A SINGLE DOSE, RANDOMIZED, OPEN-LABEL, 4-WAY CROSSOVER STUDY TO ASSESS THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF ESKETAMINE (ORAL TABLET OF 20 MG AND 100 MG, ORAL SOLUTION OF 20 MG AND IV INFUSION OF 20 MG) IN HEALTHY VOLUNTEERS.

TEV-50370 is a new oral immediate release formulation of esketamine. Esketamine
is an approved drug and already available in the market as formulation for
intravenous or intramuscular administration, in The Netherlands as Ketanest-S®.
Esketamine is used for the induction and
maintenance of anesthesia. The new formulation TEV-50370 is an investigational
compound containing esketamine that may eventually be used for the treatment of
depression. The mechanism underlying the antidepressant effects of esketamine
are not clear. It is known that
esketamine blocks NMDA (N-methyl-D-aspartate) receptors, which play a role in
transfer of electrical signals in the brain and spinal column. This probably
affects other molecular mechanisms in the brain resulting in antidepressant
effects. This is the first time that TEV-50370 is being given to humans.

The purpose of the study is to investigate to what extent esketamine is
tolerated when it is being administered as TEV-50370 and as as Ketanest-S®. It
will also be investigated how quickly and to what extent esketamine is
absorbed, metabolized, distributed and eliminated from the body (this is called
pharmacokinetics) when it is being administered as TEV-50370 and as as
Ketanest-S®. The pharmacokinetics of esketamine will be compared between oral
administration of TEV-50370 and intravenous administration of Ketanest-S®
(absolute bioavailability) and between oral tablets of TEV-50370 and an oral
solution of Ketanest-S® (relative bioavailability).

The actual study will consist of 4 periods during each of which the volunteer
will stay in the clinical research center for 5 days (4 nights): from the
afternoon of Day -1 (1 day before administration of the study compound; also
called admission) to the morning of Day 4 (Day 1 is the day of administration
of the study compound). Each period they are expected at the clinical research
center at 14:00 h in the afternoon prior to the
day of administration of the study compound. They 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 on Day 4 of each period.
The time interval between dosing in the the different treatment periods is 7
days. The post-study screening will take place 7 to 14 days after they have
left the clinical research center on Day 4 of Period 4. The appointment for the
post-study screening will be made during the study.
The participation to the entire study, from pre-study screening until the
post-study screening, will be a maximum of 67 days.

Period 1, 2, 3 or 4, Day 1; 20 mg esketamine as oral tablet (TEV-50370)
Period 1, 2, 3 or 4, Day 1; 100 mg esketamine as oral tablet (TEV-50370)
Period 1, 2, 3 or 4, Day 1; 20 mg esketamine as oral solution (prepared with
Ketanest-S®, 5 mg per mL)
Period 1, 2, 3 or 4, Day 1; 20 mg esketamine as intravenous infusion (prepared
with Ketanest-S®, 5 mg per mL)

Pain, minor bleedings, bruises, possibly an infection.