Safety and Efficacy Study of Tozadenant to Treat End of Dose Wearing Off in Parkinson's Patients

Study Overview
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Brief Summary
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Phase 3, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 3-arm safety and efficacy study (Part A) with an open-label phase (Part B).

Detailed Description
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During Part A, each patient will participate for up to 30 weeks, which includes a Screening Period of 1 to ≤ 6 weeks, followed by a Baseline Visit and 24 weeks of double-blind treatment: Screening Period: 1 - 6 weeks. Double-Blind Treatment Period: 24 weeks. After completion of Part A, patients will continue in Part B for an additional 56 weeks: Open-Label Treatment Period: 52 weeks. Post-Treatment Safety Follow Up: 4 weeks.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of Tozadenant as Adjunctive Therapy in Levodopa-Treated Patients With Parkinson's Disease Experiencing End of Dose Wearing-Off (TOZ-PD)

Conditions
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Idiopathic Parkinson's Disease

Intervention / Treatment
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* Drug: tozadenant
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient understands study requirements and has given his/her written informed consent on an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved consent form. Parkinson's disease diagnosis consistent with UK Parkinson's Disease Society Brain Bank Diagnostic criteria Minimum of 3 years since diagnosis. Meet Hoehn and Yahr PD stage Good response to levodopa Stable regimen of anti-PD medications Patients must have been taking a levodopa-containing anti-PD medication continuously for at least the previous 12 months Patient has documented a minimum amount of Off time. If of childbearing potential (male and female) must use an acceptable method of contraception Exclusion Criteria: Previous tozadenant study participation Current or recent participation in another study. Secondary or atypical parkinsonism Neurosurgical intervention for PD Patient is taking apomorphine, budipine, istradefylline, tolcapone, or DUOPA™/Duodopa® Treatment with excluded medications Untreated or uncontrolled hyperthyroidism or hypothyroidism Clinically significant out-of-range laboratory MMSE out of range Current episode of major depression (stable treatment for depression is permitted). Recent suicide attempt or suicidal ideation type 4 or type 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) Women lactating or pregnant Hypersensitivity to any components of tozadenant or excipients Abnormal findings on the physical or neurological examination, or medical history that would make the patient unsuitable for the study History of hepatitis or cholangitis

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tozadenant 60 mg BID<br>During Part A, patients took two (2) tablets, one 60 mg tozadenant and one placebo, by mouth BID for a total of four (4) tablets per day. Upon completion of Part A, all patients will begin dosing with open label tozadenant in Part B. | Drug: tozadenant<br> <br> * Other names: SYN115;|
| Experimental: Tozadenant 120 mg BID<br>During Part A, patients took two (2) tablets of 60 mg tozadenant, by mouth BID for a total of four (4) tablets per day. Upon completion of Part A, all patients will begin dosing with open label tozadenant in Part B. | Drug: tozadenant<br> <br> * Other names: SYN115;|
| Placebo Comparator: Placebo BID<br>During Part A, patients took two (2) tablets of placebo, by mouth BID for a total of four (4) tablets per day. Upon completion of Part A, all patients will begin dosing with open label tozadenant in Part B. | Drug: placebo<br> <br> * Other names: tozadenant placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in the Number of Hours Per Day Spent in OFF Time | Awake time in OFF state (hr) is the average of maximum of 3 days diary. The primary efficacy endpoint was the change from baseline to Week 24 in OFF time, where OFF time in the Hauser Parkinson's Disease Home Diary (PD) was averaged over 3 days prior to the study visit. During Screening and through Part A of the study, the Hauser Parkinson's Disease Home Diary (PD) was completed on specified days directly preceding the scheduled study visits/assessments. Motor activity was recorded as OFF, ON (mobility improved), or asleep time. Patients were asked to record ON time according to dyskinesia categories without dyskinesia, with non troublesome dyskinesia or with troublesome dyskinesia. Patients (and/or caregivers) were trained to complete the PD diary to record their status at half hourly intervals as OFF, ON without dyskinesia, ON with non troublesome dyskinesia, ON with troublesome dyskinesia, or asleep. | Baseline to 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Good ON Time From Baseline to Week 24 | The first key secondary efficacy endpoint was the change from baseline to Week 24 in good ON which was defined as ON without dyskinesia or ON with non-troublesome dyskinesia. Awake Time in Good ON State (hr) is the average of a maximum of 3 days diary. Patients were asked to record ON time according to dyskinesia categories without dyskinesia, with non troublesome dyskinesia or with troublesome dyskinesia . Patients (and/or caregivers) were trained to complete the PD diary to record their status at half hourly intervals as OFF, ON without dyskinesia, ON with non troublesome dyskinesia, ON with troublesome dyskinesia, or asleep. For patients with missing baseline or baseline was measured post-dose, screening was used as baseline in the calculation of change from baseline. | Baseline to 24 Weeks | 
| Change in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Activities of Daily Living (ADL) Subscale + Part III Motor Function | The Unified Parkinson's Disease Rating Scale (UPDRS) is a scale to monitor Parkinson's Disease related disability and impairment. The scale itself has 4 components are titled; (1) nonmotor experiences of daily living (13 items), (2) motor experiences of daily living (13 items), (3) motor examination (18 items), and (4) motor complications (six items). Each subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. In this outcome measure we are evaluating Part II and Part III. Part II: self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food Part III: clinician-scored monitored motor evaluation Range of score is 0 - 160: 0 meaning less impact and Higher score indicates greater impact of PD symptoms. | Baseline to Week 24 | 
| Change From Baseline to Week 24 in the ON State in Unified Parkinson's Disease Rating Scale (UPDRS) Part IIl | Change from Baseline to Week 24 in the Unified Parkinson's Disease Rating Scale (UPDRS) Parts III Motor Function (motor subscale) total scores. Each subscale has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Range of score is 0 - 108. Higher scores indicate greater impact of PD symptoms. Unified Parkinson's Disease Rating Scale (UPDRS) in the ON state was measured at a time representative of the ON state in that patient, not in best ON. Unified Parkinson's Disease Rating Scale Part III in OFF was not evaluated. | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Motor fluctuations, Off time, On time, Dyskinesia