Long-term Safety Study of Open-label Pramipexole ER in Patients With Advanced PD

Study Overview
=================
Brief Summary
-----------------
The general aim of this study is to obtain long-term safety and tolerability data on pramipexole extended release (ER), in daily doses from 0.375mg to 4.5mg once daily (qd), in patients who have previously completed a pramipexole double-blind study in advanced Parkinson's disease (PD) (248.525 trial).

Official Title
-----------------
Long-term Safety Study of Open-label Pramipexole Extended Release (ER) in Patients With Advanced Parkinson's Disease (PD)

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: Pramipexole
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Completion of the double-blind trial 248.525 Male or female patient with advanced idiopathic Parkinson's disease (PD), with a Modified Hoehn and Yahr stage of 2 to 4 at on-time, and a concomitant treatment with standard or controlled release L-Dopa+, or a combination of L-Dopa+ and entacapone. Patient willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. In particular the patient should be able to recognise the off-time and on-time periods during waking hours and the patient (or a family member or a guardian) should be 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 of Harmonization - Good Clinical Practice (ICH-GCP) guidelines and local legislation). Exclusion criteria: Patients prematurely withdrawn from the double-blind trial 248.525 Atypical parkinsonian syndromes due to drugs, metabolic disorders, encephalitis or degenerative diseases Any psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV 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 ECG abnormalities at baseline Clinically significant hypotension and/or symptomatic orthostatic hypotension at baseline 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 Serum levels of aspartate transaminase (AST) (serum glutamic oxaloacetic transaminase (SGOT)), alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase) (SGPT)), alkaline phosphatase (AP) or bilirubin > 2 upper limit normal (ULN) at baseline Patients with a creatinine clearance < 50 mL/min at baseline 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 Known hypersensitivity to pramipexole or its excipients Drug abuse, according to investigators judgement, within 2 years prior to baseline Participation in investigational drug studies other than the trial 248.525, 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

Ages Eligible for Study
-----------------
Minimum Age: 32 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pramipexole<br>Patients to receive Pramipexole ER 0.375 - 4.5 mg in tablet form daily | Drug: Pramipexole<br>* Pramipexole ER 0.375 -4.5 mg<br>|
| Placebo Comparator: Placebo<br>Patients to receive placebo tablets identical to Pramipexole ER tablets only during transfer phase | Drug: Placebo<br>* Placebo tablets identical to Pramipexole ER tablets<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Adverse Events, Adverse Drug Reactions, Serious Adverse Events | The aim of this study was to obtain long-term safety and tolerability data on pramipexole ER, in patients who have previously completed a pramipexole double blind study in advanced Parkinson's Disease (PD) (248.525 (NCT00466167)). Therefore these items were considered as a safety evaluation. | 80 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients Successfully Switched From Pramipexole (PPX) IR or ER to ER Assessed on UPDRS II+III | Unified Parkinson's Disease Rating Scale (UPDRS) Successfully switched means: UPDRS II+III baseline score >20 without a relative worsening of UPDRS II+III score > 15% from baseline or UPDRS II+III baseline score <=20 without an absolute worsening of UPDRS II+III score > 3 from baseline UPDRS II+III ranging from 0 (normal) to 160 (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms | One week | 
| UPDRS II+III Change From Open Label (OL) Baseline | UPDRS II+III ranging from 0 (normal) to 160 (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms | OL Baseline and week 80 | 
| Number of Participants With UPDRS II+III Response | A response means an improvement of >=20% in UPDRS II+III from OL baseline UPDRS II+III ranging from 0 (normal) to 160 (severe). UPDRS part II measures activities of daily living, part III measures motor symptoms | Week 80 | 
| Number of Patients Successfully Switched From PPX IR or ER to ER Assessed on Off-time | A patient was considered as successfully switched if he/she has converted to ER without a worsening of off time by more than 12.5% from baseline. Off-time is based on patient diary data and describes a period when the patient experiences increased parkinsonian symptoms (e.g. immobility or inability to move with ease). | One week | 
| Percentage Off Time During Waking Hours Total Score: Change From Baseline | 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). A negative change implies improvement | Baseline and week 80 | 
| Number of Participants With Response in Percentage Off Time During Waking Hours | Response means >=20% improvement relative to OL baseline in the % off-time during waking hours | 80 weeks | 
| Percentage on Time Without Dyskinesia During Waking Hours: Change From Baseline After 80 Weeks | 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. A positive change implies improvement. | Baseline and week 80 | 
| Percentage on Time With Non Troublesome Dyskinesia During Waking Hours: Change From Baseline After 80 Weeks | 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. A positive change implies improvement | Baseline and week 80 | 
| Percentage on Time Without Dyskinesia or With Non Troublesome Dyskinesia During Waking Hours: Change From Baseline After 80 Weeks | Percentage on-time without dyskinesia or 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. A positive change implies improvement | Baseline and week 80 | 
| Percentage on Time With Troublesome Dyskinesia During Waking Hours: Change From Baseline After 80 Weeks | Percentage on-time with 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. A positive change implies improvement | Baseline and week 80 | 
| Number of Participants With Response in CGI-I | Clinical Global Impression of Improvement (CGI-I), CGI-I scores ranging from '1' (very much improved) to '7' (very much worse). For patients previously treated with Placebo, all patients with at least much improved were considered as responders. For patients previously treated with PPX ER or IR, all patients with no change to very much improved were considered as responders | 32 weeks | 
| Number of Participants With Response in PGI-I | Patient Global Impression of Improvement (PGI-I), PGI-I scores ranging from '1' (very much better) to '7' (very much worse). For patients previously treated with Placebo, all patients with at least much better were considered as responders. For patients previously treated with PPX ER or IR, all patients with no change to very much better were considered as responders | 32 weeks | 
| Number of Participants With Response in PGI-I for Early Morning Off Symptoms | Patient Global Impression of Improvement (PGI-I) for early morning off symptoms, PGI-I scores ranging from '1' (very much better) to '7' (very much worse). For patients previously treated with Placebo, all patients with at least much better were considered as responders. For patients previously treated with PPX ER or IR, all patients with no change to very much better were considered as responders | 32 weeks | 
| UPDRS I Total Score and Change From OL Baseline at Week 80 | UPDRS I ranging from 0 (normal) to 16 (severe). UPDRS I measures Mentation, Behavior and Mood | OL baseline and week 80 | 
| UPDRS II Total Score and Change From OL Baseline at Week 80 | 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 | OL baseline and week 80 | 
| UPDRS III Total Score and Change From OL Baseline at Week 80 | UPDRS III ranging from 0 (normal) to 108 (severe). UPDRS part III measures motor symptoms | OL baseline and week 80 | 
| UPDRS IV Total Score and Change From OL Baseline at Week 80 | UPDRS IV ranging from 0 (normal) to 23 (severe). UPDRS IV measures complications of therapy | OL baseline and week 80 | 
| Parkinson Fatigue Scale (PFS-16) Score and Change From OL Baseline at Week 80 | PFS-16 (Parkinson fatigue scale) ranging from 16 (better perceived health status) to 80 (severe symptoms of the disease) measuring aspects of fatigue that are relevant to patients with PD | OL baseline and week 80 | 
| Number of Participants With L-dopa Daily Dose Change: Change From OL Baseline at Week 80 |  | OL baseline and week 80 | 
| Number of Participants With Changes in Pramipexole Doses After 80 Weeks Compared to Pramipexole Dose at OL Baseline |  | OL baseline and week 80 | 
| Number of Participants With Serious Adverse Events |  | 80 weeks | 
| Supine Diastolic Blood Pressure, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Standing Diastolic Blood Pressure, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Supine Systolic Blood Pressure, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Standing Systolic Blood Pressure, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Supine Pulse Rate, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Standing Pulse Rate, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Body Weight of Female Patients, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Body Weight of Male Patients, Baseline and Week 80, Vital Signs Treated Set |  | OL Baseline and Week 80 | 
| Epworth Sleepiness Scale (ESS), Baseline and End of Open Label, Treated Set | ESS Total score ranges from zero (best) to 24 (worst); scale has 8 items, each rated from zero (no chance of dozing) to 3 (high chance of dozing) | OL Baseline and Week 80 | 
| Modified Minnesota Impulsive Disorder Interview (mMIDI), Frequency of Patients With at Least One Abnormal Behavior, Treated Set | The mMIDI is a semi-structured interview designed to assess impulsive control disorders. The scale was modified to focus behaviors of: pathological gambling, compulsive buying and compulsive sexual behavioral. | Baseline, 80 weeks |