A Phase 3 Study of TVP-1012 (1 mg) in Early Parkinson's Disease Patients

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 (1 mg/day) administered to Japanese patients with early Parkinson's disease.

Detailed Description
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This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study to evaluate the efficacy and safety of TVP-1012 in Japanese participants with early Parkinson's disease. The study period consisted of a 28-week trial period. The participants who fulfill the inclusion criteria and not meeting any of the exclusion criteria were enrolled, and randomized in a 1:1 ratio to either the 1 mg of TVP-1012 or the placebo group. In each treatment group, participants received either 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 3 Study to Evaluate the Efficacy and Safety of TVP-1012 at 1 mg in Early Parkinson's Disease Patients Not Treated With Levodopa

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: TVP-1012
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Run-in period 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 with at least two of the following signs: resting tremor, akinesia/bradykinesia, and muscle rigidity. The participant has a Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III total score of >=14 at the start of the run-in period. The participant has Modified Hoehn & Yahr stage 1 to 3 at the start of the run-in period. The participant has the Parkinson's disease diagnosed within 5 years prior to the start of the run-in period. The participant is an outpatient of either sex aged >= 30 and < 80 years. 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. Treatment period - The participant has a MDS-UPDRS Part II + Part III total score of >= 14 at baseline. Exclusion Criteria: Run-in period 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 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 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 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 amantadine or anticholinergic medication for >= 180 days. The participant has received selegiline, a levodopa-containing product or dopamine agonist for >= 90 days. 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 a levodopa-containing product, dopamine agonist, amantadine or anticholinergic drug within 30 days prior to the start of the run-in period. The participant has received 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 has previously received a catechol-O-methyltransferase (COMT) inhibitor, droxidopa, zonisamide or istradefylline. 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 this study, or within 1 month after the last dose of the investigational drug; 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, cardiac arrest 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 start of the run-in period, sever 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 systolic pressure decrease of 30 mmHg or more following postural change from supine/sitting position to standing position), a history of syncope due to hypotension within 2 years prior to the start 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 who, in the opinion of the investigator or sub-investigator, is unsuitable for any other reason. Treatment period The participant whose diagonosis of Parkinson's disease is ruled out by dopamine transporter scintigraphy performed during the run-in period if conducted. 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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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 1 mg<br>For 2 weeks during the run-in period, one tablet of placebo orally, once daily before or after breakfast, followed by 26 weeks during the treatment period, one tablet of TVP-1012 1 mg orally, once daily before or after breakfast. | Drug: TVP-1012<br>* TVP-1012 1mg Tablets<br>|
| Placebo Comparator: Placebo<br>For 2 weeks during the run-in period, one tablet of placebo orally, once daily before or after breakfast, followed by 26 weeks during the treatment period, one tablet of placebo orally, once daily before or after breakfast. | 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 Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III Total Score | Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (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+III Total Score was 0-188, with higher scores reflecting greater severity. | From Baseline to Week 26 (LOCF) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in MDS-UPDRS Part I Total Score | For MDS-UPDRS Part I (non-motor experiences of daily living) scores, the scale range for Part I Total Score was 0-52, with higher scores reflecting greater severity. | Baseline and Week 26 (LOCF) | 
| Change From Baseline in MDS-UPDRS Part II Total Score | For MDS-UPDRS Part II (motor experiences of daily living) 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 | For MDS-UPDRS Part III (motor examination) scores, the scale range for Part III Total Score was 0-132, with higher scores reflecting greater severity. | 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 |  | Up to Week 26 | 
| Number of Participants With TEAE Related to Electrocardiograms (ECG) |  | Up to Week 26 | 
| Number of Participants With TEAE Related to Clinical Laboratory Tests |  | Up to Week 26 |