A Phase 3, 12-Week, Double-Blind, Placebo- and Active-Controlled, Double Dummy
Efficacy and Safety Study of Preladenant in Subjects with Moderate
to Severe Parkinson*s Disease.

• Each subject must have a diagnosis of idiopathic Parkinson disease (PD) based on the United Kingdom Parkinson's Disease Society Brain Bank Criteria and the inclusion/exclusion criteria for this protocol.
Each subject should have bradykinesia and at least one of the following symptoms:
i) Muscular rigidity
ii) Resting tremor (4 to 6 Hz, Please note that for the purposes of this study, a diagnosis based
solely on bradykinesia and postural instability is insufficient for diagnosis of idiopathic
Parkinson's Disease, and subjects diagnosed in this manner cannot be enrolled in the study).
• Each subject must have received prior therapy with L-dopa for approximately 1 or more years immediately before Screening and must continue to have a beneficial clinical response to L-dopa at Screening.
• Each subject must have been on a stable, optimal dopaminergic treatment regimen, defined as maximum therapeutic effect achieved with available anti-parkinsonian treatment, for at least the 5 weeks immediately before Randomization.
• Subjects receiving the adjunct PD medications listed in the list below are permitted to enroll in this trial. Each subject who is receiving one or more of the adjunct PD medications listed below must have been on a stable regimen of treatment for at least the 5 weeks immediately before Randomization.
Amantadine
Anticholinergics
Dopa decarboxylase inhibitors
Dopamine agonists
Entacapone
L-dopa
• Each subject*s Hoehn and Yahr stage must be >=2.5 and <=4 in de optimum "on" state at Screening.
• Each subject must be experiencing motor fluctuations with or without dyskinesias following optimum titration of treatment medications and within the 5 weeks immediately before Screening.
• Each subject must be experiencing a minimum of 2 hours/day of *off* time as estimated by the investigator and supported by the 3-day symptom diary (Daily Diary) at the Randomization.
• Each subject, with or without help of their caregiver, must be capable of maintaining an accurate and complete symptom diary (Daily Diary) as assessed at the Diary Training Visit.
• Each subject must be willing and able to provide written informed consent for the trial. Subjects who are unwilling to provide written informed consent for exploratory pharmacogenetic testing may be included in the trial; however, exploratory pharmacogenetic samples must not be obtained.
• Each subject must be >=30 to <=85 years of age. A subject may be of either sex, any race/ethnicity.
• Each subject must have results of Screening clinical laboratory tests (hematology, blood chemistries, and urinalysis) drawn within 5 weeks prior to Randomization, clinically acceptable to the investigator, and not within the parameters specified for exclusion.
• Each subject must have results of a physical examination within normal limits or clinically acceptable limits to the investigator.
• Each subject must be able to adhere to dose and visit schedules.
• All subjects that are sexually active or plan to besexually active agree to use a highly effective method of birth control while the subject is in the study and for 2 weeks after the last dose of study drug. A male subject must also not donate sperm during the trial and within 2 weeks after the last dose of study drug. Complete details regarding contraceptive requirements are specified in protocol section 7.7.2.7.

• A subject must not have a form of drug-induced or atypical parkinsonism, cognitive impairment (ie, Montreal Cognitive Assessment [MoCA] score <22), bipolar disorder, schizophrenia, or other psychotic disorder.(Subjects with non-troublesome hallucinations, stable on low dose quetiapine or clozapine are allowed to enroll.)
• A subject must not have a history of any of the following:
- repeated strokes with stepwise progression of Parkinsonian features
- repeated head injury
- definitive encephalitis
- oculogyric crises
- neuroleptic treatment at onset of symptoms
- more than one first degree relative affected
- sustained remission
- strictly unilateral features after 3 years
- supranuclear gaze palsy
- cerebellar signs
- early severe autonomic involvement
- severe symptomatic autonomic involvement unrelated to medications
- early severe dementia with disturbances of memory, language, and praxis
- Babinski sign with clear, clinically significant pyramidal tract involvement
- presence of cerebral tumor or communicating hydrocephalus on neuroimaging (by history)
- negative response to large doses of L-dopa (if malabsorption excluded)
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or known neurotoxin exposure
- hallucinations unrelated to medications
- stroke within 6 months of Screening or persistent neurological deficit that may interfere with study assessments
- surgery for PD
• A subject must not have an untreated major depressive disorder meeting Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR) criteria. (A subject who is successfully treated [Beck Depression Inventory-II {BDI-II} score <19] with stable doses of allowed antidepressant medications for at least the 4 weeks immediately before Screening is eligible to enroll in the trial.)
• A subject must not be at imminent risk of self-harm or harm to others, in the investigator*s opinion based on clinical interview and responses provided on the Columbia Suicide Severity Rating Scale (CSSRS). Subjects must be excluded if they report suicidal ideation of Type 4 or 5 in the past 2 months or suicidal behavior in the past 6 months as measured by the CSSRS during Screening or at Randomization visits.
• In the judgment of the investigator, a subject must not have sleep attacks or compulsive behavior
that would interfere with the integrity of the trial or would pose a risk to the subject in participating
in the trial.
• Blood Pressure: A subject must not have a systolic blood pressure (BP) >=150 mm Hg OR diastolic BP >=95 mm Hg at Screening and at a BP recheck prior to Randomization. Should the BP remain elevated, the subject may not enter the trial until the BP has been adequately controlled with antihypertensive medication as demonstrated by 2 BP measurements meeting this criterion at consecutive separate scheduled or unscheduled visits within 5 weeks prior to Randomization. If antihypertensive medications are used to control a subject*s BP, the subject*s BP and doses of antihypertensive medications must be stable for at least 2 weeks prior to randomization.Note: during the course of the study antihypertensive medication may be initiated or increased to control a subject's BP at any time during treatment in P04938 as needed.
• Cardiovascular Disease: A subject must not have had any clinically significant cardiovascular event or procedure for 6 months prior to Randomization, including, but not limited to, myocardial infarction, prolonged QTc interval [a subject must not have a QTcf result > 500msec], angioplasty, unstable angina, or heart failure; and a subject must not have heart failure staged New York Heart Association Class III or IV.
• Liver Enzymes: A subject must not have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >=3 x the upper limit of normal (ULN) or total bilirubin (T-BIL) >=1.5 x ULN. Should a liver function test (LFT) be abnormal (AST/ALT >ULN but <3 x ULN, T-BIL >ULN but <1.5 x ULN) at Screening. No repeat testing allowed. Subjects with suspected Gilbert's Syndrome who have isolated T-BILI >= 1.5 x ULN may enter the study upon genetic confirmation (UGT1A1 assessment).
• Liver Disease: A subject must not have known Gilbert*s syndrome or active serologically confirmed hepatic dysfunction (defined as viral infection [Hepatitis B, C or E; Epstein-Barr virus {EBV}; cytomegalovirus {CMV}]) or a history of diagnosis of drug- or alcohol-induced hepatic toxicity or frank hepatitis.
•If a subject has abnormal ALT or AST at Screening (>1,5 x ULN), the subject must have serology testing to rule out active viral hepatitis. A subject who has a history of serologically confirmed EBV or CMV may be enrolled in the trial as long as the viral infection was not associated with hepatitis in the past, and the ALT or AST are normal at Screening. Types of serology assays to be performed are specified in the table of Laboratory Tests in the section on Trial Procedures.
• A subject must not have a history within the past 5 years of a primary or recurrent malignant disease with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or in situ prostate cancer with a normal prostate-specific antigen (PSA) post resection.
• A subject must not have received any treatment listed in the table below more recently than the indicated period before Randomization.
• A subject must not need to continue to receive any treatment listed in the table below during the trial.
Tolcapone - 4 weeks
Irreversible MAO inhibitors, eg, rasagiline, selegiline, Zydis selegiline - 90 days
Reversible MAOB or MAOA inhibitor - 4 weeks
Centrally acting dopamine antagonist (including metoclopramide, sulpiride, etc.) - 4 weeks
α-methyldopa - 4 weeks
Methylphenidate - 4 weeks
Reserpine - 4 weeks
Amphetamines - 4 weeks
Flunarizine - 4 weeks
Cinnarizine - 4 weeks
Diphenhydramine used to treat parkinsonism - 4 weeks
Theophylline - 4 weeks
Meperidine, tramadol, methadone, propoxyphene, cocaine, or local anesthesia containing
sympathomimetic vasoconstrictors - 2 weeks
Dextromethorphan - 2 weeks
Mirtazapine (a tetracyclic antidepressant), and cyclobenzaprine (a tricyclic muscle
relaxant) - 2 weeks
Sympathomimetic amines including cold products, nasal and oral decongestants, and
weight-reducing preparations that contain vasoconstrictors (eg, ephedrine,
pseudoephedrine, phenylephrine, and phenylpropanolamine) - 2 weeks
St. John*s wort tricyclic antidepressants, serotonin-norepinephrine reuptake
inhibitors and selective serotonin reuptake inhibitors with the following exceptions:
citalopram <= 20 mg/day, escitalopram <= 20 mg/day, paroxetine <= 30 mg/day, amitriptyline
or nortriptyline <= 50 mg/day, trazodone or sertraline <= 100 mg/day - 2 weeks
High tyramine-containing aged cheeses (eg, Stilton) - 2 weeks
Other potentially hepatotoxic drugs (including amiodarone, azathioprine, felbamate,
imatinib, isoniazid, isotretinoin, leflunomide, methotrexate, nevirapine, pioglitazone,
rosiglitazone, pyrazinamide, valproic acid, and voriconazole) - 4 weeks
Potent CYP3A4 inhibitors (eg, ritonavir, nelfinavir, indinavir); macrolide antibiotics (eg,
erythromycin, clarithromycin, troleandomycin, telithromycin, [azithromycin is allowed]);
and systemically administered antifungal agents (eg, ketoconazole, itraconazole) - 4 weeks
CYP3A4 inducers (eg, phenytoin, phenobarbital, barbiturates, systemic glucocorticoids) - 4 weeks
Atypical and typical neuroleptics (including depot formulations) except low dose
quetiapine fumarate and clozapine - 4 weeks (12 weeks for depot formulations).;• Note: Warnings and Contraindications detailed in the Prescribing Information for the allowed medications (listed in the inclusion criteria describing stable dopaminergic treatment) should be followed.