Le Rêve 3.0: A Double-Blind, Placebo-Controlled, Randomized, Crossover Investigational Study to Determine if Defined CBD, a Capsule With a Custom Formulation of Cannabidiol (CBD) and Terpenes, Influences Sleep Physiology
Phase: PHASE2
Conditions: Insomnia
Sponsor: Defined Research

 
 
a 

 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
Le Rêve 3.0: A Double-Blind, Placebo-Controlled, Randomized, Crossover 
Investigational Study to Determine if Defined CBD, a Capsule with a 
Custom Formulation of Cannabidiol (CBD) and Terpenes, Influences Sleep 
Physiology  
 
Sponsor: 
Defined Research Institute 
 
 
 
1250 Missouri Street Unit #312 
 
 
 
San Francisco, CA 94107 
 
IND Number:   
N/A 
ClinicalTrials.gov 
NCT05233761 
 
Indication:  
 
Sleep physiology 
 
Protocol ID:   
Sleep physiology 
 
 
Protocol Number: DR-INS-101 
National Clinical Trial (NCT) Identified Number: TBD  
Principal Investigator: Dr. Paul Muchowski 
Sponsor: Defined Research 
Funded by: Defined Research 
Version Number:  v.2 
31 January 2022 
 
 

  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ........................................................................................... 1 
1 
PROTOCOL SUMMARY ............................................................................................... 1 
1.1 
Synopsis ................................................................................................................. 1 
1.2 
Schema .................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ................................................................................. 4 
2 
INTRODUCTION ........................................................................................................... 4 
2.1 
Study Rationale ..................................................................................................... 4 
2.2 
Background ............................................................................................................ 4 
2.3 
Risk/Benefit Assessment ...................................................................................... 5 
2.3.1 
Known Potential Risks .......................................................................... 5 
2.3.2 
Known Potential Benefits ...................................................................... 6 
2.3.3 
Assessment of Potential Risks and Benefits ...................................... 7 
3 
OBJECTIVES AND ENDPOINTS ................................................................................ 8 
4 
STUDY DESIGN ............................................................................................................ 9 
4.1 
Overall Design ....................................................................................................... 9 
4.2 
Scientific Rationale for Study Design .................................................................. 9 
4.3 
Justification for Dose........................................................................................... 14 
4.4 
End of Study Definition ....................................................................................... 15 
5 
STUDY POPULATION ................................................................................................ 15 
5.1 
Inclusion Criteria .................................................................................................. 15 
5.2 
Exclusion Criteria ................................................................................................ 16 
5.3 
Lifestyle Considerations ..................................................................................... 18 
5.4 
Screen Failures ..................................................... Error! Bookmark not defined. 
5.5 
Strategies for Recruitment and Retention......................................................... 18 
6 
STUDY INTERVENTION ............................................................................................ 19 
6.1 
Study Intervention(s) Administration ................................................................. 19 
6.1.1 
Study Intervention Description ........................................................... 19 
6.1.2 
Dosing and Administration ................................................................. 20 
6.2 
Preparation/Handling/Storage/Accountability ................................................... 20 
6.2.1 
Acquisition and accountability ............................................................ 20 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ....................... 20 
6.2.3 
Product Storage and Stability............................................................. 20 
6.2.4 
Preparation........................................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding .............................. 20 
6.4 
Study Intervention Compliance .......................................................................... 20 
6.5 
Concomitant Therapy ......................................................................................... 21 
6.5.1 
Rescue Medicine ................................................................................. 21 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................. 21 
7.1 
Discontinuation of Study Intervention ................................................................ 21 
7.2 
Participant Discontinuation/Withdrawal from the Study................................... 21 
7.3 
Lost to Follow-Up ................................................................................................ 21 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 22 
8.1 
Efficacy Assessments ......................................................................................... 22 
8.2 
Safety and Other Assessments ......................................................................... 22 

  
 
iii 
8.3 
Adverse Events and Serious Adverse Events .................................................. 24 
8.3.1 
Definition of Adverse Events (AE) ..................................................... 24 
8.3.2 
Definition of Serious Adverse Events (SAE) ..................................... 24 
8.3.3 
Classification of an Adverse Event .................................................... 25 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up
 
26 
8.3.5 
Adverse Event Reporting .................................................................... 26 
8.3.6 
Serious Adverse Event Reporting...................................................... 26 
8.3.7 
Reporting Events to Participants ....................................................... 26 
8.3.8 
Events of Special Interest ................................................................... 26 
8.3.9 
Reporting of Pregnancy ...................................................................... 27 
8.4 
Unanticipated Problems ....................................... Error! Bookmark not defined. 
8.4.1 
Definition of Unanticipated Problems (UP) ....... Error! Bookmark not 
defined. 
8.4.2 
Unanticipated Problem Reporting ........ Error! Bookmark not defined. 
8.4.3 
Reporting Unanticipated Problems to Participants .Error! Bookmark 
not defined. 
9 
STATISTICAL CONSIDERATIONS ........................................................................... 27 
9.1 
Statistical Hypotheses ........................................................................................ 27 
9.2 
Sample Size Determination ................................................................................ 28 
9.3 
Populations for Analyses .................................................................................... 28 
9.4 
Statistical Analyses ............................................................................................. 29 
9.4.1 
General Approach ............................................................................... 29 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) .................................... 29 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................. 29 
9.4.4 
Safety Analyses ................................................................................... 29 
9.4.5 
Baseline Descriptive Statistics ........................................................... 29 
9.4.6 
Planned Interim Analyses ................................................................... 29 
9.4.7 
Sub-Group Analyses ........................................................................... 29 
9.4.8 
Tabulation of Individual participant Data ........................................... 30 
9.4.9 
Exploratory Analyses .......................................................................... 30 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS . 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .............................. 30 
10.1.1 
Informed Consent Process ................................................................. 30 
10.1.2 
Study Discontinuation and Closure ................................................... 30 
10.1.3 
Confidentiality and Privacy ................................................................. 31 
10.1.4 
Future Use of Stored Specimens and Data ...................................... 31 
10.1.5 
Key Roles and Study Governance .................................................... 31 
10.1.6 
Safety Oversight .................................................................................. 31 
10.1.7 
Clinical Monitoring ............................................................................... 32 
10.1.8 
Quality Assurance and Quality Control ............................................. 32 
10.1.9 
Data Handling and Record Keeping .................................................. 32 
10.1.10 
Protocol Deviations ............................................................................. 33 
10.1.11 
Publication and Data Sharing Policy ................................................. 33 
10.1.12 
Conflict of Interest Policy .................................................................... 33 
10.2 
Additional Considerations ................................................................................... 33 
10.3 
Abbreviations ....................................................................................................... 34 

  
 
iv 
10.4 
Protocol Amendment History ............................................................................. 35 
11 
REFERENCES ............................................................................................................. 36 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
PROTOCOL SYNOPSIS  
 
Study Title: 
 
Le Rêve 3.0: A Double-Blind, Placebo-Controlled, Randomized, Crossover 
Investigational Study to Determine if Defined CBD, a Custom-Formulated 
Cannabidiol (CBD) Capsule, Influences Sleep Physiology.  
 
 
Study Description: 
 
Insomnia is a disorder in which people have inadequate or poor-quality 
sleep due to a number of factors, such as difficulty falling asleep, waking 
up frequently during the night with difficulty returning to sleep, waking up 
too early in the morning, or having unrefreshing sleep. Defined CBD is a 
capsule composed of highly purified (>99.9% purity) hemp-derived CBD 
and terpenes (>98% purity). Defined CBD contains no D-9-
tetrahydrocannabinol (D-9-THC). Our research study, entitled Le Rêve 3.0, 
is designed to evaluate the efficacy of Defined CBD on sleep physiology. 
This trial is not intended to treat, diagnose, prevent, or cure any disease.  
 
Objectives: 
 
 
Primary Objectives: To determine if Defined CBD influences objective 
measures of sleep physiology.  
 
Secondary Objectives: To determine if Defined CBD influences subjective 
measures of sleep physiology.   
 
Endpoints: 
Primary Endpoint: The percentage of sleep spent in deep [slow wave sleep 
(SWS)] and rapid eye movement (REM) sleep as determined using an 
objective wrist-worn sleep-tracking device called Whoop.  
 
Secondary Endpoints: Total sleep time, sleep latency, the number of sleep 
disturbances, time spent in each sleep stage, percentage of time spent in 
each sleep stage, and subjective measures of sleep physiology as collected 
via participant surveys.  

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Study Population: 
 
We will enroll 150 study participants who display chronic insomnia defined 
as a self-reported difficulty initiating (latency to persistent sleep >30 min) 
and/or maintaining sleep (>30 min awake, or waking >30 min before 
desired waking time) on three or more nights per week for at least 3 
months. Participants will also complete a brief clinically validated insomnia 
severity index, and only participants with an Insomnia Severity Index score 
>15 will be enrolled in Le Rêve 3.0. We will enroll males or females aged 
25–70 years that are located in the United States that meet inclusion and 
exclusion criteria.  
 
 
 
Phase: 
 
N/A 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
Le Rêve 3.0 will be a decentralized study completed by participants in the 
comfort of their own homes. Recruitment, enrollment, informed consent, 
and distribution of study materials to participants will all be managed by 
the contract research organization (CRO) 83 Bar, Inc.  
 
 
Description of Study 
Interventions: 
 
Study interventions will include Defined CBD or a placebo control that will 
be taken orally (p.o.) as two small capsules one hour prior to going to bed. 
Defined CBD is a capsule made to GMP standards composed of vegetable 
cellulose (gluten-free, non-GMO, vegan, certified kosher, certified halal) 
that contains 300 mg >99.9% purity hemp-derived CBD made in a GMP-
certified laboratory that is dissolved in coconut oil (USDA certified organic, 
non-GMO, dairy-free, gluten-free, vegan coconut oil). Defined CBD is a 
custom chemical formulation that also contains low concentrations (1 mg 
each) of highly purified (>98% purity) forms of the terpenes linalool, 
myrcene, phytol, limonene, a-terpinene, a -terpineol, a-pinene, and b-
caryophyllene [Food Grade (GRAS), Natural, Organic, non-GMO, dairy-free, 
gluten-free, vegan) made in GMP-certified laboratories. Defined CBD 
contains no D-9-tetrahydrocannabinol (D-9-THC). The safety of CBD1 and 
these terpenes2 at the doses found in Defined CBD is well established. 
 
 
Study Duration: 
 
The estimated time from when Le Rêve 3.0 opens enrollment until 
completion of data analyses will be 20 weeks.    
 
Participant Duration: 
 
After enrollment, the participant duration for the entire study will be 12 
weeks.   
 
 

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1.2 
SCHEMA  
   
 
Prior to  
Enrollment 
Weeks -4-0 
 
 
Weeks 1-2 
 
 
 
 
Treatment 1 
Weeks 3-6 
 
 
 
 
 
Week 7  
 
 
Treatment 2  
Weeks 8-11 
 
 
Week 12 
 
 
Weeks 13-20 
 
 
 
 
N = 150: Screen potential participants by inclusion and exclusion criteria. 
Obtain informed consent. 
Treatment Washout 
Study Participants Crossover to Placebo or Defined CBD 
Randomize to Placebo or Defined CBD 
Arm 2 (Defined CBD) 
N = 75 
N = 150:  Collect Baseline Sleep Physiology Data 
Treatment Washout 
Data Analysis/Adverse Event (AE) Review and Evaluation 
Arm 1 (Placebo)   
N= 75 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Weeks -4 to -1 
Enrollment 
Day 1 
Collect Baseline Data 
Weeks 1-2 
Treatment 1 
Weeks 3-6 
Treatment Washout 
Week 7 
Treatment 2 
Weeks 8-11 
Treatment Washout 
Week 12 
Post-Treatment 
Weeks 13-20 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
Administer study intervention 
 
 
 
X 
 
X 
 
 
Adverse event review and 
evaluation 
 
 
 
 
 
 
 
X 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Insomnia is a disorder in which people have inadequate or poor-quality sleep due to a number of 
factors, such as difficulty falling asleep, waking up frequently during the night with difficulty returning to 
sleep, waking up too early in the morning, or having unrefreshing sleep. The majority of over-the-
counter (OTC) supplements used to treat insomnia (e.g. melatonin, valerian root, lavender) have limited 
efficacy, while the best-selling prescription drugs for insomnia (e.g. Ambien, Halcion, Sonata, Lunesta) 
have serious and undesirable side effect profiles that limit their utility. There is a strong scientific 
rationale to support the hypothesis that CBD might positively impact sleep physiology, and our study, 
entitled Le Rêve 3.0, is designed to fill that void in knowledge.  
 
2.2 
BACKGROUND  
 
A survey of 1,267 adults by Consumer Reports indicates that nearly 80% of Americans have trouble 
sleeping at least once a week. Insomnia is the most common sleep disorder and is an established risk 
factor for anxiety, depression and other diseases. Insomnia is defined clinically as the perception or 
complaint of inadequate or poor-quality sleep due to a number of factors, such as difficulty falling 
asleep, waking up frequently during the night with difficulty returning to sleep, waking up too early in 
the morning, or having unrefreshing sleep. Insomnia causes significant distress and/or impairment in 
daytime functioning in people who suffer from it. The prevalence rates of clinically diagnosed insomnia 
have increased in recent years to ~19% of the adult U.S. population, representing ~46 million. Some 
studies suggest that the rate of undiagnosed insomnia in the US may be as high as 25% (~80 million)3.  
CBD is the active ingredient of Epidiolex®, a drug approved by the FDA in 2018 for the treatment of 
seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome (LGS) and 
Dravet syndrome (DS). In 2018, the U.S. congress passed the Hemp Farming Act of 2018 (the Farm Bill), 
which removed remove hemp (defined as cannabis with less than 0.3% THC) from Schedule I controlled 
substances, and made it an ordinary agricultural commodity. This Bill immediately led to the widespread 
purification, sale and interstate commerce of CBD, a molecule obtained from hemp (~$4.7 billion in U.S. 
sales in 2021). The result has been that storefronts and online retailers have flooded the market with 
CBD products, many with unsubstantiated therapeutic claims. Sadly, U.S. consumers are currently using 

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CBD to treat a variety of ailments in the absence of rigorous clinical studies. Indeed, ~14% of the U.S. 
adult population (~29 million adults) admit to using CBD (Gallup Survey, U.S. News & World Report). 
Nonetheless, rigorous clinical research on products that contain CBD is desperately lacking. Our research 
study aims to test the effects of a Defined CBD, a capsule with high purity (>99.9%) CBD, on the 
structure and function of sleep physiology.  
There is a strong scientific rationale to test a CBD-based product on sleep physiology in a properly 
controlled, well-powered and rigorous study in humans. Preclinical studies in rats indicate CBD increases 
total sleep time in a dose-dependent manner4. In one early but small (N = 10) placebo-controlled clinical 
study in Brazil, subjects with insomnia that received 160 mg of CBD reported having slept significantly 
more than those who had been given a placebo control5. However, the study was only performed in an 
extremely small number of subjects, and did not use any objective measures of sleep physiology. More 
recently, a larger study in 72 adults with clinically diagnosed anxiety, CBD (25-75 mg/day) improved 
sleep in 66% of the patients as determined by a sleep quality questionnaire [the Pittsburgh Sleep Quality 
Index (PSQI)]6. However, this was an open label study (i.e. not blinded), lacked a placebo-control, and 
also did not include any objective measures of sleep physiology. As such, no strong scientific conclusions 
regarding causality can be drawn from the clinical data.   
In a survey by Consumer Reports, ~45% of adults who reported trying CBD said they used it to help 
them sleep, and a majority of those people said they believed that it worked. Nonetheless, to this date a 
rigorous, properly-controlled, and well-powered study to determine if CBD influences sleep physiology 
has simply never been reported in the scientific literature. The Le Rêve 3.0 study is designed to fill this 
important void in scientific knowledge.  
We hypothesize that a novel CBD-based formulation in the form of an orally administered capsule 
will positively impact sleep physiology metrics in subjects with insomnia, as determined using an 
objective sleep-tracking device called “Whoop”. The capsule we will test is composed of >99.9% purity 
hemp-derived CBD with a custom chemical formulation that also contains low concentrations (1 mg 
each) of highly purified (>98%) forms of the terpenes linalool, myrcene, phytol, limonene, a-terpinene, 
a-terpineol, a-pinene, and b-caryophyllene. Preclinical studies in animals have shown that these 
terpenes are sedating7, but their potential effects on sleep physiology in humans have not been 
established. The capsules do not contain any D-9-THC. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Based on a large amount of published clinical data, the World Health Organization (WHO) has 
established that CBD (the active ingredient in Defined CBD) is non-intoxicating and has an excellent 
safety profile in humans8. Previous clinical studies indicate that adverse reactions with CBD are rare9. 
The most common adverse reactions that occurred with CBD when given at a high dose [e.g., at the 
recommended dose for the FDA approved CBD drug Epidiolex® (20 mg/kg/day), were somnolence 
(sleepiness); decreased appetite; diarrhea; transaminase elevations; fatigue; malaise; asthenia 
(abnormal physical weakness or lack of energy); rash; insomnia; sleep disorder; poor quality sleep; and 
infections. However, these adverse reactions were only observed in <15% of patients at a CBD dose (20 
mg/kg/day or ~1,800 mg for a 90 kg male) that is approximately six times greater than the dose that will 
be used in Le Rêve 3.0 study (300 mg or ~3 mg/kg/day for a 90 kg male) (see supplemental file with 
Epidiolex® Safety Information). Moreover, the frequency of these adverse events decreased significantly 
when Epidiolex® was administered at a lower dose (10 mg/kg/day or ~900 mg for a 90 kg male), a dose 
that is still three times greater than the dose we will use in Le Rêve 3.0. A recent meta-analysis of AEs 

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from 12 clinical trials with CBD indicated that associations with abnormal liver function tests, 
somnolence, sedation and pneumonia were limited exclusively to childhood epilepsy studies, where CBD 
may have interacted with other medications such as clobazam and/or sodium valproate10. After 
excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was 
diarrhea. And, again, this was only observed at doses well above the CBD dose that will be evaluated in 
Le Rêve 3.0. Therefore, due to the low dose of CBD that will be tested in Le Rêve 3.0 (300 mg p.o.), if AEs 
are observed with Defined CBD, we presume that they will be minor and occur at a lower frequency 
than what was observed in previous clinical studies.  
Although rare, some adults display hypersensitivity to CBD. Participants with known hypersensitivity 
to CBD will be excluded from participating in Le Rêve 3.0. As noted above, some recent studies indicate 
that extremely high doses of CBD (much higher than what will be used in Le Rêve 3.0) might impair liver 
function. Therefore, as a precaution, study participants in Le Rêve 3.0 will be required to refrain from 
the use of any of the following contra-indicated drugs for at least one week prior to and for the duration 
of the study: erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, 
ritonavir, telaprevir, boceprevir, amlodipine, gemfibrozil, cyclosporine, danazol, amiodarone, verapamil, 
diltiazem, rifampin, theophylline, tizanidine, bupropion, efavirenz, diflunisal, propofol, fenofibrate, 
lamotrigine, morphine, lorazepam, diazepam, clobazam, stiripentol, valproate, everolimus, sirolimus, or 
tacrolimus, and niacin (vitamin B3 greater than 1g/ day). Participants who cannot refrain from the intake 
of these contra-indicated drugs prior to and throughout the study will be excluded from participating in 
Le Rêve 3.0.    
Defined CBD also contains low concentrations (1 mg each) of highly purified (>98%) forms of the 
terpenes linalool, myrcene, phytol, limonene, a-terpinene, a-terpineol, a-pinene, and b-caryophyllene. 
Terpenes are widely used as fragrances and flavors in consumer products such as perfumes, cosmetics 
and cleaning products, as well as food and drink products. For example, the aroma and flavor of hops 
comes, in part, from sesquiterpenes (mainly α-humulene and β-caryophyllene), which are used to make 
beer. Importantly, the terpenes in Defined CBD are designated by the FDA as GRAS (Generally Regarded 
as Safe) for oral consumption. Although rare, some adults display mild skin allergies to terpenes when 
applied topically. As a precaution, participants with known hypersensitivity to terpenes will be excluded 
from participating in Le Rêve 3.0. 
Defined Research confirms the molecular composition of every batch of Defined CBD (including the 
Defined CBD to be used in Le Rêve 3.0) by an ISO-10725-accredited analytical testing laboratory. These 
analytical tests confirm the concentration and purity of Defined CBD, and ensure that it is free from any 
contaminants, including pesticides, residual solvents and heavy metals. Electronic records that 
document these lab tests are stored at Defined Research and are available upon request.   
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Epidiolex® is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, 
Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age and older. Given that the most 
common adverse reaction in patients treated with Epidiolex® is somnolence, one potential benefit that 
study participants may receive in Le Rêve 3.0 when treated with Defined CBD is a change in their sleep 
physiology that increases their somnolence. Several clinical studies indicate that CBD can decrease acute 
anxiety11. Participants with social anxiety disorder and controls were blindly allocated to receive CBD or 
a placebo control before a simulation public speaking test. CBD resulted in significantly reduced anxiety, 
cognitive impairment and discomfort, and significantly decreased hyper-alertness in anticipatory 
speech12. D-9-THC is well established as having anxiogenic (anxiety-promoting) properties in clinical 
studies, and these effects can be blocked by CBD13. Therefore, as some clinical studies indicate that CBD 

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may decrease acute anxiety, it is also possible that study participants in Le Rêve 3.0 treated with Defined 
CBD might feel less anxious. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
As described above, the potential risks of participating in Le Rêve 3.0 relate to potential adverse 
reactions that may occur in response to CBD or terpenes. However, given the relatively low dose of CBD 
found in Defined CBD (300 mg or ~3.3 mg/kg/day for a 90 kg male) that will be used in Le Rêve 3.0 
relative to that used clinically with Epidiolex® (20 mg/kg/day or 1,800 mg total for a 90 kg male), we 
anticipate that if AEs are observed, they will occur at a much lower frequency lower than in patients 
treated with Epidiolex®. Although the potential safety risks in Le Rêve 3.0 are extremely low, the 
information gained in the study on how CBD may affect sleep physiology may benefit millions of current 
CBD consumers.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective is to 
determine if Defined CBD 
influences objective measures of 
sleep physiology.  
 
 
 
The primary endpoint is the 
percentage of time spent in slow 
wave (Deep) and REM sleep as 
quantified by a non-invasive wrist-
worn sleep-tracking device called 
Whoop.   
 
 
 
Deep and REM sleep 
are thought to 
contribute significantly 
to restorative sleep. 
We will use an 
unbiased approach to 
collect objective data 
on these sleep stages 
to determine if Defined 
CBD increases deep 
and REM sleep.  
Secondary 
 
 
The secondary objective(s) are to 
determine if Defined CBD 
influences objective and subjective 
measures of sleep physiology.  
 
 
Additional objective secondary 
outcome measures that will be 
collected on the Whoop device 
include: Total sleep time, sleep 
latency, the number of sleep 
disturbances, time spent in each 
sleep stage, and the percentage of 
time spent in each sleep stage. 
 
A modified version of a clinically 
validated questionnaire entitled the 
Participant Global Impression (PGI)14 
will be used to track subjective 
measures of sleep physiology. This 
data will be collected from study 
participants in the form of a brief 
five-minute survey that will be 
completed on their smartphone at 
the end of each four-week treatment 
period. This survey measures the 
perception of the study participants 
of the effects of treatment.    
Although some early 
clinical studies suggest 
that CBD might help 
people with insomnia, 
no studies have 
addressed if it 
influences objective 
and subjective 
measures of sleep 
physiology. Therefore, 
we will include a 
number of objective 
and subjective 
secondary outcome 
measures in this study 
to fill this void in 
knowledge.   
 
 
 
 
 
 
 
 

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
We hypothesize that Defined CBD, a novel CBD-based formulation in the form of a small orally 
administered capsule, will increase the percentage of time participants spend in deep (SWS) and REM 
sleep, as measured by an objective sleep-tracking device called “Whoop”. Our research study, entitled 
Le Rêve 3.0, is a double-blind, placebo-controlled, randomized, crossover investigational study to 
determine if Defined CBD, a Custom-Formulated CBD Capsule, influences sleep physiology. This capsule 
contains no D-9-THC. As this study is only designed to evaluate the effects of Defined CBD on the 
structure and function of sleep physiology, the phase of the trial is not applicable. This trial is not 
intended to treat, diagnose, prevent, or cure any disease. 
The Le Rêve 3.0 study will involve a cross-over design in which study participants will cycle through 
two independent treatments, each for four weeks (Treatment 1: Placebo; Treatment 2: Defined CBD). 
The placebo will look, smell and taste the same as the Defined CBD capsule. The study participants will 
initially be randomized with respect to the treatment arm, and every participant will cycle through both 
treatment arms. We will use a double-blind design in which the investigator and study participants will 
both be blinded to the treatments. Baseline data for each participant will be collected for two weeks 
prior to initiating treatments, as well as for a one-week washout period following each treatment arm. 
The entire study duration will be 12 weeks (for Schema see section 1.2).  
Primary data for Le Rêve will be obtained in a completely unbiased manner from a non-invasive 
sleep-tracking wrist-worn device called “Whoop” (https://www.whoop.com), that electronically collects 
and transmits sleep data from study participants in the comfort of their own beds.  
The wristband collects hundreds of data points per second from a 3-axis accelerometer, 3-axis 
gyroscope, and heart rate sensor. The wristband can accurately measure the latency to fall asleep, total 
sleep time, sleep fragmentation, as well as the time spent in each sleep stage [Light, Slow Wave (Deep), 
Rapid Eye Movement (REM), and Awake]. The device also collects data using photoplethysmography 
(PPG), a technique that involves measuring blood flow by assessing superficial changes in blood volume. 
Heart rate, heart rate variability and respiratory rate, can all be derived from PPG data, and all of these 
metrics are used in Whoop’s sleep detection and staging algorithms. Importantly, two recent 
publications, published independently from Whoop, show that data on sleep stages collected from the 
Whoop device are highly accurate and correlate well with polysomnography (PSG), the gold-standard of 
sleep tracking used in clinical studies conducted in sleep clinics15.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
To date, a rigorous, properly-controlled, and well-powered study to determine if CBD influences 
sleep physiology has simply never been reported in the scientific literature. Defined Research’s Le Rêve 
3.0 study is designed to fill this important void in scientific knowledge.  
 
Summary Of Data From Previous Clinical Studies With Defined CBD  
Defined Research recently completed two smaller independent clinical studies to determine the 
effects of a Defined CBD on the structure and function of sleep physiology. Each of these independent 
studies were performed as a double-blind, placebo-controlled, randomized, crossover investigational 
study to determine if Defined CBD influences sleep physiology in humans. These in-house studies were 
performed under informed consent, but did not go through the IRB approval process. 

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Summary of Data From Le Rêve 1.0 
In our first study, entitled Le Rêve 1.0, participants (N = 23) were randomized to take a placebo 
control or Defined CBD (300 mg CBD, 8 mg terpenes) once daily, one hour before bedtime, for seven 
consecutive nights. An example of one participant’s data is shown in Figure 1. Participant DR11 showed 
a significant increase in REM sleep, restorative sleep (the combination of REM and deep sleep), and the 
percentage of time spent in REM and restorative sleep (Fig. 1). Indeed, on average, over seven days of 
treatment, participant DR11 benefitted from nearly an extra hour of restorative sleep each night relative 
to the placebo control (Fig. 1B). Furthermore, participant DR11 was also able to perceive an 
improvement in their sleep quality and duration relative to the placebo control when they responded to 
a clinically validated sleep survey at the end of the treatment periods (data not shown).  
 
 
Figure 1: Defined CBD increases (A) REM and (B) Restorative Sleep in study 
participant DR11 from Le Rêve 1.0, as well as the percentage of time DR11 
spends in (C) REM and (D) restorative sleep [**p < 0.01 (t test). n = 7 days per 
treatment group. Values are means ± SEM]. 
 
It is important to emphasize that these preliminary clinical studies with Defined CBD were designed 
and performed as feasibility studies, and were not statistically powered to show any significant clinical 
benefits. Nevertheless, analysis of the pooled data from all of the participants (N = 23) from Le Rêve 1.0 
indicated that Defined CBD showed a trend to increase the percentage of REM (Fig. 2) and restorative 
sleep (data not shown). 
 

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Figure 2: Defined CBD shows a trend to increase the percentage of REM sleep in Le 
Rêve 1.0 [p = 0.06; (t test). n = 23 participants per treatment group. Values are means 
± SEM]. 
 
Analysis of the pooled data from our first clinical study indicated that participants could be stratified 
into “responders” and “non-responders”. Pooled data from “responders” showed a highly significant 
increase in the percentage of REM and restorative sleep in study participants who received Defined CBD 
relative to the placebo control (Fig. 3). Indeed, when only “responders” were analyzed, they exhibited a 
~10% increase in restorative sleep when treated with Defined CBD (Fig. 3B). 
 
 
Figure 3: Defined CBD increases the percentage of REM and Restorative Sleep in 
pooled responders in Le Rêve 1.0 [**p = 0.001; ****p < 0.0001 (t test). n = 11 
responders per treatment group. Values are means ± SEM]. 
 
After more careful scrutiny of the clinical data from Le Rêve 1.0, we determined that of the 
participants who responded to treatment with Defined CBD, 9/11 exhibited insomnia or subthreshold 
insomnia as defined by a clinically validated insomnia severity index [the Pittsburgh Sleep Quality Index 
(PSQI)]16 that was completed prior to the clinical study being conducted. After taking Defined CBD, 
participants who scored as having moderate insomnia in the PSQI exhibited an increase in the 
percentage of restorative sleep that narrowly missed statistical significance, and a significant increase in 
the percentage of restorative sleep relative to the placebo control (Fig. 4).  
 

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Figure 4: Defined CBD increases the percentage of (A) REM in participants with 
moderate insomnia and (B) Restorative Sleep in pooled responders with insomnia in 
Le Rêve 1.0 [**p < 0.01; (t test). n = 7-9 responders per treatment group. Values are 
means ± SEM]. 
 
At the end of each treatment period in our clinical studies, participants completed a modified 
version of a clinically validated questionnaire entitled the Participant Global Impression (PGI)14. PGI 
assessments are based on the participant’s global perception of the effects of treatment on sleep during 
each treatment period, as compared to their sleep during the baseline period of the study. Using the PGI 
assessment, participants perceived that they slept better after taking Defined CBD relative to the 
placebo control, although this effect did not achieve statistical significance (Fig. 5). Nevertheless, based 
on post-hoc power analysis we have performed, we believe that this effect would achieve statistical 
significance with a larger sample number. Importantly, no AEs whatsoever were reported in Le Rêve 1.0.  
 
Figure 5: Study Participants in Le Rêve 1.0 Perceived That Defined CBD Helped Them 
Sleep Better [p = 0.13; (t test). n = 23 responders per treatment group. Values are 
means ± SEM]. At the end of each treatment period, study participants used a PGI 
questionnaire to determine if the treatment influenced their sleep relative to a 
baseline period before the treatments were initiated. Scoring Matrix: 1= Treatment 
Helped; 2-No Effect of Treatment; 3-Treatment Worsened. With this data, a lower 
score indicates a potential benefit to help sleep. The results showed that Defined CBD 
appeared to improve the perception of better sleep relative to the placebo control.  
 
 

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Summary of Data From Le Rêve 2.0 
After the successful completion of Le Rêve 1.0, we attempted to replicate this study in an 
independent cohort of participants. As data from our Le Rêve 1.0 indicated that participants with 
insomnia most benefitted from treatment with Defined CBD, for Le Rêve 2.0 we only enrolled study 
those who exhibited moderate or severe insomnia as defined by a clinically validated insomnia severity 
index (the PSQI)16.  
In Le Rêve 2.0 participants (N = 13) were randomized to take a placebo control or Defined CBD (300 
mg CBD, 8 mg terpenes) once daily, one hour before bedtime, for at least four nights per week, for a 
total treatment period of three weeks.  
In pooled data from Le Rêve 2.0, Defined CBD increased the percentage of REM and restorative 
sleep in participants treated with Defined CBD relative to the placebo control, although only the effect 
on restorative sleep reached statistical significance (Fig. 6). Similar to Le Rêve 1.0, our second study was 
not powered to obtain statistical significance, and, as such, we believe that this data represents an 
encouraging replication of Le Rêve 1.0 in an independent cohort of participants. Moreover, based on 
post-hoc power analysis we have performed, we believe that the effects of Defined CBD on REM sleep 
would achieve statistical significance with a larger sample number. As in Le Rêve 1.0, no AEs whatsoever 
were reported in Le Rêve 2.0.  
 
 
Figure 6: In Le Rêve 2.0 Defined CBD increases the percentage of (A) REM and (B) 
restorative sleep in an independent cohort of participants with moderate to severe 
insomnia [*p < 0.05; (t test). n = 13 participants per treatment group. Values are 
means ± SEM].  
 
Our two clinical studies were performed in a decentralized manner in which study participants self-
administered treatments and collected sleep data in the comfort of their own homes. We therefore 
decided to quantify the effects of Defined CBD on sleep physiology when we combined the data from 
our two small clinical studies. In the combined data set, Defined CBD significantly increased the 
percentage of time study participants spent in REM and restorative sleep (Fig. 7). The effects of Defined 
CBD on deep sleep in the combined data set narrowly missed statistical significance (data not shown). As 
noted previously, based on post-hoc power analysis we have performed, we believe that the effects of 
Defined CBD on deep sleep would achieve statistical significance in a larger sample number.  
 

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Figure 7: Defined CBD increases the percentage of (A) REM and (B) restorative sleep 
in a combined data set from clinical studies Le Rêve 1.0 and 2.0 [*p < 0.05; (t test). n = 
36 participants per treatment group. Values are means ± SEM].  
Conclusions and Clinical Significance Of Research Findings 
Our clinical data with Defined CBD indicates that it significantly increases the percentage of time 
people spend in REM and restorative (deep plus REM sleep), and that these effects are most 
pronounced in people suffering from insomnia. Importantly, we were able to replicate the effects of 
Defined CBD on these sleep physiology parameters in two independent participant cohorts. 
Furthermore, participants who took Defined CBD could also perceive a benefit of the treatment on their 
sleep quality, and not a single AE was reported in either clinical study.  
REM and restorative sleep appear to be critically important for good brain health, and their absence 
in human populations is often associated with chronic ailments and diseases. For example, REM sleep 
has an essential role in the process of learning and memory in the hippocampus, and disruption of REM 
sleep can lead to cognitive impairment and other manifestations17. During sleep, the brain is able to 
repair and grow cells, tissue, and nerves that regenerate and boost the hormone and immune system. 
Along with good nutrition, exercise and stress reduction, restorative sleep is vital for your optimal 
physical, mental, and emotional health. Insufficient restorative sleep increases the risk of disorders, such 
as high blood pressure, diabetes, obesity, stroke and depression. It’s also associated with cognitive 
decline and Alzheimer’s disease. 
Defined CBD is composed of a novel formulation of CBD and terpenes that we have shown 
significantly increases REM and restorative sleep in people with insomnia, and these people could 
correctly perceive the benefit of this treatment (even though they were blinded to the treatments). We 
would now like to replicate these exciting preliminary findings in a larger participant cohort under IRB 
approval.  
 
4.3 
JUSTIFICATION FOR DOSE 
 
The justification for the route of administration and planned dosage for the Le Rêve 3.0 study is 
based on published scientific literature and in-house dose range-finding studies completed at Defined 
Research. In one early but small (N = 10) placebo-controlled clinical study in Brazil, subjects with 
insomnia that received 160 mg of CBD p.o. reported having slept significantly more than those who had 
been given a placebo control5. More recently, a somewhat larger study in 72 adults with clinically 
diagnosed anxiety, 25-75 mg/day p.o. CBD improved sleep in 66% of the patients as determined by a 
sleep quality questionnaire6. Unfortunately, this particular study was an open label study (i.e. not 
blinded), lacked a placebo-control, and did not include any objective measures of sleep physiology. 
Furthermore, the study was only performed in participants with clinically diagnosed anxiety, adding a 
further confound. Previous clinical studies with Epidiolex® (which contains 99.9% CBD) indicated that 

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CBD may cause somnolence and sedation at doses between 10 mg/kg/day-20 mg/kg/day (900-1,800 
mg/day for a 90 kg male)9. In-house dose-ranging pilot studies conducted at Defined Research under 
informed consent demonstrated that Defined CBD (300 mg p.o.) was well tolerated and significantly 
increased the percentage of time participants spent in deep and REM sleep (data not shown). These 
studies formed the basis for the dose of CBD used in Le Rêve 1.0-3.0. As described above, based on a 
large amount of published clinical evidence, the WHO has established that CBD is non-intoxicating and 
has an excellent safety profile in humans1, and based on previous clinical studies with Epidiolex®9 we 
anticipate that the dose of Defined CBD that will be used in Le Rêve (300 mg/day) will result in no or 
minimal AEs.   
 
4.4 
END OF STUDY DEFINITION 
 
The Le Rêve 3.0 study will span 12 weeks in time (for Schema see section 1.2). The end of data 
collection for Le Rêve 3.0 will be defined as the last day of drug washout on the seventh day of the 
twelfth week.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1) Has provided a signed and dated informed consent form.  
 
2) Presence of chronic insomnia defined as self-reported difficulty initiating (latency to persistent sleep 
>30 min) and/or maintaining sleep (>30 mins awake during the middle of the night, or waking >30 mins 
before desired waking time on three or more nights per week) for at least 3 months. 
 
3) Insomnia Severity Index score >15. 
 
4) Male or female aged 25–70 years. 
 
5) Is willing to comply with all study procedures throughout the entire study, including: 
 
-Wearing a sleep-tracking device on their wrist throughout entire clinical study. 
-Ensuring that the sleep-tracking device is connected to their smartphone via Bluetooth on a daily basis 
so that sleep data can be collected on a daily basis. 
-Ensuring that the sleep-tracking device is charged before going to bed each night, ensuring that sleep 
data can be collected on a daily basis. 
-Is willing to receive and respond to daily text (SMS) notifications for the duration of the entire clinical 
study. 
-During the treatment phases of the study, is willing to take the treatment for at least four nights in each 
week.  
 
6) On the nights in which the participant takes the treatment, is willing to abstain from excessive alcohol 
intake (>two drinks/day). 
 

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7) On the nights in which the participant takes the treatment, is willing to refrain from drinking alcohol 
two hours before bedtime. 
 
8) Female subjects who: 
 
-Are postmenopausal, with amenorrhea for at least one year before the screening interview, OR 
 
-Are surgically sterile, OR 
 
-If of childbearing potential agree to practice effective double barrier methods of contraception (e.g., 
condom + diaphragm; condom or diaphragm + spermicidal gel or foam), from the time of the signing of 
informed consent through the last dose of study treatment, or agree to completely abstain from 
intercourse. 
 
9) Self-reported bedtime between 9 pm and midnight on four-seven nights per week. 
 
10) Owns a smartphone.  
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1) Self-reported body mass index > 32 calculated from patient's height (m) and weight (kg); weight 
(kg)/square height (m²). 
 
2) Insomnia associated with clinically diagnosed sleep apnea (AHI greater than 15 events/hour), or 
movement disorders such as restless legs, periodic limb movement (PLM) (greater than 30 events/hour 
or greater than five events/hour with associated PLM arousals). 
 
3) Are currently participating in a formal behavioral therapy program to facilitate sleep. 
 
4) History of epilepsy or seizures. 
 
5) History of liver disease.  
 
6) Serious head injury or stroke within the past year. 
 
7) Psychiatric disorders including major depression, bipolar, anxiety, or schizophrenia. 
 
8) History of suicide attempt or current suicide ideation. 
 
9) Evidence of any clinically significant, severe or unstable, acute or chronically progressive medical or 
surgical disorder (including planned medical procedures that may impact sleep), or any condition that 
may interfere with the absorption, metabolism, distribution, or excretion of the study drug. 
 
10) Patients with a history of cardiovascular disease including poorly controlled hypertension, ischemic 
heart disease, arrhythmia, or severe heart failure. 

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11) Untreated metabolic disorder such as diabetes. 
 
12) Medical conditions that result in frequent need to get out of bed (e.g. nocturia). 
 
13) History of drug or alcohol abuse, including past or present history of cannabis dependence. 
 
14) Inability to refrain from greater than two standard drinks/day of alcohol consumption for study 
duration. 
 
15) Current cigarette smoker. 
 
16) Currently chronic (daily) cannabis user. 
 
17) Use of any substance with psychotropic effects or properties known to affect sleep/wake, including 
neuroleptics, morphine/opioid derivatives, antihistamines, stimulants, anti-depressants, clonidine, 
within one week prior to screening. 
 
18) Use of any over-the-counter sleep medications including tryptophan, valerian root (Valeriana 
officinalis), kava (Piper methysticum Forst), melatonin, St John's Wort (Hypericum perforatum), Alluna 
(herbal sleep supplement with valerian root), and hemp within one week prior to screening. 
 
19) Inability to refrain from use of any of the following contra-indicated drugs for at least one week prior 
to and for the duration of the study: erythromycin, clarithromycin, itraconazole, ketoconazole, 
posaconazole, voriconazole, ritonavir, telaprevir, boceprevir, amlodipine, gemfibrozil, cyclosporine, 
danazol, amiodarone, verapamil, diltiazem, rifampin, theophylline, tizanidine, bupropion, 
efavirenz, diflunisal, propofol, fenofibrate, lamotrigine, morphine, lorazepam, diazepam, clobazam, 
stiripentol, valproate, everolimus, sirolimus, or tacrolimus, niacin (vitamin B3 greater than 1g/ day), 
grapefruit juice. 
 
20) Consumption of xanthine-containing beverages (i.e., tea, coffee, energy drinks or cola) of more than 
five cups or glasses per day.  
 
21) Inability to refrain from greater than 400mg/day of caffeine consumption for study duration. 
 
22) Participation in any other clinical trial within 30 days before the screening visit. 
 
23) Night shift workers (during the 12 months prior to the study and during the study). 
 
24) Individuals who nap three or more times per week over the preceding month. 
 
25) Current delayed sleep phase syndrome where wake-up time is regularly (>5x/week) later than 9:00 
a.m. 
 
26) Individuals having to travel across more than two time zones or outside of their country of residence 
at any time during the study. 
 
27) Females who are pregnant, are planning to become pregnant, or are breastfeeding. 

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28) History of allergies particularly to plant-based products containing terpenes, i.e. flavors and aromatic 
natural oils for example citrus, mango, lavender, thyme, cedarwood and pine products. 
 
29) Known hypersensitivity to cannabinoids, including CBD. 
 
30) Individuals may be excluded from participating in the study based on the investigator's professional 
judgement. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
 
• 
Refrain from ingesting greater than two standard drinks/day of alcohol consumption for study 
duration. 
• 
Refrain from drinking alcohol two hours before bedtime. 
• 
Abstain from ingesting greater than 400 mg/day of caffeine consumption for study duration. 
• 
Abstain from ingesting caffeine after 3 pm for study duration.   
• 
Abstain from ingesting more than five cups or glasses per day of xanthine-containing beverages 
(i.e., tea, coffee, energy drinks or cola) for study duration.  
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment Strategies 
Participant recruitment and enrollment for Le Rêve 3.0 will be performed entirely by a CRO named 
83Bar, Inc., who has extensive experience in managing all aspects of clinical trials. Recruitment materials 
will include (for details see Supplemental materials):  
 
• Digital advertisements to appear on Facebook / Instagram and Google Search  
• Landing pages  
o Landing page with embedded lead generation survey  
o Qualified results landing page  
o Not qualified results landing page  
• Lead Generation Survey  
• Emails  
• Text messages  
• Call script 
• Privacy Policy  
• Social Media Editorial Calendar  
• Social Media Comment Moderation  
 

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Design and Procedure: Prospective candidates will see a digital ad on Facebook, Instagram, or Google 
search. After a prospective candidate clicks on the ad, they will be directed to a dedicated landing page 
that includes an embedded survey. The survey is designed to pre-screen prospective candidates. Survey 
respondents that are “survey qualified” will next receive a phone call from an 83bar Contact Center 
agent. If the prospective candidate answers the call, the agent will dialogue with the prospective 
candidate using an IRB-approved script (see supplemental materials). The script is designed to provide 
additional screening for prospective candidates. Interested participants will be provided with electronic 
consent forms. Information will then be sent to the study activation team for enrollment. Study 
candidates will also receive confirmation and reminder via email and text message. 83Bar predicts that 
upon receiving IRB-approval, the recruitment process will take approximately four weeks.  
 
Target Population:  
• 
Self-identify as meeting the study inclusion/exclusion criteria 
 
Subject Recruitment:  
• 
Potential candidates will be recruited from the general population using IRB-approved 
Facebook/Instagram and Google search advertisements. Potential candidates will complete an 
IRB-approved online pre-screening survey.  
• 
Pre-screened potential candidates will be contacted by the 83bar Contact Center. The Contact 
Center will conduct verbal pre-screening using an IRB-approved script (see supplemental 
materials). If the candidate is interested in participating in the study, candidates that qualify 
based on online pre-screening and verbal pre-screening will be invited to participate in the 
study. 
Participant Compensation: 
• 
Participants who successfully complete Le Rêve 3.0 will receive a $100 gift card immediately 
upon completion of the study. Participants will also be allowed to keep their Whoop™, a non-
invasive wearable fitness and health coach, which will be active for a period of up to two 
months. After this period, if participants desire to continue using the Whoop strap they will be 
required to obtain a subscription for its use directly from Whoop™. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Defined CBD is composed of small capsules made with vegetable cellulose (gluten-free, non-GMO, 
vegan, certified kosher, certified halal) that contain >99.9% purity hemp-derived CBD dissolved in 
coconut oil (USDA certified organic, non-GMO, dairy-free, gluten-free, vegan coconut oil) with a custom 
chemical formulation that also contains highly purified (>98% purity) forms of the terpenes linalool, 
myrcene, phytol, limonene, a-terpinene, a-terpineol, a-pinene, and b-caryophyllene [Food Grade 
(GRAS), Natural, Organic, non-GMO, dairy-free, gluten-free, vegan). Participants will be required to take 
two small capsules one hour before they go to bed. These capsules will contain a total of 300 mg CBD 
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contain the placebo control will look, feel and smell exactly the same as the capsules that contain 
Defined CBD, but will contain no CBD or terpenes.   
6.1.2 DOSING AND ADMINISTRATION 
 
The dose participants will take in the study is two small capsules, that contain a total of 300 mg CBD 
and 8 mg of terpenes (1 mg each of the terpenes linalool, myrcene, phytol, limonene, a-terpinene, a-
terpineol, a-pinene, and b-caryophyllene) that will be taken orally with a glass of water one hour before 
bedtime. The participants will be required to take the study medication on a minimum of four nights per 
week for each of the four-week treatment phases of the study.   
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The CRO 83Bar will handle all of the study materials, including Defined CBD and the placebo control. 
They will ship these materials directly to study participants.   
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The treatments will come in two independent blister packs labeled “Defined Research Treatment 1” 
and “Defined Research Treatment 2”. The blister packs contain a sufficient number of capsules for a 
total of 28 days of treatment (either Defined CBD or the Placebo Control).  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
The study treatment should be stored in a cool dry location, but do not require refrigeration.  
 
6.2.4 PREPARATION 
 
The study treatments will require no preparation. The capsules are simply removed by the study 
participants from the blister packing before taking the treatment.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
After enrollment, study participants will be assigned a study participant number, and will be 
randomized to receive Defined CBD or the Placebo control first. As Le Rêve 3.0 is a crossover study, 
participants who are randomized to receive Defined CBD as the first treatment will cross-over to receive 
the Placebo Control as the second treatment, and vice-versa. Both the study participants and the PI will 
be blinded to the study treatments. Unblinding will occur at the completion of the study by the PI. In 
certain rare instances (e.g. for a SAE), the blind may be broken for an individual participant by the PI.   
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Adherence to the protocol by study participants will be assessed by two independent approaches. In 
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on a daily basis for each participant to ensure that the data is being collected consistently and accurately. 
In the second approach, study participants will be required to answer a text (SMS) message on a daily 
basis to confirm whether or not they took the study treatment.     
  
6.5 
CONCOMITANT THERAPY 
 
Not applicable. 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation of the study intervention may occur in the event of a SAE if the medical monitor on 
the CBD Sleep Study Team makes that recommendation. In the event that the medical monitor 
determines that the study intervention should be discontinued for a study participant, they will prepare 
an electronic Case Report Form (eCRF) that will capture the date and the specific underlying reason for 
discontinuation of study intervention. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Study participants may voluntarily choose to withdraw from Le Rêve 3.0 at any point before or 
during the study by sending a text (SMS) message to 415-275-2014 or by sending an email to 
support@definedresearch.org. If a study participant chooses to withdraw from the study for any reason, 
they will be required to disclose to the CBD Sleep Study Team the reason that they chose to withdraw. 
The PI may choose to withdraw a study participant(s) for significant study intervention non-compliance, 
or in the event of a SAE such that continued participation in the study would not be in the best interest 
of the participant. In the event that the PI chooses to withdraw a participant from the study, a member 
of the sleep study team will attempt to reach the participant by phone to inform them that they have 
been withdrawn from the study. The reason for participant discontinuation or withdrawal from the 
study will be recorded on the CRF. Subjects who sign the informed consent form, and are randomized 
and receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from 
the study, will not be replaced.  
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to respond to CBD Sleep Study 
Team.  
 
The following actions must be taken if a participant fails to respond to CBD Sleep Study Team: 
 

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• 
CBD Sleep Study Team will attempt to contact the participant and ascertain if the participant 
wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, up to 3 telephone calls).  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
We will enroll 150 study participants who display chronic insomnia defined as a self-reported 
difficulty initiating (latency to persistent sleep >30 min) and/or maintaining sleep (>30 min awake, or 
waking >30 min before desired waking time) on three or more nights per week for at least 3 months. 
Participants will also complete a brief clinically validated insomnia severity index, and only participants 
with an Insomnia Severity Index score >15 will be enrolled in Le Rêve 3.0. We will enroll males or 
females aged 25–70 years that are located in the United States that meet inclusion and exclusion 
criteria.  
Le Rêve 3.0 will be conducted in an entirely decentralized manner. Primary data for Le Rêve 3.0 will 
be obtained in a completely unbiased manner from a non-invasive sleep-tracking wrist-worn device 
called “Whoop” (https://www.whoop.com), that electronically collects and transmits sleep data from 
study participants in the comfort of their own beds.  
The wristband collects hundreds of data points per second from a 3-axis accelerometer, 3-axis 
gyroscope, and heart rate sensor. The wristband can accurately measure the latency to fall asleep, total 
sleep time, sleep fragmentation, as well as the time spent in each sleep stage [Light, Slow Wave (Deep), 
Rapid Eye Movement (REM), and Awake]. The device also collects data using photoplethysmography 
(PPG), a technique that involves measuring blood flow by assessing superficial changes in blood volume. 
Heart rate, heart rate variability and respiratory rate, can all be derived from PPG data, and all of these 
metrics are used in Whoop’s sleep detection and staging algorithms. Importantly, two recent 
publications, published independently from Whoop, show that data on sleep stages collected from the 
Whoop device are highly accurate and correlate well with polysomnography (PSG), the gold-standard of 
sleep tracking used in clinical studies conducted in sleep clinics18.  
The primary endpoint efficacy endpoint in Le Rêve 3.0 is the percentage of time spent in slow wave 
(Deep) and REM sleep as collected by a non-invasive wrist-worn sleep-tracking device called Whoop. 
Additional objective secondary outcome measures that will be collected on the Whoop device include: 
Total sleep time, sleep latency, the number of sleep disturbances, time spent in each sleep stage, and 
the percentage of time spent in each sleep stage. 
A modified version of a clinically validated questionnaire entitled the PGI19 will be used to track 
subjective measures of sleep physiology. This data will be collected from study participants in the form 
of a brief five-minute survey that will be completed on their smartphone at the end of each four-week 
treatment period. This survey measures the perception of the study participants of the effects of 
treatment.    
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 

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8.2.1 This is an interventional study to determine the effects of Defined CBD on sleep physiology. 
8.2.2 Defined CBD is a small capsule composed of vegetable cellulose (gluten-free, non-GMO, vegan, 
certified kosher, certified halal) that contains 300 mg of >99.9% purity hemp-derived CBD purified in a 
GMP-facility that is dissolved in coconut oil (USDA certified organic, non-GMO, dairy-free, gluten-free, 
vegan coconut oil) with a custom chemical formulation that contains a low concentration (1 mg each) of 
highly purified (>98% purity) terpenes linalool, myrcene, phytol, limonene, a-terpinene, a-terpineol, a-
pinene, and b-caryophyllene [Food Grade (GRAS), Natural, Organic, non-GMO, dairy-free, gluten-free, 
vegan]. Defined CBD contains no D-9-THC.  
8.2.3 Defined Research Inc. has >5 years of experience in manufacturing CBD products under GMP-like 
conditions, and confirms the molecular composition of every batch of Defined CBD (including the 
Defined CBD to be used in Le Rêve 3.0) by an ISO-10725-accredited analytical testing laboratory. These 
analytical tests confirm the concentration and purity of Defined CBD, and ensure that it is free from any 
contaminants, including pesticides, residual solvents and heavy metals. Electronic records of these 
laboratory tests are stored at Defined Research and are available upon request.   
8.2.4 Based on a large amount of published clinical data, the World Health Organization (WHO) has 
established that CBD (the active ingredient in Defined CBD) is non-intoxicating and has an excellent 
safety profile in humans20. Previous clinical studies indicate that adverse reactions with CBD are rare21. 
The most common adverse reactions that occurred with CBD when given at a high dose [e.g., at the 
recommended dose for the FDA approved CBD drug Epidiolex® (20 mg/kg/day), were somnolence 
(sleepiness); decreased appetite; diarrhea; transaminase elevations; fatigue; malaise; asthenia 
(abnormal physical weakness or lack of energy); rash; insomnia; sleep disorder; poor quality sleep; and 
infections. However, these adverse reactions were only observed in >10% of patients at a CBD dose (20 
mg/kg/day or ~1,800 mg for a 90 kg male) that is approximately six times greater than the dose that will 
be used in Le Rêve 3.0 study (300 mg or ~3 mg/kg/day for a 90 kg male). Moreover, the frequency of 
these adverse events decreased significantly when Epidiolex® was administered at a lower dose (10 
mg/kg/day or ~900 mg for a 90 kg male), that is still three times the dose we will use in Le Rêve 3.0. A 
recent meta-analysis of adverse events from 12 clinical trials with CBD indicated that associations with 
abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy 
studies, where CBD may have interacted with other medications such as clobazam and/or sodium 
valproate22. After excluding studies in childhood epilepsy, the only adverse outcome associated with 
CBD treatment was diarrhea. And, again, this was only observed at doses well above the CBD dose that 
will be evaluated in Le Rêve 3.0. Therefore, if adverse events are observed with Defined CBD in Le Rêve 
3.0, we presume that they will be minor and only occur at a lower frequency than what was observed in 
previous clinical studies.  
Although rare, some adults display hypersensitivity to CBD. Participants with known hypersensitivity 
to CBD will be excluded from participating in Le Rêve 3.0. As noted above, some recent studies indicate 
that extremely high doses of CBD (much higher than what will be used in Le Rêve 3.0) might impair liver 
function. Therefore, as a precaution, study participants in Le Rêve 3.0 will be required to refrain from 
the use of any of the following contra-indicated drugs for at least one week prior to and for the duration 
of the study: erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, 
ritonavir, telaprevir, boceprevir, amlodipine, gemfibrozil, cyclosporine, danazol, amiodarone, verapamil, 
diltiazem, rifampin, theophylline, tizanidine, bupropion, efavirenz, diflunisal, propofol, fenofibrate, 
lamotrigine, morphine, lorazepam, diazepam, clobazam, stiripentol, valproate, everolimus, sirolimus, or 
tacrolimus, and niacin (vitamin B3 greater than 1g/ day). Participants who cannot refrain from the intake 
of these contra-indicated drugs prior to and throughout the study will be excluded from participating in 
Le Rêve 3.0.    

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Defined CBD also contains low concentrations (1 mg each) of highly purified (>98%) forms of the 
terpenes linalool, myrcene, phytol, limonene, a-terpinene, a-terpineol, a-pinene, and b-caryophyllene. 
Terpenes are widely used as fragrances and flavors in consumer products such as perfumes, cosmetics 
and cleaning products, as well as food and drink products. For example, the aroma and flavor of hops 
comes, in part, from sesquiterpenes (mainly α-humulene and β-caryophyllene), which are used to make 
beer. Importantly, the terpenes in Defined CBD are designated by the FDA as GRAS (Generally Regarded 
as Safe) for oral human consumption. Although rare, some adults display mild skin allergies to terpenes 
when applied topically. Participants with known hypersensitivity to terpenes will be excluded from 
participating in Le Rêve 3.0.    
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event (AE) is any untoward medical occurrence in a clinical study participant 
administered an investigational product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of an investigational product, whether or not considered related to 
the investigational product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures or special situations (Section 8.3.8).  
 
An AE does not include the following: 
 
• 
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.  
 
• 
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen. 
 
• 
Situations where an untoward medical consequence has not occurred (e.g. hospitalization for 
elective surgery, social and/or convenience admissions). 
 
• 
Overdose without clinical sequelae (Section 8.3.8). 
 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the consent form is signed and not related to a protocol-associated procedure is not an AE. It is 
considered to be preexisting and should be documented as medical history.  
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
A SAE is defined as an event that, at any dose, results in the following: 
 
• 
Death. 
 
• 
Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were worse or more severe).  

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• 
New patient hospitalization due to the investigational product.  
 
• 
Persistent or significant disability/incapacity.  
 
• 
A medically important event or reaction: such events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific 
judgement must be exercised to determine whether such an event is a reportable under 
expedited reporting rules. Examples of medically important events include intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dycrasias or convulsions 
that do not result in hospitalization; and development of drug dependency or drug abuse.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
The medical monitor is responsible for assessing AEs and SAEs for causality and severity, and for 
final review and confirmation of accuracy of event information and assessments.  
8.3.3.1 SEVERITY OF EVENT 
 
The following guidelines will be used to describe severity using the CTCAE (Common Terminology 
Criteria for Adverse Events) grading system:  
 
• 
Grade 1 Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Grade 2 Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• 
Grade 3 Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
• 
Grade 4 Life Threatening – Events in which urgent medical intervention is indicated.  
• 
Grade 5 Death – If related to the event.  
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
The medical monitor is responsible for assessing the relationship to study drug using clinical judgement 
and the following considerations:  
 
• 
Not related: There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
• 
Related: The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
 

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8.3.3.3 EXPECTEDNESS  
 
The medical monitor is responsible will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention (see Section 8.2.4). 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-
UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during interviews of a 
study participant presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on 
the appropriate electronic case report form (eCRF). Information to be collected includes event 
description, time of onset, medical monitor’s assessment of severity, relationship to study product, and 
time of resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s baseline medical condition 
worsens at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The medical monitor will record all reportable events (AEs and SAEs) starting with the first day of the 
study until the study is completed. The medical monitor will follow up with the study participant up to 
three times until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Following initiation of study treatments, all AEs, regardless of cause or relationship, throughout the 
duration of the study will be reported on the eCRFs.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
All SAEs, regardless of cause or relationship, that occur after the participant first consents to 
participate in the study (i.e. the signing of the informed consent) and throughout the duration of the 
study will be reported on the eCRFs.  
The medical monitor will immediately report to Defined Research any SAE, whether or not 
considered study intervention related, and will include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study endpoints that are SAEs (e.g., all-cause 
mortality) must be reported in accordance with the protocol. All SAEs will be followed until satisfactory 
resolution or until the study investigator deems the event to be chronic or the participant is stable.  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  

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Events of special interest include all reports of medication error, abuse, misuse, overdose, and 
product complaints with AE. Medication error is any unintentional error in the prescribing, dispensing, 
preparation for administration or administration of an investigational product while the medication is in 
the control of a health care professional, patient, or consumer.  
Medication errors may be classified as a medication error without an AE, which includes situations 
of missed dose; medication error with an AE; intercepted medication error, or potential medication 
error.  
Abuse is defined as persistent or sporadic intentional excessive use of an investigational product by 
a participant.  
Misuse is defined as any intentional and inappropriate administration of an investigational product 
that is not in accordance with the protocol instructions or the local prescribing information.  
An overdose is defined as an accidental or intentional administration of a quantity of an 
investigational product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose of the 
participant in question). In cases of a discrepancy in drug accountability, overdose will be established 
only when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the participant has taken the additional dose(s).  
Product complaint is defined as complaints arising from potential deviations in the manufacturing, 
packaging, or distribution of the investigational product.  
 
8.3.9 REPORTING OF PREGNANCY  
 
Not applicable.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
The primary objective of the study is: 
 
• 
To determine if Defined CBD influences objective measures of sleep physiology.  
 
The secondary objective of the study is:  
 
• 
To determine if Defined CBD influences subjective measures of sleep physiology.   
 
The primary endpoint of the study is: 
  
• 
To determine if Defined CBD increases the percentage of sleep 
spent in deep [slow wave sleep (SWS)] and rapid eye movement 
(REM) sleep as quantified with an objective wrist-worn sleep-
tracking device called Whoop.  
 
The null hypothesis is that there is no difference in the percentage of sleep 
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and the placebo control; the alternative hypothesis is that there is a 
difference among the two treatment groups. The difference in the 
percentage of sleep spent in deep and REM sleep in participants that 
received Defined CBD and the placebo control at the end of the two four-
week treatment phases will be compared using a 2-sided test with an 
alpha level at 0.05 to evaluate superiority. The p-value and 95% 
confidence interval for the estimate of treatment difference in 
percentages will be estimated and constructed using the above-mentioned 
method.    
 
The secondary endpoints of the study are:  
 
• 
To determine if Defined CBD changes total sleep time, sleep 
latency, the number of sleep disturbances, time spent in each 
sleep stage, and the percentage of time spent in each sleep stage 
as quantified with the Whoop sleep-tracking device, and 
subjective measures of sleep physiology as collected via 
participant surveys.  
 
The null hypothesis is that there is no difference in the secondary 
endpoints in the study in participants that received Defined CBD and the 
placebo control; the alternative hypothesis is that there is a difference 
among the two treatment groups. The difference secondary endpoints in 
participants that received Defined CBD and the placebo control at the end 
of the two four-week treatment phases will be compared using a 2-sided 
test with an alpha level at 0.05 to evaluate superiority. The p-value and 
95% confidence interval for the estimate of treatment difference in 
percentages will be estimated and constructed using the above-mentioned 
method.    
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
A total of 100 participants will provide at least 90% power to detect a 15% difference in the 
percentage of time participants spend in deep and REM sleep, as quantified using the Whoop sleep-
tracking device after the four-week treatment phase. The CRO 83Bar will recruit 8,000 potential study 
participants using social media, will screen approximately 800 study participants via online screening 
surveys, will contact 440 participants from a call center, and will ultimately enroll 150 qualified study 
participants. Based on our two previous clinical studies with Defined CBD, we anticipate a maximum 
dropout rate of 33% in Le Rêve 3.0.   
 
9.3 
POPULATIONS FOR ANALYSES 
 
Analysis of the primary and second endpoints will be completed after all study participants have 
completed the 12-week study, outstanding data queries have been resolved or adjudicated as 
unresolvable, and the data have been cleaned and finalized. This analysis of the primary and secondary 
endpoints will serve as the final analysis of the endpoints. A safety analysis dataset will be composed of 
any AE and SAEs collected by the medical monitor in the form of eCRFs.   

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9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
For the primary and secondary endpoints, the difference in the means of each endpoint in 
participants that received Defined CBD and the placebo control at the end of the two four-week 
treatment phases will be compared using a 2-sided test with an alpha level at 0.05 to evaluate 
superiority. The p-value and 95% confidence interval for the estimate of treatment difference in 
percentages will be estimated and constructed using the above-mentioned method.     
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint that will be analyzed in Le Rêve 3.0 is the percentage of time study 
participants spend in deep and REM sleep as quantified using wrist-worn sleep-tracking device Whoop. 
The difference in the mean percentage of sleep spent in deep and REM sleep in participants that 
received Defined CBD and the placebo control at the end of the two four-week treatment phases will be 
compared using a 2-sided test with an alpha level at 0.05 to evaluate superiority. The p-value and 95% 
confidence interval for the estimate of treatment difference in percentages will be estimated and 
constructed using the above-mentioned method.     
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The difference secondary endpoints (total sleep time, sleep latency, the number of sleep 
disturbances, time spent in each sleep stage, percentage of time spent in each sleep stage, and 
subjective measures of sleep physiology as collected via participant surveys) in participants that received 
Defined CBD and the placebo control at the end of the two four-week treatment phases will be 
compared using a 2-sided test with an alpha level at 0.05 to evaluate superiority. The p-value and 95% 
confidence interval for the estimate of treatment difference in percentages will be estimated and 
constructed using the above-mentioned method.    
 
9.4.4 SAFETY ANALYSES 
 
The primary analysis set for safety analyses is defined as safety analysis dataset, which includes all 
participants who are randomized/enrolled and receive any dose of study treatment. All data collected 
during the study will be included in the safety summaries.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Not applicable.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Not applicable.  
 
9.4.7 SUB-GROUP ANALYSES 
 

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Demographic measurements will be summarized using standard descriptive methods by cohort and 
treatment. Demographic summaries may include sex, race/ethnicity, and age.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable.  
 
9.4.9 EXPLORATORY ANALYSES 
 
Not applicable.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
 
An informed consent form describing in detail the study intervention, study procedures, and risks 
will be given to study participants and written documentation of informed consent will be required prior 
to initiating Le Rêve 3.0.  The informed consent to be used in Le Rêve 3.0 is submitted with this protocol. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be IRB-approved 
and the participant will be asked to read and review the document. A member of the CBD Sleep Study 
Team will explain the research study to the participant and answer any questions that may arise. A 
verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think 
about it prior to agreeing to participate. The participant will sign the informed consent document prior 
to initiating the study. Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent document will 
be given to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the participant 
initiates the study. The rights and welfare of the participants will be protected by emphasizing to them 
that the quality of their medical care will not be adversely affected if they decline to participate in this 
study.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 

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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants and IRB. If the study is 
prematurely terminated or suspended, the PI will promptly inform study participants and IRB, and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable. Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor and IRB.  
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
The investigator must assure that the participants’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only an identification code will be recorded on 
any data form used in Le Rêve 3.0. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the sponsor.  
 The study participant’s contact information will be securely stored for internal use during the study. 
At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Defined Research. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
Defined Research’s staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at Defined Research. 
 
10.1.4 FUTURE USE OF DATA  
 
Data collected for this study will be analyzed and stored at Defined Research.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Paul Muchowski, Ph.D., CEO 
Chetan Gottimukkula, M.D., 
Medical Monitor 
Defined Research  
Defined Research  
1250 Missouri Street, Unit #312 
San Francisco, CA 94107 
1250 Missouri Street, Unit #312 
San Francisco, CA 94107 
415-413-8666 
415-413-8666 
paul.muchowski@definedresearch.com chetan.g@definedresearch.com 
 
10.1.6 SAFETY OVERSIGHT 
 

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Safety oversight will be under the direction of an independent safety monitor (ISM) named Dr. 
Chetan Gottimukkula. Dr. Gottimukkula has extensive experience and knowledge with National and 
International Drug Safety and Pharmacovigilance principles and Regulations (US FDA, EMA, MHRA, 
MHLW) and Clinical Trials design and development process. The ISM will provide input to Defined 
Research and the IRB as necessary.  
 
10.1.7 CLINICAL MONITORING 
 
Clinical monitoring will be conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Members of the CBD Sleep Study Team will oversee clinical monitoring via daily text (SMS) 
messages with study participants to ensure compliance and to capture any AEs and SAEs.  
• 
Members of the CBD Sleep Study Team will oversee clinical monitoring by ensuring that sleep-
tracking data is being collected on a daily basis throughout the study.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Le Rêve 3.0 will be conducted in a decentralized manner. All data will be collected electronically via 
the cloud. Quality control (QC) procedures by the CBD Sleep Study Team will be implemented to ensure 
that sleep physiology data is being collected appropriately. Data QC checks will be run on a daily basis. If 
a study participant becomes noncompliant resulting in a lack of sleep physiology data being collected 
(for example, if the battery on their sleep tracking device runs out of charge; if the participant forgets to 
wear the sleep tracking device at night; or if the participant forget to connect the sleep-tracking device 
to their smartphone via Bluetooth), then the lack of data collection will automatically trigger the 
activation of a text (SMS) based application to communicate directly with that participant to help them 
resolve the lack of compliance issue. In the event the text-based notification system does not resolve 
the lack of compliance issue, a member of the CBD Sleep Study Team may also reach out to the study 
participant by phone or email to help resolve the issues.  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
As stated above, all of the data that will be collected in Le Rêve 3.0 will be electronic and captured 
via the cloud. The investigator and CBD Sleep Study Team are responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. Clinical data will be collected by a 21 CFR 
Part 11-compliant data capture system provided by Whoop. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 2 years after completion of Le Rêve 3.0.  

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10.1.10 
PROTOCOL DEVIATIONS  
  
A protocol deviation is any noncompliance with the clinical trial protocol or International 
Conference on Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on 
the part of the participant or the investigator. As a result of deviations, corrective actions are to be 
developed by the CBD Sleep Study Team and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the CBD Sleep Study Team to use continuous vigilance to identify and 
report deviations within one working day of identification of the protocol deviation.  All deviations must 
be addressed in study source documents.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
Data from Le Rêve 3.0 will be included a manuscript that Defined Research will submit for 
publication in a peer reviewed scientific journal. In addition, this trial will be registered at 
ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. Data from 
this study may be requested from other researchers three years after the completion of the primary 
endpoint by contacting Defined Research.  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed, including in a scientific publication 
that may arise from Le Rêve 3.0. The study leadership has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not applicable.  
 
 
 

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
DHHS 
Department of Health and Human Services 
DRE 
Disease-Related Event 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
US 
United States 
 
 
 

Le Rêve 3.0 
Version 2 
Protocol #DR-INS-101 
31 January 2022 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Le Rêve 3.0 
Version 2 
Protocol #DR-INS-101 
31 January 2022 
 
 
11 REFERENCES  
1https://www.epidiolexhcp.com/efficacy-and-safety/safety 
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8https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf 
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10Chesney et al., Neuropsychopharmacology. 2020; 45(11):1799-1806.  
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18 Berryhill et al., J Clin Sleep Med. 2020; 16(5):775-783; Miller et al., Journal of Sports Sciences. 2020; 
38(22):2631-2636. 
19Krystal et al., Sleep 2008; 31:79-90. 
20https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf 
21Jadoon et al., Diabetes Care. 2016; 39(10):1777-1786; McGuire et al., Am J Psychiatry. 
2018;175(3):225-231; Lattanzi et al., CNS Drugs. 2020; 34(3):229-241; Lattanzi et al., Drugs 
2018;78(17):1791-1804. 
22Chesney et al., Neuropsychopharmacology. 2020; 45(11):1799-1806.