A Phase 3, 40-Week, Active-Controlled, Double-Blind, Double
Dummy Extension Study of Preladenant in Subjects With Moderate
to Severe Parkinson*s Disease

Parkinson's disease (PD) is an age-related, progressive, neurodegenerative
disease characterized by specific abnormal motor behaviors (resting tremors,
increased muscle tone [ie, muscular rigidity], and slowness of movements
[bradykinesia or akinesia]) associated with a progressive degeneration of the
nigrostriatal dopaminergic pathway. When a patient is initially treated with
Levo-dopa or dopamine agonists, the symptoms of PD improve or disappear. After
several years of taking L-dopa or dopamine agonists, patients notice that their
PD medications wear off sooner than when they first started taking them. This
*wearing off* is characterized by the return of symptoms (ie, tremor, slowness,
and rigidity) and may occur over the course of a few minutes to an hour. When a
patient*s PD symptoms have returned, the patient is said to be in the *off*
state. When the patient takes another dose of medication, and his/her PD
symptoms improve or resolve, the patient is said to be in the *on* state. One
potential novel approach to the treatment of PD is the use of adenosine
receptor antagonists. Adenosine exerts its biological actions through a class
of G-protein-coupled receptors.Numerous functional studies support the
hypothesis that blockade of striatal A2a receptors may provide relief of PD
symptoms. Adenosine 2a receptor antagonists have been shown to activate
dopaminergic pathways and to reverse motor impairment in rodent models of PD.
Preladenant (SCH 420814) is a potent and selective competitive antagonist of
the human A2a receptor being developed by Schering-Plough as a treatment for
PD. It has an inhibition constant (Ki) of 1.1 nM and >1000-fold selectivity for
the A2a receptor over the other three adenosine receptor subtypes (A1, A2b, and
A3) and a variety of other receptors and ion channels.

This is a active-controlled dose-range-finding study which is also designed to
assess the efficacy and safety of preladenant 2, 5, 10 mg twice daily during
long term use as an adjunct therapy to L-dopa when administered to subjects
with moderate to severe PD.

The dose-range-finding for preladenant is being performed to clarify the
findings of the Phase 2 study, P04501, where preladenant was generally well
tolerated and improved motor function in subjects with moderate to severe PD.
In P04501, 246 subjects received preladenant 1, 2, 5, or 10 mg or placebo twice
daily. There was a dose response in reduction in "off" time from Baseline to
endpoint (increasing response associated with increasing dose) and similar
responses for the two highest doses, 5 and 10 mg of preladenant twice daily,
which were statistically superior to placebo. Due to small sample sizes, it was
unclear whether the 2 mg twice daily dose might also be effective, and
therefore a larger study is being performed. More liver enzyme elevations
occurred at the 10 mg twice daily dose than at the 5 mg twice daily dose.
Criteria meeting Hy*s law, 5 subjects out of 54 subjects treated with 10 mg of
preladenant twice daily experienced increments above the normal reference range
of ALT and/or AST (<3 x ULN except for one subject whose AST peaked at between
3 and 4 x ULN 2 weeks after discontinuation of treatment). Therefore, the 10-mg
dose is included in this study to more fully characterize its efficacy and
safety. The placebo arm is included as a control. The current standard of care
for subjects still experiencing motor fluctuations while on optimal
dopaminergic therapy is to add a catechol-O-methyltransferase (COMT) inhibitor,
such as entacapone or a monoamine oxidase (MAO) inhibitor such as rasagiline in
an effort to prolong the dopaminergic benefits of L-dopa and reduce motor
fluctuations. Rasagiline 1 mg once daily is included to allow for benefit/risk
assessment. The rasagiline arm is being included as an active control to
provide descriptive comparative data for the relative efficacy and safety of
the current standard of care and preladenant.

Preladenant is a tablet. Rasagiline will be supplied as a capsule. A placebo
tablet matching preladenant tablet will be available; and a placebo capsule
matching rasagiline capsule also will be available. During the 40-week
Treatment Period, subjects will receive one tablet and one capsule orally each
morning and one tablet orally each evening in a double-blind, double-dummy
design as shown in the table below:

Morning
Preladenant Group
2 mg Preladenant Tablet + Placebo Capsule
5 mg Preladenant Tablet + Placebo Capsule
10 mg Preladenant Tablet + Placebo Capsule

Rasagiline Group
1 mg Rasagiline Capsule + Placebo Tablet



Evening (about 8 hours after morning dose 8)

Preladenant Groups
2 mg Preladenant Tablet
5 mg Preladenant Tablet
10 mg Preladenant Tablet

Tablet Rasagiline Group
Placebo Tablet

Take study medication, filling out questionaires and draw blood for blood
tests.

Each subject will participate in the trial for approximately 40 to 42 weeks
from the time the subject signs the Informed Consent Form (ICF) through the
final contact. Right after a screening, each subject will be receiving the
assigned treatment for approximately 40 weeks. The End of Treatment visit from
the P04938 study will be combined with the screening visit of the P06153
study,, in order to use the medication in a ongoing stable level. At the end of
the treatment the subject will return for a Follow-up Visit after the last
dose of study drug.