A Placebo- and Active-Controlled Study of Preladenant in Early Parkinson's Disease (PD) (P05664)

Study Overview
=================
Brief Summary
-----------------
This is a one year, 2-part study to determine the efficacy and safety of preladenant, an adenosine type 2a (A2a) receptor antagonist. The purpose of Part 1 (first 26 weeks) is to determine if preladenant is effective in the treatment of early Parkinson's Disease. The purpose of Part 2 (second 26 weeks) is to determine if preladenant is safe and well tolerated. The primary efficacy hypothesis is that at least the 10 mg twice daily dose of preladenant is superior to placebo as measured by the change from Baseline to Week 26 in the sum of Unified Parkinson's Disease Rating Scale (UPDRS) Parts 2 and 3 scores (UPDRS2+3).

Official Title
-----------------
A Phase 3, Double-Blind, Double-Dummy, Placebo- and Active-Controlled Dose-Range-Finding Efficacy and Safety Study of Preladenant in Subjects With Early Parkinson's Disease

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: Preladenant 2 mg tablet
* Drug: Preladenant 5 mg tablet
* Drug: Preladenant 10 mg tablet
* Drug: Rasagiline 1 mg capsule
* Drug: Placebo for Rasagiline 1 mg capsule
* Drug: Placebo for Preladenant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has a diagnosis of idiopathic PD for < 5 years. If receiving amantadine and/or anticholinergics, must have been on a stable regimen of treatment for at least the 5 weeks immediately before Screening. (Note: Participants who are not taking any medications for PD are permitted to enroll in this trial.) Must have a UPDRS Part 3 score of ≥10, a Hoehn and Yahr Stage ≤3, be ≥30 to ≤85 years of age, and have results of Screening clinical laboratory tests drawn within 5 weeks prior to randomization, clinically acceptable to the investigator, and not within the parameters specified for exclusion. If sexually active or plan to be sexually active, must agree to use a highly effective method of birth control while the participant is in the study and for 2 weeks after the last dose of study drug. A male participant must also not donate sperm during the trial and within 2 weeks after the last dose of study drug. Exclusion Criteria: Must not have a form of drug-induced or atypical Parkinsonism, cognitive impairment (ie, Montreal Cognitive Assessment [MoCA] score <22), bipolar disorder, untreated major depressive disorder, schizophrenia, or other psychotic disorder; history of exposure to a known neurotoxin, or any neurological features not consistent with the diagnosis of PD as assessed by the investigator. Must not have had surgery for PD. Must not have a history of repeated strokes with stepwise progression of Parkinsonism or head injuries, or a stroke within 6 months of screening; poorly controlled diabetes; abnormal renal function; or a severe or ongoing unstable medical condition. Must not have failed to show a therapeutic response if a diagnostic levodopa (L dopa) challenge had been done with a large test dose (>500 mg) of L dopa (if malabsorption excluded), or failed to respond to an adequate previous treatment with dopaminergic therapy. Must not have been treated with L dopa or dopamine agonists for 30 days or more. A participant who has been treated with L-dopa or dopamine agonists for <30 days will be allowed to enter the study. These participants must stop taking dopaminergic medication 30 days prior to Randomization. Must not be at imminent risk of self-harm or harm to others. Must not have elevated blood pressure (BP) (systolic BP ≥150 mm Hg or diastolic BP ≥95 mm Hg) that cannot be adequately controlled with antihypertensive medication, as demonstrated by 2 BP measurements meeting acceptable BP criterion at consecutive scheduled or unscheduled visits between Screening and Randomization (a 5-6 week period), one of which must be the Randomization visit. Must not have had any clinically significant cardiovascular event or procedure for 6 months prior to Randomization, including, but not limited to, myocardial infarction, angioplasty, unstable angina, or heart failure; and a participant must not have heart failure staged New York Heart Association Class III or IV. Must not have an alanine aminotransferase (ALT) or aspartate amino transferase (AST) ≥ 3 x the upper limit of normal (ULN) or total bilirubin (T BIL) ≥ 1.5 x ULN. Must not have 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, or a history of diagnosis of drug- or alcohol-induced hepatic toxicity or frank hepatitis.) 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. Must not have received certain prespecified medications or ingested high tyramine-containing aged cheeses (eg, Stilton) for a prespecified time window before the trial, during the trial, and for 2 weeks after the trial. Must not have an average daily consumption of more than three 4 ounce glasses (118 mL) of wine or the equivalent. Must not have a severe or ongoing unstable medical condition (eg, any form of clinically significant cardiac disease, symptomatic orthostatic hypotension, seizures, or alcohol/drug dependence.) Must not have allergy/sensitivity to investigational product(s) or its/their excipients. Must not be breast-feeding, considering breast-feeding, pregnant or intending to become pregnant. Must not have used preladenant ever, or any investigational drugs within 90 days immediately before screening.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Preladenant 2 mg<br>Preladenant 2 mg oral tablet and placebo for rasagiline taken in the morning (AM) followed by preladenant 2 mg oral tablet taken in the evening (PM) for 26 weeks (Part 1) and then for another 26 weeks (Part 2). | Drug: Preladenant 2 mg tablet<br>* Preladenant 2 mg oral tablet taken twice daily<br>* Other names: SCH 420814;Drug: Placebo for Rasagiline 1 mg capsule<br>* Placebo for rasagiline 1 mg oral capsule taken once daily<br>|
| Experimental: Preladenant 5 mg<br>Preladenant 5 mg oral tablet and placebo for rasagiline taken in the AM followed by preladenant 5 mg taken in the PM for 26 weeks (Part 1) and then for another 26 weeks (Part 2). | Drug: Preladenant 5 mg tablet<br>* Preladenant 5 mg oral tablet taken twice daily<br>* Other names: SCH 420814;Drug: Placebo for Rasagiline 1 mg capsule<br>* Placebo for rasagiline 1 mg oral capsule taken once daily<br>|
| Experimental: Preladenant 10 mg<br>Preladenant 10 mg oral tablet and placebo for rasagiline taken in the AM followed by preladenant 10 mg taken in the PM for 26 weeks (Part 1) and then for another 26 weeks (Part 2). | Drug: Preladenant 10 mg tablet<br>* Preladenant 10 mg oral tablet taken twice daily<br>* Other names: SCH 420814;Drug: Placebo for Rasagiline 1 mg capsule<br>* Placebo for rasagiline 1 mg oral capsule taken once daily<br>|
| Placebo Comparator: Placebo<br>Placebo for preladenant and placebo for rasagiline taken in the AM followed by placebo for preladenant taken in the PM for 26 weeks (Part 1); preladenant 5 mg was taken twice daily for 26 weeks (Part 2). | Drug: Preladenant 5 mg tablet<br>* Preladenant 5 mg oral tablet taken twice daily<br>* Other names: SCH 420814;Drug: Placebo for Rasagiline 1 mg capsule<br>* Placebo for rasagiline 1 mg oral capsule taken once daily<br>Drug: Placebo for Preladenant<br>* Placebo for preladenant 2 mg, 5 mg, or 10 mg oral tablet taken twice daily<br>|
| Active Comparator: Rasagiline<br>Rasagiline 1 mg oral capsule and placebo for preladenant taken in the AM followed by placebo for preladenant taken in the PM for 26 weeks (Part 1) and then for another 26 weeks (Part 2). | Drug: Rasagiline 1 mg capsule<br>* Rasagiline 1 mg oral capsule taken once daily<br>* Other names: Azilect;Drug: Placebo for Preladenant<br>* Placebo for preladenant 2 mg, 5 mg, or 10 mg oral tablet taken twice daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Sum of Unified Parkinson's Disease Rating Scale Parts 2 and 3 Scores (UPDRS2+3) | The UPDRS is a clinician based rating scale used to measure motor impairments and disability. The UPDRS assesses six features of PD impairment. These are evaluated using a combination of data collected by interview and examination of the participant. The UPDRS Part 2 is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The UPDRS Part 3 is the Motor Examination (Total Motor Score [TMS]) and is defined as the total score, ranging from 0-108 as determined by the physician, of the tests given in the motor examination section. The combined scores of Parts 2 and 3 can range from 0-160 with the higher score indicating the worse condition. Change from baseline was analyzed using a constrained longitudinal analysis (cLDA) model with treatment, time, strata and treatment-by-time interaction as fixed effects and participant as a random effect. | Baseline and Week 26 | 
| Number of Participants With Adverse Events (AEs) in Part 1 | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. | Day 1 to Week 26 | 
| Number of Participants Who Discontinued Study Due to an AE in Part 1 | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. | Day 1 to Week 26 | 
| Number of Participants With Adverse Events (AEs) in Part 2 | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. | Week 27 to Week 52 | 
| Number of Participants Who Discontinued Study Due to an AE in Part 2 | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. | Week 27 to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders (Participants With a ≥20% Improvement in UPDRS2+3) | UPDRS is a clinician based rating scale used to measure motor impairments and disability; it assesses 6 features of PD impairment. These are evaluated using a combination of data collected by interview and examination of the participant. UPDRS Part 2 is Activities of Daily Living score and ranges from 0-52. UPDRS Part 3 is Motor Examination and ranges from 0-108. The combined scores of Parts 2 and 3 can range from 0-160 with the higher score indicating the worse condition. A Responder is defined as a participant with at least 20% improvement in UPDRS2+3 from Baseline to Week 26 (End of Part 1 Treatment); a participant with at least a 20% decrease from Baseline score in UPDRS2+3 is defined as a responder. The proportion of Responders was analyzed using a generalized linear mixed model with treatment effect, strata and Baseline UPDRS2+3 as a covariate, and treatment-by-time interaction as fixed effects and subject as random effect. | Baseline and Week 26 | 
| Change From Baseline in the UPDRS Part 2 Score (Activities of Daily Living [ADL]) | The UPDRS is a clinician based rating scale used to measure motor impairments and disability. The UPDRS assesses six features of PD impairment. These are evaluated using a combination of data collected by interview and examination of the participant. The UPDRS Part 2 is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician with the higher score indicating the worse condition. Change from baseline was analyzed using a cLDA model with treatment, time, strata and treatment-by-time interaction as fixed effects and participant as a random effect. | Baseline and Week 26 |