| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The Primary Efficacy Objective of this trial is to evaluate the efficacy of a range of preladenant doses compared with placebo in subjects with moderate to severe Parkinson's disease (PD) experienceing motor fluctuations and receiving a stable dose of levodopa (L-dopa), as measured by "off" time. |
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| E.2.2 | Secondary objectives of the trial |
| The Key Secondary Efficacy Objective for this trial is to evaluate the efficacy of a range of preladenant doses compared with placebo in subjects with moderate to severe PD experiencing motor fluctuations and receiving a stable dose of L-dopa, as measured by the proportion of Responders and by “on” time without troublesome dyskinesia. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Each subject must have a diagnosis of idiopathic PD based on the UK Parkinson’s Disease Society Brain Bank Criteria (Appendix 1) 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 regime 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 Table 1 are permitted to enroll in this trial. Each subject who is receiving one or more of the adjunct PD medications listed in Table 1 must have been on a stable regimen of treatment for at least the 5 weeks immediately before Randomization.
• Each subject’s Hoehn and Yahr stage must be >= 2.5 and <= 4 n the 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 Randomization.
• Each subject, with or without the help of a caregiver, must be capable of maintaining an accurate and complete symptom diary (Daily Diary) as assessed at the Diary Training Visit.
• Each subject (or subject’s legal representative) must be willing and able to provide written informed consent for the trial. For a subject who is unable to provide independent consent, a legal representative may provide written informed consent. 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 (below).
• 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 be sexually 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 within 2 weeks after the last dose of study drug. Complete details regarding contraceptive requirements are specified in protocol Section 7.7.2.7. |
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| E.4 | Principal exclusion criteria |
• 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, 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, 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 or Beck Depression Inventory II] {BDI II} score ≥19. (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 5 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 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.
• A subject must not have a systolic blood pressure (BP) >= 150mm Hg OR diastolic BP >= 95mm Hg at Screening or 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 visits (scheduled or unscheduled) 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 maybe initiated or increased to control a subject's BP at anytime during treatment in P04938 as needed.
• 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 QTc result > 500 msec], angioplasty, unstable angina, or heart failure; and a subject must not have heart failure staged New York Heart Association Class III or IV.
• 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, the investigator should attempt to characterize at entry the reason(s) for elevation(s), e.g., alcohol abuse (see next exclusion criterion), metabolic syndrome with fatty liver, etc. 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).
• A subject 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. 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 his/her viral infection was not associated with hepatitis in the past, and his/her ALT or AST are normal at Screening. Types of serology assays to be performed are specified in the table of Laboratory Tests (Table 6). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Change from Baseline to End of Treatment (Week 12) in mean "off" time in hours per day. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- The proportion of Responders, where a Responder is defined as a subject with at least a 30% reduction in mean "off" time from Baseline to Week 12.
- The change from Baseline to Week 12 in mean "on" time without troublesome dyskinesia in hours per day.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Brazil |
| Bulgaria |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| India |
| Israel |
| Italy |
| Netherlands |
| Peru |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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