A Study to Evaluate the Efficacy and Safety of Safinamide, as add-on Therapy, in Idiopathic Chinese Parkinson's Disease (PD) Patients With Motor Fluctuations Treated With Stable Doses of Levodopa

Study Overview
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Brief Summary
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This is a Phase III, multicentre, randomised, double-blind, placebo-controlled study to evaluate the effects of 100 mg safinamide, administered orally once daily (OD), in Chinese Parkinson's disease (PD) patients, experiencing motor fluctuations while on stable doses of Levodopa (L-dopa) (alone or in combination with other anti-Parkinson drugs). Eligible patients are required to meet the United Kingdom PD Society Brain Bank Clinical Diagnostic Criteria. The study involves a placebo group. Placebo will be added to the standard stabilized treatment as a control of the safinamide group, hence patients on placebo will have benefit from other ongoing anti-PD medication. A total of 306 patients will be randomised into this study (153 in the safinamide and 153 in the placebo groups).

Official Title
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A Randomised, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Safinamide, as add-on Therapy, in Idiopathic Chinese Parkinson's Disease (PD) Patients With Motor Fluctuations Treated With Stable Doses of Levodopa

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Safinamide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged ≥18 years old. Chinese ethnicity. Able to understand and willing to provide written informed consent. Able to maintain an accurate and complete 24-hour diary with the help of a caregiver. Diagnosis of idiopathic Parkinson's Disease (IPD) using the United Kingdom Parkinson's Disease Society Brain Bank criteria of more than 3 years duration. Be levodopa responsive and receiving treatment with stable daily doses of oral L-dopa, with or without benserazide/carbidopa, with or without addition of a catechol-O-methyltransferase (COMT) inhibitor and may be receiving concomitant treatment with stable doses of dopamine agonists, anticholinergics and/or amantadine for at least 4 weeks prior to the screening visit. A Hoehn and Yahr stage between 1-4 inclusive during the ON phase. Experiencing motor fluctuations with a minimum of 1.5 hours/day of OFF time during the day (excluding morning akinesia), based on historical data. If female, be post-menopausal for at least one year or have undergone hysterectomy or, if of child-bearing potential, must have a negative pregnancy test, must not be breast-feeding nor become pregnant during the study and must use adequate contraception for 1 month prior to randomisation and for up to 1 month after the last dose of study drug. Adequate contraception is defined as: Hormonal oral, implantable, transdermal, or injectable contraceptives or a non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit; a male sexual partner who agrees to use a male condom with spermicide or a sterile sexual partner . For all women of child-bearing potential, urine pregnancy test result at screening must be negative. For all women of child-bearing potential, urine pregnancy test result at screening must be negative. Exclusion Criteria: Any form of Parkinsonism other than IPD. Diagnosis of chronic migraine (>15 days per month) or cancer pain. L-dopa infusion. Hoehn and Yahr stage 5 during the ON phase. If female, pregnancy or breast-feeding. Neurosurgical intervention of PD or stereotactic brain surgery. Severe peak dose or biphasic dyskinesia, unpredictable or widely swinging fluctuations. History of major depression or other clinically significant psychotic disorder which compromise the ability to provide the informed consent or to participate to the study. Drug and/or alcohol abuse within 12 months prior to the screening visit. History of dementia or severe cognitive dysfunction. Use of any investigational drug or device within 30 days prior to screening or 5 half-lives, whichever is the longest, or during the study. Allergy/sensitivity or contraindications to the investigational medicinal products (IMPs) or their excipients, to anticonvulsants or to anti-Parkinson drugs. Any clinically significant condition (including laboratory values) which, in the opinion of the Investigator, would not be compatible with study participation or represent a risk for patients while in the study. Moderate or severe liver failure using the Child-Pugh classification score, or human immunodeficiency virus (HIV) infection. Treatment with monoamine oxidase inhibitors (MAOIs), pethidine, opiates, opioids, fluoxetine, fluvoxamine in the 4 weeks prior to the screening visit. These drugs are not allowed throughout the study and up 2 weeks after the last dose of study drug. Ophthalmologic history including any of the following conditions: albinism, uveitis, retinitis pigmentosa, retinal degeneration, active retinopathy, severe progressive diabetic retinopathy, inherited retinopathy or family history of hereditary retinal disease.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safinamide<br>Patient will receive film-coated Safinamide tablets orally at an initial dose of 50 mg once daily (OD) and then will be increased the day after the Visit 3/week 2 (ideally at day 15) to the final dose of 100 mg OD. Treatment will continue daily for a total of 16 weeks. | Drug: Safinamide<br>* At baseline (Day 1), eligible patients will be randomised to receive safinamide (initial 50 mg titrated to 100 mg the day after the Visit 3/week 2, ideally at day 15). The investigational medicinal product (IMP) will be taken in the morning at breakfast time, in addition to the morning dose of L-dopa and other (if any) PD medications.<br>|
| Placebo Comparator: Placebo<br>Patient will receive matching placebo orally at an initial dose of 50 mg once daily (OD) and then will be increased the day after the Visit 3/week 2 (ideally at day 15) to the final dose of 100 mg OD. Treatment will continue daily for a total of 16 weeks. | Other: Placebo<br>* At baseline (Day 1), eligible patients will be randomised to receive matching placebo, orally OD. Placebo will be added to the standard stabilized treatment as a control of the safinamide group, hence patients on placebo will have benefit from other ongoing anti-PD medication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to week 16 in the mean total daily OFF time, as assessed by 24-hour patient diary cards, of safinamide 100 mg/day compared to placebo, given as add-on therapy in PD patients with motor fluctuations on stable doses of L-dopa. | The analysis of primary efficacy parameter will be done using an analysis of co-variance (ANCOVA) with treatment and centre as independent factor, baseline mean OFF time measurement as covariate and change from baseline as dependent variable. Results will be reported as Least-Square Means for treatment differences with associated two-tailed 95% confidence intervals and corresponding two-sided p-values. The main time point for comparison between treatment groups is week 16, but other available measurements at other visits will be analysed as well. | At baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change from baseline to week 16 in pain severity, as assessed by an 11 point Numerical Rating Scale (NRS). | The analysis of key secondary efficacy parameter will be done using an analysis of co-variance (ANCOVA) with treatment and centre as independent factor, baseline NRS measurement as covariate and change from baseline as dependent variable. Results will be reported as Least-Square Means for treatment differences with associated two-tailed 95% confidence intervals and corresponding two-sided p-values. The main time point for comparison between treatment groups is week 16, but other available measurements at other visits will be analyzed as well. The NRS is a segmented numeric version of the visual analogue scale (VAS) in which a patient selects a whole number that best reflects the intensity of his/her pain, ranging from '0' (no pain) to '10' (worst possible pain). | At baseline and Week 16 | 
| The change from baseline to week 16 in the mean total daily ON time, as assessed by 24-hour patient diary cards | The hypothesis of superiority of safinamide compared to placebo will be assessed using an ANCOVA model parameterized, with point estimate of treatment differences reported as Least-Square Mean with associated two-tailed 95% confidence intervals and two-sided p-value. | At baseline and Week 16 | 
| The change from baseline to week 16 in the mean daily ON time with no/non troublesome dyskinesia, as assessed by 24-hour patient diary cards | The hypothesis of superiority of safinamide compared to placebo will be assessed using an ANCOVA model, with point estimate of treatment differences reported as Least-Square Mean with associated two-tailed 95% confidence intervals and two sided p-value. | At baseline and Week 16 | 
| The change from baseline to week 16 in the Unified Parkinson's Disease Rating Scale (UPDRS) total score during the ON phase | The UPDRS comprises 3 parts to evaluate the following key areas of disability, plus a fourth part that evaluates any complication of treatment: Part I: Evaluation of mentation or cognition, behavior and mood. Part II: Evaluation of the activities of daily life. Part III: Evaluation of motor function. Part IV: Evaluation of complications of therapy. The UPDRS should be performed by the Investigator with points assigned to each item in the scale based on the patient's response as well as observation and physical examination. Together Parts I-III contain 44 items, with each item scored on a 5-point scale. Part IV contains 11 questions with a scale ranging from 0 to 23. Thus, the final total score may range from 0 (no disability) to 199 (total disability). | At baseline and Week 16 | 
| Change from baseline to week 16 in the UPDRS part II (ADL) score during the ON phase | The UPDRS comprises 3 parts to evaluate the following key areas of disability, plus a fourth part that evaluates any complication of treatment: Part I: Evaluation of mentation or cognition, behavior and mood. Part II: Evaluation of the activities of daily life. Part III: Evaluation of motor function. Part IV: Evaluation of complications of therapy. The UPDRS should be performed by the Investigator with points assigned to each item in the scale based on the patient's response as well as observation and physical examination. Together Parts I-III contain 44 items, with each item scored on a 5-point scale. Part IV contains 11 questions with a scale ranging from 0 to 23. Thus, the final total score may range from 0 (no disability) to 199 (total disability). | At baseline and Week 16 | 
| Change from baseline to week 16 in the UPDRS part III (motor function) score during the ON phase | The UPDRS comprises 3 parts to evaluate the following key areas of disability, plus a fourth part that evaluates any complication of treatment: Part I: Evaluation of mentation or cognition, behavior and mood. Part II: Evaluation of the activities of daily life. Part III: Evaluation of motor function. Part IV: Evaluation of complications of therapy. The UPDRS should be performed by the Investigator with points assigned to each item in the scale based on the patient's response as well as observation and physical examination. Together Parts I-III contain 44 items, with each item scored on a 5-point scale. Part IV contains 11 questions with a scale ranging from 0 to 23. Thus, the final total score may range from 0 (no disability) to 199 (total disability). | At baseline and Week 16 | 
| Clinical Global Impression of Severity (CGI-S) score assessed at week 16 | The hypothesis of superiority of safinamide compared to placebo will be assessed using the Wilcoxon-Mann-Whitney test stratified by centre, whilst point estimate of treatment differences will be reported as Hodges-Lehmann estimators together with associated two-sided nonparametric 95% confidence intervals. The CGI-S scale measures global severity of illness at a given point in time. It will be rated on a 7-point Likert-type scale ranging from 1 (normal, not ill at all) to 7 (extremely severe). The CGI-S will be assessed at all visits, starting at baseline. | At week 16 | 
| Change from baseline to week 16 in the Clinical Global Impression of Change(CGI-C) | The hypothesis of superiority of safinamide compared to placebo will be assessed using the Wilcoxon-Mann-Whitney test stratified by centre, whilst point estimate of treatment differences will be reported as Hodges-Lehmann estimators together with associated two-sided nonparametric 95% confidence intervals. The CGI-C scale will measure the change in the patient's clinical status from baseline using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. The change from the patient's baseline condition will be assessed by the Investigator at all post-baseline visits. In completing the CGI-C, the rater will review all efficacy-related data, and assess its clinical meaningfulness. | At baseline and Week 16 | 
| Change from baseline to week 16 in the Parkinson's Disease Questionnaire-39 items (PDQ-39) score | The hypothesis of superiority of safinamide compared to placebo will be assessed using an ANCOVA model, with point estimate of treatment differences reported as Least-Square Mean with associated two-tailed 95% confidence intervals and two-sided p-value. The PDQ-39 comprises 39 questions measuring eight dimensions of health: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication and bodily pain. Dimension scores are coded on a scale of 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the measure). | At baseline and Week 16 |