An exploratory, open-label, randomized, 2 treatments, 2 periods, 2 sequences crossover study to assess the pharmacokinetics of two FT218 batches (single dose administered at the dose of 6g) in healthy volunteers

FT218 is a new compound that may eventually be used 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. FT218 is a new
formulation of the drug sodium oxybate/GHB, a substance that has depressant or
sedating effects in people.

Sodium oxybate is a registered drug under the tradename Xyrem®. 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 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). The Sponsor
has conducted 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.

FT218 is a new formulation of the drug sodium oxybate (also known as the sodium
salt of gamma-hydroxybutyric acid [GHB]), a registered drug under the tradename
Xyrem® for the treatment of narcolepsy. FT218 has been administered to humans
before.

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. It will also be investigated how safe FT218 is and
how well it is tolerated (i.e., possible side effects). In addition, the effect
of FT218 on sleep efficiency and quality will be explored. The volunteer will
receive both batches of FT218 once each. For this, the volunteer will stay 2
times in the research center.

The actual study will consist of 2 periods during which the volunteer will stay
in the research center at the Martini Hospital location in Groningen. Each
period will be 3 days (2 nights). 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 FT218.
For both periods, the volunteer is expected at the research center at 14:00 h
in the afternoon prior to the day of administration (so on Day -1). The
volunteer will be required not to have consumed any food or drinks during the 4
hours prior to arrival in the research center (with the exception of water).
He/she will leave the research center in the afternoon of Day 2.

During the study, the volunteer will receive 6 gram (g) of FT218 twice (once
from Batch A and once from Batch B). The order in which the volunteer will
receive both batches will be determined by chance.

Administration of the study compound will occur in the evening (around 22:00
h), 2 hours after completion of a standardized dinner, as an oral drink (a
suspension) of 50 milliliters (mL). After administration of the study compound,
the dosing cup will be rinsed once with 20 mL of water, which the volunteer is
also be required to drink.

Please refer to the table below to see the planned dose levels. The study will
be discontinued if, in the opinion of the investigators, unacceptable side
effects appear.

Period Day Treatment Dose How often
1 1 Drink with FT218 Batch A or Batch B 6 grams Once
2 1 Drink with FT218 Batch A or Batch B 6 grams Once

During the study, the volunteer will receive 6 gram (g) of FT218 twice (once
from Batch A and once from Batch B). The order in which the volunteer will
receive both batches will be determined by chance.

Administration of the study compound will occur in the evening (around 22:00
h), 2 hours after completion of a standardized dinner, as an oral drink (a
suspension) of 50 milliliters (mL). After administration of the study compound,
the dosing cup will be rinsed once with 20 mL of water, which the volunteer is
also be required to drink.

The active substance in FT218 (sodium oxybate) is the same as the active
substance in Xyrem®, a registered drug. The risks associated with FT218 are
expected to be similar to those associated with Xyrem®.

FT218 has so far been administered to humans in multiple studies. The following
side effects are most frequently observed: abdominal pain, nausea, dizziness
and headache. Rarely occurring but important effects to mention are vomiting
and respiratory depression. Because of the latter, you will be intensively
monitored during the first 6 hours after administration of the study compound.

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. During your stay in the research center, you will be monitored
continuously for any symptoms of an allergic reaction.

The study compound may also have side effects that are still unknown. As
information becomes available, the volunteers will be informed about any
changes in the way the study will be done and about any newly identified risks
to which the volunteers may be exposed that may affect theirwillingness to
participate in the study.

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 the current FT218 oral drink, and other FT218 oral
drinks with a slightly different composition than the drink used in this study.
All tested FT218 oral drinks were well tolerated. Adverse events that were
observed after FT218 administration were similar as after Xyrem®
administration. The reported side effects in this previous study included upper
abdominal pain, nausea, stuffy nose, dizziness, joint pain and sore throat. All
of these side effects were reported as being either mild or moderate and these
side effects resolved quickly without any long-term effects noted.

In another study of FT218, single doses of 4.5 grams, 7.5 grams and 9 grams
FT218 were studied in 20 healthy volunteers. In this study, the doses of 4.5
grams and 7.5 grams were well tolerated and reported adverse events were
consistent with what was observed in the earlier study. Following
administration of the highest dose level of 9 grams (1.5 times as high as the
dose level that will be given in the current study), significant adverse events
were reported in 2 out of the 12 volunteers who received this dose. A serious,
but transient adverse effect occurred in 1 of the 12 volunteers who experienced
deep sedation (loss of consciousness) with vomiting, necessitating
hospitalization. After admittance to the hospital, the volunteer recovered
fully within a few hours. A second volunteer experienced deep sedation but was
aroused following stimulation at the time the event was noted by the clinical
staff. Both volunteers made a full recovery with no lasting consequences.

In a third study, 22 additional healthy volunteers received 2 doses of 4.5 g
FT218 without any safety concern. The 3 most recent studies, including 68
healthy volunteers receiving 2 doses of 6.0 g FT218 (or Xyrem®), also provided
no new safety information.

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), paranoia,
hallucination (seeing or hearing things that are not real), abnormal thinking,
agitation, initial insomnia (trouble falling asleep), myoclonus (muscle
twitches), amnesia (memory loss /memory impairment), restless leg syndrome, and
fecal incontinence.

Side effects for which frequency is not known are dehydration, suicidal
ideation, euphoric mood, homicidal ideation, aggression, sleep-related eating
disorder, panic attack, mania / bipolar disorder, delusion, bruxism (teeth
grinding), irritability, convulsion (abnormal, involuntary contraction of the
muscles), loss of consciousness, dyskinesia (involuntary repetitive movements),
tinnitus (ringing or buzzing in the ears), respiratory depression (reduced urge
to breathe), sleep apnea (pauses in breathing or shallow breaths while you
sleep), dry mouth, urticaria (hives), angioedema (swelling), pain in extremity,
nocturia (excessive nighttime urination), pollakiuria (abnormally frequent
urination) / micturition urgency, and hangover.

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).

Procedures: pain, minor bleeding, bruising, possible infection