Rotigotine Versus Placebo, A Study To Evaluate The Efficacy In Advanced Stage Idiopathic Parkinson's Disease Patients

• Response analysis: subject's response to therapy, defined as a ≥30 % decrease in absolute time spent "off" from Baseline to the end of the double-blind Maintenance Period [ Time Frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 12) ] [ Designated as safety issue: No ]
• Percent change in absolute and relative time spent "off" from Baseline to the end of double-blind Maintenance Period [ Time Frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 12) ] [ Designated as safety issue: No ]
• Change and percent change in absolute and relative time spent "on" from Baseline to the end of double-blind Maintenance Period [ Time Frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 12) ] [ Designated as safety issue: No ]
• Change in the number of "off" periods from Baseline to the end of double-blind Maintenance Period [ Time Frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 12) ] [ Designated as safety issue: No ]
• Change in status of the subject (on/off) after wake-up from Baseline to the end of double-blind Maintenance Period [ Time Frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 12) ] [ Designated as safety issue: No ]
• Change in Unified Parkinson's Disease Rating Scale (UPDRS Part III motor examination) during "on" periods from Baseline to the end of double-blind Maintenance Period [ Time Frame: From Baseline (Week 0) to end of Maintenance Period (up to Week 12) ] [ Designated as safety issue: No ]

The primary objective of this study is to demonstrate that Rotigotine transdermal patch is efficacious in Chinese subjects with advanced-stage Idiopathic Parkinson's Disease as an adjuvant therapy.

The study includes a maximum 4-week Screening Period, a maximum 7-week Titration Period for advanced-stage Parkinson's disease, 12-week Maintenance Period, a maximum 12-day De-escalation Period for advanced-stage Parkinson's Disease and 30-day Safety Follow-Up Period. The maximum study durations for an individual subject with advanced-stage Parkinson's disease will be 27 weeks.

• Drug: Rotigotine

  Transdermal Patch

  Content:

  4 mg /24 h (20 cm^2), 6 mg /24 h (30 cm^2), 8 mg /24 h (40 cm^2)

  For advanced-stage Parkinson's Disease, receive Rotigotine patches in escalating weekly dose (starting with daily doses 4 mg/24 h to 16 mg/24 h) for a maximum 7-week Titration Period, then 12 week maintenance period

• Drug: Placebo Patch

  Transdermal Patch

  Size:

  20 cm^2, 30 cm^2, 40 cm^2

  Subjects randomized to placebo will receive matching placebo patches

• Experimental: Rotigotine
  Rotigotine, daily doses, treatment group
  Intervention: Drug: Rotigotine
• Placebo Comparator: Placebo
  Placebo, daily doses, placebo group
  Intervention: Drug: Placebo Patch

Inclusion Criteria:

• An Independent Ethics Committee (IEC)-approved written informed consent is signed and dated by the subject or by the legal representative
• Subject/legal representative is considered reliable and capable of adhering to the protocol (eg, able to understand and complete diaries), visit schedule, and medication application according to the judgment of the investigator
• Subject has Idiopathic Parkinson's Disease of more than 3 years' duration, defined by the cardinal sign, Bradykinesia, plus the presence of at least 1 of the following: resting tremor, rigidity, or impairment of postural reflexes, and without any other known or suspected cause of Parkinsonism
• The investigator must observe the subject in both the "on" and "off" state and determine that the subject is Hoehn & Yahr stage 2 through 4 in both the "on" and "off" state
• Subject is male or female and aged ≥30 years at Screening (Visit 1)
• Subject has a Mini Mental State Examination (MMSE) score of ≥25 at Screening (Visit 1)
• Subject must be on a stable dose of L-dopa (either short-acting or sustained release [in combination with Benserazide or Carbidopa]) of at least 200 mg/day, administered in at least 2 intakes, for at least 28 days prior to Baseline (Visit 2)
• Subject is not adequately controlled on a L-dopa dose (in combination with Benserazide or Carbidopa) which was judged by the treating physician to be optimal
• Subject must be willing and able to accurately complete a subject diary on designated days (with assistance from caregivers, if required), recording periods when they are "on without troublesome Dyskinesia", "on with troublesome Dyskinesia", "off", and sleeping
• As part of the Screening (pretreatment) assessments, the subject must complete a diary over a period of 6 days, with 4 of the 6 diaries being "valid" as determined by the investigator (see Section 9.1.1)
• It must be clear to the investigator that the subject is able to differentiate between the "on" and "off" state and the "valid" diaries confirm that the subject has an average of ≥2.5 h/day spent in the "off" state
• If the subject is receiving an Anticholinergic agent (eg, Benztropine, Trihexyphenidyl, Parsitan, Procyclidine, Biperiden), a monoamine oxidase (MAO)-B inhibitor (eg, Selegiline), and/or an N-methyl-d-aspartate (NMDA) antagonist (eg, Amantadine), he/she must have been on a stable dose for at least 28 days prior to Baseline (Visit 2) and be maintained on that dose for the duration of the study
• Subject must be on a stable dose of all anti-Parkinsonian medications for at least 20 days prior to completing the 6 Baseline diaries

Exclusion Criteria:

• Subject has previously participated in this study or subject has previously received the study medication under investigation in this study
• Subject is participating in another study of an investigational drug or has done so within 28 days prior to the Baseline Visit (Visit 2)
• Subject has a history of significant skin hypersensitivity to adhesive or other transdermal preparations, or recent unresolved contact dermatitis
• Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ("Yes") to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening (Visit 1)
• Subject has atypical Parkinson's syndrome(s) due to drugs (eg, Metoclopramide, Flunarizine), Metabolic Neurogenetic Disorders (eg, Wilson's Disease), Encephalitis, Cerebrovascular Disease, or Degenerative Disease (eg, Progressive Supranuclear Palsy)
• Subject has a history of Pallidotomy, Thalamotomy, deep brain stimulation, or fetal tissue transplant
• Subject has dementia, active psychosis or hallucinations, or severe depression
• Subject is receiving therapy with a Dopamine agonist either concurrently or has done so within 28 days prior to the Baseline Visit (Visit 2)
• Subject is receiving therapy with 1 of the following drugs either concurrently or within 28 days prior to Baseline (Visit 2): Alpha-methyl dopa, Metoclopramide, Reserpine, Neuroleptics (except specific atypical neuroleptics: Olanzapine, Ziprasidone, Aripiprazole, Clozapine, quetiapine), MAO-A inhibitors, Methylphenidate, or Amphetamine
• Subject is currently receiving central nervous system (CNS) active therapy (eg, sedatives, hypnotics, antidepressants, anxiolytics), unless the dose has been stable for at least 28 days prior to Baseline (Visit 2) and is likely to remain stable for the duration of the study
• Subject has a current diagnosis of Epilepsy, has a history of seizures as an adult, has a history of stroke, or has had a transient ischemic attack within 1 year prior to Screening (Visit 1)
• Subject has clinically relevant hepatic dysfunction (as defined as a total bilirubin >2.0 mg/dL, or Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) >2 times the upper limit of the reference range)
• Subject has clinically relevant renal dysfunction (serum creatinine >2.0 mg/dL [>178 μmol/L])
• Subject has clinically relevant cardiac dysfunction (any cardiac disorder which in the opinion of the investigator would put the subject at risk of clinically relevant arrhythmia) and/or myocardial infarction within the last 12 months
• Subject has a QT interval corrected for heart rate according to Bazett's formula (QTcB) of ≥500 ms at Screening (Visit 1)
• Subject has a history of only symptomatic (not asymptomatic) orthostatic hypotension, with a decrease of systolic blood pressure (SBP) from supine to standing position of ≥2 0 mmHg or of ≥10 mmHg in DBP after 1 or 3 minutes within 28 days prior to Baseline (Visit 2), or SBP <105 mmHg at study entry 17. Subject has evidence of an impulse control disorder (ICD) at Screening (Visit 1)
• Subject has a history of known intolerance/hypersensitivity to the following Antiemetics: Domperidone, Trimethobenzamide, Ondansetron, Tropisetron, Granisetron, and Glycopyrrolate
• Subject has a history of chronic alcohol or drug abuse within the last 5 years
• Subject is pregnant or nursing, or is of childbearing potential but (i) not surgically sterile or (ii) not using adequate birth control methods (including at least a double barrier method) or (iii) not sexually abstinent or (iv) not at least 2 years post-menopausal
• Subject has any other clinically relevant medical condition, psychiatric condition, or laboratory abnormality which would, in the judgment of the investigator, interfere with the subject's ability to participate in the study