A randomized, double-blind, placebo-controlled, single ascending dose and multiple dose study to evaluate the safety, tolerability and pharmacokinetics of Cannabidiol (GWP42003-P) oral liquid formulation with an open label two-period cross-over part to study food effects in healthy subjects

Cannabidiol (CBD) is a new investigational compound that may eventually be used
for the treatment of epilepsy. It is extracted from cannabis plants under
highly controlled conditions to ensure the product is always the same. Within
the human body there is a biological system named the endogenous cannabinoid
system (ECS). CBD is absorbed and distributed very rapidly to tissues and a
number of the therapeutic actions of CBD are thought to be produced via the
body*s own ECS.
CBD is not yet registered as a drug but has been given to humans in both
clinical studies and as part of an approved product in combination with another
drug in a number of countries.

The purpose of the study is to investigate to what extent CBD is safe and
tolerated. It will also be investigated how quickly and to what extent CBD is
absorbed and eliminated from the body (this is called pharmacokinetics).
Furthermore the effect of food on the pharmacokinetics of CBD will be
investigated.This study is not intended to improve the volunteer health, but is
necessary for the further development of CBD.

The study will be performed in 2 parts (single ascending dose [SAD] part with
integrated food effect [FE] part and multiple dose [MD] part).
The study exists of 1 period for the the SAD, 3 periods for the SAD with FE and
1 period for the MD. The volunteers will stay in the clinical research center
in Zuidlaren for 4 days (3 nights) in the SAD, for 5 days (4 nights in the FE
periods and for 11 days (10 nights) in the MD part.

The SAD part of the study will consist of 1 study period during which you will
receive either CBD or placebo once. CBD and placebo will be given in the form
of an oral solution

The FE part of the study will consist of 2 study periods (Study Periods 2 and
3) during which the volunteers will receive CBD, once with a breakfast and once
without a breakfast, however the order in which this will occur will be
determined by chance. CBD will be given in the form of an oral solution. Thus,
participants participating in both the SAD part and FE part will receive the
study compound in 3 study periods.

The MD part of study will consist of 1 period during which the volunteers will
receive CBD or placebo twice daily for 6 days with a single dose in the
morning of day 7. CBD and placebo will be given in the form of an oral
solution.

The following side effects were experienced among a portion of the 213 patients
who have taken CBD oral solution; however this was not within a formal clinical
study (there was no placebo treatment). All were considered to be caused by the
study compound. They have been categorized by the likelihood of them occurring,
and listed in the order they have most commonly been reported.
Very common side effects which may affect more than one person in every 10 are:
Feeling drunk, sleepy or abnormal, feeling tired, diarrhea and eating less than
usual.
Common side effects which may affect more than one person in every 100 are
(excluding the very common side effects above): Eating more than usual, weight
gain, weight loss, convulsions, difficulty walking and amounts of medicines in
the body were higher than usual (increases of levels of other medicines),
increased appetite, decreased appetite, feeling drugged.
Some patients have also developed rashes during treatment with CBD oral
solution.
The following side effects have been seen in 107 patients who have previously
taken other CBD medicines (either CBD botanical drug substance or purified CBD)
within clinical studies. It should be noted that 87 of these patients took a
formulation containing small amounts of other cannabinoids including
tetrahydrocannabinol (THC) and so may have resulted in a higher incidence of
side effects than with the study compound you will be using. They have been
categorized by the likelihood of them occurring, and listed in the order they
have most commonly been reported. A lot of these effects have also been seen
with the placebo medication. The side effects in bold have been seen in 20
patients who have previously taken study medication of purified CBD, all being
classed as common, with the exceptions of headache and diarrhea which were very
common.

Very common side effects which may affect more than one person in every 10 are:
Diarrhea, headache, feeling sick.
Common side effects which may affect more than one person in every 100 are
(excluding the very common side effects above): Mouth problems (including,
pain, discomfort, change in sense of taste or loss of sense of taste, dry
mouth, reduction in or loss of sensation), feeling tired,indigestion, sickness,
eating less than usual, feeling drunk or abnormal, feeling dizzy, neck pain,
belching, urgency to pass motions, increased frequency in passing water,
rashes, change in liver function blood tests or hematology blood tests, cold
symptoms, abdominal pain, constipation, feeling depressed or confused, abnormal
dreams, nose bleed, feeling weak or unwell, flushing, muscle spasms.
If you suffer from any of the following side effects, you should immediately
inform the study doctor about this: Serious allergic reaction, such as a severe
rash, swelling in the mouth or throat, tightness in the throat or feeling like
the throat or airways are closing, difficulty breathing, severe
light-headedness or a faint feeling, or any thoughts of suicide.

Procedures:

Registration of side effects:
During the entire study all side effects you report will be documented.

Blood sampling, indwelling cannula (SAD, FE):
During this study less than 500 milliliters of blood will be drawn.
An indwelling cannula (a needle that is inserted into a vein into the arm) will
be used each study period to sample blood on Day 1 (SAD, FE) and on Day 7 (MD)
will be removed before you go home. Remaining blood samples between the
pre-study screening and the post-study screening will be drawn by direct
puncture of the vein.

Vital signs:
Respiratory rate, blood pressure, pulse rate and body temperature will be
measured regularly in supine position. Blood pressure and pulse rate will also
be measured in standing position.

Heart trace (ECG):
ECGs will be taken regularly.

Meals:
Volunteers will receive a high fat breakfast once during FE

Sleep disruption and Epworth Sleepiness Scale questionnaires:
During the study volunteers will need to complete 2 separate questionnaires to
measure sleep disruption during the night and your daytime sleepiness.

Cannabis withdrawal scale:
During the study volunteers will receive a questionnaire to measure any
symptoms of withdrawal reactions.

Columbia Suicide Severity Rating Scale:
During the study volunteers will receive a questionnaire to measure any
suicide-related thoughts or behaviors.