Efficacy, Safety, Tolerability of Pramipexol ER Versus Pramipexol IR Versus Placebo in Early PD Patients

Study Overview
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Brief Summary
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The objectives of this trial conducted in early Parkinson's Disease (PD) patients are to determine the efficacy (as measured by the change from baseline to the end of the maintenance phase in the total score for the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III combined), safety, and tolerability of Pramipexole Extended Release (ER) (in daily doses from 0.375mg to 4.5mg q.d.) in comparison to placebo, and to test for non-inferiority between the two formulations (ER and IR) of pramipexole. In addition, the efficacy of Pramipexole Immediate Release (IR) will 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 ER Versus Placebo and Versus Pramipexole IR Administered Orally Over a 26-week Maintenance Phase in Patients With Early Parkinsons Disease (PD).

Conditions
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Early Parkinson Disease (Early PD)

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 idiopathic Parkinsons disease (PD) confirmed by at least two of the following signs: resting tremor, bradykinesia, rigidity. Parkinsons disease diagnosed within 5 years. Patients 30 years of age or older at the time of diagnosis. Modified Hoehn and Yahr stage of 1 to 3. Patients requiring additional therapy/ introduction of therapy (for de novo patients) to treat their parkinsonian symptoms at the time of enrollment (screening visit, V1) according to the investigators judgement. Exclusion Criteria: Atypical parkinsonian syndromes due to drugs (e.g., metoclopramide, flunarizine), metabolic disorders (e.g., Wilson's disease), encephalitis or degenerative diseases (e.g., progressive supranuclear palsy). 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 (DSM-IV) History of psychosis Clinically significant electrocardiogram (ECG) abnormalities at screening visit Clinically significant hypotension 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 Sexually active female of childbearing potential not using a medically approved method of birth control Serum levels of Aspartate Aminotransferase (AST) , Alanine Aminotransferase (ALT), alkaline phosphatases or bilirubin > 2 Upper Limit of Normal (ULN) Patients with a creatinine clearance < 50 mL/min Any dopamine agonist (including pramipexole) within 4 weeks prior to baseline visit, or L-Dopa within 8 weeks prior to baseline visit. Total cumulative duration of prior exposure to Levodopa of more than 3 months. Any medication (including intra-muscular formulations) with central dopaminergic antagonist activity within 4 weeks prior to the baseline visit Any of the following drugs within 4 weeks prior to the baseline visit: methylphenidate, cinnarizine, amphetamines. Flunarizine within 3 months prior to baseline visit Known hypersensitivity to Pramipexole or its excipients Drug abuse (including alcohol), 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

Ages Eligible for Study
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Minimum Age: 30 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramipexole Extended Release (PPX ER)<br> | Drug: Pramipexol Extended Release<br> <br> |
| Experimental: Pramipexole Immediate Release (PPX 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 Total Score | Activities of daily living are scored from 0-52 in UPDRS II, result of motor examination scored 0-108 in UPDRS III. A decrease in the score means improvement. | baseline and after 33 weeks treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders on the Clinical Global Impressions of Improvement (CGI-I) Scale | Clinicians evaluation in a rating scale of 7 steps, 1 meaning very much improved to 7 meaning very much worse. Responders are the patients with 'much improved' and 'very much improved' on the scale | after 18 weeks of treatment compared to baseline | 
| Percentage of Responders on the Patients Global Impressions of Improvement (PGI-I) Scale | Patient rated evaluation of the PD symptoms on a rating scale of 7 steps, 1 meaning very much better to 7 meaning very much worse. Responders are the patients with 'much better' and 'very much better' on the score. | after 18 weeks of treatment compared to baseline | 
| UPDRS II+III Responder Rate (at Least 20% Improvement) | Responders are defined as at least 20% decrease in the UPDRS II+III score. UPDRS II+III ranges 0-160 scores from best to worse. | after 33 weeks treatment | 
| UPDRS Part I Change From Baseline | UPDRS I evaluates mentation behaviour and mood with a total score of 0-16. Decrease in the scores means improvement | baseline and after 33 weeks treatment | 
| UPDRS Part II Total Score | UPDRS II evaluates activities of daily living in a score 0-52. Decrease of the score means improvement | after 33 weeks treatment | 
| UPDRS Part III Total Score | UPDRS III is the result of a motor examination with the scores 0-108. A decrease in the scores means improvement | after 33 weeks treatment | 
| Beck's Depression Inventory Version I A | The Beck's Depression Inventory (BDI) is a 21-item self-rating scale that was originally designed as an instrument to assess the intensity of depressive symptoms (sadness, pessimism, sense of failure, dissatisfaction, guilt, expectation of punishment, dislike of self, self-accusation, suicidal ideation, episodes of crying, irritability, social withdrawal, indecisiveness, changes in body image, retardation, insomnia, fatigability, loss of appetite and weight, somatic preoccupation, low level of energy). Each item is scored from 0 (absent) to 3 (severe). The patients select the score which best describes their status in the last 7 days. Since its introduction in 1961, its use has been extended (also to PD patients) and today it is used also as a screening instrument as well as an outcome measure in depression treatment trials. The total score sums the 21 individual items yielding a score that can range from zero (minimal depression) to 63 (severe depression). | after 33 weeks treatment | 
| Likert Scale for Pain Related to PD | Patient assessed 11 units on a scale from 'no pain' to 'unbearable pain'. Decrease of the score means improvement | after 33 weeks treatment | 
| Parkinson's Disease Sleep Scale (PDSS) | PDSS is a self-rated instrument addressing 15 commonly reported symptoms associated with sleep disturbance on 15 visual analogue scales (VAS: 0 to 10 cm) each ranging from worst score ('awful or always' at the left extremity to the best score ('excellent or never' at the right extremity) An increase in the score means improvement. Worst possible score 0, best score 150) | after 33 weeks treatment | 
| Change From Baseline in Parkinson's Disease Quality of Life Questionnaire Total Score | The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing 8 domains of health which patients consider to be adversely affected by the disease. Higher scores are consistently associated with more severe symptoms of the disease such as tremor and stiffness, while lower scores indicate a better perceived health status. The 8 domains include: mobility (e.g. fear of falling when walking): 10 items activities of daily living (e.g. difficulty cutting food): 6 items emotional well-being (e.g. feelings of isolation): 6 items stigma (e.g. social embarrassment): 4 items social support: 3 items cognition: 4 items communication: 3 items bodily discomfort: 3 items. A total score is calculated by summing the responses to the 39 individual items and the total ranges from 0 (no problem at all) to 156 (maximum level of problem). A negative change in the total score indicates improvement. | after 33 weeks treatment | 
| Change From Baseline in European Quality of Life Visual Analog Scale | European Quality of Life Visual Analog Scale (EQ-5D VAS) is a 20 centimeter vertical analog scale assessing the patient's general health status with scores ranging from 0 (worst imaginable health) to 100 (perfect health). A positive change in the scale indicates improvement in health status. | after 33 weeks treatment | 
| Patients Who Started to Use L-Dopa Rescue Medication | L-dopa could be introduced as rescue medication based upon the clinical judgement of the investigator. descriptive on the Full Analysis Set (FAS) population | from trial start on to any time before final assessment of the patient, up to 33 weeks | 
| Number of Patients With Treatment Emergent Abnormal Behaviour as Indicated by the Modified Minnesota Impulsive Disorders Interview (mMIDI Questionnaire) | mMIDI is a semi-structured clinical interview to assess pathological gambling (12 questions, positive screen if patient answers 'yes' to question 1 and to at least 5 of the rest of the questions), compulsive buying (9 questions from 1a to 4c, positive screen if the patient answers 'yes' to 1a, 2a, 3a, and 4a) and compulsive sexual behaviour (4 questions, positive screen if patient answers 'yes' to question 1,2,3, or 4). | from trial start on to any time before final assessment of the patient, up to 33 weeks | 
| Possible Clinically Significant Abnormal Laboratory Parameters | The significant abnormality of values was based on standard criteria defined in appendix 16.1.10, LISTING 4 Criteria for clinically significant abnormalities based on normalized laboratory values. | baseline and after 33 weeks of treatment | 
| Clinical Relevant Abnormal Findings in Vital Signs and Physical Examination as Reported in Adverse Events |  | baseline and after 33 weeks of treatment |