Pivotal Study in Advanced Parkinsons Disease Patients
Pivotal Study in Advanced Parkinsons Disease Patients
The general aim of this trial is to determine the efficacy (as measured by the change from
 baseline to the end of the maintenance phase in the total score for Unified Parkinsons
 Disease Rating Scale Parts II and III combined), safety, and tolerability of pramipexole ER,
 in daily doses from 0.375 milligram to 4.5 milligram once a day, in comparison to placebo, in
 Levodopa combined with a Dopa-Decarboxylase-inhibitor treated Parkinson patients with
 advanced Parkinsons Disease and motor fluctuations.

 In addition, a numerical comparison of the efficacy of pramipexole extended release versus
 pramipexole immediate release will be done.

 The efficacy of pramipexole immediate release will also be compared to placebo, for assay
 sensitivity.
Inclusion Criteria:

 1. Male or female patient with advanced idiopathic Parkinsons disease confirmed by at
 least two of the following signs: resting tremor, bradykinesia, rigidity.

 2. Parkinsons disease diagnosed for at least 2 years.

 3. Patients 30 years of age or older at the time of diagnosis.

 4. Modified Hoehn and Yahr stage of 2 to 4 at on-time.

 5. Treatment with standard or controlled release Levodopa combined with a
 Dopa-Decarboxylase-inhibitor, or with Levodopa combined with a
 Dopa-Decarboxylase-inhibitor/entacapone, at an optimised dose according to
 investigators judgement, this dose being stable for at least 4 weeks prior to baseline
 visit.

 6. Motor fluctuations, with at least 2 cumulative hours of off-time every day during
 waking hours (documented on a patient diary completed for 2 consecutive days before
 baseline visit).

 7. Patient willing and able to comply with scheduled visits, treatment plan, laboratory
 tests and other study procedures. In particular, after training, it has to be
 documented at baseline visit that the patient is able to recognise the off-time and
 on-time periods during waking hours and that the patient (or a family member or a
 guardian) is able to record them accurately in the patient diary.

 8. Signed informed consent obtained before any study procedures are carried out (in
 accordance with International Conference on Harmonisation-Good Clinical Practice
 guidelines and local legislation).

 Exclusion Criteria:

 1. Atypical parkinsonian syndromes due to drugs, metabolic disorders, encephalitis or
 degenerative diseases

 2. Dementia, as defined by a Mini-Mental State Exam score < 24 at screening visit

 3. Any psychiatric disorder according to Diagnostic and Statistical Manual of Mental
 Disorders 4th edition criteria that could prevent compliance or completion of the
 study and/or put the patient at risk if he/she takes part in the study

 4. History of psychosis, except history of drug induced hallucinations

 5. History of deep brain stimulation

 6. Clinically significant Electrocardiogram abnormalities at screening visit

 7. Clinically significant hypotension and/or symptomatic orthostatic hypotension at
 screening or baseline visit

 8. Malignant melanoma or history of previously treated malignant melanoma

 9. Any other clinically significant disease, whether treated or not, that could put the
 patient at risk or could prevent compliance or completion of the study

 10. Pregnancy or breast-feeding

 11. Sexually active female of childbearing potential not using a medically approved method
 of birth control for at least one month prior to the screening visit and throughout
 the study period

 12. Serum levels of Aspartate Aminotransferase (Serum Glutamic-Oxaloacetic Transaminase),
 Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase), alkaline phosphatases
 or bilirubin > 2 Upper Limit of Normal

 13. Patients with a creatinine clearance < 50 millilitres/minute

 14. Any dopamine agonist (including pramipexole) within 4 weeks prior to baseline visit

 15. Any medication with central dopaminergic antagonist activity within 4 weeks prior to
 the baseline visit

 16. Any of the following drugs within 4 weeks prior to baseline visit: methylphenidate,
 cinnarizine, amphetamines

 17. Flunarizine within 3 months prior to baseline visit

 18. Known hypersensitivity to pramipexole or its excipients

 19. Drug abuse according to investigators judgement, within 2 years prior to screening

 20. Participation in other investigational drug studies, or use of other investigational
 drugs within one month or five times the half-life of the investigational drug
 (whichever is longer) prior to baseline visit