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 | 16.0 |
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 early Parkinson's disease as measured by the sum of UPDRS Parts 2 and 3 scores. The primary safety objective of this trial is to evaluate the safety and tolerability of preladenant compared to placebo in subjects with early PD. |
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E.2.2 | Secondary objectives of the trial |
The Key Secondary Objective of this trial is to evaluate the efficacy of a range of preladenant doses compared with placebo in subjects with early PD as measured by the proportion of Responders and by the the UPDRS Part 2 score. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subjects with a diagnosis of idiopathic PD for less than 5 years based on the United Kingdom Parkinson’s Disease Society Brain Bank Criteria (see Appendix 1) and the inclusion/exclusion criteria for this protocol.
a. 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)
b. If resting tremor is not present at screening, the rigidity and/or bradykinesia must be asymmetric.
• Subject who is receiving amantadine and/or anticholinergics must have been on a stable regimen of treatment for at least the 5 weeks before Screening.
• Each subject must have a UPDRS Part 3 score of >= 10.
• Each subject's Hoehn and Yahr Stage must be <= 3.
• Each subject 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 gender and 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).
• 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 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. |
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E.4 | Principal exclusion criteria |
• A subject must not have a form of drug induced or atypical parkinsonism, cognitive impairment (Montreal Cognitive Assessment [MoCA] score<22), bipolar disorder, schizophrenia or other psychotic disorder.
• A subject must not have a history of 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; negative response to large doses of L-dopa (if malabsorption excluded); MPTP or known neurotoxin exposure; hallucinations unrelated to medications; surgery for PD.
• A subject must not have been treated with L dopa or dopamine agonists for other than diagnostic purposes within 30 days before Randomization.
• 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).
• A subject must not have a systolic BP >=150mm Hg OR diastolic BP >=95mm 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 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 may be initiated or increased to control a subject's BP at any time during treatment in P05664 as needed.
• A subject must not have an untreated major depressive disorder meeting Diagnostic and Statistical Manual of Mental Disorders IV Text Revision criteria or Beck Depression Inventory II] {BDI II} score ≥19. A subject who is successfully treated 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 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 > 500 msec], angioplasty, unstable angina, or heart failure; and a subject must not have heart failure staged NYHA Class III or IV.
• A subject must not have an ALT or AST >=3 x ULN or total bilirubin (T-BIL) >=1.5 x ULN. Should an LFT be abnormal (ALT/AST >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), eg, alcohol abuse (see next exclusion criterion), metabolic syndrome with fatty liver, etc. No repeat testing is 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.
• 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 more recently than the indicated period before Randomization, or continue to receive any treatment listed during the trial, unless expressly prescribed by the investigator during the trial. (see table in protocol)
• A female subject must not be breast-feeding or considering breast-feeding.
• A female subject must not be pregnant or intending to become pregnant. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from Baseline to Week 26 (End of Part 1 treatment) in the sum of the UPDRS Parts 2 and 3 scores. |
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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 Key Secondary Efficacy Endpoints are:
• The proportion of Responders, where a Responder is defined as a subject with at least a 20% improvement in UPDRS2+3 from Baseline to Week 26 (End of Part 1 Treatment).
• The change from Baseline in the UPDRS Part 2 score (Activities of Daily Living [ADL]) at Week 26. |
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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 | Yes |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Argentina |
Austria |
Brazil |
Bulgaria |
Canada |
Chile |
Colombia |
Czech Republic |
Finland |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Mexico |
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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The overall trial ends when the last remaining subject has ended participation in the trial, by completing the trial, being discontinued from the trial, or being lost to follow-up. A subject is considered to have fulfilled participation when he/she has completed the last protocol-specified contact (eg, visits or telephone contacts). |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |