The SUSTAIN Study Compares the Effects of Sustained and Immediate-release Pramipexole on the noctUrnal Symptoms of paTients With Advanced ParkInsoN's Disease Who Also Take L-Dopa

Study Overview
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Brief Summary
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The main objective of the study is to explore firstly, then further evaluate and confirm the efficacy between Pramipexole Sustained Release (SR) versus Pramipexole Immediate Release (IR) on nocturnal symptoms (as measured by the change from baseline to the end of the maintenance period in Parkinson's Disease Sleep Scale 2nd version (PDSS-2) score) in L-dopa+ treated patients with advanced Parkinson's disease (PD).

Official Title
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A Two- Stage Multicenter, Open-label, Randomized, Active Controlled Parallel Group Study Comparing the Efficacy and Safety of Pramipexole SR Versus Pramipexole IR Administered Orally Over an 18-week Treatment on Nocturnal Symptoms in L-Dopa+ Treated Patients With Advanced Parkinson's Disease (PD)

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Pramipexole SR
* Drug: Pramipexole IR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient with advanced idiopathic Parkinson's disease (PD) confirmed by at least bradykinesia and one of the following signs: resting tremor, rigidity. Diagnosed as Parkinson's disease, with at least 2 years' PD history. Of age ≥ 30 years at time of diagnosis. Modified Hoehn and Yahr stage of 2 to 4 at on-time. They must have clinically relevant sleep disturbances (i.e. Parkinson's Disease Sleep Scale 2nd version (PDSS-2) total score ≥18 at baseline). They must feel uncomfortable at night because they were unable to turn around in bed or move due to immobility (i.e. the scoring of question 9 in PDSS-2 ≥ 2, that means frequency is at least 2 to 3 days during the past week). They must have early morning off (i.e. the frequency of feeling like bodily movements are poor when you wake up? is at least 2 to 3 days during the past week). Patient must have motor fluctuations (at least 2 cumulative hours of off-time every day during waking hours, documented on a patient diary completed for 2 consecutive days before randomization visit). Patients must be treated with Levodopa combined with a Dopa-Decarboxylase-inhibitor (L-Dopa+) (i.e. standard and/or controlled release Levodopa/DDC inhibitor), or with a combination of L-Dopa+ and entacapone, at an optimized dose according to investigator's judgment, this dose being stable for at least 4 weeks prior to randomization visit. Patients must not have been treated with sustained release dopaminergic drug (i.e. sustained release Levodopa/Dopa-Decarboxylase (DDC) inhibitor) after supper, or any anti-PD medication after 9pm within 4 weeks prior to randomization visit. Patients must not have been treated with dopamine agonists within 4 weeks prior to randomization visit. A concomitant treatment with one or more of the following drugs will be allowed (at a stable dose for at least 4 weeks prior to randomization visit and the investigator does not intend to change this treatment during the treatment phase): Anti-parkinsonian anticholinergics; Selegiline, rasagiline, or other Monoamine Oxydase (MAO)-B-Inhibitor; Amantadine; Entacapone (or other Catechol-O-Methyltransferase (COMT)-Inhibitor). Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. Exclusion criteria: Secondary 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 DSM-V Diagnostic and Statistical Manual of Mental Disorders, 5th 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 (provided the investigator considers that participation to the trial would not represent a significant risk for the patient). History of deep brain stimulation. History of nucleus lesioning. Clinically significant electrocardiogram (ECG) abnormalities at screening visit, according to investigator's judgement. Clinically significant hypotension (i.e. supine systolic blood pressure < 90 mmHg) and/or symptomatic orthostatic hypotension (i.e. clinical symptoms of orthostatic hypotension associated with a decline ≥ 20 mmHg in systolic blood pressure and a decline ≥ 10 mmHg in diastolic blood pressure, at 1 minute after standing compared with the previous supine systolic and diastolic blood pressure obtained after 5 minutes of quiet rest) at screening or randomization visit. Major surgery (major according to the investigator's assessment) performed within 12 weeks prior to randomization or planned within 12 months after screening, e.g. hip replacement. 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. Serious Sleep Apnea Hypopnea Syndrome (i.e. the scoring of question 15 in Parkinson's Disease Sleep Scale 2nd version (PDSS-2)≥ 3, that means frequency is at least 4 to 5 days during the past week ) Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix. Serum levels of Aspartate Aminotransferase (AST)(SGOT), Alanine Aminotransferase (ALT)(SGPT), alkaline phosphatases or total bilirubin >2 ULN (on screening lab test). Patients with a creatinine clearance < 50 mL/min (estimated by the local lab / the investigator using the Modification of Diet in Renal Disease (MDRD, please refer to Appendix 10.1), and calculated on screening lab test). Any hypnotic medication within 4 weeks prior to the randomization visit (i.e. diazepam, clonazepam, estazolam, alprazolam, zolpidem, etc.). Any medication (including intra-muscular formulations) with central dopaminergic antagonist activity within 4 weeks prior to the randomization visit (i.e. typical neuroleptics, atypical antipsychotics, reserpine, methyldopa, centrally-active antiemetics, etc.). Any of the following drugs within 4 weeks prior to randomization visit: methylphenidate, cinnarizine, amphetamines. Flunarizine within 3 months prior to randomization visit. Known hypersensitivity to Pramipexole or its excipients. Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial. Previous enrolment in this trial. Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s), or receiving other investigational treatment(s). Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes them an unreliable trial patient or unlikely to complete the trial. Women who are pregnant, nursing, or who plan to become pregnant in the trial.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramipexole SR<br> | Drug: Pramipexole SR<br>* Tablets<br>* Other names: MIRAPEX®/SIFROL;|
| Active Comparator: Pramipexole IR<br> | Drug: Pramipexole IR<br>* Tablets<br>* Other names: MIRAPEX®/SIFROL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 18 in Parkinson's Disease Sleep Scale 2nd Version (PDSS-2) Total Score | Parkinson's disease Sleep Scale 2nd version (PDSS-2) consists of 15 questions about various sleep and nocturnal disturbances which are to be rated by the patients using one of five categories, from 0 (never) to 4 (very often). Patients were asked to rate the severity of each question based on their experience during the past week (7 days) from 0 (Never) to 4 (Very often, that meant 6 to 7 days a week). PDSS-2 total score ranges from 0 (no disturbance) to 60 (maximum nocturnal disturbance). | Baseline and Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nocturnal Hypokinesia Questionnaire (NHQ) Score (Change From Baseline) | The Nocturnal Hypokinesia Questionnaire (NHQ) is designed to assess hypokinesia symptoms in night in Parkinson's disease (PD) patients, composed of two sections. Section 1 is assessed by PD patients with 10 one-point items evaluating turning over in bed, getting out of bed, parkinsonian motor symptoms, and others. Section 2 is assessed by spouses or caregivers who are with the patients during the night with 10 one-point items evaluating the same aspects as Section 1. The score for each section is by summing up points from the items in the respective section. Score of each of the two Sections is from 0 to 10, with a higher score indicating worse symptoms. The score was reported by section: Section 1 by patients, Section 2 by caregivers. | Baseline and Week 18 | 
| Scale for Outcomes in Parkinson's Disease (SCOPA)-Sleep Score (Change From Baseline) | SCOPA-Sleep score is composed of three parts: a night-time scale (5 item scale with 4 Response Options (0-not at all to 3-very much) addressing night time disturbances. Total night-time scale score runs from 0 to 15, with a higher score indicating more severe problems, a single-item about perceived quality of nocturnal sleep (7-point scale ranging from slept very well to slept very badly.), and a daytime sleepiness scale (6 items with 4 Response options, from 0 (never) to 3 (often), and a maximum total score of 18.). | Baseline and Week 18 | 
| Early Morning Off (EMO) Score (Change From Baseline) | The EMO is measured by the question of do you feel like your bodily movements are poor when you wake up? Patients answered this question according to the frequency during the previous one week by scoring from 0 (never) to 4 (very often or 6 to 7 days a week). | Baseline and Week 18 | 
| Responder Rate for Parkinson's Disease Sleep Scale 2nd Version (PDSS-2) Total Score<18 | Parkinson's disease Sleep Scale 2nd version (PDSS-2) consists of 15 questions about various sleep and nocturnal disturbances which are to be rated by the patients using one of five categories, from 0 (never) to 4 (very often) based on their experience during the past week. PDSS-2 total score ranges from 0 (no disturbance) to 60 (maximum nocturnal disturbance). The PDSS-2 total score less < 18 were compared between groups. | At Week 18 | 
| Responder Rate for Early Morning Off (EMO) Score | The responder of EMO is the patient with an improvement of at least 1 comparing to his/her baseline condition. The EMO is measured by the question of do you feel like your bodily movements are poor when you wake up? Patients answered this question according to the frequency during the previous one week by scoring from 0 (never) to 4 (very often or 6 to 7 days a week). | At Week 18 | 
| The Parkinson's Disease Questionnaire (PDQ)-8 Score (Change From Baseline) | The PDQ-8 is a self-reported questionnaire consisting of 8 questions regarding the subject's disease symptoms. The total score summed up the items together and transformed onto a score from 0 (never have problems/issues) to 100 (always have problems or cannot do at all). | Baseline and Week 18 | 
| Responder Rate for Clinical Global Impression of Improvement (CGI-I) | The responder of CGI-I is the patient rated of any improvement (1 = Very much better, 2 = Much better, or 3 = A little better). The CGI-I was rated (from 1: very much improved, to 7: very much worse) by the same evaluator to assess the overall status of Parkinson's disease. | At Week 18 | 
| Responder Rate for Patient Global Impression of Improvement (PGI-I) | The responder of PGI-I is the patient rated of any improvement (1 = Very much better, 2 = Much better, or 3 = A little better). The PGI-I scale is a patient-rated instrument (from 1: very much better, to 7: very much worse) which was used to measure the improvement of the patient's Parkinson disease symptoms throughout the study. | At Week 18 | 
| Epworth Sleepiness Scale (ESS) Score (Change From Baseline) | The ESS is a patient-rated scale about how likely one is to fall asleep during situations of passive and inconsequential to active. The total score ranges from 0-24 where higher values indicate greater daytime sleepiness. | Baseline and Week 18 |