A Randomized, Double-Blind, Placebo- and Active-Controlled, 4 Period Crossover Study to Evaluate the Effect of Lemborexant versus Placebo on Driving Performance in Healthy Adult and Elderly Subjects.

The Sponsor is studying a drug called lemborexant or E2006, being developed to
treat people with insomnia disorder. A problem with the use of sleeping pills
(hypnotic agent) is that sometimes in the morning these sleeping pills may
still have some effect and patients may feel drowsy or sleepy after waking up.
This could have an effect on driving performance. This study will be conducted
in healthy male and female volunteers. The purpose of this study is to
determine if the new study drug lemborexant can affect driving performance.
These effects are compared to those of another sleeping pill (zopiclone 7.5 mg)
and a placebo.

Primary Objective
The primary objective of the study is to evaluate the effect of lemborexant
2.5, 5, and 10 mg compared to placebo on standard deviation of lateral position
(SDLP) during an on-road driving test in the morning following a single dose
and multiple doses of lemborexant administered at bedtime.

Secondary Objectives
The secondary objectives of the study are to:
* Evaluate the effect of lemborexant 2.5, 5, and 10 mg compared to placebo on
the number of lapses during an on-road driving test in the morning following a
single dose and multiple doses.
* Evaluate the proportion of subjects who are significantly impaired compared
to placebo following a single dose and multiple doses of lemborexant 2.5, 5, or
10 mg.
* Evaluate the relationship between plasma concentrations of lemborexant
following the driving test and selected outcome variables including SDLP and
number of lapses following a single dose and multiple doses.
* Evaluate the effects of lemborexant 2.5, 5, and 10 mg compared to placebo on
SDLP and number of lapses by age group.
* Evaluate the safety and tolerability of lemborexant 2.5, 5, and 10 mg

Exploratory Objectives
The exploratory objectives of the study are to:
* Compare the difference in SDLP between placebo and the active control
treatment (zopiclone 7.5 mg) for assay sensitivity
* Evaluate the effects on SDLP and number of lapses between pairs of
lemborexant dose levels and between each lemborexant dose level and zopiclone
7.5 mg
* Evaluate the difference in number of lapses for lemborexant 2.5, 5, and 10
mg, and zopiclone 7.5 mg compared to placebo by time on task, approximately
every 10 km

This is a single-center, single- and multiple-dose, randomized, double-blind,
placebo- and active-controlled, 4-period crossover study of 3 dose levels of
lemborexant (2.5, 5, and 10 mg) in healthy adult and elderly subjects.

The study will have 2 phases, Prerandomization and Randomization. The
Prerandomization Phase will consist of 2 periods that will last up to a maximum
of 21 days: Screening and Baseline. The Randomization Phase will comprise four,
9-day treatment periods (Treatment Period 1 * Treatment Period 4) with a
minimum 14-day washout between treatment periods, and a follow-up interval
after Treatment Period 4 before the end-of-study (EOS) visit.

All subjects will come to the clinic for screening procedures and will undergo
eligibility assessments. Potentially eligible subjects will then complete a
Sleep Diary within the first 30 minutes after morning waketime for at least 7
consecutive days, in which they will provide information about the timing,
quantity, and quality of the previous night*s sleep. Information in the Sleep
Diary completed during the Screening Period will be used to confirm eligibility
with regard to absence of symptoms of insomnia, and regularity of sleep timing
and time in bed. Between Days -14 and -2, subjects will be acclimated to the
study procedures by sleeping overnight at the site, followed by a practice
driving test during the morning of the next day. The order of acclimatization
night followed by the practice drive may be changed in individual cases, after
informing the sponsor, to permit flexibility if needed. Any subject whose
practice driving test is considered by the driving instructor to be inadequate
(eg, does not follow instructions to maintain speed at 95 km/h, drives in a
timid or aggressive manner) will be excluded from the study.

At Baseline (Day 1), subjects will return to the clinic for baseline
procedures. They will undergo alcohol breathalyzer, urine drug tests, and
females of child-bearing potential will have a urine pregnancy test. On the
evening of Day 1, subjects will be administered the first dose of study drug
for Treatment Period 1 within 5 minutes before bedtime. Bedtime will be at
23:30 for all subjects on all nights in the clinic, in order to maintain a
regular approximately 9-hour interval between dosing and start of the driving
test the following morning.

Up to 60 subjects will be randomized to 1 of 12 sequences in an incomplete
block design in order to have complete data sets on 48 subjects. There will be
4 Treatment Periods, during which each subject will be assigned to receive
lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg, or placebo. While all
subjects will receive zopiclone 7.5 mg and placebo, each subject will be
assigned to receive only 2 of the 3 dose levels of lemborexant. During
lemborexant treatment periods, subjects will take a dose of lemborexant at
bedtime for 8 consecutive nights and a placebo
matched to zopiclone at bedtime on nights spent in the clinic. During the
placebo treatment periods, subjects will take a dose of lemborexant-matched
placebo at bedtime for 8 consecutive nights and a placebo matched to zopiclone
at bedtime on nights spent in the clinic. During the
zopiclone treatment period, subjects will take a dose of zopiclone and placebo
matched to lemborexant at bedtime on nights in the clinic, and a
lemborexant-matched placebo at bedtime on each night at home. Randomization
will be stratified by age group (adult: 21 to 64 years versus
elderly: *65 years) in a 1:1 ratio and will be balanced for sex such that there
are no fewer than 10 males or 10 females per age group.

After receiving the first dose of study drug, subjects will sleep overnight in
the clinic. On this and each night spent in the clinic, a subject must remain
in bed for at least the habitual time in bed calculated from the Sleep Diary
during screening, and will be awakened at 08:00 if not
already awake by then. After waketime, subjects will complete the Sleep Diary,
then will be provided a light breakfast, following which they will undergo the
driving test. After the driving test, a blood sample will be taken for analysis
of plasma concentrations of lemborexant and metabolites M4, M9, and M10
(collectively referred to as metabolites), or S-zopiclone. They will then be
dispensed study drug to be taken for 6 nights at home during Treatment Period
1, and will be discharged from the clinic and transported home after the
investigator determines that it is safe to do so.

Subjects will return to the clinic on Day 8. They will undergo breathalyzer and
urine drug tests and be admitted to the clinic. A pharmacokinetic (PK) blood
sample will be taken. They will be administered the last dose of study drug for
Treatment Period 1 within 5 minutes before bedtime.
They will sleep overnight at the clinic. After waketime, subjects will complete
the Sleep Diary then will be provided a light breakfast, following which they
will undergo the driving test. After the driving test, a blood sample will be
taken for analysis of plasma concentrations of lemborexant and metabolites, or
S-zopiclone, the Columbia Suicide Severity Rating Scale (C-SSRS) will be
administered, and the subject will be discharged from the clinic and
transported home after the investigator determines that it is safe to do so.

There will be a minimum 14-day washout interval after Treatment Period 1.
Subjects will return to the clinic for Treatment Period 2, Treatment Period 3,
and Treatment Period 4. The same schedule as for Treatment Period 1 will be
followed, with the exception that a predose PK sample will be taken on the
first day of the treatment period. A minimum 14-day washout interval will occur
after Treatment Period 2 and Treatment Period 3, with a minimum 14-day washout
interval between subsequent treatment periods. If a subject starts a treatment
period, but is unable to
complete all assessments related to driving performance for that treatment
period due to a reason other than experiencing a treatment-related adverse
event (AE) or discontinuing from the study, the entire treatment period may be
repeated and will occur before any subsequent treatment
period starts. A subject is permitted to repeat only one treatment period.
Pharmacodynamic (PD) and PK data from the incomplete treatment period data will
not be used for the analysis and reporting of the study.

After Treatment Period 4 there will be follow-up interval of at least 14 days,
during which the subjects will not receive any treatment. Subjects will return
to the clinic for end-of-study (EOS) procedures. If a subject discontinues
prematurely, they should undergo an Early Termination
Visit.

8 consecutive evenings at bedtime: lemborexant-matched placebo; 2.5 mg, 5, mg,
or 10 mg lemborexant (before driving next morning)
2 evenings at bedtime, separated by 6 evenings: zopiclone-matched placebo;
zopiclone 7.5 mg (before driving next morning).

Assuming a maximum estimated participation period of approximately 17 weeks:
Visit 1 (medical examination),
Visit 2 (habituation night and training of the driving test)
Visits 3-10 (test sessions)
Visit 11 (final follow-up medical examination)

Also refer to tables 3 and 4 of the protocol for a complete overview of the
study visits and procedures.

There are no personal benefit to subjects from participation in this research
besides financial compensation. Disadvantages of participation are the many
rules that subjects need to live by and the fact that they will have to take
medication for a number of weeks, and the possible side effects that may occur.
Subjects can experience drowsiness the day after ingestion of drugs that helps
people sleep and could be slightly less alert. Subjects are therefore advised
not to drive a car on those days. During the driving test on the motorway
subject safety is ensured as they will be escorted by an experienced and
qualified driving instructor who can intervene directly. The research car is
fitted with dual controls.

Lemborexant has been tested in 9 studies in humans so far, in single doses up
to 200 mg and multiple doses up to 75 mg for up to 2 weeks. Side effects that
have been observed or reported in these studies include:

Sleepiness/drowsiness, headache, vivid or unusual dreams, or nightmares, muscle
weakness, dizziness, sleep paralysis, and cataplexy. These side effects listed
have generally been mild, although at higher doses more moderate levels of
these side effects have been reported.
There are potential effects of lemborexant that are related to the way it may
work in the body. These potential effects include symptoms of narcolepsy, a
sleep disorder in which individuals are very sleepy, have little control over
sleepiness and may fall asleep suddenly.

The most common side effects of zopiclone are daytime sleepiness, dizziness,
decreased alertness, memory problems, headache and dry mouth. Common side
effects which are less frequent are depression, confusion, gastrointestinal
disturbances, nausea and vomiting. Rare side effects are more common in the
elderly, include irritability, aggressive behaviour and strange or bad dreams.
In very rare cases, skin rash and reported a severe allergic reaction. These
side effects, if they occur, are usually mild and transient.

Additional information on the potential side effects of lemborexant and
zopiclone are detailed in Appendix 2 of the Subject Information Sheet and
Informed Consent Form.