A 12-week Study of Pramipexole Extended Release (ER) in Patients With Parkinson's Disease (PD), Followed by a 52-week Long-term Treatment Period

Study Overview
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Brief Summary
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The objective of this trial is to investigate the safety, tolerability, trough plasma concentration, and efficacy of pramipexole ER in comparison with those of pramipexole IR administrated orally for 12 weeks in patients with PD on levodopa (L-DOPA) therapy (the double-blind period). The double-blind period will be followed by the open-label 52 week administration of pramipexole ER to evaluate the long term safety and efficacy (the open-label period).

Official Title
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A Double-blind, Double-dummy, Randomised, Parallel-group Study to Investigate the Safety, Tolerability, Trough Plasma Concentration, and Efficacy of Pramipexole ER Versus Pramipexole Immediate Release (IR) Administered Orally for 12 Weeks in Patients With Parkinson's Disease (PD) on L-dopa Therapy, Followed by a 52-week Open-label Long-term Treatment Period to Evaluate the Long-term Safety and Efficacy of Pramipexole ER

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Pramipexole Immediate Release
* Drug: Pramipexole Extended Release


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female patients with diagnosis of PD including juvenile Parkinsonism, in whom the onset began at the age of forty or younger. Patients with a modified Hoehn and Yahr scale of II to IV at on time. Patients who have received an individual dosage of L-DOPA (either standard L-DOPA or L-DOPA with dopa-decarboxylase inhibitor) at a stable dose for at least 4 weeks before the baseline visit (Visit 2). Patients who exhibit any therapeutically problematic issues or status based on L-DOPA therapy: wearing-off phenomena no on /delayed on dystonia at off time on-off phenomena freezing phenomena at off time the sub-optimal dose of L-DOPA had been administered due to side effects (such as dyskinesia), or therapeutical strategy Exclusion criteria Atypical parkinsonian syndromes due to drugs, metabolic disorders, encephalitis or degenerative diseases. Dementia, as defined by a Mini-Mental State Examination (MMSE) score <24 at screening visit. Any psychiatric disorder according to DSM-IV criteria that could prevent compliance or completion of the trial and/or put the patient at risk if he/she takes part in the trial. History of psychosis, except history of drug induced hallucinations (provided the investigator considers that participation in the trial would not represent a significant risk for the patient). Clinically significant ECG abnormalities at screening visit, according to investigator's judgement. Clinically significant hypotension or symptomatic orthostatic hypotension (i.e., clinical symptoms of orthostatic hypotension such as dizziness postural etc associated with a decline >=20 mmHg in systolic blood pressure and a decline >=10 mmHg in diastolic blood pressure, at one minute after standing compared with the previous supine systolic and diastolic blood pressure obtained after 5 minutes of quiet rest) either at screening visit or at baseline visit. Any other clinically significant disease, whether treated or not, that could put the patient at risk or could prevent compliance or completion of the trial. Pregnancy (to be excluded by serum pregnancy test at screening visit) or breast-feeding. Sexually active female of childbearing potential not using a medically approved method of birth control within one month before to the screening visit and throughout the trial period. Serum levels of AST, ALT, alkaline phosphatases or bilirubin >2 upper limits of normal . Patients with a creatinine clearance <50 mL/min Patients with a complication or signs of malignant tumours or those within 5 years after the treatment.

Ages Eligible for Study
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Minimum Age: 1 Year

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramipexole Extended Release<br>patient to receive a tablet containing 0.375 mg Pramipexole ER once a day plus containing 0.125 mg Pramipexole IR placebo twice a day -> a tablet containing 1.5 mg Pramipexole ER three times daily (TID) plus 0.5 mg Pramipexole IR placebo TID | Drug: Pramipexole Extended Release<br>* titration as individually needed (0.375 mg -4.5 mg daily)<br>|
| Active Comparator: Pramipexole Immediate Release<br>patient to receive a tablet containing 0.125 mg Pramipexole IR twice a day plus containing 0.375 mg Pramipexole ER placebo once a day -> a tablet containing 0.5 mg Pramipexole IR three times daily (TID) plus 1.5 mg Pramipexole ER placebo TID | Drug: Pramipexole Immediate Release<br>* titrated as individually needed (0.25 mg - 4.5 mg daily)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Adverse Events | An adverse event is defined as any untoward medical occurrence | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Parts II+III Total Score | UPDRS II+III ranging from 0 point(normal) to 160 point (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms | baseline and after 12 weeks treatment | 
| Change From Baseline in Percentage Off-time | Percentage off-time during waking hours in the last two days 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 after 12 weeks treatment | 
| Change From Baseline in Percentage On-time Without Dyskinesia | Percentage on-time without dyskinesia during waking hours in the last two days 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 after 12 weeks treatment | 
| Change From Baseline in Percentage On-time With Non-troublesome Dyskinesia | Percentage on-time with non-troublesome dyskinesia during waking hours in the last two days 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 after 12 weeks treatment | 
| Change From Baseline in Percentage On-time Without Dyskinesia or With Non-troublesome Dyskinesia | Percentage on-time without dyskinesia or non-troublesome dyskinesia during waking hours in the last two days 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 after 12 weeks treatment | 
| Change From Baseline in Percentage On-time With Troublesome Dyskinesia | Percentage on-time with troublesome dyskinesia during waking hours in the last two days 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 after 12 weeks treatment | 
| Responder Rate For Clinical Global Impression of Improvement (CGI-I) | 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) | baseline and after 12 weeks treatment | 
| Responder Rate For Patient Global Impression of Improvement (PGI-I) | PGI-I scores ranging from '1' (very much better) to '7' (very much worse), PGI-I responder have scoring of 1 or 2 (at least much better) | baseline and after 12 weeks treatment | 
| Change From Baseline in UPDRS Part I Score | UPDRS Part I ranging from 0 (normal) to 16 (severe). UPDRS Part I measures Mentation, Behavior and Mood | baseline and after 12 weeks treatment | 
| Change From Baseline in UPDRS Part II Score | UPDRS Part 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 after 12 weeks treatment | 
| Change From Baseline in UPDRS Part III Score | UPDRS Part III ranging from 0 (normal) to 108 (severe). UPDRS Part III measures motor symptoms | baseline and after 12 weeks treatment | 
| Change From Baseline in UPDRS Part IV Score | UPDRS Part IV ranging from 0 (normal) to 23 (severe). UPDRS Part IV measures complications of therapy | baseline and after 12 weeks treatment | 
| UPDRS Parts II+III Total Score Responder Rate (at Least 20% Improvement) | Responders are defined as at least 20% decrease in the UPDRS Parts II+III Total Score ranges 0-160 scores from best to worse | baseline and after 12 weeks treatment | 
| Change From Baseline in L-dopa Daily Dose | The L-dopa daily dose was recorded in the electronic case report form (eCRF) at each trial visit. | baseline and after 12 weeks treatment | 
| Trough Plasma Concentration at Steady State | Geometric mean (gMean) was calculated for trough plasma concentrations of pramipexole at steady state after administration of pramipexole IR 4.5mg and pramipexole ER 4.5mg. | at Visit 8 after pramipexole ER 4.5mg and IR 4.5mg treatment | 
| Dose Proportionality of Trough Plasma Concentration at Steady State After Pramipexole ER Treatment | Dose proportionality of trough plasma concentrations at steady state is explored by using the power model that described the functional relationship between the dose and plasma concentration | from Visit 1 to Visit 8 after pramipexole ER | 
| Change From End of Double-Blind Period in UPDRS (Unified Parkinson's Disease Rating Scale) Parts II+III Total Score (Open-label: Dose Adjustment Phase) | UPDRS II+III ranging from 0 point(normal) to 160 point (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms. Least square means and standard errors presented are from ANCOVA with factors treatment and covariate baseline. | Week 12 to Week 16 | 
| Percentage of Patients With no Worsening of UPDRS Parts II+III Total Score by More Than 15% From Week 12 to Week 16 (Open-label: Dose Adjustment Phase) | Percentage of patients with no worsening of UPDRS Parts II+III Total Score by more than 15% from week 12 to week 16 (Open-label: Dose Adjustment Phase) | Week 12 to Week 16 | 
| Clinical Global Impression of Improvement (CGI-I) at Week 16 Compared to Patient's CGI-I Status at Week 12 (Open-label: Dose Adjustment Phase) | Clinical Global Impression of Improvement (CGI-I) at week 16 compared to patient's CGI-I status at week 12. CGI-I scores ranging from '1' (very much improved) to '7' (very much worse) | Week 12 to Week 16 | 
| Patient Global Impression of Improvement (PGI-I) at Week 16 Compared to Patient's PGI-I Status at Week 12 (Open-label: Dose Adjustment Phase) | Patient Global Impression of Improvement (PGI-I) at week 16 compared to patient's PGI-I status at week 12. PGI-I scores ranging from '1' (very much better) to '7' (very much worse). | Week 12 to Week 16 | 
| Change From Baseline in UPDRS (Unified Parkinson's Disease Rating Scale) Parts II+III Total Score (Open-label: Maintenance Phase) | UPDRS II+III ranging from 0 point(normal) to 160 point (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms | Baseline and after 64 weeks treatment | 
| UPDRS Parts II+III Total Score Responder Rate (at Least 20% Improvement) (Open-label: Maintenance Phase) | Responders are defined as at least 20% decrease in the UPDRS Parts II+III Total Score ranges 0-160 scores from best to worse | baseline and after 64 weeks treatment | 
| Change From Baseline in Percentage Off-time (Open-label: Maintenance Phase) | Percentage off-time during waking hours in the last two days 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 after 64 weeks treatment | 
| Change From Baseline in Percentage On-time Without Dyskinesia (Open-label: Maintenance Phase) | Percentage on-time without dyskinesia during waking hours in the last two days 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 after 64 weeks treatment | 
| Change From Baseline in Percentage On-time With Non-troublesome Dyskinesia (Open-label Maintenance Phase) | Percentage on-time with non-troublesome dyskinesia during waking hours in the last two days 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 after 64 weeks treatment | 
| Change From Baseline in Percentage On-time Without Dyskinesia or With Non-troublesome Dyskinesia (Open-label Maintenance Phase) | Percentage on-time without dyskinesia or non-troublesome dyskinesia during waking hours in the last two days 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 after 64 weeks treatment | 
| Change From Baseline in Percentage On-time With Troublesome Dyskinesia (Open-label Maintenance Phase) | Percentage on-time with troublesome dyskinesia during waking hours in the last two days 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 after 64 weeks treatment | 
| Change From Baseline in L-dopa Daily Dose (Open-label Maintenance Phase) | The L-dopa daily dose was recorded in the electronic case report form (eCRF) at each trial visit. | baseline and after 64 weeks treatment | 
| Change From Baseline in UPDRS Part I Score (Open-label: Maintenance Phase) | UPDRS Part I ranging from 0 (normal) to 16 (severe). UPDRS Part I measures Mentation, Behavior and Mood | baseline and after 64 weeks treatment | 
| Change From Baseline in UPDRS Part II Score (Open-label: Maintenance Phase) | UPDRS Part 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 after 64 weeks treatment | 
| Change From Baseline in UPDRS Part III Score (Open-label: Maintenance Phase) | UPDRS Part III ranging from 0 (normal) to 108 (severe). UPDRS Part III measures motor symptoms | baseline and after 64 weeks treatment | 
| Change From Baseline in UPDRS Part IV Score (Open-label: Maintenance Phase) | UPDRS Part IV ranging from 0 (normal) to 23 (severe). UPDRS Part IV measures complications of therapy | baseline and after 64 weeks treatment |