A PHASE 1, OPEN-LABEL, PHARMACOKINETIC TRIAL TO INVESTIGATE POSSIBLE DRUG-DRUG INTERACTIONS BETWEEN CLOBAZAM, STIRIPENTOL OR VALPROATE AND CANNABIDIOL (GWP42003-P) 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. In GW studies CBD is not known to have the hallucinating effect
that is known of cannabis.
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 other compounds that will be given in this study are clobazam, stiripentol
and valproate which are approved drugs and already available in the market
under several dosages and formulations. They are prescribed for the treatment
of epilepsy.

It is possible that cannabidiol and clobazam, stiripentol or valproate will be
co-administered in the future.

During this study it will be investigated what the effect is of multiple doses
of CBD on the absorption and elimination from the body (this is called
pharmacokinetics) of clobazam, stiripentol or valproate. It will also be
investigated what the effect is of multiple doses of clobazam, stiripentol or
valproate on the pharmacokinetics of CBD. The study will also look at how safe
and well tolerated the combined administration of CBD and clobazam, stiripentol
or valproate is.

The study will be performed in 77 healthy male and/or female participants,
divided over 6 groups.

This study is not intended to improve your health, but is necessary for the
further development of CBD.

In this study 2 study compounds will be administered: CBD and clobazam, CBD and
stiripentol or CBD and valproate. Day 1 is the first day of administration of
study compound. Should, in the opinion of the investigators, unacceptable
adverse effects appear, the study will be discontinued.
During the study, the volunteer will stay in the clinical research center in
Groningen for 3 periods.

In this study 2 study compounds will be administered: CBD and clobazam, CBD and
stiripentol or CBD and valproate.

CBD
All potential drugs cause side effects; the extent to which this occurs
differs.
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 in walking and amounts of medicines
in the body were higher than usual (increases of levels of other medicines),
increased appetite, decreased appetite, feeling drugged.

Previously in this study an unusually high number of non-serious and temporary
rash events was seen. Despite the changes that have now been introduced in the
study, skin rash may still occur after CBD intake.

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. 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.

As CBD may affect some blood tests, if you need a blood test please tell the
doctor or nurse you are taking this study compound.

Clobazam
Clobazam is a drug that is already available in the market under several
dosages and formulations. It is prescribed for the treatment of epilepsy. The
most frequently observed side effects are: sleepiness and drowsiness. Please
also carefully read the patient information leaflet of clobazam.

Stiripentol
Stiripentol is a drug that is already available in the market under several
dosages and formulations. It is prescribed for the treatment of epilepsy. The
most frequently observed side effects are: anorexia, weight loss, insomnia,
drowsiness, ataxia (lack of voluntary coordination of muscle movements),
hypotonia (low muscle tone) and dystonia (twisting and repetitive movements or
abnormal postures). Please also carefully read the patient information leaflet
of stiripentol.

Valproate
Valproate is a drug that is already available in the market under several
dosages and formulations. It is prescribed for the treatment of epilepsy. The
most frequently observed side effects are: thrombocytopenia (decrease of
platelets), nausea, vomiting, diarrhea, gastrointestinal disorders, increased
ammonemia (too much ammoniac or ammonium), temporary hair loss, irregular
menstruations and weight gain. Please also carefully read the patient
information leaflet of valproate.