Combined Effects of Prunus Cerasus (Montmorency Tart Cherry) and Apocynum Venetum (Venetron®) On Sleep and Anxiety in Adults With Insomnia
Phase: NA
Conditions: Insomnia
Sponsor: Lakshmi Nutraceuticals LLC

1 
 
 
 
Study Protocol 
A Pilot Observational Study Examining the Outcomes of Sip2Sleep®, a supplement 
containing Montmorency tart cherry extract and Venetron® on Sleep Disturbance In 
Adults. 
 
 
Version Date: 
24 March 2023 
Protocol Version: 
Protocol Number: 
02 
PS03 
 
 
 
Sponsor: 
Lakshmi Nutraceuticals, LLC 
9746 N 90th Pl, Suite 207 
Scottsdale, AZ 85258 
 
Principal Investigator: 
Noah Craft, M.D., Ph.D.  
People Science, Inc. 
8605 Santa Monica Blvd,  
Suite 85089 
West Hollywood, CA 90069  
310-770-5332  
noah@peoplescience.health   
 
Participating Sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
People Science, Single study site 

2 
 
 
 
 
 
TABLE OF CONTENTS 
SECTION 
 
 
 
 
 
 
 
 
     
             PAGE 
1.0 OBJECTIVES AND ENDPOINTS 
5 
2.0 INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC RATIONALE 
6 
2.1 Introduction/Rationale for Development 
6 
 2.2 Overview of and Rationale for the Study Design 
6 
3.0 Sample Size, Cohort Characteristics, Eligibility and Involvement 
7 
3.1 Sample Size and Cohort Characteristics 
7 
3.2 Eligibility 
8 
3.3 Duration of Participation and Overview of What is Expected from Participants 
9 
3.4 Participant Recruitment 
9 
4.0 STUDY ACTIVITY CALENDAR 
9 
Table 4.1 Study Calendar 
9 
5.0 RECRUITMENT, CONSENT AND ENROLLMENT 
10 
5.1 Recruitment 
10 
5.2 Consent 
10 
5.3 Enrollment 
10 
6.0 STUDY PROCEDURES 
11 
6.1 Study Overview 
11 
7.0 DATA COLLECTION AND MANAGEMENT 
12 
7.1 Data Collection Elements, Source, And Method Of Collection 
12 
7.2 Data Management 
12 
Research Data Capture System 
12 
7.3 Data Management at Study Completion 
13 
8.0 CODING OF DATA 
13 
9.0 STATISTICAL CONSIDERATIONS. 
13 
9.1 Sample Size Estimation and Justification 
13 
9.2 Projected Study Timeline - Accrual, Data/Sample Collection, Completion 
13 

3 
 
9.3 Evaluable Participants 
13 
9.4 Covariates and Subgroups 
13 
9.5 Missing Data 
14 
9.6 Statistical Analysis Plan 
14 
9.7 Reporting Conventions 
14 
9.8 Quality Assurance of Statistical Programing 
15 
10.0 STUDY COMPLIANCE AND REPORTING OF DEVIATIONS FROM APPROVED PROCEDURES 15 
11.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
15 
12.0 Ethical and Regulatory Considerations 
15 
12.1 Ethical and Regulatory Standard 
15 
Ethical Standard 
15 
Regulatory Standard 
15 
Institutional Review Board 
16 
12.2 Risk Benefit Considerations 
16 
Discomforts, Risks, and Risk Mitigation 
16 
Risk Level Determination 
16 
Direct benefit to research participants 
16 
Importance of the knowledge that may reasonably be expected 
16 
12.3 Participant Characteristics 
17 
Research equity 
17 
Vulnerable Populations 
17 
12.4 Financial Obligation, Burden, and Compensation to Participants 
17 
Completing research activities (not from results/findings or injury) 
17 
Research results or clinical findings arising from research activities 
17 
12.4 Confidentiality/Sharing/Publication 
17 
Return or Clinical Use of Research Results 
17 
Confidentiality 
17 
Information/Data Retention, Future Use, and Sharing 
17 
Publication 
17 
       12.5 Alternatives to Participation, Withdrawal, and Early Termination 
18 
Alternatives to Participation 
18 
Participant Withdrawal from Research/ Research Activities 
18 

4 
 
12.6 Informed Consent, HIPAA Authorization, and California Subject’s Bill of Rights 
18 
Informed Consent 
18 
Privacy Authorization 
18 
State of California Human Experimentation Requirements 
19 
12.7 Investigator Conflict of Interest 
19 
13.0 REFERENCES 
19 
 
 
 
Abbreviation Meaning 
AE 
App 
CAPA 
CFR 
CHLOE 
DTC 
GAD-7 
GCP 
HIPAA 
ICH 
IRB 
ISI 
NIH 
OTC 
PHI 
PI 
VAS 
 
 
Adverse Event 
Application 
Corrective and Preventive Action 
Code of Federal Regulations 
Consumer Health Learning and Organizing Ecosystem 
Direct to Consumer 
Generalized Anxiety Disorder-7 Scale 
Good Clinical Practice 
Health Insurance Portability and Accountability Act 
International Council for Harmonisation 
Institutional Review Board 
Insomnia Severity Index 
National Institutes of Health 
Over the Counter 
Protected Health Information 
Principal Investigator 
Visual Analogue Scale 
 
 
 
 
 
 
 
 
 
 
 
 

5 
 
 
 
 
 
 
 
 
 
 
1.0 OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints/ Measurements 
Primary Objective 
1. To observe the effect of the 
Sip2Sleep® product on sleep quality 
for participants with self-reported 
sleep disturbance 
1. Change in average sleep quality 
score by 1 point as measured by daily 
10-point visual analogue rating scale 
(VAS) from baseline and 1 week of no 
product use 
Secondary Objectives 
1. To assess the effect of 
Sip2Sleep® product on symptoms 
of sleep disturbance  
 
2. To assess the effect of 
Sip2Sleep® product on anxiety 
 
 
3. To assess the effect of 
Sip2Sleep® product on the level of 
alertness during the daytime 
1. Change in Insomnia Sleep Index (ISI) 
by 4.5 points from baseline and 1 
week of no product use 
 
2. Change in Generalized Anxiety 
Disorder-7 (GAD-7) by 4.5 points 
from baseline and 1 week of no 
product use 
3. Change in average level of alertness 
during the daytime score by 1 point 
as measured by daily 10-point visual 
analogue rating scale (VAS) from 
baseline and 1 week of no product 
use 
Exploratory Objectives 
1. To observe the change in sleep 
duration via personal health 
tracking wearable device 
 
2. To observe the change in sleep 
latency via personal health 
1. Change in average nightly sleep 
duration as measured via personal 
health tracking wearable device from 
baseline and 1 week of no product 
use 
2. Change in average nightly sleep 

6 
 
tracking wearable device 
 
3. To identify improvements for future 
participant-centered study designs 
using feedback 
latency as measured via personal 
health tracking wearable device from 
baseline and 1 week of no product 
use 
3. Assessment of patient satisfaction 
survey of study experience including  
design and use of app-based data 
collection tools 
 2.0 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC RATIONALE 
2.1 Introduction/Rationale for Development 
Insomnia occurs in up to 50% of adults in the U.S., while chronic insomnia disorder is estimated 
to impair 10-15%.1 Lack of quality and quantity of sleep negatively affects every part of an 
individual's life, both personally and professionally. Poor sleep is associated with various 
comorbidities including depression, stroke, cardiovascular disease, obesity, dementia and 
Alzheimer’s disease, and increased risk of developing type 2 diabetes.2,3,4,5 Furthermore, there 
has been an increase in evidence of the long-term harm (i.e., increased risk of cognitive 
dysfunction and impairment such as Alzheimer’s disease) of taking prescription sleep aids such 
as Ambien, Lunesta, benzodiazepines, and OTC sleep aids like Benadryl.6 
  
Sip2Sleep® was developed in conjunction with a leading sleep physician who has focused efforts 
in assisting patients improve sleep problems and insomnia by identifying the root cause(s) of the 
issues. Sip2Sleep® uses a proprietary formula of Montmorency tart cherry extract and Venetron®. 
 
Montmorency tart cherry is a special kind of cherry that is known to provide a natural source of 
melatonin. The ruby red pigments in this specific cherry are proanthocyanidins, natural 
compounds that help increase the brain availability of tryptophan—an essential amino acid and 
precursor to the natural sleep aid serotonin. Proanthocyanidins inhibit an enzyme (indoleamine 
2,3 dioxygenase) that degrades tryptophan, a known predictor of insomnia. The minimization of 
tryptophan degradation may allow tryptophan to work more effectively in the body while increasing 
bioavailability for serotonin synthesis, leading to a positive effect on sleep while improving mood 
and decreasing inflammation.7,8  
 
Researchers at Louisiana State University presented data in 2018 showing that drinking 
Montmorency tart cherry juice just twice a day for two weeks helped increase total sleep time by 
nearly 90 minutes among older adults with insomnia. Greater than 75% of participants reported a 
positive response to the cherry juice with a significantly reduced amount of time to initiate sleep 
and improved ability to maintain sleep.7 
 
Venetron® is a patented, purified, powdered extract derived from the Rafuma leaf, Apocynum 
venetum, which is a safe botanical alternative to St. John’s Wort. It helps insomnia by:9,10,11 
● Not affecting the CYP3A pathway in the liver that many OTC natural substances (St. 
John’s Wort) and medications can impact. This means it does not increase the risk of side 
effects and other drug interaction  
● Containing bioactive flavonoids  
● Supporting serotonin concentrations in clinical trials by reducing the degradation of 
serotonin in the blood and brain, thus helping sleep and improving mood   
● Producing a calming effect by acting on the GABA-ergic system  
 

7 
 
Together, Montmorency tart cherry extract and Venetron® are a powerful, natural solution to 
insomnia. They work synergistically to increase the presence of serotonin in the brain to improve 
sleep. Additionally, together they improve mood because Venetron® exerts a calming effect on 
the mind and helps the overactive mind relax for quicker, longer-lasting sleep.  
 
 2.2 Overview of and Rationale for the Study Design 
The rationale for this study is to determine the effect of a consumer-grade, unique formula called 
Sip2Sleep®, which is a combination of Montmorency tart cherry extract and Venetron®, a 
patented, purified, powdered extract derived from the Rafuma leaf, Apocynum venetum, on sleep 
disturbance in adults. Because this product is currently available in the OTC market across the 
United States, a consumer-driven, decentralized observational clinical research study is well-
suited for examining the effect of this formulation on sleep.   
Sleep disturbance is highly prevalent and impacted by many interdependent variables.  We will 
examine self-reported sleep disturbance in a broad age-range of adults who have chosen to use 
this product. The study will incorporate participant reported outcome questionnaires, daily 
surveys, and the participants’ personal health tracking wearable device (e.g. Apple Watch, Fitbit, 
Smartwatch, etc.) to engage the participant in their sleep health and explore objective digital 
outcome measures of sleep. An important feature of this consumer-driven study design is to help 
individual consumers observe the effects of this product on their own sleep patterns during the 
study itself. There is no “doctor-patient” relationship as part of this research since the participant 
as a consumer is making the informed choice to take the product and take part in the observational 
process with self-reported measures. Findings from this study will contribute knowledge toward 
the design of future sleep research studies, the improvement of the Sip2Sleep® product 
formulation, and may help inform clinical recommendations for adults interested in using 
alternative products for sleep. 
The following self-reporting measures are used in order to evaluate the effect of Sip2Sleep® in 
adults with self-reported sleep disturbance: 
Surveys to reflect sleep quality, sleep latency, total sleep duration and level of alertness during 
the day to be distributed daily. Sleep quality and level of alertness during the day will be evaluated 
with a single 10-point visual analogue scale (VAS) and objective sleep data reflecting sleep 
latency and total sleep duration will be collected from personal wearable devices.  
Insomnia Sleep Index (ISI) is a brief self-report instrument measuring the patient’s perception of 
both nocturnal and diurnal symptoms of insomnia during the past two weeks. The ISI comprises 
seven items assessing the perceived severity of difficulties initiating sleep, staying asleep, and 
early morning awakenings, satisfaction with current sleep pattern, interference with daily 
functioning, noticeability of impairment attributed to the sleep problem, and degree of distress or 
concern caused by the sleep problem. Each item is rated on a five-point scale and the total score 
indicates the severity of insomnia, with a range of possible scores from 0-28. A score higher than 
14 has been indicated to be the optimal cut-off for insomnia as a disorder. The ISI has been widely 
used in clinical and research settings as it is brief and easy to administer, and can provide valuable 
information for diagnosis and treatment planning. Research has found that the ISI is sensitive in 
detecting changes in the patient's perception of treatment outcome, and a good degree of 
convergence exists between the patient and the clinician's evaluation of insomnia severity.13,14  
Generalized Anxiety Disorder-7 (GAD-7) is a self-reported anxiety survey utilized in primary care 
consisting of a 7-item anxiety scale. The instrument is well supported to use in a general 
population and normative data can be used to compare a subject’s GAD-7 score with those 
determined from a general population reference group, with evidence of significant reliability and 
validity with congruent agreement in self-reported and interviewer-administered versions of the 

8 
 
scale. GAD and Depression symptoms frequently occur together, but previous studies have 
supported via factor analysis that this measure can detect GAD and depression as distinct 
dimensions.15 This measure will be used in combination with other scales to observe self-reported 
effects on sleep disturbances and insomnia, such as anxiety or other psychiatric disorders.  
3.0 SAMPLE SIZE, COHORT CHARACTERISTICS, ELIGIBILITY AND INVOLVEMENT 
3.1 Sample Size and Cohort Characteristics 
The sample size for this study will be 47 volunteers who meet the participant eligibility.    
3.2 Eligibility 
Participants must meet all the following criteria on screening examination to be eligible to 
participate in the study:  
Inclusion 
1. Age > 18 years old 
2. Has self-reported sleep disturbance 
3. Insomnia Severity Index (ISI) score of > 15 at screening 
4. Interested in understanding more about the quality of their sleep and chose to use the 
Sip2Sleep product for sleep 
5. Willingness to do a minimum of 1 week wash out of current OTC or other products for 
sleep (e.g. melatonin, anticholinergics) 
6. Willingness to do a minimum of 1 week wash out of any cannabis products  
7. Able to receive shipment of the product at an address within the United States 
8. If taking prescription hypnotics (e.g. zolpidem, zaleplon, benzodiazepines) or other class 
of medication for sleep, must be on a stable dose for at least 4 weeks. 
9. Able to read and understand English 
10. Able to use a personal smartphone 
11. Has and is able to use a personal health tracking wearable device (e.g., Apple Watch, 
Fitbit Smartwatch, Oura Ring, etc.) 
12. Able to understand and provide informed consent 
13. Able to complete study assessments over 5 weeks 
Exclusion 
1. Research participants who have no computer, smartphone, and internet access and/or 
do not use a computer or smartphone 
2. Concomitant Therapies: 
a. Participants taking daily prescription medication for sleep (for example, 
prescription hypnotics like zolpidem, zaleplon, benzodiazepines) not on a stable 
dose for at least 4 weeks 
b. Participants receiving Cognitive Behavioral Therapy for Insomnia (CBTi) 

9 
 
c. Participants receiving any investigational therapies or treatments 
3. Other Illnesses or Conditions: Participants who have the following co-morbidities are 
excluded:  
a. Confirmed diagnoses of the following sleep disorders: Narcolepsy, Restless Leg 
Syndrome, Circadian Rhythm Disorders 
b. Confirmed diagnosis of Sleep Apnea that is untreated or not well controlled 
c. Current or prior psychotic disorder 
d. Current or prior Substance Abuse Disorder 
e. Current or prior cardiac dysrhythmias (for example, atrial fibrillation, 
supraventricular tachycardia) 
f. Currently pregnant, planning to become pregnant in the next 1 month, or 
breastfeeding 
g. Allergies or adverse reactions (for example, anxiety) to Montmorency tart cherry 
extract and/or Venetron® 
 
3.3 Duration of Participation and Overview of What is Expected from Participants 
Participants will complete a 5-week study consisting of screening assessments, baseline scales 
and surveys, objective digital measure, 2 weeks of product use (1 week on - 1 week off - 1 week 
on), scales and surveys, and end of study assessments and surveys.  This is a remote 
observational study that will use the People Science app-based data collection platform 
Consumer Health Learning and Organizing Ecosystem (CHLOE) for study participants to report 
their assessments and collect objective sleep data from personal wearable devices. Participants 
will receive the study product during the baseline period. Demographic and medical history data 
will be collected for the study. 
3.4 Participant Recruitment 
Participants will be recruited through professional networks and email/social media channels. 
Advertisement will be in digital format and will link to a study landing page to enable sign up.  
4.0 STUDY ACTIVITY CALENDAR 
Table 4.1 Study Calendar 
Protocol Activities 
 
 
Screeninga
 
Study Durationb  
Baseline 
Product 
Usec 
No 
Product 
Use 
Product 
Usec 
End of 
Study 
Week 
Up to 1 Week 
Week 1 
Week 2 
Week 3 
Week 4 
 
Day 
Day -7 to -1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Insomnia Severity Index 
X 
X 
X 
X 
X 
X 
Eligibility  
X 
 
 
 
 
 

10 
 
Daily Objective Data 
Collection and Surveysd 
 
X 
X 
X 
X 
X 
Use of Study Product 
 
 
X 
 
X 
 
Generalized Anxiety 
Disorder-7 
 
X 
X 
X 
X 
X 
Experience Survey 
 
 
 
 
 
X 
 
a. Screening to occur within 7 days prior to Baseline (Day 1) 
b. Planned duration of study is 4 weeks 
c. Participants to consume Sip2Sleep® product 30-60 minutes prior to lying down in bed.  
d. Participants will complete daily surveys to review objective data from wearable device collection and answer 
questions about their prior night’s sleep quality and level of alertness since waking.  
 
5.0 RECRUITMENT, CONSENT AND ENROLLMENT  
5.1 Recruitment 
Participants will be recruited from several channels including outreach to sleep clinics, sleep 
physicians and providers, Sip2Sleep® customer base via the product website, People Science 
community base and social media. Social media channels may include Facebook, Reddit, 
Instagram, and Google. 
Recruitment outreach will consist of IRB approved advertising by email, digital flyers/postcards, 
printed flyers and word of mouth to patients. 
A study landing page will provide information about the study and criteria for qualification. The 
landing page will lead to an IRB approved pre-screening questionnaire to determine qualification 
and then collect first and last name, email, phone number, and zip code of qualified individuals. 
New leads will receive further instructions by email to continue the enrollment process. 
5.2 Consent 
Virtual electronic informed consent, including a study specific privacy authorization and the 
California subject’s bill of rights (as applicable) will be conducted through a HIPAA compliant 
cloud-based platform to obtain electronic consent that will ensure that the consenting process 
follows all required elements (see Section 7.0). A digital copy of the signed consent will be stored 
with the participant’s profile in the study data platform which is the same technology used for 
electronic consent. In addition, a copy of the signed consent document will be available to the 
participant within the CHLOE app. 
5.3 Enrollment 
Eligible participants who provide virtual electronic consent will be automatically registered into the 
study by CHLOE (see Section 12.6). Participants will be asked to complete a screening ISI 
assessment and 3 additional screening surveys to review demographics, medical history, and 
product shipment address if eligible.  
After confirmation of eligibility, the participant will be enrolled in the study and receive an email 
with instructions to start study assessment in CHLOE and await Direct to Consumer (DTC) 
shipment of the Sip2Sleep® study product.  
 

11 
 
6.0 STUDY PROCEDURES 
6.1 Study Overview 
 
Figure 1. Study Design 
 
Upon enrollment, the study assessments can be accessed via CHLOE mobile app available on 
Apple iOS and Android devices as well as any web browser.  The participant’s activities are as 
follows: 
Screening (Day -7 to Day -1):  
● Informed Consent 
● Complete demographic and medical history data intake. 
● Screening Insomnia Severity Index (ISI) assessment. 
● Provide preferred shipment address for product shipment during Baseline. 
 
Baseline Period (Day 1 to Day 7):  
● Complete Insomnia Severity Index and Generalized Anxiety Disorder-7 (Day 1 only). 
● Begin discontinuation of non-prescription products used for sleep.  
● Begin nightly use of personal health tracking wearable device through Day 28.   
● Complete daily survey to review objective data (sleep duration and sleep latency) from 
wearable device collection and answer questions about their prior night’s sleep quality and 
level of alertness since waking. 
● Receive shipment of study product and instructions for use. 
 
Product Use Period (Day 8 to Day 14):  
● Complete Insomnia Severity Index and Generalized Anxiety Disorder-7 (Day 8 only). 
● Continue nightly use of personal health tracking wearable device through Day 28.   
● Complete daily surveys to review objective data (sleep duration and sleep latency) from 
wearable device collection and answer questions about their prior night’s sleep quality and 
level of alertness since waking. 
● Administer nightly dose of study product 30-60 minutes prior to lying down in bed 
through Day 14. 

12 
 
 
No Product Use Period (Day 15 to Day 21):  
● Complete Insomnia Severity Index and Generalized Anxiety Disorder-7 (Day 15 only). 
● Continue nightly use of personal health tracking wearable device through Day 28.   
● Complete daily surveys to review objective data (sleep duration and sleep latency) from 
wearable device collection and answer questions about their prior night’s sleep quality and 
level of alertness since waking. 
 
Product Use Period (Day 22 to Day 28):  
● Complete Insomnia Severity Index and Generalized Anxiety Disorder-7 (Day 22 only). 
● Continue nightly use of personal health tracking wearable device through Day 28.   
● Complete daily surveys to review objective data (sleep duration and sleep latency) from 
wearable device collection and answer questions about their prior night’s sleep quality and 
level of alertness since waking. 
● Administer nightly dose of study product 30-60 minutes prior to lying down in bed 
through Day 28. 
 
End of Study (Day 29): 
● Complete Insomnia Severity Index and Generalized Anxiety Disorder-7. 
● Complete surveys to review objective data (sleep duration and sleep latency) from 
wearable device collection and answer questions about their prior night’s sleep quality and 
level of alertness since waking. 
● Complete Experience Survey. 
 
7.0 DATA COLLECTION AND MANAGEMENT 
7.1 Data Collection Elements, Source, and Method of Collection 
For recruitment purposes only, a data set limited to name, email, telephone number, and Study 
ID number will be generated manually.  For analysis, data from the assessments and sleep data 
will include the Study ID number and demographic factors (age, gender, race, ethnicity), 
medications, and supplements. 
7.2 Data Management 
Research Data Capture System 
This project will be utilizing People Science’s proprietary platform, CHLOE.  All data is securely 
stored on People Science Amazon Web Services HIPAA compliant servers. The platform contains 
modules for building and managing forms / surveys, landing pages, marketing outreach with 
tracking tools for recruitment, audited electronic consent forms, data management and analytics 
using an integrated relational database.  Data from completed assessments will automatically be 
collected for analysis.  Study monitoring can be done using reporting features. 

13 
 
7.3 Data Management at Study Completion  
For longer term storage of the data that will reduce risk of a data breach while still permitting 
that the data be verifiable (audited) the dataset will be de-identified - no names, etc., and all 
dates turned into time- and coded, and the key to the code will be housed in a separate location.  
The data will be maintained under password protection in the database. 
8.0 CODING OF DATA 
The data set for recruitment (name, telephone number and Study ID number) and the data listed 
in Section 7.1 for analysis will be stored on a password secured database with access only to 
designated study team members and the PI.  
9.0 STATISTICAL CONSIDERATIONS.  
9.1 Sample Size Estimation and Justification 
We anticipate needing to screen approximately 200 individuals to enroll up to 80 individuals and 
achieve a final sample size of approximately 47 evaluable participants. For our primary outcome 
(i.e. change in average sleep quality VAS scores), we assume a common standard deviation = 2 
and a conservative 0.50 correlation between VAS scores. We will have at least 90% power to 
detect a mean VAS score difference of 1 with alpha = 0.05 using a two-sided Wilcoxon signed-
rank test for the difference between dependent means with a final sample of 47 participants. 
Previous research on participants with insomnia and depression have suggested that single item 
sleep quality score can effectively detect meaningful changes in sleep quality over time relative 
to lengthier questionnaires.16 
The secondary objectives include evaluating changes in the ISI, GAD-7 and daytime alertness 
VAS score. As above, we anticipate at least 90% power to detect a 4.5-point change in the ISI 
and GAD-7 with an expected standard deviation of 5. For daytime alertness, we anticipate at least 
90% power to detect a 1-point change with an expected standard deviation of 2.  
9.2 Projected Study Timeline - Accrual, Data/Sample Collection, Completion 
The final sample size for this observational study will be 47 participants. 
We anticipate screening, enrollment and data collection to be complete in 3-4 months. Study 
closeout will be complete in 2 weeks, Data analysis will be complete in 2 months and a CSR and 
lay summary will be complete in 3-4 weeks.  Altogether, the study duration is estimated to be 8 
months. 
The final analysis will take place after approximately 47 evaluable patients have completed all 
final study instruments. These activities will be completed approximately 29 days after enrollees 
initiate participation in the study. 
9.3 Evaluable Participants 
Participants will be considered evaluable for analysis if: 
1. They complete all the study assessments, with at least 60% completed daily assessments 
in each arm (Product Use vs. No Product Use); AND 
2. Objective sleep data from personal wearable devices are collected. 
9.4 Covariates and Subgroups 
Demographic and baseline values will be collected and analyzed on all participants. Data on age, 
gender, race/ethnicity, medical diagnoses, sleep prescriptions, sleep supplements, alcohol and 
cannabis use, smartphone operating system (Android or iOS), and use of personal health tracker 

14 
 
(e.g. Apple Watch, Fitbit) will all be collected and included in univariate, bivariate, and multivariate 
analyses. Subgroup analyses will be conducted to examine differences in outcome by all 
covariates available.  
9.5 Missing Data 
Missing data will be imputed with a value of “999”.  The proportion of missingness will be evaluated 
among all covariates and outcome variables.  If data are missing on a variable in under 5% of 
cases and the assumption of missing completely at random can reasonably be made, only 
observed data will be used in the analysis. If a variable is missing within a range of 5%-40% of 
cases, use of multiple imputation will be evaluated.  Regression analyses will be conducted using 
only complete cases.  
9.6 Statistical Analysis Plan 
The primary objective of this study is to determine the impact of Sip2Sleep® use on symptoms of 
sleep disturbance, as measured by the change in sleep quality VAS scores from 47 participants. 
Univariate statistics will be generated to describe the distribution of patient characteristics and 
outcome data. Continuous variables will be described using means, standard deviations, 
minimums and maximums while categorical variables will be described using counts and 
percentages. Sleep quality VAS scores will be compared from baseline pre-treatment; and at end 
of study (post-treatment) of the same individuals. We will enroll up to 80 participants to achieve 
at least 90% power to detect a mean change in sleep quality VAS scores of 1 points (SD=2) from 
baseline with a type I error of 0.05 (two-sided) assuming a paired means, dependent Wilcoxon 
Signed-Rank test. We are testing the null hypothesis that there is no difference between pre-
treatment and post-treatment mean sleep quality VAS scores within study participants. Summary 
statistics will be generated, and paired differences between pre-treatment and post-treatment 
sleep quality VAS scores will be reported, along with 95% confidence intervals. 
Additionally, parametric linear mixed models will be employed to simultaneously account for 
correlated observations and adjust for confounding variables (Proc Mixed, SAS). Several 
covariance structures, including compound symmetry and unstructured, will be evaluated by 
comparing AIC and BIC to identify optimal model fit.  Random slope and intercept will also be 
considered in a similar manner. Patient characteristics (i.e. age and sex) will be included in 
adjusted models a priori for confounding control. Directed acyclic graphs will be employed to 
select other potential confounding variables and identify biases during the model fitting process.  
Large differences will be further examined and may help identify where further calibration of 
estimation models are needed.   
Stratified and interaction analyses will be employed to detect between-subgroup differences in 
outcomes. Specifically, we will test the difference in sleep quality VAS score change between 
sexes and those who reported moderate-to-severe insomnia disorder on the ISI (i.e. ISI score > 
14) and those who did not (i.e. ISI score ≤ 14). Testing of these differences will be conducted by 
including 2-way product terms between the exposure and covariate of interest in linear mixed 
modeling. A significant interaction will be defined by an interaction coefficient with a p-value < 
0.05. 
9.7 Reporting Conventions 
Confidence intervals and p-values will be reported at two decimal places, except when p-values 
are less than 0.01. P-values less than 0.01 will be reported as “< 0.01” and p-values less than 
0.001 will be reported as “<0.001”. 

15 
 
9.8 Quality Assurance of Statistical Programing 
SAS 9.4 will be used for all data analyses in a Microsoft Windows environment. All analysis code 
will include the author’s name, date/time of writing, reference to location and nature of inputs, 
reference to any parent code, and detailed comments to aid in its interpretation and 
implementation. A secondary statistician will have access to raw data and the opportunity to 
independently create the main analyses. They will also be given access to the primary code to 
review its validity.  
10.0 STUDY COMPLIANCE AND REPORTING OF DEVIATIONS FROM APPROVED 
PROCEDURES 
Deviations  
A deviation is a divergence from a specific element of a protocol and that occurred without prior 
IRB approval. Deviations from the approved protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. All deviations from the protocol will be 
documented in study source documents and promptly reported to the IRB.  
 
Reporting Deviations  
Investigators may deviate from the protocol to eliminate immediate hazards for the protection, 
safety, and well-being of the study subjects without prior IRB approval.  For any such deviation, 
the PI will notify the IRB, within 5 calendar days of its occurrence by electronic submission of a 
deviation notice. 
11.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY 
MONITORING 
The study team will be familiar with anticipated and unanticipated adverse experiences. The 
Principal Investigator (PI) is responsible for monitoring protocol conduct and reporting to the 
Institutional Review Board (IRB). 
12.0 ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Ethical and Regulatory Standard 
Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects of Research (US National 
Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, April 
18, 1979) and the Declaration of Helsinki. 
Regulatory Standard 
This study is to be conducted in compliance with the IRB approved protocol and according to 
applicable federal, state, local and tribal laws including the following: 
● US Code of Federal Regulations (CFR) governing clinical study conduct: Title 45 Part 46 
– Protection of Human Subjects 
● US Code of Federal Regulations relating to the Health Insurance Portability and 
Accountability Act of 1996: Title 45 Part 164 – Security and Privacy – Subpart E -  
○ Subpart E—Privacy of Individually Identifiable Health Information 
● State of California Health and Safety Code, Title 17, for research conducted in California 
 

16 
 
In addition, this study is to be conducted in compliance with applicable policies and procedures 
of the IRB(s) of record, applicable institutional research policies and procedures, applicable 
institutional clinical policies and procedures, and applicable NIH policies and procedures. 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials and all participant materials will 
be submitted to the IRB of record for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any participant is enrolled.  Any amendments to the 
protocol or consent materials will require review and approval by the IRB before the changes 
are implemented in the study.   
Per the federal regulations at 45 CFR 46 and State of California Health and Safety code, Title 17, 
must review and approve this protocol and the informed consent process and its documents prior 
to initiation of the study. All institutional, NIH, Federal, and State of California regulations must be 
fulfilled. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, consent forms, information concerning participant recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB. The IRB’s 
written unconditional approval of the study protocol and the informed consent document will be in 
the possession of the investigator before the study is initiated. 
Any amendment to the protocol document and accompanying informed consent documents, as 
developed and provided by the PI, will require review and approval by the IRB of record before 
the changes are implemented in the study. 
12.2 Risk Benefit Considerations 
Discomforts, Risks, and Risk Mitigation  
● Risks associated with the Survey: The questions used in this survey may cause temporary 
discomfort or distress to the participant. The survey is designed to be simple and short 
and is a commonly used tool in clinical studies for sleep. The participant may choose not 
to complete the questionnaire. 
● Risks associated with Breach of Confidentiality: There is a small risk that people who are 
not connected with this study will learn of the participant’s identity or personal information. 
The study staff will be GCP trained and will utilize best practices when using the data 
platform to ensure participant privacy protections.  
Risk Level Determination 
The risks to the study are minimal or unanticipated due to appropriate mitigation measures (e.g. 
breach of confidentiality, loss of internet access). This research meets the federally defined 
definition of minimal risk (45CFR 46.102(j)). 
Direct benefit to research participants 
Research participants have the opportunity to engage with scientists in tracking their sleep and 
use of the Sip2Sleep product. They will receive $25 upon completion of study activities. 
Importance of the knowledge that may reasonably be expected  
This research is significant and important because it facilitates an innovative way of science where 
participants can be engaged to learn about their own response to their chosen intervention and 
the Sponsor and the public may gain knowledge about a potentially effective and safe sleep 
remedy.  

17 
 
12.3 Participant Characteristics  
Research equity  
This research has no direct exclusions related to gender. There are also no direct exclusions 
related to race or ethnicity.   
Vulnerable Populations 
Pregnancy and lactation are exclusions due to the unknown risks of product use to fetuses and 
newborns. 
There are exclusions for individuals with specific sleep diagnoses that require medical 
intervention.   
Volunteers with impaired decision-making capacity are excluded. 
Volunteers unable to personally provide informed consent (including but not exclusive of inability 
to speak and read English, hearing or sight impaired, etc.) will be excluded from participating in 
this research.  
12.4 Financial Obligation, Burden, and Compensation to Participants 
Completing research activities (not from results/findings or injury) 
Research activities will be conducted virtually.   
Participants will receive compensation for their time. A $25 gift card will be provided by study staff 
to participants upon study completion.   
Research results or clinical findings arising from research activities 
Due to the nature of the study, it is unlikely that research results or findings from research activities 
will result in further medical-related expenses for the participant. 
12.4 Confidentiality/Sharing/Publication 
Return or Clinical Use of Research Results  
Participants will be shown their study data in real time as they go through the data visualization 
modules in the CHLOE platform.  
Research results will be shared with participants at completion of data analysis. The results of 
this research may help the participant make decisions in future product purchases and participate 
in future research studies. 
There are no anticipated burdens or financial obligations to research subjects.  
Confidentiality 
All documents and electronic data will be stored on secure, password-protected computers.  
Participant confidentiality will be strictly held in trust by the investigators, study personnel, and 
sponsor. No identifiers will be used in any subsequent publication of these results.   
Information/Data Retention, Future Use, and Sharing 
Prior to the completion of this research, information will be coded, destroyed, de-identified, or 
provided to a privacy officer.  
Publication 
The publication or presentation of any study results shall comply with all applicable privacy laws, 
including, but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
Neither the complete nor any part of the results of the study carried out under this protocol, nor 

18 
 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the written approval of the Study PI. Any 
investigator involved with this study is obligated to provide the sponsor with all data derived from 
the study. 
 
12.5 Alternatives to Participation, Withdrawal, and Early Termination 
Alternatives to Participation 
The individual can choose not to participate.   
Participant Withdrawal from Research/ Research Activities 
Research activities are limited to five weeks. 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented. 
12.6 Informed Consent, HIPAA Authorization, and California Subject’s Bill of Rights 
Informed Consent 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. Operational details specific to the consenting 
process that occurs prior to any research evaluations/interventions are described in Section 6.0.   
All participants will undergo virtual electronic informed consent after they are determined to qualify 
for the study. An electronic informed consent document will describe the nature, duration, purpose 
of the study, potential risks, alternatives and potential benefits, and all other IRB approved 
information. In addition, the experimental participant’s bill of rights and the HIPAA research 
authorization form will be provided. Prospective research participants will be informed that they 
may withdraw from the study at any time and for any reason without prejudice.  Prospective 
research participants will be afforded sufficient time to consider whether to participate in the 
research. 
Virtual informed consent will be conducted through the app-based consent form at the 
participant’s convenience. After reading the consent, participants will be able to contact study staff 
about any study related questions. Once the prospective participant expresses full understanding, 
virtual informed consent will be obtained through electronic signature from either the prospective 
participant before study participation. The method of obtaining and documenting the informed 
consent and the contents of the consent must comply with the ICH-GCP and all applicable 
regulatory requirements. A copy of the signed consent document will be available to the 
participant within the CHLOE app. The signed consent must be maintained by the investigator 
and available for inspection by sponsor designated representatives, or regulatory authority at any 
time. 
Privacy Authorization 
The informed consent process will include a privacy authorization compliant with 
45CFR164.508(c) via the inclusion/incorporation of: 
- 
all core elements specified in 508(c)(1) including the signature of the individual (or 
representative) and date of signature, 
- 
all required statements specified in 508(c)(2) 
- 
the plain language requirement as specified in 508(c)(3), and 

19 
 
- 
the provision to the participant (or representative) a copy of the signed authorization 
(508(c)(4) 
State of California Human Experimentation Requirements 
This research involves the collection of information via validated questionnaires and obtaining 
information from the medical record. Research activities do not encompass those that are 
requisite for a participant to be involved in a “medical experiment” as defined by California State 
Law 24174. The ‘California Experimental Subject’s Bill of Rights’ will be administered as part of 
the informed consent process; as part of that process participants will receive a copy of the ‘Bill 
of Rights’ marked with their signature.  
12.7 Investigator Conflict of Interest 
Investigators will disclose any conflict of interest from People Science. 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study Sponsor prior to 
participation in this study.  All investigators will follow the conflict of interest policy. 
13.0 REFERENCES 
1. Foley L. Sleep Foundation: Insomnia. 
2. Knutson KL, Ryden AM, Mander VA, Van Cauter E. Role of sleep duration and quality in the risk and 
severity of type 2 diabetes mellitus. Arch Intern Med 2006;166:1768–1764. 
3. Kasasbeh E, Chi DS, Krishnaswamy G. Inflammatory aspects of sleep apnea and their 
cardiovascular consequences. South Med J 2006;99:58–67. 
4. Taheri S. The link between short sleep duration and obesity: We should recommend more sleep to 
prevent obesity. Arch Dis Child 2006;91:881–884. 
5. Zimmerman M, McGlinchey JB, Young D, Chelminski I. Diagnosing major depressive disorder I: A 
psychometric evaluation of the DSM-IV symptom criteria. J Nerv Ment Dis 2006;194:158–163. 
6. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic Drug Exposure 
and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. 2019;179(8):1084–1093. 
7. Losso JN, Finley JW, Karki N, Liu AG, Prudente A, Tipton R, Yu Y, Greenway FL. Pilot Study of the 
Tart Cherry Juice for the Treatment of Insomnia and Investigation of Mechanisms. Am J Ther. 2018 
Mar/Apr;25(2):e194-e201. 
8. Pigeon WR, Carr M, Gorman C, Perlis ML. Effects of a tart cherry juice beverage on the sleep of 
older adults with insomnia: a pilot study. J Med Food. 2010 Jun;13(3):579-83. 
9. Grundmann, O., J. Nakajima, S. Seo, V. Butterweck. 2007.J Ethnopharmacol (April 4) 110(3): 406–
11. Epub 2006 Oct 13. [Apocynum venetum L.] 
10. Yang, J. et al. 2009. Safety study of Apocynum venetum extract in healthy adults. Journal of 
Nutritional Food, no. 12:1–9. 
11. Vissiennon, C., K. Nieber, O. Kelber, V. Butterweck. 2012. J Nutr Biochem (July) 23(7): 733–40. 
[Apocynum venetum L.] 
12. Balomenos V, Ntanasi E, Anastasiou CA, et al. Association Between Sleep Disturbances and Frailty: 
Evidence From a Population-Based Study. J Am Med Dir Assoc. 2020. 
13. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure 
for insomnia research. Sleep Med. 2001;2(4):297-307. 

20 
 
14. Gu NY, Botteman MF, Ji X, Bell CF, Carter JA, van Hout B. Mapping of the Insomnia Severity Index 
and other sleep measures to EuroQol EQ-5D health state utilities. Health Qual Life Outcomes. 
2011;9:119. 
15. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety 
disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. 
16. Snyder E, Cai B, DeMuro C, Morrison MF, Ball W. A New Single-Item Sleep Quality Scale: Results 
of Psychometric Evaluation in Patients With Chronic Primary Insomnia and Depression. J Clin Sleep 
Med. 2018 Nov 15;14(11):1849-1857.