A multiple dose study to evaluate next day effects of MK-4305 on driving performance in healthy non-elderly subjects

MK-4305 is a potent dual orexin receptor antagonist that is being developed as
a novel hypnotic agent for insomnia. MK-4305 is currently in Phase III
development with two dose levels being evaluated in non-elderly patients (20-
and 40-mg). Phase I and Phase II studies in healthy subjects and insomnia
patients have not revealed evidence of significant next-day residual effects at
the dose levels used in Phase III. Since the on road highway driving test has
been demonstrated to be a valid and sensitive measurement of next-day residual
effects of hypnotics, the current car driving study is being performed to
formally evaluate the next-day residual effects of MK-4305 in healthy
non-elderly subjects. In addition, attention, somnolence, mood, memory and
balance tests will also be evaluated the morning after MK-4305 dosing.
Zopiclone is used as an active control since it has consistently demonstrated
next-day impairment on driving performance.

The key objective of this study is to assess next-day residual effects of
MK-4305 (20 and 40 mg) via driving performance after 1 day of dosing and after
8 days of dosing.

This study will be conducted according to a randomized, double-blind,
double-dummy, placebo and active controlled, multiple oral dose, 4-period
crossover design.

In each of the 4 treatment periods the volunteers will receive 1 of the
following treatments:
- 20 mg MK-4305 on day 1 till 8 before going to sleep
- 40 mg MK-4305 on day 1 till 8 before going to sleep
- 7,5 mg zopiclon on day 1 till 8 and placebo on day 2 till 7 before going to
sleep
- placebo on day 1 till 8 before going to sleep

Volunteers undergo 4 treatment periods of 8 days each. In these periods they
are given on days 1 through 8 at bedtime a sleep aid or placebo. On day 1 and
day 8 of each period, 9 hours after taking the medication the residual effects
on driving ability are measured by a driving test. Approximately 11 hours after
ingestion, the residual effects on memory, reaction time and balance are
tested. Through a questionnaire the effect on mood is measured and it is
checked whether there are thoughts of suicide. Also, a blood sample (8 ml) is
taken on each day of testing to determine the concentration of the study
medicine in the body. Before and during the treatment periods, the use of
drugs, alcohol, caffeine and nicotine is limited. During the treatment periods,
volunteers advised not to drive a car by themselves. Prior to the test periods,
the subjects are medically screened. This takes about 1 hour and during the
test 12 ml of blood is drawn for clinical blood analysis. Furthermore, the
tests (driving test and computer test) and trained during 3 hours and subjects
sleep 1 night for habituation to the environment and practice of the
procedures. This habituation night lasts 12 hours. After the last test period,
participants again undergo a medical examination. During this last examination
12 ml of blood is drawn for clinical blood analysis.
Adverse reactions which were most commonly reported by healthy volunteers in
studies with MK4305 and which, according to the study doctor, relate to the use
of MK-4305, include somnolence / drowsiness, headache, fatigue and dizziness.
Less common side effects are nausea, dry mouth, insomnia, strange or bad
dreams, muscle weakness, memory problems and mild disturbances in coordination.
Adverse reactions which were classified as serious and which, according to the
study doctor, were related to the use of MK4305 include chest pain, fever,
chills, nausea, vomiting, abdominal pain and confusion.
The most common side effects of zopiclone are daytime sleepiness, dizziness,
decreased alertness, memory problems, headache and dry mouth. Less common side
effects are depressed mood, confusion, gastrointestinal disturbances, nausea
and vomiting. Rare side effects, which occur more often in older people, are
irritability, aggressive behavior and strange or bad dreams. In very rare cases
a skin rash and severe allergic reaction is reported.
All side-effects are known to be mostly mild and transient.