A comparative, open-label, randomized, 2-stage sequential design, 2 periods, crossover study to demonstrate the bioequivalence of 2 FT218 batches (single dose of 4.5 gram) in healthy volunteers

FT218 is a new formulation (composition) of the registered drug sodium oxybate.
Sodium oxybate (also known as the sodium salt of gamma-hydroxybutyric acid
[GHB]) is registered under the name Xyrem® for the treatment of narcolepsy.
Narcolepsy is a sleeping disorder that involves excessive daytime sleepiness.
For some people with narcolepsy it also involves a sudden loss of muscle tone
(cataplexy), usually triggered by strong emotion. Sodium oxybate/GHB is a
substance that has depressant or sedating effects in people. Xyrem® is an oral
solution that has to be taken at bedtime, and then again 2.5 to 4 hours later.
This dosing schedule is considered inconvenient for the patients because they
have to wake up in the middle of the night to take the second dose. FT218
contains the same active molecule or substance (sodium oxybate) as Xyrem®, but
in a special formulation which provides slower and longer release of the active
substance. As a result, FT218 only has to be taken once at bedtime. FT218 is in
development and is not registered as a drug, but it has been given to humans
before.

FT218 is made of the active ingredient sodium oxybate encapsulated in very
small particles made of naturally occurring substances (polymers). Flamel has
conducted all research and studies needed to show that the particles used can
be broken down by the human body and that the components are not harmful. These
particles have been used previously in humans without any safety concern.

The purpose of the study is to investigate how quickly and to what extent 2
different production batches of FT218 (batch A and batch B) are absorbed and
eliminated from the body (this is called pharmacokinetics). In this study it is
investigated whether these characteristics are the same for both batches (this
is also called bioequivalence). It will also be investigated to what extent
FT218 is tolerated.

The actual study will consist of 2 periods during which the volunteer will stay
in the clinical research center in Groningen (location Martini Hospital) for 2
days (1 night) during each period. The time interval between the 2 periods is
at least 3 days.

Day 1 of each period is the day of administration of the study compound. In
each period, the volunteer is expected at the clinical research center at 10:00
AM in the morning of Day 1. The volunteer will be required not to have consumed
any food or drinks during the 4 hours prior to arrival in the clinical research
center (with the exception of water). The volunteer will leave the clinical
research center in the afternoon of Day 2.

The post-study visit will take place 2 - 4 days after the volunteer has
received the last dose of FT218. The appointment for the post-study visit will
be made with the volunteer during the study.

The participation in the entire study, from the pre-study screening until the
post study visit, will be approximately 4.5 weeks.

During the study the volunteer will receive FT218 in each period in the evening
(around 22:00 h) of Day 1, 2 hours after completion of a standard dinner, as an
oral drink (a suspension) of 50 milliliters. After administration of the study
compound, the dosing cup will be rinsed once with 20 milliliters of water,
which the volunteer will also be required to drink.

The study will consist of 2 study periods during which the volunteer will
receive a 4.5 grams dose of FT218 once in each study period. FT218 will be
given as an oral drink (a suspension) of approximately 50 milliliters. The
volunteer will receive one dose from each batch over the two periods. The order
in which the volunteer will receive both batches will be determined by chance.
The dose level of 4.5 grams matches one of the authorized nightly dose levels
of Xyrem®.

Please refer to the table below to see the planned dose levels for the groups.
Should, in the opinion of the investigators, unacceptable adverse effects
appear, the study will be discontinued

The planning of the study is as follows:

Period Day Treatment How often
1 1 4.5 grams FT218 Once
2 1 4.5 grams FT218 Once

All drugs have the potential to cause adverse events. The active substance in
FT218 is the same as the active substance in Xyrem® (sodium oxybate). The risks
associated with FT218 are expected to be similar to those associated with
Xyrem®.

In a previous study, FT218 was investigated in 40 healthy volunteers as single
doses of 4.5 grams, 6 grams and 7.5 grams. In this study, Xyrem® was also
administered, as well as other FT218 oral drinks with a slightly different
composition than the drink used in this study. All tested FT218 formulations
were well tolerated. Adverse events that were observed after FT218
administration were similar as after Xyrem® administration.

The following is a list of the known potential side effects of sodium oxybate:

The most commonly reported adverse reactions are dizziness, nausea, and
headache, all occurring in 10% to 20% of patients.

Less common side effects (in 1% to 10% of patients) are nasopharyngitis (common
cold), sinusitis (sinus infection), anorexia, decreased appetite, depression,
cataplexy (muscle weakness), anxiety (feeling of worry), abnormal dreams,
confused state, disorientation (loss of sense of direction, position),
nightmares, sleepwalking, sleep disorder, insomnia, insomnia in the middle of
the night, nervousness, sleep paralysis (not able to move when falling asleep
or at awakening), somnolence (sleepiness), tremor (muscle twitching), balance
disorder, disturbance in attention (not being able to concentrate),
hypoesthesia (reduced sense of touch), paresthesia (sensation of *pins and
needles*), sedation (reduced state of awareness), dysgeusia (bad taste in the
mouth), blurred vision, vertigo (feeling of spinning), palpitations (rapid or
irregular heartbeat), hypertension (high blood pressure), dyspnea (shortness of
breath), snoring, nasal congestion, vomiting, diarrhea, upper abdominal pain,
hyperhidrosis (increased sweating), rash, arthralgia (joint pain), muscle
spasms, back pain, enuresis nocturna (bedwetting), urinary incontinence,
asthenia (lack of energy), fatigue, feeling drunk, edema peripheral (swelling
due to fluid retention), increased blood pressure, decreased weight, and risk
of a fall.

Uncommon side effects in 0.1% to 1% of patients) include hypersensitivity,
suicide attempt, psychosis (loss of contact with reality), hallucination
(seeing or hearing things that are not real), abnormal thinking, agitation,
initial insomnia (trouble falling asleep), myoclonus (muscle twitches), amnesia
(memory loss), restless leg syndrome, and fecal incontinence.

Side effects for which frequency is not known are dehydration, suicidal
ideation, euphoric mood, convulsion (abnormal, involuntary contraction of the
muscles), respiratory depression (reduced urge to breathe), sleep apnea (pauses
in breathing or shallow breaths while you sleep), dry mouth, urticaria (hives),
and angioedema (swelling).

The most serious (but uncommon) adverse reactions are suicidal attempt,
psychosis (loss of contact with reality), respiratory depression (reduced urge
to breathe) and convulsion (abnormal, involuntary contraction of the muscles).

As with taking any drug, there is a risk of allergic reaction. Some symptoms of
allergic reactions are: rash, difficulty breathing, and wheezing, sudden drop
in blood pressure, a fast heart rate sweating, and swelling around the mouth,
throat or eyes.

Procedures: pain, minor bleeding, bruising, possible infection