Pivotal Study in Advanced Parkinsons Disease Patients

Study Overview
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Brief Summary
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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.

Official Title
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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).

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Pramipexol Extended Release
* Drug: Pramipexol Immediate Release
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient with advanced idiopathic Parkinsons disease confirmed by at least two of the following signs: resting tremor, bradykinesia, rigidity. Parkinsons disease diagnosed for at least 2 years. Patients 30 years of age or older at the time of diagnosis. Modified Hoehn and Yahr stage of 2 to 4 at on-time. 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. 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). 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. 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: Atypical parkinsonian syndromes due to drugs, metabolic disorders, encephalitis or degenerative diseases Dementia, as defined by a Mini-Mental State Exam score < 24 at screening visit 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 History of psychosis, except history of drug induced hallucinations History of deep brain stimulation Clinically significant Electrocardiogram abnormalities at screening visit Clinically significant hypotension and/or symptomatic orthostatic hypotension at screening or baseline visit Malignant melanoma or history of previously treated malignant melanoma 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 Pregnancy or breast-feeding 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 Serum levels of Aspartate Aminotransferase (Serum Glutamic-Oxaloacetic Transaminase), Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase), alkaline phosphatases or bilirubin > 2 Upper Limit of Normal Patients with a creatinine clearance < 50 millilitres/minute Any dopamine agonist (including pramipexole) within 4 weeks prior to baseline visit Any medication with central dopaminergic antagonist activity within 4 weeks prior to the baseline visit Any of the following drugs within 4 weeks prior to baseline visit: methylphenidate, cinnarizine, amphetamines Flunarizine within 3 months prior to baseline visit Known hypersensitivity to pramipexole or its excipients Drug abuse according to investigators judgement, within 2 years prior to screening 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

Ages Eligible for Study
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Minimum Age: 32 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Pramipexole ER<br> | Drug: Pramipexol Extended Release<br> <br> |
| Other: Pramipexole IR<br> | Drug: Pramipexol Immediate Release<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Parts II+III Score at Week 18 | UPDRS II+III total score on Full Analysis Set (FAS)with LOCF (Last observation carried forward), week 18 - baseline, UPDRS II+III ranging from 0 (normal) to 160 (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms | baseline and week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Percentage Off-time at Week 18 | Percentage off-time based on patient diary data, percentage ranging from 0 (best case) to 100 (worst case). Off-time describes a period when the patient experiences increased parkinsonian symptoms (e.g. immobility or inability to move with ease). | baseline and week 18 | 
| Change From Baseline in Percentage On-time Without Dyskinesia at Week 18 | Percentage on-time based on patient diary data, percentage ranging from 0 (worst case) to 100 (best case). On-time describes a period when the patient has no symptoms of off-time and is not asleep. | baseline and week 18 | 
| Change From Baseline in Percentage On-time With Non-troublesome Dyskinesia at Week 18 | Percentage on-time with non-troublesome dyskinesia based on patient diary data, percentage ranging from 0 (worst case) to 100 (best case). On-time describes a period when the patient has no symptoms of off-time and is not asleep. | baseline and week 18 | 
| Change From Baseline in Percentage On-time With Troublesome Dyskinesia at Week 18 | Percentage on-time with troublesome dyskinesia based on patient diary data, percentage ranging from 0 (best case) to 100 (worst case). On-time describes a period when the patient has no symptoms of off-time and is not asleep. | baseline and week 18 | 
| Clinical Global Impression - Global Improvement (CGI-I) Responder | CGI-I scores ranging from '1' (very much improved) to '7' (very much worse), CGI-I responder have scoring of 1 or 2 (at least much improved) | after 18 weeks of treatment | 
| Response in Patient Global Impression (PGI-I) | PGI-I scores ranging from '1' (very much better) to '7' (very much worse), PGI-I responder have scoring 1 or 2 (at least much better) | after 18 weeks of treatment | 
| Change From Baseline in UPDRS I Score After 18 Weeks | UPDRS I ranging from 0 (normal) to 16 (severe). UPDRS I measures Mentation, Behavior and Mood | baseline and 18 weeks | 
| Change From Baseline in UPDRS II Score After 18 Weeks, Average at on and Off-period | UPDRS II ranging from 0 (normal) to 52 (severe). UPDRS Part II is calculated as the average of UPDRS part II at on and UPDRS part II at off-period for each of the 13 activities. | baseline and 18 weeks | 
| Change From Baseline in UPDRS III Score After 18 Weeks | UPDRS III ranging from 0 (normal) to 108 (severe). UPDRS part III measures motor symptoms | baseline and 18 weeks | 
| Change From Baseline in UPDRS IV Score After 18 Weeks | UPDRS IV ranging from 0 (normal) to 23 (severe). UPDRS IV measures complications of therapy | baseline and 18 weeks | 
| Change From Baseline in Beck's Depression Inventory (BDI) After 18 Weeks | ranging from 0 (best case) to 63 (worst case) | baseline and 18 weeks | 
| Change From Baseline in Parkinson's Disease Sleep Scale (PDSS) After 18 Weeks | ranging from 0 (worst case) to 150 (best case) | baseline and 18 weeks | 
| Change From Baseline in Parkinson's Disease Quality of Life Questionnaire 39 After 18 Weeks | Ranging from 0 (best case) to 156 (worst case) | baseline and 18 weeks | 
| Change From Baseline in European Quality of Life (EuroQol) Scale After 18 Weeks | ranging from 0 (worst case) to 100 (best case) | baseline and 18 weeks | 
| Change From Baseline in 11-point Likert Scale for Pain Related to PD at Week 18 | Likert scale is a method used for the measurement of pain. The patients were asked to rate their pain related to PD by ticking the number that best described their pain on the average in the previous week, from zero for no pain to ten for unbearable pain. | baseline and week 18 | 
| Clinically Significant Abnormalities: Clinical Laboratory Evaluations (Biochemistry and Haematology) |  | baseline and week 18 |