Clinical trial NCT05032807
Conditions: Absorption; Chemicals
Sponsor: King's College London
Start date: 2022-07-01; Completion date: 2022-09-10
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Cannabidiol (CBD) has been approved as a treatment for rare childhood epilepsies and could be an effective treatment for psychotic disorders, anxiety disorders and addictions. It is available as an oral liquid and as standard oral capsules.

The bioavailability of oral cannabidiol is poor (only around 5-10% is absorbed), particularly in the fasted state. With food, its absorption is much higher. In one study, a high-fat breakfast increased the maximum plasma concentration by 4-5 times. As a result of this food effect, when prescribing standard oral formulations of CBD, clinicians should provide advice on dosing the drug according to mealtimes, otherwise, there may be an increased risk of side effects or limited effectiveness.

One way to reduce the food effect and improve bioavailability is to use lipid excipients. In the present study, the investigators will evaluate CBD at the dose that is effective in patients with chronic psychosis (1000mg). The novel formulation will use lipids that are all EU pharmacopoeia approved and have been used in medicinal products before.

The study aims to assess whether a novel lipid formulation can increase the bioavailability of oral CBD in the fasting state.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Standard formulation intervention 2: Novel formulation
Intervention descriptions: intervention 1: Cannabidiol 1000mg standard formulation, single dose, oral intervention 2: Cannabidiol 1000mg with lipid matrix, single dose, oral

Protocol documents:
Prot_001.pdf: 
Pharmacokinetic study of a novel lipid 
formulation of cannabidiol (CBD) 
 
CBD-Lipid-PK (CLiP) Study 
 
 
Version 1.3 
19/05/2022 
 
 
 
IRAS: 288415 
EudraCT number: 2020-004551-33 
ClinicalTrials.gov: NCT05032807 
ISRCTN: 18067579 
 
 
 
 
 
 
 
 
 
 
 
 
 


Table of Contents 
1. KEY TRIAL CONTACTS ...................................................................................................... 4 
2. STUDY SYNOPSIS ............................................................................................................... 5 
Pharmacokinetic Abbreviations ............................................................................................................. 6 
3. BACKGROUND & RATIONALE .......................................................................................... 7 
4. OBJECTIVES AND OUTCOME MEASURES ...................................................................... 9 
4.1 Primary objective ............................................................................................................................. 9 
Primary outcome .................................................................................................................................... 9 
4.2 Secondary objectives ........................................................................................................................ 9 
Secondary outcomes ............................................................................................................................... 9 
4.3 Exploratory objective ..................................................................................................................... 10 
4.4 TRIAL DESIGN .............................................................................................................................. 10 
4.5 Trial Flow Chart ............................................................................................................................ 10 
5. TRIAL MEDICATION .......................................................................................................... 12 
5.1 Study Drug ..................................................................................................................................... 12 
5.2 Risks, known drug reactions and interaction with other therapies ................................................ 12 
5.3 Formulation .................................................................................................................................... 12 
5.4 Drug storage and supply ................................................................................................................ 13 
5.5 Preparation of Investigational Medicinal Product ........................................................................ 13 
5.6 Dosing, Compliance & Drug Accountability ................................................................................. 13 
5.7 Concomitant Medication ................................................................................................................ 13 
6. SELECTION AND WITHDRAWAL OF PARTICIPANTS ................................................... 14 
6.1 Inclusion criteria ............................................................................................................................ 14 
6.2 Exclusion criteria ........................................................................................................................... 15 
6.3 Recruitment .................................................................................................................................... 15 
6.4 Payment .......................................................................................................................................... 16 
6.5 Pre-screening ................................................................................................................................. 16 
6.6 Screening ........................................................................................................................................ 16 
6.7 Consent ........................................................................................................................................... 16 
6.8 Randomisation ................................................................................................................................ 17 
6.9 Blinding and Emergency Unblinding ............................................................................................. 17 
6.10 Withdrawal criteria ...................................................................................................................... 18 
6. 11 Expected duration of the trial ..................................................................................................... 18 
7. TRIAL PROCEDURES ....................................................................................................... 18 
7.1 Setting ............................................................................................................................................. 18 
7.2 Eligibility Review ........................................................................................................................... 18 
7.3 Fasting Requirements ..................................................................................................................... 18 
7.4 Administration ................................................................................................................................ 18 
7.5 Trial assessments ........................................................................................................................... 19 
7.6 Laboratory Procedures .................................................................................................................. 19 
7.7 Visit by visit events ......................................................................................................................... 20 
7.8 Planned analyses ............................................................................................................................ 21 
8. COVID-19 ............................................................................................................................ 22 
9. SAFETY .............................................................................................................................. 22 
9.1 Definitions ...................................................................................................................................... 22 


 
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9.2 Investigator Assessment ................................................................................................................. 22 
9.3 Reporting Responsibilities ............................................................................................................. 23 
9.4 Premature Termination of the Trial ............................................................................................... 23 
10. STATISTICS AND DATA ANALYSIS .............................................................................. 24 
10.1 Power analysis ............................................................................................................................. 24 
10.2 Planned recruitment ..................................................................................................................... 24 
10.3 Statistical analysis plan ................................................................................................................ 24 
11. TRIAL STEERING, DATA MONITORING AND ETHICS  MONITORING COMMITTEES
 ................................................................................................................................................ 25 
12. DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ........................................... 25 
13. ETHICS AND REGULATORY APPROVALS ................................................................... 25 
14. QUALITY ASSURANCE ................................................................................................... 26 
15. DATA HANDLING AND MANAGEMENT ........................................................................ 26 
16. DISSEMINIATION POLICY .............................................................................................. 26 
17. INDEMNITY ....................................................................................................................... 27 
18. FINANCIAL ASPECTS ..................................................................................................... 27 
29. ARCHIVING ...................................................................................................................... 27 
20. AMENDMENT HISTORY .................................................................................................. 27 
21. SIGNATURES ................................................................................................................... 27 
 
 
 
 
 
 
 


1. KEY TRIAL CONTACTS 
Chief Investigator/Principal 
Investigator 
Professor Philip McGuire 
Institute of Psychiatry, Psychology and Neuroscience, De 
Crespigny Park, SE5 8AF, London 
 
Trial Co-ordinator/Co-investigator 
Dr Edward Chesney 
Institute of Psychiatry, Psychology and Neuroscience, De 
Crespigny Park, SE5 8AF, London 
 
Co-investigators 
Mitul Mehta 
The Centre for Innovative Therapeutics (C-FIT) 
Institute of Psychiatry, Psychology and Neuroscience, De 
Crespigny Park, SE5 8AF, London 
 
Eric Lynch 
The Centre for Innovative Therapeutics (C-FIT) 
Institute of Psychiatry, Psychology and Neuroscience, De 
Crespigny Park, SE5 8AF, London 
 
 
Ndabezinhle Mazibuko  
The Centre for Innovative Therapeutics (C-FIT) 
Institute of Psychiatry, Psychology and Neuroscience, De 
Crespigny Park, SE5 8AF, London 
Sponsor 
King's College London 
Amy Holton, King’s Health Partners Clinical Trials Office, 
F16, Tower Wing, Guys Hospital, Great Maze Pond, 
London, SE1 9RT 
+44 (0) 207 188 5732 
amy.holton@kcl.ac.uk 
 
Funder 
NIHR Senior Investigator Award – Prof Philip McGuire 
[RE13018] 
Other External Support 
 
SEEK Pharmaceuticals (https://seekacure.com/): 
Provision the study drug and formulation 
 
Grand Pacific CRO 
Statistical support 
 
Trial Statisticians 
Oranuch Nampaisan 
Grand Pacific CRO 
Dr John Hodsoll  
Institute of Psychiatry, Psychology and Neuroscience, De 
Crespigny Park, SE5 8AF, London 
 
Pharmacy 
Maudsley Pharmacy, Maudsley Hospital, Denmark 
Hill, London, Greater London, SE5 8AZ 
 


 
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2. STUDY SYNOPSIS 
Trial Title 
Pharmacokinetic study of a novel lipid formulation of cannabidiol (CBD) 
Short title 
CLiP Study 
Type of Study 
CTIMP Pharmacokinetic study 
Trial Design 
Single-centre double-blind two-period crossover pharmacokinetic study 
Planned Sample Size 
14 
Participants 
Healthy volunteers 
Eligibility Criteria 
Inclusion criteria 
i. 
Healthy volunteers. Defined as healthy on the basis of a clinical history, 
physical examination, ECG, vital signs, and laboratory tests of blood and 
urine. 
ii. 
Age 18-45 
iii. 
Agreeing to fast 15 hours; 10pm-1pm on dosing days 
iv. 
Capable of giving informed consent 
v. 
Written informed consent from participant 
 
Exclusion criteria 
i. 
Clinically relevant medical history, physical findings, ECG, or 
laboratory values at the pre-trial screening assessment that could 
interfere with the objectives of the trial or the safety of the participant. 
ii. 
Presence of acute or chronic illness or history of chronic illness 
sufficient to invalidate the volunteer’s participation in the trial or make 
it unnecessarily hazardous. 
iii. 
Impaired endocrine, thyroid, hepatic, respiratory or renal function, 
diabetes mellitus, coronary heart disease, or history of any neurological 
or mental illness. 
iv. 
Surgery or medical condition that might affect absorption of medicines. 
v. 
Blood pressure and heart rate in supine position at the screening 
examination outside the ranges: blood pressure 90–140 mm Hg systolic, 
40–90 mm Hg diastolic; heart rate 40–100 beats/min. Repeat 
measurements are permitted if values are borderline (i.e. values that are 
within 5 mm Hg for blood pressure or 5 beats/min for heart rate) or if 
requested by the investigator. Subjects can be included if the repeat 
value is within range or still borderline but deemed not clinically 
significant by the investigator. 
vi. 
Loss of more than 400 mL blood during the 3 months before the trial, 
e.g. as a blood donor. 
vii. 
Any prescribed medication (apart from contraceptives) 
viii. 
Use of any CBD products within six months of IMP administration 
ix. 
Use of any over-the-counter medications or health supplements within 
the past 2 weeks 
x. 
BMI <18 or >30.0kg/m2 
xi. 
History of alcohol or substance misuse disorder 
xii. 
Intake of more than 14 units of alcohol weekly. 
xiii. 
Smokes more than 10 cigarettes per day 
xiv. 
Use of any illicit substances within the last six months of IMP 
administration 
xv. 
Pregnant or breastfeeding 
xvi. 
Women of childbearing potential (as defined in CTFG guidelines, see 
5.7 Concomitant Medication) not willing to use a highly effective form 
of contraception (as defined in CTFG guidelines, see section 5.7 
Concomitant Medication) during participation in the study or male 


patients not willing to ensure use of a condom during participation in 
the study. 
xvii. 
eGFR≤ 70 mls/min 
xviii. 
Any liver function or renal function test abnormality. A repeat is 
allowed on one occasion for determination of eligibility. 
xix. 
Urine drug screen positive for any substances 
xx. 
Positive alcohol breath test  
xxi. 
Participant in any other clinical trial or experimental drug study in the 
past 3 months 
xxii. 
Known hypersensitivity to CBD and/or SEEK formulation excipients 
xxiii. 
Participant is not able to swallow capsules 
 
Study Drug 
Cannabidiol (CBD) [GMP approved source] 
Formulation 
Novel lipid formulation (SEEK-CBD) 
 
Standard formulation (STD-CBD)  
Dose 
1000mg 
Fed/fasting 
Fasting 
Route of Administration 
Oral 
Treatment Arms 
 
SEEK-CBD then STD-CBD 
STD-CBD then SEEK-CBD 
Treatment duration 
One dose per experimental visit 
 
Two experimental visits lasting 48 hours each 
Follow up duration 
 
48 hours per dose/experiment 
 
2 week washout between experiments 
 
Final visit 7-14 days after second dosing session 
 
Planned Trial Duration  
4 months 
Primary objective & outcome 
measure 
To assess whether a novel lipid- formulation can 
improve the bioavailability of oral CBD in the fasting 
state. 
 
AUCinf 
 
Secondary objectives & outcome 
measures 
 
To characterise and compare the pharmacokinetic 
profiles of a novel CBD formulation and a standard 
formulation 
Cmax 
Tmax 
AUC0–48 
t½ 
 
 
 
 
Pharmacokinetic Abbreviations 
AUCt 
 
 
Area under the plasma concentration-time curve from time zero to time t. 


 
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AUCinf  
 
Area under the plasma concentration-time curve from time zero to time infinity. 
Bioavailability  
The proportion of drug absorbed into the systemic circulation 
Cmax 
 
 
The maximum serum concentration that a drug achieves 
Cmean  
 
The mean serum concentration that a drug achieves over a specified period of time 
CBD 
Cannabidiol 
CRF 
Clinical Research Facility 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
King’s CRF 
NIHR Wellcome Kings Clinical Research Facility 
KHPCTO 
The King's Health Partners Clinical Trials Office 
MHRA 
Medicines and Healthcare products Regulatory Agency 
REC 
Research Ethics Committee 
SLaM 
South London and Maudsley NHS Foundation Trust 
Tmax 
 
 
The time after administration of a drug that the Cmax is observed 
T½ 
 
 
The time taken for the plasma concentration to fall by half its original value 
 
3. BACKGROUND & RATIONALE 
Cannabidiol (CBD) has been approved as a treatment for rare childhood epilepsies(1) and could be an 
effective treatment for psychotic disorders(2), anxiety disorders(3) and addictions(4). It is available as 
an oral liquid and as standard oral capsules. 
 
The pharmacokinetics of CBD have been described in the review by Millar et al.(5). CBD is highly 
lipophilic and has poor oral bioavailability (around 5-10% in the fasted state). It also has very high 
protein binding capability (>97%) reducing the proportion of the drug which may cross the blood‐brain 
barrier and have pharmacological activity in the brain(6). CBD also undergoes extensive first-pass 
metabolism in the liver by cytochrome P450 enzymes such as CYP3A4 and CYP2C19(7). 
 
If taken with food, the absorption and bioavailability of CBD are much higher(5). In one study, a high-
fat breakfast increased maximum plasma concentration (Cmax) of CBD by 4.9x (90% CI 4.0–5.9) and 
area under the plasma concentration-time curve (AUC) by 4.2-fold (90% CI 3.6–4.9)(8). Other studies 
have similar results(9)(10). As a result of this food effect, when prescribing standard formulations of 
CBD, patients must carefully schedule their medication according to mealtimes. Otherwise, there may 
be large day-to-day variation in absorption, which will increase the risk of adverse effects or reduced 
efficacy. 
 
One way to improve the bioavailability and reduce the food effect is by using a lipid encapsulation. 
Lipids enhance intestinal absorption by forming micelles, lipid molecules arranged in a spherical form 
in aqueous solutions. Around a third of CBD is absorbed into micelles(11). Once inside enterocytes, 
lipids are incorporated into chylomicrons, also known as ultra low-density lipoproteins. These are 
assembled in enterocytes using long-chain triglycerides, phospholipids, cholesterol and 
lipoproteins(12). Chylomicrons facilitate intestinal lymphatic transport, bypassing the portal vein (and 
avoiding first-pass metabolism)(13)(14). For most drugs, absorption through the lymphatic system is 
negligible, however, for highly lipid-soluble drugs such as CBD, passage into the intestinal lymphatic 
system may represent an alternative route of delivery into the general circulation(13). Preclinical 


research using rats found that administering a lipid alongside CBD increased its peak concentration at 
mesenteric lymph nodes by 6x(15). 
 
A few studies have examined the pharmacokinetics of novel formulations of CBD in humans, though 
most of these were at very low, sub-therapeutic doses(16). One study using CBD 25mg found that, 
compared to a medium-chain triglyceride formulation, a ‘novel self-emulsifying drug delivery system’ 
increased Cmax by 4x and AUC by 2-3x(17). Another study using CBD 90mg showed that, compared to 
a powder formulation, a lipid formulation increased Cmax by 22x and AUC by 7x (18). Finally, in a pilot 
study of a lipid formulation of CBD 10mg, the mean AUC was 7x higher compared to a standard 
formulation(19).  
 
The formulation used in this study uses a range of fats that are designed to facilitate absorption by 
enterocytes in the ileum. The lipids that are all EU pharmacopoeia approved and have been used in 
medicinal products before. The effectiveness of the formulation has already been demonstrated with 
ibuprofen in the proprietary drug Flarin(20). 
 
This study will compare the pharmacokinetics of this novel lipid formulation of CBD with the standard 
formulation. It will use a dose of 1000mg as this is the dose that is effective in patients with chronic 
psychotic disorders(2). 
 
Scientific rationale for the choice of CBD dose 
There have been two major clinical trials of CBD in patients with schizophrenia. (2)(21) McGuire et al. 
demonstrated efficacy at a dose of 1000mg/day CBD (Epidiolex in the fed state), while Boggs et al. 
found no beneficial effect at a lower dose of 600mg/day (in an alternative formulation). However, the 
current consensus is that these doses were relatively low, and that the optimal dose for treating 
schizophrenia is higher. Most evidence on the efficacy and safety of CBD is from epilepsy research. In 
a recent long-term open-label trial in children and adolescents with epilepsy (n=368, mean age 16 
years, followed up for 3 years), participants were prescribed doses of CBD up to 30mg/kg/day 
(Epidiolex in the fed state).(22) After dose titration, the majority of participants were prescribed a daily 
dose greater than 20mg/kg/day, equivalent to 1400mg/day in a 70kg man. Because that study used 
Epidiolex in the fed state, the bioavailability is approximately equivalent to that with a 1000mg dose of 
the novel formulation (which mimics the effect of the fed state) in the study that we propose. In the 
epilepsy study by Patel et al., ‘doses above 20 mg/kg/day had acceptable tolerability, and no new safety 
issues emerged.’  
 
We have selected a dose of 1000mg/day of the novel (formulation of CBD SEEK-CBD) for the 
proposed study because we plan to use this dose and formulation in subsequent clinical trials in patients 
with schizophrenia. This is therefore the appropriate dose for collecting pharmacokinetic data prior to 
its use in patients. Establishing its bioavailability empirically is particularly important, as CBD does not 
demonstrate dose-proportionality. (Cmax slope 0.73; AUCt slope 0.64).(Taylor et al. 2018) 
 
A 7-fold increase in CBD exposure with 1000mg of SEEK-CBD would be dose equivalent to a 4-5 fold 
increase in exposure with 1500mg of regular CBD following a meal. In a study by Taylor et al (8),  
healthy volunteers received a single oral dose of conventional 1500 mg CBD in either the fed (high-fat 
breakfast) or fasted state. Food increased Cmax by 4.85-fold (95% CI: 4.01–5.87) and AUCt by 4.2-fold 
(90% CI 3.63–4.85). Critically, this study found that ‘there was no worsening in the severity of TEAEs 
in the fed state [compared to the unfed state], hence there is no appreciable safety concern’. Moreover, 
there were no serious adverse events: the most common were nausea, headache, and somnolence.  
 


 
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Several features of the proposed study’s design will ensure the safety of the participants. The drugs will 
be administered in a state of the art NIHR Clinical Research Facility at King’s College Hospital, which 
is purpose-built for pharmacokinetic studies of novel compounds. Adverse events will be monitored 
regularly, with medical staff will be on hand at all times. Participants will only leave the facility when 
all clinical and phsyiological measures are normal, and will be able to contact the investigators at any 
time after they leave. Participants will be able to remain in hospital overnight if required. The safety 
blood tests (LFTs, U&Es, FBC) are taken 4 hours post-dosing and the results will be available within 
24 hours. If unexpected adverse events do arise, subsequent experimental sessions can be suspended 
and the study drug dose can be reduced. This contingency has been explicitly incorporated into the 
protocol (see section 9.5). We have also limited the maximum number of dosing sessions per day to 
three, so that action can be taken before multiple participants receive the study drug. 
 
 
The gut microbiome and the endocannabinoid system 
Commensal gut bacteria synthetise endocannabinoid precursors and influence the systemic availability 
of endocannabinoid agonists (e.g., anandamide).(23) This is important as endocannabinoids may 
mediate CBD’s therapeutic effects.(24) This study will therefore complete a novel, exploratory analysis 
by comparing endocannabinoid levels within the two treatment arms to assess whether they are affected 
by the gut microbiome (ie. not between arms as the novel CBD should result in increased 
bioavailability, independent of the microbiome). The gut microbiome can also affect the activity of 
CYP3A4, a key enzyme involved in the breakdown of CBD.(25) 
 
4. OBJECTIVES AND OUTCOME MEASURES 
 
4.1 Primary objective 
To assess whether the novel formulation is able to increase the bioavailability of oral CBD in the 
fasting state. 
 
Hypothesis: the novel formulation will increase the AUCinf for a single dose of oral CBD in the fasting 
state. 
 
Primary outcome 
Difference in AUCinf for a single dose of oral CBD between the novel and standard formulations in the 
fasting state. 
 
4.2 Secondary objectives 
To characterise and compare the pharmacokinetic profiles of the novel CBD formulation and a standard 
formulation 
 
Secondary outcomes 
Differences between novel and standard formulations for: 
i. 
Maximum plasma concentration (Cmax) 
ii. 
Time after administration of drug when maximum plasma concentration is reached (Tmax) 


iii. 
Plasma half-life (t½) 
iv. 
Area under the concentration-time curve from time zero to 48hours (AUC0-48) 
 
4.3 Exploratory objective 
To assess the effect of the gut microbiome on endocannabinoid and CBD metabolism. Outcomes are 
not pre-specified as this is an exploratory analysis. 
 
4.4 TRIAL DESIGN 
Single-centre double-blind two-period crossover pharmacokinetic study.  
 
The study includes one baseline screening visit followed by two experimental visits each lasting 48 
hours, separated by a minimum 2 weeks washout. Participants will return home each day and will not 
stay in the hospital overnight. 
4.5 Trial Flow Chart  
 
Screening 
Visit 
Day -28 to day 0 
Experimental visits 1 & 2* 
Follow up visit 
 
Day 1 
Day 2 
Day 3 
7-14 days after 
experiment 2 day 1 
Consent 
X 
 
 
 
 
Demographic information 
X 
 
 
 
 
Medical Assessment** 
X 
 
Height, weight, body fat 
X 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
Urine Pregnancy test 
X 
X 
 
 
X 
Urine Drug Screen 
X 
X 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
Fasting 
 
X 
 
 
 
Drug Administration 
 
X 
 
 
 
Intravenous Cannulation 
 
X 
 
 
 
Blood sampling (FBC, LFTS, U&Es) 
X 
X 
 
 
 
Blood sampling (CBD and metabolites) 
 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
Drug Effects Questionnaire (DEQ-5) 
 
X 
X 
X 
 
Gastrointestinal Symptom Rating Scale  
 
X 
X 
X 
 
Stool Sample Kits 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
Washout period* 
 
 
 
X 
 
*Minimum 2 weeks between experimental visits 
**Includes physical exam, vital signs, urine drug screen, alcohol breath test, blood test (U&Es, LFTs, FBC) 
 
 
 


 
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5. TRIAL MEDICATION 
5.1 Study Drug 
The study drug is cannabidiol, a naturally occurring phytocannabinoid with minimal adverse effects. 
CBD oral solution is an approved treatment for rare childhood epilepsy syndromes. 
 
The trial will use two formulations of CBD: 
 
1. CBD standard formulation (STD-CBD) 
2. CBD novel lipid formulation (SEEK-CBD). 
 
Participants will be administered the same total dose of CBD in both arms (1000mg). Both STD-CBD 
and SEEK-CBD capsules contain 200mg CBD. Participants will therefore be administered 5x 200mg 
capsules. 
 
The study drug will be provided by SEEK pharmaceuticals. The trial will use the same source of CBD 
for both arms. 
 
The two formulations will have an identical appearance so that participants cannot tell which 
formulation they have been administered. 
 
5.2 Risks, known drug reactions and interaction with other therapies 
The risks associated with the study are minimal. CBD has few adverse effects. A meta-analysis of 
randomized controlled clinical trials found that when prescribed alone, diarrhoea was the only adverse 
effect (26). CBD also has pharmacokinetic interactions with other medicines via hepatic CYP enzymes, 
but these are highly unlikely to be relevant to this study as concomitant medications (apart from 
contraceptives) are prohibited. Previous studies have tested oral doses of CBD (Epidiolex) as high as 
4500mg and 6000mg without severe or serious adverse events(8) (27). 
 
The BNF recommends that clinicians should avoid prescribing enzyme-inducing drugs alongside 
contraceptive medications. CBD is a potent inhibitor of CYP2C19 and CYP3A4 and is not known to 
have any other clinically relevant enzyme interactions(6). 
 
CBD is not known to cause drug reactions. 
  
5.3 Formulation 
SEEK pharmaceuticals will provide both formulations.  
 
The novel SEEK-CBD formulation contains the following excipients: 
• Gelucire 43/01 (glycerides only; hard fat [EP]), manufactured by Gattefosse 
• Maisine CC (glyceryl monolinoleate), manufactured by Gattefosse 
• PEG 400 (polyethylene glycol 400) 
 


 
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Each 200mg CBD capsule contains 400mg Gelucire 43/01, 200mg Maisine CC and 0.008mls PEG 400. 
The Maisine CC, Gellucire 43/01 and PEG400 are mixed with heating in a closed vessel to 50oC 
degrees. CBD is added in a single portion and is stirred at 50oC for 30 minutes. The mixture is cooled 
to approximately 40oC and then filled into the hard gelatin capsules. The top part of the capsule is 
replaced and the filled capped capsules are left to stand at room temperature until solidified. The 
capsules are then stored in a plastic bag. All excipients are GMP approved. The materials used in the 
manufacture of the capsules is of plant origin. 
 
5.4 Drug storage and supply  
The investigational product will be purchased from the manufacturer free of charge. It will be stored 
below 25oC°C in the Maudsley Pharmacy. At the end of the study, any unused study drug will either 
be returned to the manufacturer or will be destroyed by the Maudsley Pharmacy according to standard 
local procedures. 
 
5.5 Preparation of Investigational Medicinal Product 
The study drug will be manufactured by Eurofins. It will be sent to IPS Pharma who will add the 
Annex 13 labels. IPS Pharma will complete the final Qualified Person (QP) release. The labels will 
have been approved by Maudsley Pharmacy. The study drug will dispensed by the Maudsley pharmacy 
according to standard procedures. 
 
5.6 Dosing, Compliance & Drug Accountability 
Participants will be administered a dose of CBD 1000mg on each experimental visit. There will be a 
minimum of 2 weeks washout between study drug administrations (i.e. between day 1 of each 
experiment). There is no maximum timeframe between doses. Eligibility for the study will be 
reassessed on Day 1 of experimental visit 2. 
 
There are not expected to be any issues with either compliance or drug accountability. Full IMP 
accountability will be maintained. If medication is dispensed by the Maudsley Pharmacy but is not 
administered (for example, if a participant withdraws from the study during an experimental visit) the 
drug will be returned to the Maudsley Pharmacy to be disposed of according to standard local 
procedures. 
 
 
5.7 Concomitant Medication 
Apart from contraceptives, concomitant medications are not permitted during the study and are an 
exclusion criterion. 
 
There is inadequate information on the effects of cannabidiol on the foetus. Female participants of 
child-bearing potential* should use a highly effective method of contraception** for the duration of the 
trial and for 4 weeks after the completion of the trial.  
 
*A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined 
as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone 


(FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. 
 
 ** Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include: 
 
• combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
• 
oral 
• 
intravaginal 
• 
transdermal 
 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
oral 
• 
injectable 
• 
implantable 
 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system ( IUS) 
• bilateral tubal occlusion 
• vasectomised partner 
• sexual abstinence (abstinence should only be used as a contraceptive method if it is in line with 
the subjects’ usual and preferred lifestyle. Periodic abstinence (calendar, symptothermal, post-
ovulation methods) is not an acceptable method of contraception) 
Males participants must be willing to use a condom throughout the duration of the study. 
 
6. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
 
6.1 Inclusion criteria 
i. 
Healthy volunteers. Defined as healthy on the basis of a clinical history, physical examination, 
ECG, vital signs, and laboratory tests of blood and urine. 
ii. 
Age 18-45 
iii. 
Agreeing to fast 15 hours; 10pm-1pm on dosing days 
iv. 
Capable of giving informed consent 
v. 
Written informed consent from participant 
 


 
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6.2 Exclusion criteria 
i. 
Clinically relevant medical history, physical findings, ECG, or laboratory values at the pre-trial 
screening assessment that could interfere with the objectives of the trial or the safety of the 
participant. 
ii. 
Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the 
volunteer’s participation in the trial or make it unnecessarily hazardous. 
iii. 
Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary 
heart disease, or history of any neurological or mental illness. 
iv. 
Surgery or medical condition that might affect absorption of medicines. 
v. 
Blood pressure and heart rate in supine position at the screening examination outside the 
ranges: blood pressure 90–140 mm Hg systolic, 40–90 mm Hg diastolic; heart rate 40–100 
beats/min. Repeat measurements are permitted if values are borderline (i.e. values that are 
within 5 mm Hg for blood pressure or 5 beats/min for heart rate) or if requested by the 
investigator. Subjects can be included if the repeat value is within range or still borderline but 
deemed not clinically significant by the investigator. 
vi. 
Loss of more than 400 mL blood during the 3 months before the trial, e.g. as a blood donor. 
vii. 
Any prescribed medication (apart from contraceptives) 
viii. 
Use of any CBD products within six months of IMP administration 
ix. 
Use of any over-the-counter medications or health supplements within the past 2 weeks 
x. 
BMI <18 or >30.0kg/m2 
xi. 
History of alcohol or substance misuse disorder 
xii. 
Intake of more than 14 units of alcohol weekly. 
xiii. 
Smokes more than 10 cigarettes per day 
xiv. 
Use of any illicit substances within the last six months 
xv. 
Pregnant or breastfeeding 
xvi. 
Women of childbearing potential (as defined in CTFG guidelines, see 5.7 Concomitant 
Medication) not willing to use a highly effective form of contraception (as defined in CTFG 
guidelines, see section 5.7 Concomitant Medication) during participation in the study or male 
patients not willing to ensure use of a condom during participation in the study. 
xvii. 
eGFR≤ 70 mls/min 
xviii. 
Any liver function or renal function test abnormality. A repeat is allowed on one occasion for 
determination of eligibility. 
xix. 
Urine drug screen positive for any substances 
xx. 
Positive alcohol breath test  
xxi. 
Participant in any other clinical trial or experimental drug study in the past 3 months 
xxii. 
Known hypersensitivity to CBD and/or SEEK formulation excipients 
xxiii. 
Participant is not able to swallow capsules 
 
6.3 Recruitment 
Participants will contact the research team via email in response to the recruitment advertisements if 
they are interested in taking part in the study. 


 
6.4 Payment  
Participants will be reimbursed for their time at a rate equivalent to £10.55/hour. The total time 
commitment for each participant is 34 hours. The payment to participants on successful completion of 
the whole study will be £360. It is essential that participants attend on time for all blood tests across 
both experiments, therefore, participants will only be paid on successful completion of all aspects of 
the study. If a participant completes the baseline visit but does not complete experimental visits they 
will be paid £40. If a participant successfully completes the optional stool sampling assessments they 
will receive an additional £20. The total potential reimbursement is therefore £380. 
 
6.5 Pre-screening 
Prior to the pre-screen, the participant will be emailed a Participant Information Sheet (PIS). This will 
be done at least 24 hours before the experimental visit. Potential participants will be allowed as much 
time as need to decide to whether or not to participate. They will then be contacted by one of the 
researchers by telephone and asked to answer questions relating to their eligibility for the study. They 
will have the opportunity to ask the researcher questions about the study during the call. If the 
participants’ responses are satisfactory, the participant will be invited for a screening visit.  
 
6.6 Screening 
The screening visit will be held at the King’s CRF. It will be performed no longer than 28 days prior to 
IMP administration. 
• Gaining informed consent 
• Recording demographic details: sex, date-of-birth, ethnicity, previous medical history, 
medication history, and alcohol and substance use history  
• Recording vital signs, height, weight, BMI and body fat content 
• Urine drug screen for illicit drug use and pregnancy 
• Urinalysis, alcohol breath test 
• Blood tests: full blood count (FBC), urea and electrolytes (U&Es) and liver function tests 
(LFTs) 
• Stool sample provided to take home (optional) 
 
6.7 Consent  
Informed consent will be obtained prior to the participant undergoing procedures that are specifically 
for the purposes of the trial. The right of a participant to refuse participation without giving reasons will 
be respected. The participant will remain free to withdraw at any time from the trial without giving 
reasons. They will be provided with a contact point where they may obtain further information about 
the trial. Potential participants should be able to give consent and a person is assumed to have mental 
capacity to make a decision unless it is shown to be absent. Consent will be taken by medical doctors 
who are duly authorised, trained and competent to participate according to the ethically approved 
protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki. 
 
Written material consisting of participant information leaflet and consent documentation will be 
approved by the Research Ethics Committee and will be in compliance with GCP, local regulatory and 
legal requirements. There will be opportunity for the participant to ask questions to a member of the 
research team. The patient will be given as much time as required to consider the information and 
consider their participation. A copy of the consent form and PIS will be given to the participant, with 


 
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the original consent filed in the investigator site file and a copy of the consent form in the Case Report 
Form.  
 
6.8 Randomisation 
Subjects will be randomised into the study provided they have satisfied all subject selection criteria. A 
web based randomisation system will be designed, using the bespoke King’s Clinical Trials Unit 
(KCTU) randomisation system and will ensure each treatment is equally distributed across each study 
period. The randomisation system will be created in collaboration with the study team and maintained 
by the KCTU for the duration of the project. It will be hosted on a dedicated server within KCL. The 
Chief Investigator (CI) or delegate will request usernames and passwords from the KCTU. System 
access will be strictly restricted through user-specific passwords to the authorised research team 
members. It is a legal requirement that passwords to the randomisation system are not shared, and that 
only those authorised to access the system are allowed to do so. If new staff members join the study, a 
user-specific username and password must be requested via the CI or delegate from the KCTU team 
and a request for access to be revoked must be requested when staff members leave the project. Study 
site staff experiencing issues with system access or functionality should contact the CI or delegate in 
the first instance. 
 
Participant initials and date of birth will be entered on the randomisation system, NHS number, email 
addresses, participant names and addresses and full postcodes will not be entered into the 
randomisation system. No data will be entered onto the randomisation system unless a participant has 
signed a consent form to participate in the study. Randomisation will be undertaken by authorised staff 
onto the randomisation system by going to www.ctu.co.uk and clicking the link to access the 
randomisation system. A full audit trail of data entry will be automatically date and time stamped, 
alongside information about the user making the entry within the system. 
 
The CI team will undertake appropriate reviews of the entered data, for the purpose of data 
cleaning.  No data can be amended in the system, however CI or delegate may request King’s Clinical 
Trials Unit to add notes against individual subject entries to clarify data entry errors. 
Upon request, KCTU will provide a copy of the final exported dataset to the CI in .csv format and the 
CI will onward distribute as appropriate.  
 
6.9 Blinding and Emergency Unblinding 
The study will be double-blind with unblinding occurring at the end of data collection on approval by 
the Principal Investigator. The capsules will be identical in appearance so both the investigators and 
participants will remain blinded to treatment allocation. The Maudsley pharmacy will hold treatment 
allocation information for each participant, with 24-hour non-resident on-call access and can be called 
at any time to unblind a specific session. 
 
Participants will be monitored before and after dosing and not discharged until medically cleared. 
Delayed adverse effects to study medications after discharge are unlikely, however, if required 
emergency unblinding will be provided by the on-call pharmacist. Unblinding protocol and reporting 
will be applied according to the local pharmacy procedures. 
 
Out of Hours Emergency Contact  


Participants will be provided with a contact card when receiving the study medication, so that they can 
contact the investigators in case of emergency out of hours. The investigator will contact the on-call 
pharmacist if unblinding is required. Participants will also be instructed to dial 999 or 111 in case of 
emergency. 
 
6.10 Withdrawal criteria  
i. 
Withdrawal of consent 
ii. 
Significant abnormalities detected during the medical assessment or blood tests at the 
screening visit 
iii. 
Use of alcohol, illicit substances 24hour before or during experiments 
iv. 
Use of over-the counter medications, health supplements or CBD products 
v. 
Use of prescribed medications (excluding the intrauterine device or intrauterine system) 
vi. 
Suspected Unexpected Serious Adverse Reaction  
vii. 
Participant does not attend follow-up point 
viii. 
Investigator discretion 
 
 
Participants have the right to withdraw from the study at any time for any reason. The investigator also 
has the right to withdraw participants from the study drug in the event of inter-current illness, AEs, 
SAEs, SUSARs, protocol violations, cure, administrative reasons or other reasons.  It is understood by 
all concerned that an excessive rate of withdrawals can render the study un-interpretable; therefore, 
unnecessary withdrawal of participants should be avoided.  Should a participant decide to withdraw 
from the study, all efforts will be made to report the reason for withdrawal as thoroughly as possible. 
Withdrawn participants will be replaced. 
 
6. 11 Expected duration of the trial 
The end of trial will be defined as the database lock. 
7. TRIAL PROCEDURES  
7.1 Setting 
NIHR-Wellcome Trust Kings Clinical Research Facility (CRF) 
7.2 Eligibility Review 
The study team will review participants eligibility for the study at the start of each experimental visit. 
This will include a urine drug screen and alcohol breath test. 
7.3 Fasting Requirements 
Participants will fast from 10pm the previous evening and will not eat until 4 hours after drug 
administration on the first day of each experimental visit. Participants will be allowed to drink water 
only. 
7.4 Administration 
Drug administration will be at approximately 9am on the first day of each experiment.  
Oral administration. 
Participants will not be informed which formulation of drug they are being administered. 


 
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7.5 Trial assessments 
7.5.1 Blood sampling 
Blood samples will be drawn at the following time-points on experimental visits: 
Pre-dose (0-5mins), 0.5, 1, 2, 3, 4, 5, 6, 8, 24, and 48hrs post-dose. The 24hr and 48hour samples 
should be taken within 15minutes of the target time. 
 
7.5.2 Vital signs 
Vital signs (HR, RR, BP, Temp) will be recorded on experimental visits at the following times: pre-
dose and 1, 2 4, 8, 24 and 48hrs post-dose. Urinalysis will be completed 4hrs post-dose. The 24hr and 
48hour readings should be taken within 15minutes of the target time. 
 
7.5.3 Adverse events 
Participants will be asked to report adverse events at each blood sampling timepoint i.e. pre-dose (0-
5mins), 0.5, 1, 2, 3, 4, 5, 6, 8, 24, 48hrs post-dose and at the 7-14 day follow-up visit . Participants will 
be asked specifically about adverse events including, but not limited to, anxiety, irritability, 
somnolence, dizziness, disorientation, nausea, abdominal pain, abdominal distension, diarrhoea, 
vomiting, and flatulence. 
 
7.5.4 Drug Effects Questionnaire (DEQ-5) 
The DEQ-5 is questionnaire with five items, for example ‘‘Do you feel a drug effect, right now?’ with 
the response anchors ‘Not at all’ and ‘Extremely’ (Morean et al. 2013 [9]). It will be recorded on 
experimental visits at the following times: pre dose and at 1, 2, 4, 8, 24 and 48hrs post-dose. 
 
7.5.5 Gastrointestinal Symptom Rating Scale (GSRS) 
The GSRS is a 15-item rating scale which assesses five symptom clusters: reflux, abdominal pain, 
indigestion, diarrhoea and constipation. Each item is assessed with a 7-point Likert scale. The standard 
recall period for the scale is 7 days; this will be amended so that it assesses past 24 hours only. The 
scale will be used pre-dose and at 24 and 48 hours post dose. (28) 
 
7.5.6 Stool Sample / Gut Microbiome (Exploratory analysis) 
To assess the effect of the gut microbiome on the CBD’s pharmacokinetics and circulating 
endocannabinoid levels, a stool sample will be collected prior to each drug administration. Participants 
will be provided with stool sampling kits at the screening visit. This part of the study is optional. 
 
 
7.6 Laboratory Procedures 
At the screening visit, a blood sample will be taken to test for haematology (FBC) renal function (urea 
and electrolytes) and hepatic function (liver function tests, including bile acids). These tests will be 
repeated on experimental visits pre-dose and 4-hours post-dose on experimental visits. The test will be 
completed by ViaPath and be processed according to standard local procedures. 
 
Urine samples for urinalysis, drug and pregnancy testing will be collected in standard collection pots. 
The samples will be disposed of as soon as tests are successfully completed. 
 
At the screening visit, participants will be provided with pre-packaged and pre-addressed kits for at-
home stool collection. Participants will be asked to mail stool kits before day 1 of each experimental 


visits. Kits will be mailed to the Oxford Centre for Microbiome Studies for analysis on the gut 
microbiome.  
 
On day 1 of each experimental visit, participants will have a venous cannula inserted for collection of 
blood samples. On days 2 and 3 of each experiment, for the 24 hour and 48 hour time-points, 
venepuncture will be performed a single sample will be taken. Blood samples will be collected in 5ml 
EDTA tubes.  
 
Within 10min of collection, the samples will be centrifuged (3000rpm for 10minutes). The plasma will 
be decanted from the tube into two screw-cap collection tubes and immediately placed in a -20oC 
freezer in the CRF. The stored samples will be anonymised with participant ID, visit number and time 
point. Only the research team will be able to link ID number to participant details. At the end of each 
day, the samples will be moved to a -80oC freezer for longer term storage in the King’s Clinical Trials 
Facility. 
 
Only plasma will be stored so that analyses can be completed. No human tissue will be stored at the 
end of the research. Biological samples collected from participants as part of this trial will be 
transported, stored, accessed and processed in accordance with the 2004 Human Tissue Act. 
 
 
7.7 Visit by visit events 
7.7.1 Recruitment 
Participants will contact the research team via email in response to the recruitment advertisements if 
they are interested in taking part in the study. 
 
7.7.2 Screening visit 
The following interventions and assessments will be completed in order at the screening visits: 
i. 
Informed consent 
ii. 
Collection of demographic information 
iii. 
Medical review and examination 
iv. 
Height, weight, body fat 
v. 
Review of eligibility 
vi. 
Urine sample for urinalysis, pregnancy and illicit drugs testing 
vii. 
Alcohol breath test 
viii. 
Blood sampling 
ix. 
Vital Signs 
x. 
Stool sampling kit provided to take home (optional) 
xi. 
Fasting instructions 
xii. 
Alert card and safety instructions 
 
7.7.3 Experimental Visit 
7.7.3.1 Day 1 
The following interventions and assessments will be completed in order: 
i. 
Fasting (previous night from 10pm) 
ii. 
Eligibility review 
iii. 
Urine sample for pregnancy and illicit drugs testing 


 
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iv. 
Alcohol breath test 
v. 
GSRS 
vi. 
Intravenous cannulation 
vii. 
Pre dose; 0-5mins: blood sampling; vital signs; DEQ-5  
viii. 
0 mins: drug administration 
ix. 
30mins: blood sampling 
x. 
1 hour: blood sampling; vital signs; DEQ-5 
xi. 
2 hours: blood sampling; vital signs; DEQ-5 
xii. 
3 hours: blood sampling 
xiii. 
4 hours: blood sampling; vital signs; DEQ-5; urinalysis 
xiv. 
5 hours: blood sampling 
xv. 
6 hours: blood sampling 
xvi. 
8 hours: blood sampling; vital signs; DEQ-5; adverse events assessment 
 
7.7.3.1 Day 2 
i. 
24 hours post dose: blood sampling; vital signs; DEQ-5; GSRS; adverse events assessment 
 
7.7.3.1 Day 3 
i. 
48 hours post dose: blood sampling; vital signs; DEQ-5; GSRS; adverse events assessment. 
ii. 
Payment via bank transfer (if final visit) 
iii. 
Book follow-up visit (if final visit) and provide a urine pregnancy test (if female) 
 
7.7.4 Washout 
There will be a minimum 2 week washout between experimental visits. 
 
7.7.5 Follow-up visit 
The follow-up visit will be completed via remote video call 7-14 days after day 1 of experiment 2. 
Participants will be asked to report adverse events. Female participants of childbearing potential will be 
asked to confirm the result of a urine pregnancy test completed on that day. 
 
 
7.8 Planned analyses 
Blood samples will be analysed for CBD and its metabolites (including 6-OH-CBD, 7-OH-CBD, 7-
COOH-CBD) CBDA, THC, endocannabinoids (including anandamide and 2-arachidonoylglycerol). 
Additional unplanned analyses of relevant metabolites, biomarkers or inflammatory markers may also 
be completed. The laboratory analyses will be completed at the University of Turku, Finland. Analyses 
will be completed once all samples have been collected, at the end of the study. All analyses will be 
completed in accordance with relevant guidance and legislation. 
 
 


8. COVID-19 
The study’s COVID risk assessment highlighted no trial procedures which present risks beyond those 
which are encountered in routine clinical care (i.e. there are no vulnerable participants and no aerosol 
generating procedures). Therefore, standard King’s College Hospital’s guidance on the management of 
SARS-CoV-2 associated risks will be followed throughout the study. Vaccinations and vaccination 
status are not relevant to the trial or any of its procedures. If the CRF were to close due to any reason, 
follow-up and safety assessments will be completed at an appropriate NHS or KCL facility or online. 
9. SAFETY 
 
9.1 Definitions 
The Medicines for Human Use (Clinical Trials) Regulations 2004 and Amended Regulations 2006 
gives the following definitions: 
 
• Adverse Event (AE): Any untoward medical occurrence in a participant to whom a medicinal 
product has been administered, including occurrences which are not necessarily caused by or 
related to that product. 
 
• Adverse Reaction (AR): Any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose administered to that participant. 
 
• Unexpected Adverse Reaction (UAR): An adverse reaction the nature and severity of which is 
not consistent with the information about the medicinal product in question set out in the 
investigator’s brochure for CBD. 
 
• Serious adverse Event (SAE), Serious Adverse Reaction (SAR) or Suspected Unexpected 
Serious Adverse Reaction (SUSAR): Any adverse event, adverse reaction or unexpected 
adverse reaction, respectively, that: 
o results in death; 
o is life-threatening; 
o required hospitalisation or prolongation of existing hospitalisation; 
o results in persistent or significant disability or incapacity; 
o consists of a congenital anomaly or birth defect. 
 
• Important Medical Events (IME) & Pregnancy: Events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above should 
also be considered serious. Although not a serious adverse event, any unplanned pregnancy will 
also be reported via the SAE reporting system. 
 
9.2 Investigator Assessment  
The investigator will seek information on adverse events from participants at 8 hours, 24 hours and 48 
hours after each drug administration. Participants will also be able to spontaneously report adverse 
events throughout the lifetime of the trial. The investigator will use specific questioning and, as 
appropriate, examination. Information elicited will be recorded participant’s Case Report Form. All 


 
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clearly related signs, symptoms, and abnormal diagnostic procedures will be recorded. The clinical 
course of each event should be followed until resolution or stabilisation. 
 
 
9.3 Reporting Responsibilities 
The sponsors have delegated the delivery of the Sponsor’s responsibility for Pharmacovigilance (as 
defined in Regulation 5 of the Medicines for Human Use (Clinical Trials) Regulations 2004 to the 
King’s Health Partners Clinical Trials Office (KHP-CTO).  
 
All SAEs, SARs and SUSARs will be reported immediately (and certainly no later than 24hrs) by the 
Investigator to the KHP-CTO and CI for review in accordance with the current Pharmacovigilance 
Policy. The KHP-CTO will report SUSARs to the MHRA. 
 
The Chief Investigator will report to the relevant ethics committee. Reporting timelines are as follows: 
• SUSARs which are fatal or life-threatening must be reported not later than 7 days after the 
sponsor is first aware of the reaction. Any additional relevant information must be reported 
within a further 8 days; 
• SUSARs that are not fatal or life-threatening must be reported within 15 days of the sponsor 
first becoming aware of the reaction.   
 
The Chief Investigator and KHP-CTO (on behalf of the sponsor), will submit a Development Safety 
Update Report (DSUR) relating to this trial IMP, to the MHRA and REC annually. 
 
King’s College London will undertake all sponsor duties and pharmacovigilance. The Investigator is 
responsible for ensuring that all adverse events occurring during the study treatment period are 
recorded on Case Report Forms. 
 
9.4 Premature Termination of the Trial 
The trial may be prematurely discontinued by the Sponsor, Chief Investigator or Regulatory Authority 
on the basis of new safety information or for other reasons given by the trial’s research team, regulatory 
authority or ethics committee concerned. If the trial is prematurely discontinued, active participants 
will be informed and no further participant data will be collected. The Competent Authority and 
Research Ethics Committee will be informed within 15 days of the early termination of the trial. There 
are no pre-specified treatment stopping rules. 
 
9.5 Dose adjustment  
If the study drug is associated with adverse effects that are a cause for concern, the study can be paused 
and the dose reduced before further experiments are completed. The study’s Principal Investigator will 
be responsible for this decision and will take into account the incidence of adverse effects, their 
severity and other relevant factors. If necessary, the sample size of the study may be increased to 
ensure that the planned number of subjects receive both formulations at the same dose. 


10. STATISTICS AND DATA ANALYSIS 
10.1 Power analysis 
As the means are unknown, we base the power calculation on minimum detectable difference assuming 
the AUC coefficient of variation in CBD is 50% (Taylor et al. 2018(8)). Since there is no carry-over 
effect in the study, an appropriate analysis of continuous data from a two-period, two-intervention 
cross-over trial is a paired t-test (29). For the primary outcome, the bioavailability of lipid versus 
standard formulation in the fasted state, a paired t-test with n=12 has 80% power, at alpha=0.05 (2 
tailed) to detect a 44.5% difference in means. 
 
Previous studies demonstrated increased bioavailability with lipid formulations of 7x(19). The study is 
adequately powered to demonstrate these differences. This sample size and design satisfies EMA 
recommendations for design and minimum sample size (n=12) in pharmacokinetic studies for 
comparing formulations. 
 
10.2 Planned recruitment 
The study requires 12 complete datasets. With an expected drop-out rate of 15%, we expect to recruit 
14 participants. 
 
10.3 Statistical analysis plan 
 
Pharmacokinetics parameters 
Pharmacokinetic parameters will be summarized descriptively. Continuous outcomes will be reported 
as means with standard deviation. Categorical outcomes will be reported as frequencies. Individual 
participant’s pharmacokinetic data may also be presented in tables and graphs. The plasma 
concentration-time data will be subject to non-compartmental pharmacokinetic analysis using 
appropriate computer software applications. Linear and/or log-linear plots will be presented.  To assess 
bioavailability between the formulations, log transformed AUC, Cmax observations will be entered into 
a linear mixed model to account for the repeated measures and between subject conditions. Linear 
contrasts representing the difference between conditions will be expressed as ratio of geometric means 
along with 95% CI and inference based on p < 0.05. Planned analysis will be per protocol. 
 
Protocol violations  
All protocol violations, including inclusion/exclusion criteria violations and violations during the trial, 
will be listed, even if they are believed not to influence any of the results. 
 
Demographics 
For all participants, descriptive statistics of demographic (e.g., sex, age, BMI, and other baseline 
characteristics) will be presented by overall. 
 
Safety measures 
Summary tables showing vital signs e.g., body temperature, respiratory rate, pulse rate, and SBP and 
DBP will be provided at each study time point and changes from baseline. 
Individual physical examination will be listed and summarised at each study time point. 
Important Medical Event, drug, pregnancy test results during the study will be listed. 
 
Visual Analogue Scales & Drug Effects Questionnaire (DEQ-5) 
A summary table of DEQ-5 will be summarised descriptively. 


 
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Laboratory results 
Laboratory parameters including haematology, blood chemistry, and urinalysis will be listed 
accompanied by an indication if the parameter is outside the reference range. A summary of all data 
outside the reference range of the clinical laboratory will be provided. Clinical laboratory data will be 
presented descriptively, where applicable. 
 
Adverse events 
A listing of all individual AEs, AR, UAR, SAE, SAR, and SUSAR will be provided. Summary tables 
of TEAEs will be presented by system organ class based on the MedDRA terminology list (preferred 
terms): 1 containing the number of TEAEs (frequency of occurrence, number of participants/patients 
experiencing the event) by treatment and 1 containing the number of drug related TEAEs (frequency of 
occurrence, number of participants/patients experiencing the event) per treatment. Additional tables of 
total counts by treatment and relationship and by treatment and severity will be given. 
 
The final statistical analysis plan will be in place prior to study database lock. 
11. TRIAL STEERING, DATA MONITORING AND ETHICS  
MONITORING COMMITTEES 
This is a small pharmacokinetic study with a short duration and short follow-up. Safety and 
pharmacovigilance are important components of the study but costs of running these committees have 
to offset against the benefit in such a small trial, and also the minimal expected risk from previous 
published data where cannabidiol has been used in healthy participants and patients. Therefore, there 
will be no data monitoring or trial steering committees for this study.  
 
12. DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
The Investigators will permit trial-related monitoring, audits, REC review, and regulatory inspections 
by providing the Sponsors, Regulators and REC direct access to source data and other documents (e.g. 
participants’ case sheets, blood test reports). 
 
13. ETHICS AND REGULATORY APPROVALS 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the 
principles of GCP and in accordance with all applicable regulatory requirements including but not 
limited to the Research Governance Framework and the Medicines for Human Use (Clinical Trial) 
Regulations 2004, as amended in 2006 and any subsequent amendments. 
 
This protocol and related documents will be submitted for review to Health Research Authority (HRA), 
Research Ethics Committee (REC), and to the Medicines and Healthcare products Regulatory Agency 
(MHRA) for Clinical Trial Authorisation. 
 


The Chief Investigator will submit a final report at conclusion of the trial to the KHP-CTO (on behalf 
of the Sponsor) and the REC within the timelines defined in the Regulations. The KHP-CTO or 
delegate will upload the final report to EudraCT on behalf of the Sponsor. 
 
14. QUALITY ASSURANCE 
This is a small pharmacokinetic study with a short duration and short follow-up where the majority of 
outcome data will not be available until after laboratory analysis. The benefits of data audit are 
therefore limited. Data will be made available for inspection and monitoring by relevant authorities on 
request.  Monitoring of this trial will be to ensure compliance with Good Clinical Practice and 
scientific integrity will be managed and oversight retained, by the KHP-CTO Quality Team. 
15. DATA HANDLING AND MANAGEMENT 
The study will adhere to KCL’s policy on data management, security and sharing. Participants will 
provide mobile phone numbers so that we can contact them during the study. If a participant requests, 
they will be contacted with the study outcome. 
 
The Chief Investigator will act as custodian for the study data and all participant data will be pseudo-
anonymised. Data will be collected using source data questionnaires (pen and paper). Each study 
participant will be given a study ID. Source documents will be named with this ID. The source 
documents will be kept in locked cabinets. Study data will be transcribed to the Elsevier MACRO EDC 
system.  
 
All trial data will be stored in line with the Medicines for Human Use (Clinical Trials) Amended 
Regulations 2006 and the Data Protection Act and archived in line with the Medicines for Human Use 
(Clinical Trials) Amended Regulations 2006 as defined in the Kings Health Partners Clinical Trials 
Office Archiving Standard Operating Procedure (SOP). 
 
Research data will be stored for a minimum of 10 years following the completion of the study. Case 
report forms will be scanned so that they can be stored electronically along with other data from the 
study. We plan to store the data on King's College London Research Data Management system. 
 
Access to the final trial dataset 
The trial steering group will have access to the final dataset of the trial. The dataset will also be made 
available to the study investigators, and the trial statistician. 
16. DISSEMINIATION POLICY 
Data arising from the trial will be owned by King’s College London. It is intended that the results of 
the study will be reported and disseminated at international conferences and in peer-reviewed scientific 
journals. Where appropriate, the results will be disseminated to the general public by means of press 
releases, posts on social media and at public engagement events. The Consort Guidelines and checklist 
will be reviewed prior to generating any publications for the trial. Individual participants will not be 
identifiable in publications. 
 


 
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17. INDEMNITY 
Insurance and indemnity will be provided by King’s College London policies. 
18. FINANCIAL ASPECTS 
Philip McGuire NIHR Senior Investigator Award, Activity Code: RE13018 
 
The study drug and formulation will be provided by SEEK pharmaceuticals. 
29. ARCHIVING 
At the end of this trial, all trial data will be stored in line with the Medicines for Human Use (Clinical 
Trials) Amended Regulations 2006 and the 2018 Data Protection Act and archived in line with the 
Medicines for Human Use (Clinical Trials) Amended Regulations 2006 as defined in the Sponsor 
Archiving SOP. 
20. AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
1.1 
10/01/2022 
Edward 
Chesney 
MHRA recommended changes 
1 
1.2 
07/03/2022 
Edward 
Chesney 
Non-substantial 
 
21. SIGNATURES 
 
 
 
 
______________________________________ 
 
_________________________ 
Chief Investigator 
 
 
 
 
 
Date 
Prof Philip McGuire 
 
 
 
 
  
 
 
 
 
12/04/2022 
______________________________________ 
 
_________________________ 
Trial Co-ordinator 
 
 
 
 
 
Date 
Dr Edward Chesney 
 
 
 


______________________________________ 
 
_________________________ 
Trial Statistician   
 
 
 
 
 
Date 
Oranuch Nampaisan 
 
 
 
 
 
 
 
 
 
 
REFERENCES 
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Lattanzi S, Brigo F, Trinka E, Zaccara G, Cagnetti C, Del Giovane C, et al. Efficacy and 
Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs 
[Internet]. 2018;78(17):1791–804.  
2.  
McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, et al. Cannabidiol 
(CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled 
trial. Am J Psychiatry. 2018;175(3):225–31.  
3.  
Linares IM, Zuardi AW, Pereira LC, Queiroz RH, Mechoulam R, Guimaraes FS, et al. 
Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public 
speaking test. Brazilian J Psychiatry. 2019;41(1):9–14.  
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Prud’homme M, Cata R, Jutras-Aswad D. Cannabidiol as an Intervention for Addictive 
Behaviors: A Systematic Review of the Evidence TL  - 9. Subst Abus Res Treat 
[Internet]. 2015;9 VN-re:33–8.  
5.  
Millar SA, Stone NL, Yates AS, O’Sullivan SE. A systematic review on the 
pharmacokinetics of cannabidiol in humans. Vol. 9, Frontiers in Pharmacology. 
Frontiers; 2018. p. 1365.  
6.  
Landmark CJ, Brandl U. Pharmacology and drug interactions of cannabinoids. Epileptic 
Disord. 2020;22:S16–22.  
7.  
Ujváry I, Hanuš L. Human metabolites of cannabidiol: a review on their formation, 
biological activity, and relevance in therapy. Cannabis cannabinoid Res. 2016;1(1):90–
101.  
8.  
Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, 
placebo-controlled, single ascending dose, multiple dose, and food effect trial of the 
safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy 
subjects. CNS Drugs. 2018;32(11):1053–67.  
9.  
Crockett J, Critchley D, Tayo B, Berwaerts J, Morrison G. A phase 1, randomized, 
pharmacokinetic trial of the effect of different meal compositions, whole milk, and 
alcohol on cannabidiol exposure and safety in healthy subjects. Epilepsia. 
2020;61(2):267–77.  
10.  Birnbaum AK, Karanam A, Marino SE, Barkley CM, Remmel RP, Roslawski M, et al. 
Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with 
refractory epilepsy. Epilepsia. 2019;60(8):1586–92.  
11.  Zgair A, Wong JCM, Lee JB, Mistry J, Sivak O, Wasan KM, et al. Dietary fats and 
pharmaceutical lipid excipients increase systemic exposure to orally administered 
cannabis and cannabis-based medicines. Am J Transl Res. 2016;8(8):3448.  
12.  Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Metab. 
2009;296(6):E1183–94.  
13.  Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: 
optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6(3):231–48.  
14.  Franco V, Gershkovich P, Perucca E, Bialer M. The Interplay Between Liver First-Pass 
Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol 
Oral Formulations. Clin Pharmacokinet. 2020;1–8.  
15.  Zgair A, Lee JB, Wong JCM, Taha DA, Aram J, Di Virgilio D, et al. Oral administration 
of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic 
system and prominent immunomodulation. Sci Rep. 2017;7(1):1–12.  
16.  Millar SA, Maguire RF, Yates AS, O’Sullivan SE. Towards Better Delivery of 


 
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IRAS: 288415 
 
Version 1.2 07/03/2022 
29 
 
Cannabidiol (CBD). Pharmaceuticals. 2020;13(9):219.  
17.  Knaub K, Sartorius T, Dharsono T, Wacker R, Wilhelm M, Schön C. A Novel Self-
Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb® Formulation 
Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects. 
Molecules. 2019;24(16):2967.  
18.  Izgelov D, Davidson E, Barasch D, Regev A, Domb AJ, Hoffman A. Pharmacokinetic 
investigation of synthetic cannabidiol oral formulations in healthy volunteers. Eur J 
Pharm Biopharm. 2020;154:108–15.  
19.  Blair E. Liposomal Cannabidiol Delivery: A Pilot Study. Am J Endocannabinoid Med. 
2020;2(1).  
20.  Bierma-Zeinstra SMA, Brew J, Stoner K, Wilson R, Kilbourn A, Conaghan PG. A new 
lipid formulation of low dose ibuprofen shows non-inferiority to high dose standard 
ibuprofen: the FLARE study (flaring arthralgia relief evaluation in episodic flaring knee 
pain)–a randomised double-blind study. Osteoarthr Cartil. 2017;25(12):1942–51.  
21.  Boggs DL, Surti T, Gupta A, Gupta S, Niciu M, Pittman B, et al. The effects of 
cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia 
a randomized placebo controlled trial. Psychopharmacology (Berl). 2018;235(7):1923–
32.  
22.  Patel AD, Mazurkiewicz-Bełdzińska M, Chin RF, Gil-Nagel A, Gunning B, Halford JJ, et 
al. Long-term safety and efficacy of add-on cannabidiol in patients with Lennox–Gastaut 
syndrome: Results of a long-term open-label extension trial. Epilepsia. 
2021;62(9):2228–39.  
23.  Minichino A, Jackson MA, Francesconi M, Steves CJ, Menni C, Burnet PWJ, et al. 
Endocannabinoid system mediates the association between gut-microbial diversity and 
anhedonia/amotivation in a general population cohort. Mol Psychiatry. 2021;1–8.  
24.  Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al. Cannabidiol 
enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. 
Transl Psychiatry. 2012;2(3):e94–e94.  
25.  Mun SJ, Lee J, Chung KS, Son MY, Son MJ. Effect of microbial short-chain fatty acids 
on cyp3a4-mediated metabolic activation of human pluripotent stem cell-derived liver 
organoids. Cells. 2021;10(1):1–13.  
26.  Chesney E, Oliver D, Green A, Sovi S, Wilson J, Englund A, et al. Adverse effects of 
cannabidiol: a systematic review and meta-analysis of randomized clinical trials. 
Neuropsychopharmacology. 2020;45(11):1799–806.  
27.  Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-Cooperman N, Mills C, et al. Abuse 
potential assessment of cannabidiol (CBD) in recreational polydrug users: A 
randomized, double-blind, controlled trial. Epilepsy Behav. 2018;88:162–71.  
28.  Astra Zeneca. The Gastrointestinal Symptom Rating Scale (GSRS).  
29.  Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington H V, Vail A. Meta-
analyses involving cross-over trials: methodological issues. Int J Epidemiol. 
2002;31(1):140–9.  
 

SAP_000.pdf: 
  
 
 
 
CLIP Study 
Statistical Analysis Plan 
 
 
Version 1.0 
Date 06/05/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRAS: 288415 
EudraCT number: 2020-004551-33 
ClinicalTrials.gov: NCT05032807 
ISRCTN: 18067579 
 
Oranuch Nampaisan 
Senior Statistician 
Grand Pacific CRO 
 
Dr Edward Chesney 
CLIP Trial Manager 
Institute of Psychiatry, Psychology and Neuroscience, London 
 
 
 


 
CLiP Study 
Statistical Analysis Plan  
 
Version: 1.0   Date: 06/05/2022 
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Page 2 of 8 
Table of Contents 
 
1. 
Pharmacokinetic Abbreviations .................................................................................. 3 
2. 
Source Documents ....................................................................................................... 3 
3. 
Trial Design ................................................................................................................... 3 
4. 
Primary objective .......................................................................................................... 4 
5. 
Primary outcome .......................................................................................................... 4 
6. 
Secondary objectives ................................................................................................... 4 
7. 
Secondary outcomes ................................................................................................... 4 
8. 
Trial assessments ......................................................................................................... 4 
8.1. 
Blood sampling ................................................................................................................... 4 
8.2. 
Vital signs ............................................................................................................................ 4 
8.3. 
Adverse events .................................................................................................................... 4 
8.4. 
Drug Effects Questionnaire (DEQ-5) .................................................................................. 5 
8.5. 
Gastrointestinal Symptom Rating Scale (GSRS) ................................................................ 5 
8.6. 
Stool Sample / Gut Microbiome (Exploratory analysis) ..................................................... 5 
9. 
Laboratory Analyses .................................................................................................... 5 
10. 
Statistics and Data Analysis ........................................................................................ 5 
10.1. 
Power analysis ..................................................................................................................... 5 
10.2. 
Planned recruitment ............................................................................................................. 5 
10.3. 
Statistical analysis plan ..................................................... Error! Bookmark not defined. 
10.3.1. 
Pharmacokinetics parameters ............................................ Error! Bookmark not defined. 
10.3.2. 
Protocol violations ............................................................. Error! Bookmark not defined. 
10.3.3. 
Demographics .................................................................... Error! Bookmark not defined. 
10.3.4. 
Safety measures ................................................................. Error! Bookmark not defined. 
10.3.5. 
Visual Analogue Scales & Drug Effects Questionnaire (DEQ-5) ... Error! Bookmark not 
defined. 
10.3.6. 
Laboratory results .............................................................. Error! Bookmark not defined. 
10.3.7. 
Adverse events .................................................................. Error! Bookmark not defined. 
10.4. 
Analysis populations ........................................................................................................... 5 
10.4.1. 
Full Analysis Set ................................................................................................................. 5 
10.4.2. 
Per Protocol Set (PPS) ......................................................................................................... 6 
10.4.2.1. Important Protocol Deviations Leading to Exclude from the PPS Analysis ............. Error! 
Bookmark not defined. 
  
 
 
 


 
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Page 3 of 8 
1. Abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUCt 
 
 
Area under the plasma concentration-time curve from time zero to time t. 
AUCinf  
 
Area under the plasma concentration-time curve from time zero to time infinity. 
Bioavailability  
The proportion of drug absorbed into the systemic circulation 
BP 
Blood Pressure 
Cmax 
 
 
The maximum serum concentration that a drug achieves 
Cmean  
 
The mean serum concentration that a drug achieves over a specified period of time 
CBD 
Cannabidiol 
CRF 
Clinical Research Facility 
DEQ-5 
Drug Effects Questionnaire 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GSRS 
Gastrointestinal Symptom Rating Scale 
HR 
Heart Rate 
King’s CRF 
NIHR Wellcome Kings Clinical Research Facility 
KHPCTO 
The King's Health Partners Clinical Trials Office 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NA 
Not Applicable 
PK 
Pharmacokinetic 
REC 
Research Ethics Committee 
RR 
Respiratory Rate 
PI 
Principal Investigator 
PPS 
Per Protocol Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Drug Reactions 
SLaM 
South London and Maudsley NHS Foundation Trust 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
Temp 
Temperature 
Tmax 
 
 
The time after administration of a drug that the Cmax is observed 
T½ 
 
 
The time taken for the plasma concentration to fall by half its original value 
UAR 
Unexpected Adverse Reactions 
2. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following documentation: 
 
Document 
Date 
Version 
Protocol 
1.2 
07/MAR/2022 
CRF 
2.0 
26/APR/2022 
3. Trial Design 
Single-centre double-blind two-period crossover pharmacokinetic study.  
 


 
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The study includes one baseline screening visit followed by two experimental visits each lasting 48 
hours, separated by a minimum 2 weeks washout. Participants will return home each day and will not 
stay in the hospital overnight. 
4. Primary objective 
To assess whether the novel formulation is able to increase the bioavailability of oral CBD in the 
fasting state. 
 
Hypothesis: the novel formulation will increase the AUCinf for a single dose of oral CBD in the fasting 
state. 
5. Primary outcome 
Difference in AUCinf for a single dose of oral CBD between the novel and standard formulations in the 
fasting state. 
6. Secondary objectives 
To characterise and compare the pharmacokinetic profiles of the novel CBD formulation and a standard 
formulation 
7. Secondary outcomes 
Differences between novel and standard formulations for: 
i. 
Maximum plasma concentration (Cmax) 
ii. 
Time after administration of drug when maximum plasma concentration is reached (Tmax) 
iii. 
Plasma half-life (t½) 
iv. 
Area under the concentration-time curve from time zero to 48hours (AUC0-48) 
8. Trial assessments 
8.1. Blood sampling 
Blood samples will be drawn at the following time-points on experimental visits: 
Pre-dose (0-5mins), 0.5, 1, 2, 3, 4, 5, 6, 8, 24, and 48hrs post-dose. The 24hr and 48hour samples 
should be taken within 15minutes of the target time. 
8.2. Vital signs 
Vital signs (HR, RR, BP, Temp) will be recorded on experimental visits at the following times: pre-
dose and 1, 2 4, 8, 24 and 48hrs post-dose. Urinalysis will be completed 4hrs post-dose. The 24hr and 
48hour readings should be taken within 15minutes of the target time. 
8.3. Adverse events 
Participants will be asked to report adverse events at each blood sampling timepoint i.e. pre-dose (0-
5mins), 0.5, 1, 2, 3, 4, 5, 6, 8, 24, 48hrs post-dose and at the 7-14 day follow-up visit . Participants will 
be asked specifically about adverse events including, but not limited to, anxiety, irritability, 
somnolence, dizziness, disorientation, nausea, abdominal pain, abdominal distension, diarrhoea, 
vomiting, and flatulence. 


 
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8.4. Drug Effects Questionnaire (DEQ-5) 
The DEQ-5 is questionnaire with five items, for example ‘‘Do you feel a drug effect, right now?’ with 
the response anchors ‘Not at all’ and ‘Extremely’ (Morean et al. 2013). It will be recorded on 
experimental visits at the following times: pre dose and at 1, 2, 4, 8, 24 and 48hrs post-dose. 
8.5. Gastrointestinal Symptom Rating Scale (GSRS) 
The GSRS is a 15-item rating scale which assesses five symptom clusters: reflux, abdominal pain, 
indigestion, diarrhoea and constipation. Each item is assessed with a 7-point Likert scale. The standard 
recall period for the scale is 7 days; this will be amended so that it assesses past 24 hours only. The 
scale will be used pre-dose and at 24 and 48 hours post dose. 
8.6. Stool Sample / Gut Microbiome (Exploratory analysis) 
To assess the effect of the gut microbiome on the CBD’s pharmacokinetics and circulating 
endocannabinoid levels, a stool sample will be collected prior to each drug administration. Participants 
will be provided with stool sampling kits at the screening visit. This part of the study is optional. 
9. Laboratory Analyses 
Blood samples will be analysed for CBD and its metabolites (including 6-OH-CBD, 7-OH-CBD, 7-
COOH-CBD) CBDA, THC, endocannabinoids (including anandamide and 2-arachidonoylglycerol). 
Additional unplanned analyses of relevant metabolites, biomarkers or inflammatory markers may also 
be completed. The laboratory analyses will be completed at the University of Turku, Finland. Analyses 
will be completed once all samples have been collected, at the end of the study. All analyses will be 
completed in accordance with relevant guidance and legislation. 
10. Statistics and Data Analysis 
10.1. Power analysis 
As the means are unknown, we base the power calculation on minimum detectable difference assuming 
the AUC coefficient of variation in CBD is 50% (Taylor et al. 2018). Since there is no carry-over effect 
in the study, an appropriate analysis of continuous data from a two-period, two-intervention cross-over 
trial is a paired t-test. For the primary outcome, the bioavailability of lipid versus standard formulation 
in the fasted state, a paired t-test with n=12 has 80% power, at alpha=0.05 (2 tailed) to detect a 44.5% 
difference in means. 
 
Previous studies demonstrated increased bioavailability with lipid formulations of 7x. The study is 
adequately powered to demonstrate these differences. This sample size and design satisfies EMA 
recommendations for design and minimum sample size (n=12) in pharmacokinetic studies for 
comparing formulations. 
10.2. Planned recruitment 
The study requires 12 complete datasets. With an expected drop-out rate of 15%, we expect to recruit 
14 participants. 
10.3. Analysis populations 
10.3.1. Full Analysis Set (FAS) 
The FAS will consist of all randomized/assigned participants who had at least one dose of treatment. 
FAS participants are analysed according to their randomized/assigned treatment. 


 
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10.3.2. Per Protocol Population Set (PPS) or PK analysis population 
The PPS will consist of all participants with completed two experimental visits and have a measurable 
level for all timepoints. 
10.4. Data handling 
10.4.1. Visit windows 
The visits are outlined as below table. 
Visit 
Target Day of Visit 
Acceptable visit window 
Experimental visit 1 
Screening visit 
Day 1 visit 
Day 2 visit 
Day 3 visit 
 
Day -28 to 0 
Day 1 
Day 2 
Day 3 
 
NA 
NA 
NA 
NA 
Washout period 2 weeks 
 
 
Experimental visit 2 
Day 1 visit 
Day 2 visit 
Day 3 visit 
Follow up visit 
 
Day 1 
Day 2 
Day 3 
Day 7-14 
 
NA 
NA 
NA 
NA 
10.4.2. PK time points windows 
The target sampling days and times with windows for PK samples in Experimental visit 1 and 2 are 
shown in below table. In the event of repeat values within a window, the last non-missing value per 
study day/time will be used. 
 
Target Day of Visit 
Timepoints with window 
Day 1 
Pre-dose (0-5mins) 
0.5-hour (post dose) +/- 5 mins  
1-hour (post dose) +/- 5 mins 
2-hours (post dose) +/- 5 mins 
3-hours (post dose) +/- 5 mins 
4-hours (post dose) +/- 5 mins 
5-hours (post dose) +/- 5 mins 
6-hours (post dose) +/- 5 mins 
8-hours (post dose) +/- 5 mins 
Day 2 
24-hours (post dose) +/- 5 mins 
Day 3 
48-hours (post dose) +/- 5 mins 
10.4.3. Handling of Dropouts, Missing Data, and Outliers 
There are no imputations planed for missing data. 
 
Partial dates and missing dates will not be imputed. Any classifications based on partial or missing 
dates will assume a “worse case” scenario. If a medication cannot be classified as either prior or 
concomitant due to missing or partial start and stop dates, it will be considered to be concomitant. If an 
AE cannot be classified as resolved prior to the end of the study period due to missing or partial stop 
dates, it will be assumed to be ongoing. 


 
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10.5. Statistical Methods 
10.5.1. General Principles 
All data processing, summarization and analyses will be performed using Greenlight Clinical’s SAS 
Environment / Version 9.4 (or later) of the SASÒ statistical software package. 
The following principles will be applied to all tables, listing and figures unless otherwise stated in 
below table. 
Principle 
Value 
Significant tests 
Two-sided and use a 5% significance level for main effects and 
10% significance level for interaction terms. 
Treatment group labels and order 
presented 
SEEK-CBD 
STD-CBD 
Tables 
Data in summary tables presented by treatment formulation and 
visit (where applicable).  
Listings 
All data collected presented by treatment formulation, subject 
number and visit (where applicable), unless otherwise specified. 
Descriptive summary statistics for 
continuous variables 
Number of subjects/observations (N), mean, standard deviation 
(SD), median, minimum(min) and maximum(max) 
Descriptive summary statistics for 
categorical variables 
Frequency counts and percentages [n (%)] 
Denominator for percentages 
Number of subjects in the analysis population, unless stated 
otherwise in table shell(s) 
Include “Missing” as category 
No, N will change, unless stated otherwise 
Display for 0 percentages 
- 
Display to one more decimal place 
than collected value 
Mean 
Standard Error 
Standard Deviation  
Mean Difference 
Median 
Minimum 
Maximum 
Display to two more decimal places 
than collected value 
Confidence Interval 
Limit of precision for displays 
3 decimal places 
Date Format 
YYYY-MM-DD 
10.5.2. Subject Disposition and Data Sets Analysed 
Subject disposition will be listed and summarized by treatment group and will include the number and 
percentage of subjects: 
• Screening 
• Randomized 
• Randomized and not treated 
• Randomized and treated 
• Included in the FAS 
• Included in the PK analysis population 
• Complete study 
In addition, the number and percentage of subjects who complete the study and who discontinue early, 
including a breakdown of the primary reasons for discontinuation, will be presented for all analysis 
populations. 


 
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Subject disposition will be presented in a listing and the reason for discontinuation.  
10.6. Statistical analysis plan 
10.6.1. Protocol violations  
All protocol violations, including inclusion/exclusion criteria violations and violations during the trial, 
will be listed, even if they are believed not to influence any of the results. 
10.6.2. Demographics 
For all participants, descriptive statistics of demographic (e.g., sex, age, BMI, and other baseline 
characteristics) will be presented by overall. 
10.6.3. Safety measures 
Summary tables showing vital signs e.g., body temperature, respiratory rate, pulse rate, and SBP and 
DBP will be provided at each study time point and changes from baseline. 
Individual physical examination will be listed and summarised at each study time point. 
Important Medical Event, drug, pregnancy test results during the study will be listed. 
10.6.4. Visual Analogue Scales & Drug Effects Questionnaire (DEQ-5) 
A summary table of DEQ-5 will be summarised descriptively. 
10.6.5. Laboratory results 
Laboratory parameters including haematology, blood chemistry, and urinalysis will be listed 
accompanied by an indication if the parameter is outside the reference range. A summary of all data 
outside the reference range of the clinical laboratory will be provided. Clinical laboratory data will be 
presented descriptively, where applicable. 
10.6.6. Pharmacokinetics parameters 
Pharmacokinetic parameters will be summarized descriptively. Continuous outcomes will be reported 
as means with standard deviation. Categorical outcomes will be reported as frequencies. Individual 
participant’s pharmacokinetic data may also be presented in tables and graphs. The plasma 
concentration-time data will be subject to non-compartmental pharmacokinetic analysis using 
appropriate computer software applications. Linear and/or log-linear plots will be presented.  To assess 
bioavailability between the formulations, log transformed AUC, Cmax observations will be entered into 
a linear mixed model to account for the repeated measures and between subject conditions. Linear 
contrasts representing the difference between conditions will be expressed as ratio of geometric means 
along with 95% CI and inference based on p < 0.05. Planned analysis will be per protocol. 
10.6.7. Adverse events 
A listing of all individual AEs, AR, UAR, SAE, SAR, and SUSAR will be provided. Summary tables 
of TEAEs will be presented by system organ class based on the MedDRA terminology list (preferred 
terms): 1 containing the number of TEAEs (frequency of occurrence, number of participants/patients 
experiencing the event) by treatment and 1 containing the number of drug related TEAEs (frequency of 
occurrence, number of participants/patients experiencing the event) per treatment. Additional tables of 
total counts by treatment and relationship and by treatment and severity will be given. 
 
The final statistical analysis plan will be in place prior to study database lock.