. Throughout the intervention, individuals will be 
asked to avoid cherry containing foods/beverages.  
 
Individuals will then be randomized to either start with the intervention or the control product. This is a double-
blinded study, so the study staff nor the participant will know what juice the participants are assigned to. Those 
randomized to the intervention group will be asked to consume approximately 8 fluid ounces of tart cherry 
juice, twice per evening for approximately 4 weeks. Individuals randomized to the control group will be asked to 
consume approximately 8 fluid ounces of cherry-flavored Kool-aid, that is matched for color, as well as calories 
and sugar content. Participants will be asked to consume half of their dose (i.e., 8 fluid ounces) at around 5 pm 
and the remaining half (i.e., 8 fluid ounces) about an hour before bed.  
 
The two juices will be bottled in identical bottles. The placebo will be labeled with a differing letter/number than 
the intervention product.   
 
At visits 2 and 5, participants will be given an allotment of bottles of their assigned beverage, depending on 
their ability to store them. These bottles can remain at room temperature until they are opened. Subsequent 
deliveries will be made by our staff as necessary to ensure participants have a stock of their assigned 
beverage.  
 
Participants will be given a premeasured cup that indicates how much 8 oz. is to allow participant to easily 
measure their assigned dose. 
 
5.4 Outcome Measures 
Our primary endpoints are aspects of feasibility. Secondary endpoints include sleep quantity and quality, as 
well as sleep-related biomarkers (e.g., melatonin, serotonin, cortisol, inflammatory markers.  Exploratory 
outcomes include sleep-related factors (e.g., mood, stress, pain). We will also explore other alternative 
outcomes.  
 
Name 
Type 
Timeframe 
Brief description 
Recruitment Rate 
Primary 
Throughout the entire 
study 
Number of individuals that need to be 
screened to be enrolled that are 
randomized to the intervention. 
Attrition 
Primary 
Throughout the entire 
study 
Number of individuals randomized that 
withdraw from the intervention in media 
res. 
Compliance of Dose 
Primary 
Throughout the entire 
study 
The number of intended doses 
consumed.  
Ability to Collect Data 
Primary 
Throughout the entire 
study 
The percentage of missing data points 
from electronic capture data devices. 
Practicality 
Primary 
Throughout the entire 
study 
Self-reported willingness to continue the 
dietary regimen after study completion. 
Sleep Quantity 
Secondary 
Throughout the entire 
study 
Individuals will be asked to wear a 
polysomnographic device (e.g., Garmin 

 
 
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watch) to continuously measure aspects 
related to sleep quantity (e.g., total sleep 
time, time spent awake). 
Sleep Quality 
Secondary 
Week 1, 5, 8, 12  
The validated self-report questionnaire, 
the Pittsburg Sleep Quality Index, which 
ranges from 0-21 points.  
Melatonin 
Secondary 
Week 1, 5, 8, 12  
Melatonin will be estimated by 
measuring the major urinary metabolite 
of melatonin, 6-sulphatoxymelatonin, 
utilizing a commercially available 
quantitative immunoassay. 
Serotonin 
Secondary 
Week 1, 5, 8, 12 
Serotonin production will be estimated 
by measuring the kynurenine/tryptophan 
ratio in blood collected from participants 
utilizing a commercially available 
quantitative immunoassay. 
Cortisol 
Secondary 
Week 1, 5, 8, 12 
Urinary cortisol will be estimated utilizing 
a commercially available quantitative 
immunoassay. 
Inflammatory Markers 
Secondary 
Week 1, 5, 8, 12 
A panel of several serum biomarkers 
related to inflammation (e.g., C-reactive 
protein, interleukin-6) will be measured 
in blood collected from participants 
utilizing a commercially available 
quantitative immunoassay. 
Mood 
Exploratory 
Week 1, 3, 5, 8, 10, 12  A validated self-report questionnaire 
(e.g., the CES-D/CESD R, which ranges 
from 0-60 points or the PHQ-9, which 
ranges from 0-27 points) 
Stress  
Exploratory 
Week 1, 3, 5, 8, 10, 12  The validated self-report questionnaire, 
the Perceived Stress Scale, which 
ranges from 0-56 points.  
Pain 
Exploratory 
Week 1, 3, 5, 8, 10, 12  The validated self-report questionnaire, 
the Geriatric Pain Measure, which 
ranges from 0-42 points.  
 
 
CHAPTER 6. STATISTICAL DESIGN 
 
6.1 Statistical Analysis 
All analyses will be performed by intent to treat, and further evaluated per protocol. As a first step, we will 
assess distribution characteristics of the primary and secondary outcomes. Where appropriate, transformation 
of variables to combat skew or other irregularities will be employed. Participant characteristics will be 
summarized using means, medians, standard deviations, interquartile regions and ranges for continuous 
variables and sample counts and proportions generated for discrete characteristics. Comparability of treatment 
arms will be assessed on potentially confounding characteristics using tabular and graphical methods. 
 
6.2 Outcome Variables 
Below are the specific outcome variables planned for the study.  
 
Primary Endpoints 
 

 
 
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Study feasibility is evaluated by several identified measures listed in §5.4, however others will be explored. 
Feasibility outcomes will be summarized using sample quantities and corresponding 80% confidence interval 
estimates. The specific thresholds that will determine study feasibility will be fully described in the manual of 
procedures.  
 
Secondary Endpoints 
 
Sleep quantity will be captured via a device that has polysomnographic capacity (e.g., Garmin WatchTM), 
which continuously measures quantitative aspects of sleep (e.g., total sleep time, number of awakenings, wake 
time after sleep onset, etc.). The sleep diary that a participant logs their time in bed and time out of bed will 
help us correct any issues with the objective measures. The primary aspect of sleep quantity will be total sleep 
time, however others will be explored. Participants will be asked to wear the device all day and night during the 
study. Change in measures of sleep quantity will be calculated between baseline and midpoint, as well as 
baseline and final follow-up visit. The distribution of change in sleep quantity scores will be summarized using 
means and standard deviations or medians and interquartile ranges, as appropriate. We will develop 80% 
confidence interval estimates of inter- and intra- individual variation (i.e., standard deviation) of change in these 
measures. 
 
Sleep quality will be measured by a validated self-report questionnaire: the Pittsburg Sleep Quality Index 
(range: 0-21),38 where higher scores indicate worse sleep. Change in sleep quality scores will be calculated 
between baseline and final follow-up visit. The distribution of change in sleep quality scores will be using 
means and standard deviations or medians and interquartile ranges, as appropriate. We will develop 80% 
confidence interval estimates of inter- and intra-individual variation (i.e., standard deviation) of change in these 
measures. 
 
Biomarkers (i.e., melatonin, serotonin, cortisol, and inflammatory markers) will be measured by a 
reputable lab (e.g., University of Connecticut) utilizing commercially available quantitative immunoassays 
(ELISA). Melatonin will be estimated by measuring the major urinary metabolite of melatonin, 6-
sulphatoxymelatonin. Serotonin production will be estimated by measuring the serum kynurenine/tryptophan 
ratio, which reflects the rate at which tryptophan is converted to kynurenine rather than serotonin.18 Therefore, 
lower rates of the kynurenine/tryptophan ratio indicate that more tryptophan is blunted towards the serotonin 
pathway. Cortisol will be estimated by measuring the urinary cortisol. Serum inflammatory markers (e.g., 
interleukins and tumor necrosis factor) will be estimated using a panel of several biomarkers, since 
inflammation is a heterogeneous/complex process.43 These markers will be consolidated into one composite 
inflammatory score as previously described.44-46 Change in the biomarker measures will be calculated between 
baseline and final follow-up visit. The distribution of change in biomarker measures will be summarized using 
means and standard deviations or medians and interquartile ranges, as appropriate. We will develop 80% 
confidence interval estimates of inter- and intra- individual variation (i.e., standard deviation) of change in these 
measures. 
 
Exploratory Outcomes 
Sleep-related factors (i.e., mood, stress, and pain) will be measured. Mood will be evaluated by the 
validated questionnaire, the Center for Epidemiological Studies Depression scale39,40, which measures severity 
of depressive symptoms (range: 0-60, with higher scores indicating more severe symptoms). Stress will be 
evaluated by the validated 14-item questionnaire, the Perceived Stress Scale41 (range: 0-56, with higher 
scores indicating more stress). Pain will be reported via a validated 24-item questionnaire, the Geriatric Pain 
Measure42 (range: 0-42, with higher scores indicating more pain). Change in measures of sleep-related factors 
will be calculated between baseline and final follow-up visit, as well as baseline and mid-point if data is 
available. The distribution of change in sleep-related factors will be summarized using means and standard 
deviations or medians and interquartile ranges, as appropriate. We will develop 80% confidence interval 
estimates of inter- and intra- individual variation (i.e., standard deviation) of change in these measures. 
 
6.3 Statistical Methods 

 
 
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For both arms of the study, change over time will be calculated for each outcome variable and summarized 
using means and standard deviations or medians and interquartile ranges, as appropriate. For the majority of 
outcomes, week 1 and week 8 (i.e., visits that are before intake of the intervention products) will serve as the 
baseline assessment and those conducted at week 5 and week 12 (i.e., visits that are 4 weeks after intake of 
the intervention products) will serve as the follow-up assessment. However, due to the variable nature of sleep 
quantity we will collect several nights of data from 1 week before the intervention products are administered for 
baseline and during the last week of the intervention as follow-up. The median value during those weeks will 
be used to avoid skewing. Then the change between the 1-week estimated medians will be calculated. 
Additionally, change between baseline and midpoint (week 3 and week 10) will also be calculated and explored 
when data is available. The specific analyses for each aim are listed below.  
 
Aim 1: Determine the feasibility of recruiting individuals for and implementing a tart cherry juice intervention in 
older adults with self-reported insomnia.  
 
The aspects of feasibility that are indicated in §5.4 will be tabulated to determine feasibility. This is a 
descriptive analysis, thus no formal statistical methods will be implored. However pre-specified gradient 
thresholds that determine if each metric is feasible, in need of modification, or not feasible are documented in 
the Manual of Procedures.  
 
Aim 2: Generate preliminary data for sleep quantity, sleep quality, and relevant biomarkers in older adults with 
self-reported insomnia enrolled in a double blind randomized placebo controlled tart cherry juice intervention.  
 
The changes computed for the indicated measures as described in §6.2 will be averaged within each treatment 
arm (i.e., tart cherry juice vs placebo) and compared with a paired Student’s t-test. A p-value less than 0.05 will 
be used to determine statistical significance.  
 
Exploratory Aim: Explore the impact of tart cherry juice intake on sleep-related factors that may be impacted 
by the Aim 2 biomarkers in older adults.  
 
The changes computed for the sleep related factors as described in §6.2 will be averaged within each 
treatment arm (i.e., tart cherry juice vs placebo) and compared with a paired Student’s t-test. Additionally the 
changes in sleep related factors will be correlated (via Spearman Correlation) with change in biomarkers within 
each treatment arm (i.e., tart cherry juice vs placebo). A p-value less than 0.05 will be used to determine 
statistical significance.  
 
CHAPTER 7 DATA MANAGEMNT AND QUALITY 
 
7.1 Data Management  
All data collected for analysis will be de-identified and assigned a unique study number. Any data collected on 
paper forms will be kept in a locked file cabinet at HRC. Data collected on paper forms will be entered and 
stored on a password-protected secure server at HRC. When possible, data will be collected directly via our 
electronic data capture system (e.g., REDCap).  
 
The Marcus Institute for Aging Research primarily employs the REDCap system to facilitate data management 
operations. REDCap is a full-featured clinical trials data management system (DMS) accessible to data entry 
and data analysis workstations using secure Web technologies. The REDCap product is developed and 
maintained by Vanderbilt University in cooperation with REDCap Consortium members, including HRC. HSL 
hosts and maintains a dedicated instance of REDCap for use across our research enterprise. Each research 
study is provided separate project workspace in which all of the study data are stored in a MySQL relational 
database on the private corporate network behind several firewalls and located physically within the HSL data 
center. 
 
7.2 Participant Tracking 

 
 
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Each recruited participant will be tracked closely throughout study enrollment. If desired, a study events 
calendar will be created for each participant.  Any outstanding or incomplete visits will be accessible in real 
time to the study team. The study team will maintain regular communications with each study participant 
throughout enrollment, through regularly scheduled follow up calls, and established retention strategies will be 
used as discussed in §4.7. 
 
 
CHAPTER 8 DATA SAFETY MONITORING PLAN 
 
8.1 Participant Risks 
Participation in this study may be associated with minor risks or safety concerns. The potential risks of this 
study fall into 5 categories: 1) those related to research participation; 2) those related to testing procedures; 3) 
those related to the intervention or placebo products; 4) those related to sleep; and 5) those related to optional 
study assessments. The risks are outlined for each category below: 
 
Minor Risk of Participation in Research: With any study, risk of breach of confidentiality is possible 
since we are collecting personal health information.  
 
Minor Risk of Testing Procedures: The potential risks of the testing procedures are minor since the 
majority will be questionnaire based assessments. It is possible that participants may find the 
questionnaires tedious or may be uncomfortable being asked about sensitive topics like suicidality. The 
participants are also asked to wear a sensor to objectively measure physiological data. This device may 
cause slight discomfort or potential rash and be tedious to maintain charged and/or continuously wear. 
The participants may also experience pain or bruising that results from the blood draw. With any 
puncture of the skin, there is an increased likelihood for infection, although this is minor. It is also 
possible that since we are asking participants to consume liquids closer to bed-time, that it might cause 
frequent urinations during the night.  
 
Minor Risk Related to Intervention or Control Products: We do not anticipate any major risks for the 
participants with consumption of either the intervention or placebo products. Participants might grow 
weary and uninterested in consuming the products each day over the 4-week periods.  
 
Minor Risk Related to Sleep: Individuals are eligible for this study because they have reported difficulty 
sleeping. Individuals with sleep problems are more likely to have increased pain, stress, and depressive 
symptoms during our study.   
 
Minor Risk Related to Optional Study Assessments: It may be tedious and inconvenient to collect a 24 
hour urine sample. It may also be unpleasant to collect fecal samples for the study. 
 
 
8.2 Risk Minimization  
We will attempt to minimize the identified risks as specified below:  
 
Risk Minimization of Participation in Research: To minimize the risk of breach in confidentiality, all 
primary study data will be recorded with computer tablets on electronic case report forms (CRF) or as 
digital files generated from laboratory equipment. All data recording will be in accordance with 
procedures and guidelines outlined in the study’s Manual of Procedures (MOP) authored by the study 
team. Participant confidentiality will be maintained by recording subject data using a unique subject 
identifier. Identifiable data, such as contact information and medical record numbers, will be recorded 
and stored separately from the clinical study data. Any paper-based study material and any identifiable 
data will be kept separate in a locked file cabinet accessible by authorized study staff only. Only the 
study staff directly responsible for the data collection and the safety of the participant will have access 
to identifiable information. All electronic CRF data will be stored securely in an electronic data capture 

 
 
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and management system. Raw electronic instrumentation data will be organized and saved on a private 
network file dedicated to the research project. Only those listed on the approved IRB protocol will have 
access to subject data. Subject data will be coded and locked in a file cabinet in a locked office. 
Identifying information will not be used during discussion, presentation or research publication. All 
documents and electronic data will be archived for a minimum of three years, or as required by the IRB 
and federal regulations, after the completion of the clinical trial. The study will be registered at 
clinicaltrials.gov.  
 
The Hinda and Arthur Marcus Institute for Aging Research employs the Research Electronic Data 
Capture (REDCap) system for data capture and data management operations. REDCap is a full-
featured clinical trials data management system (DMS) accessible to data entry and data analysis 
workstations using secure Web technologies. While REDCap can be used to collect virtually any type of 
data (including 21 CFR Part 11, FISMA, and HIPAA-compliant environments), it is specifically geared to 
support online or offline data capture for research studies and operations. REDCap is developed and 
maintained by Vanderbilt University in cooperation with REDCap Consortium members, including HRC. 
HSL hosts and maintains a dedicated instance of REDCap for use across our research enterprise. 
Each research project is provided separate workspace in which all of the study data are stored in a 
MySQL relational database on the private corporate network behind several firewalls and located 
physically within the HSL data center. 
 
Risk Minimization of Testing Procedures: The majority of the testing procedures will be questionnaire 
based and/or passively obtained via wearable devices. Participants will be advised that they can refuse 
to answer any of the questions. Participants will be permitted to rest between studies to prevent fatigue. 
To minimize the risk of being uncomfortable during questionnaires on sensitive topics like suicidality, 
only trained research staff will administer the questionnaires. Research staff will be trained to 
administer them in a calm, welcoming demeanor and will reassure the participants that the 
assessment(s) can stop at any time.  
 
To minimize risk associated with the sensor, individuals will be provided detailed instruction on how to 
maintain and wear the sensor. 
 
To avoid any risk associated with blood draws, only individuals with trained phlebotomist skills will draw 
blood using standard, sterile safety procedures to minimize risk of infection. Unless performed at the 
participant’s home/residence or other HSL housing facility, blood draws will be done at our study clinic 
that resides in the Hebrew Rehabilitation Center, which is a functioning hospital. Thus, in the rare case 
a participant needs additional care that the study team is not qualified to provide, the individual will be 
transferred immediately to the adjacent hospital.  
 
To minimize any risk associated with fluid intake close to bed time, participants will be called within 5 
days of starting their intervention arm to check in to see if nocturia is occurring. If the participant reports 
that they are urinating in the night more than usual which is disturbing their sleep, then the study staff 
will work with the participant to modify their consumption schedule to avoid the sleep disturbance.  
 
Risk Minimization of Intervention Product: Individuals with allergies to intervention products will not be 
included in this study to avoid any adverse effects/allergic reactions. We anticipate that the intervention 
products will be well-tolerated by participants since they consist of dietary products that are regularly 
consumed. Regardless, we will ask participants about any complaints or adverse events that are 
directly related to the study intervention products. We plan to track diarrhea, gas, bloating, abdominal 
pain, constipation etc. If a participant develops a health problem or a potential health problem (in 
addition to the ones outlined below), the PI will be notified ASAP to help decide whether the participant 
should continue in the study, and/or what further steps regarding medical evaluation should be 
performed. 
 

 
 
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Risk Minimization of Sleep: We will proactively assess pain, stress, and depressive symptoms. These 
scores will be regularly reviewed by the PI of the study. If any of the scores concern the PI for the 
participant’s safety or the participant informs study staff that symptoms have become more severe than 
usual, they will contact the study participant and may contact their physician, providing the participant 
has given consent to do so. Additionally, suicidal ideation will also be monitored at visits while the 
participant is on the intervention products to identify individuals who may need psychiatric care outside 
this study. If the participant is deemed to be dangerous or at imminent risk of harm, study staff will 
contact emergency services (i.e., #911) for immediate medical assistance. 
 
Risk Minimization of Optional Study Assessments: To minimize risk associated with collecting 24-hour 
urine sample, individuals will be provided detailed instruction on how to collect the urine sample. They 
will also be reminded a few days prior of when to collect their urine. All materials for urine collection will 
be provided to that participants. To avoid any unpleasant experience collected a fecal sample, study 
staff will provide detailed instruction on how to collect the sample. Furthermore, to avoid the burden of 
storing it in the participants freezer, study staff will pick up the collected samples as soon as possible 
from the study participant.  
 
General Risk Minimization: The proposed protocol requires up to 7 visits over a total 12 weeks and 
therefore imposes a moderate amount of participant burden with respect to time and effort. Our institute 
has a strong track record of successful clinical research requiring similar participation, and retention 
has been high in these projects. The Clinical Research Laboratory at the Marcus Institute is located 
near a cafeteria and rest room, and is equipped with comfortable seating. TV or movies can be 
accessed via the internet to keep individuals occupied during rest periods. Several additional strategies 
will be employed to minimize participant burden and maximize adherence to the protocol. We will: 
- 
Develop a personal relationship between participants and members of the staff. 
- 
Schedule appointments at convenient times with familiar staff. 
- 
Explain to participants all aspects of their participation and follow up. We will demonstrate and 
practice study procedures before beginning data collection. 
- 
Provide reminders of all appointments and follow-up phone calls. 
- 
Include personal notes in the participant’s data file to remember events in the life of the 
participant; these can be commented on at the next visit (e.g., birthday, birth of a grandchild). 
- 
Provide snacks during all visits. 
- 
Provide transportation for all visits, if required. 
- 
Provide free on-site parking. 
- 
Compensate participants for visits. 
 
8.3 Quality Assurance and Safety Monitoring 
The PI will assume primary responsible for ensuring participants’ safety on a daily basis. Since this is a single-
site, phase 1/2 pilot study, without high risk, our study will not require an official Data and Safety Monitoring 
Board (DSMB).  
 
8.4 Adverse Event Collection and Reporting 
 
Any adverse event (AE) or serious adverse event (SAE) will be logged using forms either provided by or 
modeled after the forms that are provided by the NIA Clinical Research Toolbox .  
 
Adverse Event Definition and Categorization 
An AE is any untoward medical occurrence in a participant, whether or not it is causally related to the study. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom or disease temporally associated with the study. We have defined specified thresholds of 
change in some of our assessments (e.g., change in related symptom severity) that will qualify as an AE, 
which is outlined in our manual of procedures. All adverse events will be recorded on the appropriate case 
report forms, source documents and logs. The PI and/or trained staff member will evaluate all adverse events 
as to their severity and relation to the intervention. The severity of AEs will be graded as follows: 

 
 
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Mild: Awareness of a sign or symptom but easily tolerated. 
Moderate: Discomfort sufficient to cause interference with usual activity or to affect clinical status. 
Severe: Incapacitating with inability to do usual activity or to significantly affect clinical status. 
Life Threatening: The participant was at immediate risk of death from the adverse event as it occurred. 
 
The PI will also assess the relationship of any AE to the study, based upon available information, using the 
following guidelines: 
0 = Unlikely: No temporal association, or the cause of the event has been identified 
1 = Possible: Temporal association, but other etiologies are likely to be the cause; however, 
involvement of the study procedures cannot be excluded. 
2 = Probable: Temporal association, other etiologies are possible, but not likely. 
 
To determine the attribution and temporal association of an adverse event we will consider the following: 
1)  Whether the participant reports they have experienced the same symptom prior to the study 
intervention. 
2)  Whether the symptom occurred and resolved within 24 hours of taking the study intervention. 
The PI and/or study staff will consider the symptom according to the conditions stated above and determine 
temporality. 
 
Definition of a Serious Adverse Event 
A serious adverse event (SAE) is any experience that results in any of the following outcomes: 
·  Death 
·  Is life-threatening 
·  Inpatient hospitalization or prolongation of hospitalization 
A persistent or significant disability/incapacity. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. We do not anticipant any Serious 
Adverse Events with our intervention. 
 
Adverse and Serious Adverse Event Reporting 
There is a potential for adverse events and incidental findings during this study. A structured questionnaire 
asking about adverse events will be assessed during each visit of the intervention period. However, when any 
adverse has been identified, the study team will take appropriate action necessary to protect the study subject 
and then complete the Adverse Event form that will be modeled after the form provided by the NIA Clinical 
Research Toolbox. This form requires Principal Investigator review and signature. After review by the Principal 
Investigator any adverse event will be reported to the IRB as appropriate.  
 
AE’s that 1) are unexpected in nature, severity, or frequency, 2) are possibly, probably, or definitely related, and 
3) suggests that the research places participants at a greater risk of harm than previously known or recognized, 
will be reported to the IRB within 2 weeks of the event.   
 
If a serious event occurs, it will be brought immediately to the attention of the Principal Investigator to decide if 
immediate treatment is necessary, initiate such treatment an appropriate hospital or urgent care setting, contact 
the primary care physician if the participant provides consent to do so, and notify the IRB. A Serious Adverse 
Event form that is modeled after the one provided by the NIA Clinical Research Toolbox will be completed, which 
requires Principal Investigator review and signature. If an AE is defined as a SAE, the Principal Investigator will 
be notified as soon as the event is known about. Routine reporting of expected SAEs will be monthly or quarterly 
as appropriate. If the SAE is unexpected or unanticipated, the Principal Investigator will notify the IRB within 48 
hours of being notified. 
 
Unanticipated problems or adverse events will be reported according to the IRB’s written guidelines for 
interventional studies. Unanticipated problems and serious adverse events that are probably, possibly, or 
definitely related to the study will be reported as soon as possible from the time of learning of the event, but 

 
 
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reported within 10 days to the IRB per written IRB guidelines. The IRB will be provided a written report submitted 
and a submission of the incident via the eIRB system. This form will record any adverse symptoms and/or study 
protocol deviations. Study staff will reference a Subject Safety Event Reporting Decision Chart provided and 
regularly updated by the IRB to determine whether an event needs to be reported to the Advarra IRB. 
 
All other adverse events/study incidents will be logged on an Adverse Event log and reported to the IRB 
following the appropriate reporting times as defined by the IRB. 
 
For less serious or incidental findings the Principal Investigator will speak with the participant about the 
finding. If necessary, the PI may suggest appropriate follow-up with the participant’s primary care and/or provide 
a letter describing the findings and need for follow-up. 
 
Any adverse events that take place during testing will be reported to the PI and recorded in the database. The 
PI will have ultimate responsibility for monitoring participant safety in the trial. The investigators will be 
responsible for reviewing each adverse event in a timely fashion, and reporting all incidents to the appropriate 
regulatory agencies according to written guidelines. 
 
8.5 Participant and Study Stopping Rules 
Participant Stopping Rules: If a participant experiences any adverse event that is deemed “severe” as 
outlined in §8.4 (Adverse Events Collection and Reporting) their continuation in the study will be determined by 
the PI. Additionally, if a serious adverse event (SAE) occurs, it will be carefully reviewed by the PI. Any report 
of a serious adverse event (SAE) that is thought to be directly related to the study products or study 
procedures, will result in the participant’s discontinuation from the study.  
 
Study Stopping Rules: Similar to the participant stopping rules, all serious adverse events (SAE) will be 
carefully reviewed by the PI to determine if study termination is warranted. 
 
8.6 Potential Benefits  
Participants may not receive any significant health benefit from participation, although some may benefit from 
knowledge of their health status, as well as potential therapeutic effects from the tart cherry juice. If our findings 
confirm that our intervention is feasible and demonstrates preliminary efficacy, subsequent trials will be 
appropriately designed using the variation in change in the outcomes gathered from this study. Such a study 
will be adequately powered to determine definitive efficacy of a dietary intervention to target biological 
pathways related to sleep quantity and quality. 
 
8.7 Participant Compensation 
Participants will be provided up to $550 stipend to compensate them for their time spent completing study 
procedures and optional assessments. 
 
 
CHAPTER 9. TRAINING 
 
A manual of operations will be created with standard participant instructions for each question and assessment. 
All research staff will review and sign the Site Signature Log – Delegation of Authority Log that is modeled after 
the log provided by the NIA Clinical Research Toolbox to confirm their responsibilities related to the study. During 
startup, staff will undergo intensive training. New staff will conduct study procedures on several adult volunteers 
with oversight from the PI/trained study staff to ensure consistency of raters and equipment setup.  
 
Training will be based on standardized materials developed for the study, and coordinated by the PI. If necessary, 
the staff will undergo training review and quality checks on all assessments and drug distribution protocols. 
Additionally, any time there is an amendment to the study protocol, the change will be logged on a Change in 
Protocol Log. All study staff will be provided a summary of the protocol modifications and under-go re-training 

 
 
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for the new protocol. The date, duration, and certification of all training will be documented and signed by the 
Principal Investigator on the appropriate training logs.  
 
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