| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 15.0 |
| 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 |
|
| 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. |
|
| 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. |
|
| 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
(which can be extended by no more than 7 days, if the Sponsor's
approval is obtained for the extension)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. |
|
| E.4 | Principal exclusion criteria |
Subjects must not have/be:
• A form of drug induced or atypical parkinsonism, cognitive impairment (MoCA score<22), bipolar disorder, schizophrenia or other psychotic disorder.
• 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) or failure to respond to an adequate previous treatment with dopaminergic therapy; MPTP or known neurotoxin exposure; hallucinations unrelated to medications; surgery for PD.
• Treated with L-dopa or dopamine agonists for 30 days or more. A subject who has been treated with L-dopa or dopamine agonists for <30 days at any time will be allowed to enrol. Subjects who are still taking dopaminergic medication at Screening or who stopped taking dopaminergic medication within 30 days of Randomization must still wash out from dopaminergic medication for a total of 30 days prior Randomization. Motor scores (UPDRS Pt3) should be evaluated at wash out Day 15, at an unscheduled Visit during the mandatory 30 day washout period for those subjects who stop taking their dopaminergic medications at Screening.
• At imminent risk of self-harm or to others (in the investigator's opinion based on CSSRS).
• A systolic BP >=150mm Hg OR diastolic BP >=95mm Hg at Screening and at a BP recheck prior Randomization. Measures to control/adjust BP can be taken to meet the BP entry criterion up to Randomization (Day 1), but if the subject's BP is not within range on Day 1 then s/he cannot enrol. Repeated BP measurements intended to obtain acceptable BP entry criteria are not allowed, ie if the subject's BP is not within the range as per BP exclusion criterion on Day 1 then s/he cannot be randomized. If BP is elevated at the Screening Visit, initiation or alteration of the dose of antihypertensive medicine can be done to obtain 2 BP measurements meeting this criterion at consecutive separate visits (scheduled or unscheduled) between the Screening Visit and the Randomization Visit (which is 5 weeks and may be extended by no more than 7days if the Sponsor's approval is obtained for the extension).
• An untreated major depressive disorder meeting Diagnostic and Statistical Manual of Mental Disorders IV Text Revision criteria or BDI II score ≥19. A subject is eligible to enrol if successfully treated with stable doses of allowed antidepressant medications for at least 5 weeks immediately before Screening.
• Any clinically significant cardiovascular event/procedure for 6 months prior 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 (staged NYHA Class III or IV).
• 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, 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).
• Active serologically confirmed hepatic dysfunction (defined as viral infection [Hepatitis B, C, or E; EBV; 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 with history of serologically confirmed EBV or CMV may enrol 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 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/prostate cancer with a normal PSA post resection.
• Received any treatment listed more recently than the indicated period before Randomization. Note: Subjects who have been treated with Ldopa or dopamine agonists for <30 days may enrol provided they washout for 30 days prior Randomization.
• A female subject must not be breast-feeding or considering breastfeeding or be pregnant or intending to become pregnant. |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 5 |
| 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 |
|
| 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
|
| 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). |
|
| 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 |
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