A RANDOMIZED, DOUBLE-BLIND DRUG-DRUG INTERACTION STUDY TO ASSESS THE EFFECT OF ZOLPIDEM ON THE PHARMACOKINETICS, PHARMACODYNAMICS AND SAFETY AND TOLERABILITY OF DS-5565 IN HEALTHY SUBJECTS

DS-5565 is a new investigational compound that may eventually be used for the
treatment of neuropathic pain associated with diabetes and herpes. DS-5565 is
not registered as a drug but has been given to humans before. Zolpidem is a
registered drug in the Netherlands and is used for the treatment of insomnia.

Primary:
To examine the effect of zolpidem on the pharmacokinetics (PK) of DS-5565 in
human plasma
To assess the safety and tolerability of concomitant administration of DS-5565
and zolpidem as defined by the adverse event (AE) profile.

Secondary:
To examine the effect of DS-5565 on the PK of zolpidem in human plasma
To examine the effect of DS-5565 on the pharmacodynamics (PD) of zolpidem
To examine the effect of zolpidem on the PD of DS-5565
To assess the safety and tolerability of concomitant administration of DS-5565
and zolpidem with respect to clinical laboratory evaluation, vital signs, ECG,
physical examination, respiratory function and the Columbia Suicide Severity
Rating Scale (C SSRS).

A randomized, double- blind, drug-drug interaction study in healthy volunteers

This study consists of 4 periods, during each period you will receive DS-5565
or placebo at a single dose of 10 mg and a single dose of 10 mg zolpidem or
placebo.

Procedures and assessments during the study:
Screening and follow-up: clinical laboratory (including serum chemistry,
hematology and urinalysis), vital signs, (including respiratory function),
physical examination, 12-lead ECG, prior and concomitant medication, pregnancy
test (females only), adverse effects (AE) reporting, C-SSRS;
at eligibility screening: FSH level, medical history, demography, weight,
height, drug and alcohol screen, HBsAg, anti-HCV, anti-HIV 1/2 and pregnancy
test (femalesonly);
to be repeated upon each admission: physical examination, weight, drug and
alcohol screen, clinical laboratory, vital signs (incl. respiratory rate),
12-lead ECG, pregnancy test (females only), prior and concomitant medication
and AE reporting

Blood sampling:
for pharmacokinetics of DS-5565 in plasma: pre-morning dose Day 1 until 24 hr
post-dose Day 2
for pharmacokinetics of zolpidem in plasma: pre-morning dose Day 1 until 24 hr
post-dose Day 2

Cognitive tests:
VSS-SF, Bond & Lader VAS, Body Sway, DSST, BARS: pre-morning dose Day 1 until
24 hr post-dose Day 2

Safety:
clinical laboratory, vital signs, respiratory measurements, ECG: pre-dose Day 1
until 24 hrs post-dose Day 2

This study consists of 4 periods, during each period you will receive DS-5565
or placebo at a single dose of 10 mg for 3 occasions (as a morning and evening
dose on Day 1 and as a morning dose on Day 2) and a single dose of 10 mg
zolpidem or placebo in the morning of Day 2.

* Treatment A: DS-5565 placebo plus zolpidem placebo
* Treatment B: 10 mg DS-5565 plus zolpidem placebo
* Treatment C: DS-5565 placebo plus 10 mg zolpidem
* Treatment D: 10 mg DS-5565 plus 10 mg zolpidem

All participants will receive all 4 treatment combinations over the 4 periods,
however the order in which this will occur will be determined by chance.

Four studies with 171 healthy volunteers had been performed to date, with
single doses of DS-5565 from 3 to 75 mg and multiple doses from 5 to 25 mg. The
most important adverse events reported were: dizziness, somnolence, nausea,
headache, vision blurred, tremor, dysmenorrhoea, diarrhoea, palpitations,
constipation, visual impairment, balance disorder, cognitive disorder,
flatulence, gait disturbance, disturbance in attention, insomnia, and a change
in liver function.
The most common side effects of zolpidem include drowsiness, dizziness, and a
"drugged" feeling, which probably reflect the action of the drug. Other side
effects include confusion, insomnia, euphoria, ataxia (balance problems), and
visual changes. Zolpidem can cause abnormal behavior with confusion,
paradoxical insomnia or "complex sleep-related behaviors," which may include
sleep-driving (driving with no memory of having done so).
With the doses used in this study no serious adverse effects are expected.
However, the occurrence of known or other effects cannot be excluded.

During the study several assessments will be conducted differing in extent and
the nature of burden:
- Registration af adverse effects: During the entire investigation all adverse
effects the subject experience and report will be documented.
- Blood draw, indwelling canula: During this study less then 500 ml of blood
will be drawn. It is anticipated that on Day -1 an indwelling canula will be
inserted for most of the blood sampling on Day 1 and 2. On the other days
during this study, blood will be drawn by direct puncture of the vein.
- Heart trace (ECG*s): ECG*s will be performed regularly at various time
points: specifically on Days 1 and 2.
- Columbia Suicide Severity Rating Scale (C-SSRS): This is a questionnaire
taken by the physician to asses any depressive or suicidal feelings the
subjects may have at the screening visit. This test is a safety measure.
However, there is currently no evidence that this investigational medicine will
have this risk.
- Cognitive tests (Body Sway Test, several questionnaires, a neurological
examination): These tests will be performed throughout the study but primarily
on Day 2 of each period. On the day of arrival for period 1 the subject will
receive training on these tests.
- Blood sample for DNA tests: On Day 1 a blood sample will be taken for
possible DNA tests. Participation in this part of the study is optional. If the
subjects do not wish to participate in this part of the study this will be
stated so on the form at the end of the ICF.