Pivotal Study in Advanced Parkinsons Disease Patients

A Double-blind, Double-dummy, Placebo-controlled, Randomized, Three Parallel Groups Study Comparing the Efficacy, Safety and Tolerability of Pramipexole Extended Release (ER) Versus Placebo and Versus Pramipexole Immediate Release (IR) Administered Orally Over a 26-week Maintenance Phase in L-Dopa+ Treated Patients With Advanced Parkinsons Disease (PD).

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