A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Carisbamate as Adjunctive Therapy in Subjects With Partial Onset Seizures, Followed by an Open-Label Extension Study

RWJ-333369 [(S)-2-O-carbamoyl-1-O-chlorophenyl-ethanol; (carisbamate)] is a new
chemical entity with anticonvulsant activity currently under investigation for
the treatment of epilepsy. Its mechanism of action has not yet been determined,
but it has broad anticonvulsant activity in multiple animal models.

Double-Blind Study CARISEPY3013:
The primary objectives of this study are to compare the efficacy safety, and
tolerability of carisbamate as adjunctive treatment of partial onset seizures,
relative to placebo.

The secondary objectives of this study are: To evaluate the effect of
carisbamate on percent reduction in partial onset seizure frequency, To
evaluate the effect of carisbamate on percent reduction in secondarily
generalized seizures, To evaluate the time to onset of treatment effect of
carisbamate on partial onset seizure frequency reduction, To determine the
pharmacokinetics of carisbamate using a limited sampling strategy, in which all
subjects will participate, followed by population pharmacokinetic (PK)
analyses. The potential impact of carisbamate on the trough concentrations of
select concomitant antiepileptic drugs (AEDs) will also be assessed.

Overall safety and tolerability of carisbamate will be evaluated.

The exploratory objectives of this study are: To evaluate the impact of
carisbamate on subject functioning and well-being using the Quality of Life in
Epilepsy- 31 (QOLIE-31) Patient Inventory, To collect medical resource
utilization (MRU) data that may be used in future economic modeling (the
construction and reporting of the economic model will be conducted separately
from this study), To evaluate the exposure-response relationship using an
estimate of individual subject exposures from the population PK analysis, and
the endpoint, percent reduction in partial onset seizures

The primary hypothesis is that 800 mg/day of carisbamate is superior to placebo
in the adjunctive treatment of partial onset seizures, as measured by the
primary efficacy endpoints.
The secondary hypothesis, which will be evaluated if 800 mg/day of carisbamate
is superior to placebo, is that 1,200 mg/day of carisbamate is superior to
placebo in the adjunctive treatment of partial onset seizures, as measured by
the primary efficacy endpoints.

Open-Label Extension Study CARISEPY3014
The primary of objective of this study is: To obtain long-term safety and
tolerability data on subjects with partial onset seizures treated with
open-label carisbamate
The exploratory objectives of this study are: To evaluate the impact of
carisbamate on subject functioning and well-being using the QOLIE-31 Patient
Inventory after 3 months of treatment with open-label carisbamate, To collect
MRU data that may be used in future economic modeling (the construction and
reporting of the economic model will be conducted separately from this study)
This is an open-label extension study. There is no statistical hypothesis for
this study.

Double-Blind Study CARISEPY3013:
This is a randomized, double-blind, placebo-controlled, parallel-group,
multicenter study. The study consists of an 8-week pretreatment phase including
screening and a baseline period, a 14-week double blind treatment phase,
including a 2-week titration period and a 12-week maintenance period, and a 4
week posttreatment phase. Subjects who complete the double-blind treatment
phase will be eligible to enter the separate open-label extension study
CARISEPY3014. Approximately 600 eligible subjects 16 years of age or older with
an established diagnosis of partial onset seizures will be enrolled in the
study to ensure that 510 subjects (approximately 170 per treatment group) are
randomly assigned in a 1:1:1 ratio to receive either 800 mg/day carisbamate,
1,200 mg/day carisbamate or placebo for 14 weeks. The randomization will be
stratified by uridine diphosphoglucuronosyl transferase (UGT) induction status
of concomitant AEDs and country/geographic region. The total duration of study
CARISEPY3013 is approximately 26 weeks for each subject.
Eligible subjects who meet the study entry criteria will begin the 8-week
prospective baseline period during which they will continue to take their
prescribed AEDs without change in dosage(s); new concomitant AEDs may not be
added. During the baseline period, subjects will record seizure information
(type and frequency of seizures) and adverse events in subject diaries.
Subjects or their legally acceptable representatives must be compliant with the
recording of information in the subject diaries throughout the study.
Subjects who continue to meet study entry criteria at the end of the baseline
period will be randomly assigned to treatment in the double-blind treatment
phase of the study. On Day 1 of the double-blind treatment phase, subjects will
be randomly assigned to 1 of 3 treatment groups, 800 mg/day carisbamate, 1,200
mg/day carisbamate, or placebo. The dosage(s) of concomitant AEDs may not be
increased and new concomitant AEDs may not be added to the treatment regimen.
Subjects will begin the titration period on Day 1, increasing to their assigned
dosage by Day 14. On Day 15, subjects will enter the maintenance period, and
will continue to receive their assigned dosage through Day 99.
An Independent Data Monitoring Committee (IDMC) has been commissioned for study
CARISEPY3013. The IDMC will meet during the course of the study in accordance
with the charter agreed on before the first meeting to ensure the safety of the
subjects and monitor any clinically relevant trends.
After completion of the 14-week double-blind treatment phase, subjects will be
eligible to enroll in the separate open-label extension study (CARISEPY3014),
based on the judgment of the investigator and consistent with the safety of the
subjects. Subjects who do not enter the open-label extension study or are
withdrawn from the double-blind treatment phase will have a blinded taper and
discontinuation of study drug over a 3 week period, unless for safety reasons
the investigator judges it necessary to discontinue study drug immediately. A
final follow-up visit will occur 7 days after the subject*s last dose of study
drug to adjust concomitant AEDs, as deemed appropriate by the investigator, and
to perform final study evaluations.

Open-Label Extension Study CARISEPY3014:
Subjects who enroll in the open-label extension study will have a 1-week
blinded transition to open label treatment with carisbamate. Subjects will
receive open-label carisbamate beginning at Week 2 at a dosage of 800 mg/day.
Subsequent dosage changes will be based on the judgment of the investigator;
however, the dosage of carisbamate should be within 400 mg/day to 1,200 mg/day
during the open label extension study and the dosage may not exceed 1,200
mg/day at any time. If 400 mg/day is not tolerated, the dosage may be decreased
to 200 mg/day, based on the judgment of the investigator. Monotherapy with
carisbamate will be not allowed. The investigator may add, remove, or adjust
the dosage of concomitant AEDs, as clinically indicated.
Subjects who complete or who are withdrawn from the open-label extension study
will have a taper and discontinuation of study drug over a 2- to 3 week period
(depending on the dosage of study drug the subject is taking). Study drug may
be tapered more gradually or immediately discontinued without tapering if for
safety reasons the investigator judges it to be necessary. A final follow-up
visit will occur 7 days after the subject*s last dose of study drug to adjust
concomitant AEDs, as deemed appropriate by the investigator, and to perform
final follow-up evaluations.

Study drug will be administered in 2 equally divided doses twice daily, with or
without food, and taken with noncarbonated water. All morning and evening doses
should be taken at approximately the same times each day and approximately 12
hours apart for each subject. Subjects may not chew, divide, dissolve, or crush
study drug.

Double-Blind Study CARISEPY3013:
On Day 1 of the double-blind treatment phase, subjects will be randomly
assigned to receive 1 of 3 treatments: 800 mg/day carisbamate, 1,200 mg/day
carisbamate, or placebo. In Week 1 of the titration period, the dosage of
carisbamate will be 400 mg/day, and in Week 2 the dosage will increase to 800
mg/day for both carisbamate treatment groups. In Weeks 3 to 14 of the
maintenance period, the 800-mg/day group will stay at the same dosage and the
1,200-mg/day group will increase to 1,200 mg/day. Dosage reduction of study
drug will be allowed once during the double-blind treatment phase.
Subjects who complete or are withdrawn from the double-blind treatment phase
and do not enter the open label extension study will have a blinded taper and
discontinuation of study drug over a 3 week period. The study drug may be
discontinued immediately without tapering if for safety reasons the
investigator judges it to be necessary.

Open-Label Extension Study CARISEPY3014:
Subjects who complete the 14-week double-blind treatment phase (i.e., Day 99)
and enter the open label extension study CARISEPY3014 will have a 1-week
blinded dosage transition to treatment with open label carisbamate. The dosage
of study drug may not exceed 1,200 mg/day during the open label extension
study. Monotherapy with carisbamate will not be allowed. The investigator may
add, remove, or adjust the dosage of the other allowed AEDs, as clinically
indicated.
Subjects who complete or are withdrawn from the open-label extension study will
have study drug tapered and discontinued over a 2- to 3-week period (depending
on the dosage of study drug the subject is taking). Study drug may be tapered
more gradually or discontinued immediately without tapering if for safety
reasons the investigator judges it to be necessary.

In clinical studies of carisbamate, the following side effects were reported in
more than 5% of people: headache, dizziness, somnolence (sleepiness), nausea,
and fatigue (tiredness). These side effects also occurred in people taking
placebo but not as frequently.

Other side effects that were reported less frequently in people who took
carisbamate included constipation, balance and walking difficulty, anxiety,
insomnia, vertigo (a feeling that the room is spinning), double vision, blurred
vision, vomiting, stomach ache, decreased appetite, rash, hyponatremia (low
sodium levels in your blood) slurred speech, confusion, increased blood
pressure, psychosis (irrational thinking or behavior), and euphoria (a happy
feeling).

Over 2,400 subjects have received more than one dose of carisbamate.
Approximately 1% have developed abnormal blood tests that indicated that the
liver was not functioning normally. In most of these subjects, the abnormal
blood tests returned to normal or near normal after the medication was stopped
or the dosage was reduced. In several patients the abnormal blood tests
returned to normal without a reduction in dosage. This may indicate reversible
injury to the liver. Two patients developed jaundice while on carisbamate; one
patient had a viral infection of the liver and another patient had signs of
gall bladder dysfunction. At this time the risk of liver injury from
carisbamate is not known with certainty, and may be higher than for some other
drugs used to treat seizures.

A study of the cardiac safety of carisbamate found a slight shortening in the
time it takes the heart muscle to electrically re-set itself between beats, as
detected on ECG. This time period is known as the QT interval. The medical
significance of this effect is unknown, but in theory it could lead to abnormal
heart rhythms. Also, a rare inherited disorder of very short QT intervals has
been associated with serious abnormal heart rhythms and cases of sudden cardiac
death.

Recently the U.S. Food and Drug Administration (FDA) studied 11 available
seizure medications and advised that any seizure medication may increase the
risk of having suicidal thoughts or actions. It is not known if carisbamate
increases such a risk.

There have been a small number of sudden and unexplained deaths in epilepsy
subjects in a study with carisbamate after receiving the medication. Sudden
unexplained death in epilepsy is a recognized syndrome in people with epilepsy
that can occur with or without anti-seizure medication that may apply to these
cases.

Since the possibility of an interaction between carisbamate and your other AEDs
exists, it is possible that the blood plasma levels of these drugs may increase
or decrease when they are administered together. Health problems likely to
result from too high a level of other AED include drowsiness, dizziness, vision
disturbances, poor co-ordination, and movement difficulties. If the level of
the other AEDs drop too low, it is possible that more seizures are
experienced. Health problems likely to result from too high a level of
carisbamate include sleepiness, dizziness, headaches, and numbness and
tingling.