A Phase 2/3 Study of TVP-1012 at 0.5 mg or 1 mg in Levodopa Treated Parkinson's Disease Participants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of TVP-1012 (0.5 mg or 1 mg/day) as an add-on to levodopa in Japanese participants with Parkinson's disease with wearing-off phenomenon.

Detailed Description
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This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, phase 2/3 study to evaluate the efficacy and safety of TVP-1012 as an add-on to levodopa in Japanese participants with Parkinson's disease with wearing-off phenomenon. The study period consisted of a 28-week trial period. The participants who fulfilled the inclusion criteria and did not meeting any of the exclusion criteria were enrolled, and randomized in a 1:1:1 ratio to the 0.5 mg of TVP-1012, the 1 mg of TVP-1012, or the placebo group. In each treatment group, participants received 0.5 mg of TVP-1012, 1 mg of TVP-1012, or placebo once daily in a double-blinded manner.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 2/3 Study to Evaluate the Efficacy and Safety of TVP-1012 at 0.5 mg or 1 mg in Levodopa Treated Parkinson's Disease Patients With Wearing Off

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: TVP-1012 1mg
* Drug: TVP-1012 0.5mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In the opinion of the investigator or sub-investigator, the participant is capable of understanding and complying with protocol requirements. The participant signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. The participant has a diagnosis of Parkinson's disease according to the diagnostic criteria of the UK Parkinson's Disease Society Brain Bank. The participant has Modified Hoehn & Yahr stage 2 to 4 (in the Off state) at the start of the run-in period. The participant has wearing off phenomenon and has been continuously receiving a levodopa combination drug for >= 6 months prior to the start of the run-in period. The participant has been receiving a levodopa combination drug with a stable dose regimen (dosing frequency, at least 3 times a day) since the start of the run-in period. For participants receiving eantacapone concomitantly,the participant has been receiving entacapone with a stable dose regimen from the start of the run-in period. For participants receiving a dopamine agonist, anticholinergic drug, amantadine, droxidopa, istradefylline, or zonisamide concomitantly, the participant has been receiving those drugs with a stable dose regimen since 14 days prior to the start of the run-in period. The participant is an outpatient of either sex aged >= 30 and < 80 years at the time of consent. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent to 1 month after the last dose of the investigational drug. The participant has completed patient diary for at least 4 of the 7 days preceding the study visit at the end of the run-in period. The participant has mean daily off-time of >= 2.5 hours at the end of the run-in period Exclusion Criteria: The participant has received any investigational medication within 90 days prior to the start of the run-in period. The participant has received TVP-1012 in the past. The participant is a study site employee, an immediate family member, or in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress. Participant has donated 400 mL or more of his or her blood volume within 90 days prior to the start of the run-in period. The participant has unstable systemic disease. The participant has severe dyskinesia. The participant has Mini-Mental State Examination (MMSE) score of <= 24 at the start of the run-in period. The participant has known or a history of schizophrenia, major or severe depression, or any other clinically significant psychiatric disease The participant has major depression or severe depression, or any other clinically significant psychiatric disease. The participant has a history of hypersensitivity or allergies to TVP-1012 (including any associated excipients) or selegiline. The participant has a history of clinically significant hypertension or other reactions associated with ingestion of tyramine-rich food (e.g., cheese, lever, herring, yeast, horsebean, banana, beer or wine). The participant has a history or concurrent of drug abuse or alcohol dependence. The participant has received neurosurgical intervention for Parkinson's disease (e.g., pallidotomy, thalamotomy, deep brain stimulation). The participant has received transcranial magnetic stimulation within 6 months prior to the start of the run-in period. The participant has received selegiline, pethidine, tramadol, reserpine or methyldopa within 90 days prior to the start of the run-in period. The participant has received single agent of levodopa, any psychoneurotic agent or antiemetic medication of dopamine antagonist within 14 days prior to the start of the run-in period. However, the participant has been receiving quetiapine or domperidone with a stable dose regimen for >= 14 days prior to the start of the run-in period may be included in the study. The participant is required to take any of the prohibited concomitant medications or treatments. If female, the participant is pregnant or lactating or intending to become pregnant during, or within 1 month after the last administration of study medication in this study; or intending to donate ova during such time period. The participant has clinically significant neurologic, cardiovascular, pulmonary, hepatic (including mild cirrhosis), renal, metabolic, gastrointestinal, urological, endocrine, or hematological disease. The participant has clinically significant or unstable brain or cardiovascular disease, such as: clinically significant arrhythmia or cardiac valvulopathy, heart failure of NYHA Class II or higher, concurrent or a history of ischemic cardiac disease within 6 months prior to the start of the run-in period, concurrent or a history of clinically significant cerebrovascular disease within 6 months prior to the stat of the run-in period, severe hypertension (systolic blood pressure of 180 mmHg or higher, or diastolic blood pressure of 110 mmHg or higher), clinically significant orthostatic hypotension (including those with diastolic pressure decrease of 30 mmHg or more following postural change from supine/sitting position to standing position), or a history of syncope due to hypotension within 2 years prior to the stat of the run-in period. The participant is required surgery or hospitalization for surgery during the study period. Participant has a history of cancer within 5 years prior to the start of the run-in period, except cervix carcinoma in situ which has completely cured. The participant has acquired immunodeficiency syndrome (AIDS) [including human immunodeficiency virus (HIV) carrier], or hepatitis [including viral hepatitis carrier such as hepatitis B surface (HBs) antigen or hepatitis C antibody (HCV) positive]. However, the participant who has a negative result for HCV antigen or HCV-RNA can be included in the study. The participant has laboratory data meeting any of the following at the start of the run-in period: Creatinine >= 2 x upper limit of normal (ULN) Total bilirubin >= 2 x ULN ALT or AST >= 1.5 x ULN ALP >= 3 x ULN The participant has received any of the prohibited concomitant medications or treatments during the run-in period. The participant who, in the opinion of the investigator or sub-investigator, is unsuitable for any other reason.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 79 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TVP-1012 1mg<br>TVP-1012 1 mg once daily orally, before or after breakfast, concomitantly with levodopa tablet for 26 weeks as treatment period after 2 weeks of run-in period. | Drug: TVP-1012 1mg<br>* TVP-1012 1mg Tablets<br>|
| Experimental: TVP-1012 0.5mg<br>TVP-1012 0.5 mg once daily orally, before or after breakfast, concomitantly with levodopa tablet for 26 weeks as treatment period after 2 weeks of run-in period. | Drug: TVP-1012 0.5mg<br>* TVP-1012 0.5mg Tablets<br>|
| Placebo Comparator: Placebo<br>One placebo tablet once daily orally, before or after breakfast, concomitantly with levodopa tablet for 26 weeks as treatment period after 2 weeks of run-in period. | Drug: Placebo<br>* Placebo Tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Daily OFF-time During Treatment Period | Reported change from baseline during treatment period which was calculated as follows: Mean for a total of 21 days, consisting of three separate 7-day periods preceding the visits at Week 6, 14 and 26 of the treatment period - Mean for the 7 days preceding the visit at the end of the run-in period. Off-time refers to times when levodopa is not working well, causing worsening symptoms. | From Baseline to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 (LOCF) in Mean Daily OFF-time |  | Baseline and Week 26 (LOCF) | 
| Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II Total Score | MDS-UPDRS retains the four-scale structure with a reorganization of the various subscale; (Part I; 13 items) non-motor experiences of daily living, (Part II; 13) motor experiences of daily living, (Part III; 34) motor examination, and (Part IV; 6) motor complications. Each items had 0-4 ratings, where 0 (normal) to 4 (severe) and score for each was summed to calculate the total scores. The scale range for Part II Total Score was 0-52, with higher scores reflecting greater severity. | Baseline and Week 26 (LOCF) | 
| Change From Baseline in MDS-UPDRS Part III Total Score | MDS-UPDRS retains the four-scale structure with a reorganization of the various subscale; (Part I; 13 items) non-motor experiences of daily living, (Part II; 13) motor experiences of daily living, (Part III; 34) motor examination, and (Part IV; 6) motor complications. Each items had 0-4 ratings, where 0 (normal) to 4 (severe) and score for each was summed to calculate the total scores. The scale range for Part III Total Score was 0-136, with higher scores reflecting greater severity. | Baseline and Week 26 (LOCF) | 
| Change From Baseline in Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index Score | PDQ-39 is a self-administered questionnaire. PDQ-39 comprises of 39 questions, relating to eight key areas (Mobility, Activities of Daily Living, Emotional Well-being, Stigma, Social Support, Cognitions, Communication, and Bodily Discomfort) of health and daily activities, including both Motor and Non-motor symptoms. It is scored on a scale of zero to 100, with lower scores indicating better health and high scores more severe symptoms. | Baseline and Week 26 (LOCF) | 
| Change From Baseline in Parkinson's Disease Questionnaire-39 (PDQ-39) Each Domain Score | PDQ-39 is a self-administered questionnaire. PDQ-39 comprises of 39 questions, relating to eight key areas (Mobility, Activities of Daily Living, Emotional Well-being, Stigma, Social Support, Cognitions, Communication, and Bodily Discomfort) of health and daily activities, including both Motor and Non-motor symptoms. It is scored on a scale of zero to 100, with lower scores indicating better health and high scores more severe symptoms. | Baseline and Week 26 (LOCF) | 
| Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Up to Week 26 | 
| Number of Participants With Markedly Abnormal Vital Signs Values |  | Up to Week 26 | 
| Number of Participants With TEAE Related to Body Weight (Weight Decreased) |  | Up to Week 26 | 
| Number of Participants With TEAE Related to Electrocardiograms (ECG) (Sinus Bradycardia) |  | Up to Week 26 | 
| Number of Participants With TEAE Related to Clinical Laboratory Tests |  | Up to Week 26 |