SINGLE CENTER, OPEN LABEL, RANDOMIZED TWO-WAY CROSSOVER STUDY OF THE EFFECT OF LACOSAMIDE 200MG TWICE DAILY ON THE SINGLE-DOSE PHARMACOKINETICS AND PHARMACODYNAMICS OF WARFARIN (25 MG) IN HEALTHY MALE VOLUNTEERS

LCM is an investigational compound that is used for the treatment of epilepsy.
In 2008 LCM was registered as adjunctive therapy in the treatment of partial
onset seizures (epileptic attacks from one part of the brain) with or without
secondary generalization (the epileptic attack begins in one part of the brain
and expands to the whole brain) in patients with epilepsy, aged 16 years and
older.

The purpose of the study is to investigate the interaction between LCM and
Warfarin (this is called pharmacodynamics). In addition, it will be
investigated how quickly and to what extent LCM is absorbed and eliminated from
the body (this is called pharmacokinetics).
This study is not intended to improve your health, but is necessary for the
further development of LCM in Elderly people. Warfarin is frequently
administered in elderly people who may be at risk of epileptic attacks.
Therefore, prior to initiating a clinical study in elderly patients with
epilepsy, it is deemed important to rule out the possibility that the
interaction between LCM and Warfarin might result in negative changes in the so
called PK and PD effects of Warfarin (often used in elderly).

Primary objective:
The primary objective of this study is to evaluate the effect of LCM 200mg bid
on the single dose PK and PD of a single warfarin 25mg dose.

Secondary objective:
The secondary objective of this study is to monitor the safety and tolerability
of LCM 200mg bid, before and following concomitant administration of a single
warfarin 25mg dose.

SINGLE CENTER, OPEN LABEL, RANDOMIZED TWO-WAY CROSSOVER STUDY OF THE EFFECT OF
LACOSAMIDE 200MG TWICE DAILY ON THE SINGLE-DOSE PHARMACOKINETICS AND
PHARMACODYNAMICS OF WARFARIN (25 MG) IN HEALTHY MALE VOLUNTEERS.

The total treatment period will be up to 31 days with treatment A being 1 day
and Treatment B being 1 * 9 days. The 2 treatments will be separated by a
wash-out period of at least two weeks form the last blood sample of the first
treatment period to the first dose of the second treatment period.

Treatment A will consist of a single 25mg oral dose of Warfarin (5 tablets).
Treatment B will consist of multiple oral dose administrations of LCM 200mg (1
tablet) twice daily (bid) and a single 25mg oral dose of Warfarin (5 tablets)
on the third day of LCM treatment.

Further the study will consist of 2 period(s) during which you will stay in the
clinical research centre in Zuidlaren.
Group 1 will stay in the clinic for Period 1 for 5 days (4 nights) and in
Period 2 for 7 days (6 nights).
Group 2 will stay in the clinic for Period 1 for 7 days (6 nights) and in
Period 2 for 5 days (4 nights).
For all groups, each period will be followed by 4 days during which you will
visit the clinical research centre in Zuidlaren. The time interval between the
2 periods is at least 2 weeks.

Procedures:
Registration af adverse effects: During the entire investigation all adverse
effects you report will be documented.

Blood draw, indwelling canula: During this study approximately 330 ml of blood
will be drawn. It is anticipated that 2 time(s) an indwelling canula will be
used and 52 blood draws will be drawn by direct puncture of the vein..

Collection of urine and feces: Urine samples for safety laboratory tests will
be taken in the morning at predose, ie, before the first administration of
Warfarin (Treatment A) or LCM (Treatment B). Feces will be collected only at
screening visit.

Heart trace (ECG*s): Group 1: ECG*s will be made regularly (also pre-dose):
specifically on Days 1 and 2 (period 1) and Days 24 and 25 (Period 2). Group 2:
ECG*s will be made regularly (also pre-dose): specifically on Days 3 and 4
(Period 1) and Days 24 and 25 (Period 2).

Vital signs: Vital signs will be assessed pre-dose and 4 and 12h after first
administration of LCM in each Treatment Period.
Vital signs will be assessed pre-dose and 4, 12, and 24h after the Warfarin
single dose in each Treatment Period.

Columbia Suicide Severity Rating Scale (C-SSRS): During the screening, stay at
the research clinic and follow-up subjects will be asked to fill out the
questionnaire of the Columbia Suicide Severity Rating Scale. This scale records
the possibility, severity and frequency of suicide-related thoughts and
behaviors during the study period. The questions asked may be confronting. This
test is a safety measure.

Genotyping (bloodsampling): bloodsampling will be done only post-dose on Day 1.

Meals: Standard meals will be provided during confinement at the clinical
center.

n/a.

Procedures: pain, light bleeding, heamatoma, possibly an infection.

With the doses used in this study no serious adverse effects are expected. The
occurrence of known or other effects cannot be excluded. All potential drugs
cause adverse events to some extent. See SmPC of Lacosamide and Warfarin.