Safety and Efficacy Study of Tozadenant to Treat End of Dose Wearing Off in Parkinson's Patients (TOZ-PD)

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)

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).

Study Overview

• Status: Terminated
• Conditions: Idiopathic Parkinson's Disease
• Intervention / Treatment: Drug: placebo; Drug: tozadenant

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 449
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
  • Vienna, Austria
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
  • Ontario
    • Ottawa, Ontario, Canada
    • Toronto, Ontario, Canada
• Czechia
  • Brno, Czechia
  • Chocen, Czechia
  • Pardubice, Czechia
  • Prague, Czechia
  • Rychnov nad Kneznou, Czechia
• Germany
  • Beelitz-Heilstätten, Germany
  • Berlin, Germany
  • Dresden, Germany
  • Haag in Oberbayern, Germany
  • Marburg, Germany
  • Ulm, Germany
• Italy
  • Arcugnano, Italy
  • Cassino, Italy
  • Chieti, Italy
  • Grosseto, Italy
  • Pavia, Italy
  • Pisa, Italy
  • Rome, Italy
  • Salerno, Italy
  • Venice, Italy
• Spain
  • Barcelona, Spain
  • Madrid, Spain
  • Barcelona
    • Manresa, Barcelona, Spain
    • Sant Cugat del Valles, Barcelona, Spain
    • Terrassa, Barcelona, Spain
  • Guipuzcoa
    • San Sebastian, Guipuzcoa, Spain
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35005
  • Arizona
    • Sun City, Arizona, United States, 85351
  • California
    • Loma Linda, California, United States, 92318
    • Los Angeles, California, United States, 90001
    • Oxnard, California, United States, 93030
    • Reseda, California, United States, 91335
    • Sacramento, California, United States, 914203
    • Sunnyvale, California, United States, 94043
  • Colorado
    • Englewood, Colorado, United States, 80110
  • Connecticut
    • Vernon, Connecticut, United States, 06029
  • Florida
    • Boca Raton, Florida, United States, 33428
    • Gainesville, Florida, United States, 32601
    • Jacksonville, Florida, United States, 32034
    • Tampa, Florida, United States, 33601
  • Georgia
    • Atlanta, Georgia, United States, 30301
    • Augusta, Georgia, United States, 30805
  • Illinois
    • Chicago, Illinois, United States, 60007
  • Kansas
    • Kansas City, Kansas, United States, 66012
  • Kentucky
    • Lexington, Kentucky, United States, 40502
  • Maryland
    • Baltimore, Maryland, United States, 21201
  • Massachusetts
    • Boston, Massachusetts, United States, 02101
  • Michigan
    • East Lansing, Michigan, United States, 48808
    • Farmington Hills, Michigan, United States, 48167
    • West Bloomfield, Michigan, United States, 48302
  • Missouri
    • Saint Louis, Missouri, United States, 63101
  • New York
    • Albany, New York, United States, 12084
    • Commack, New York, United States, 11725
    • Rochester, New York, United States, 14602
  • North Carolina
    • Asheville, North Carolina, United States, 28715
    • Durham, North Carolina, United States, 27517
  • Ohio
    • Cincinnati, Ohio, United States, 41073
    • Cleveland, Ohio, United States, 44101
    • Toledo, Ohio, United States, 43460
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74008
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19019
  • Tennessee
    • Nashville, Tennessee, United States, 37011
  • Texas
    • Houston, Texas, United States, 77001
  • Vermont
    • Burlington, Vermont, United States, 05401
  • Virginia
    • Roanoke, Virginia, United States, 24001
  • Washington
    • Kirkland, Washington, United States, 98033

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tozadenant 60 mg BID; 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; Other Names: SYN115
Experimental: Tozadenant 120 mg BID; 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; Other Names: SYN115
Placebo Comparator: Placebo BID; 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; Other Names: tozadenant placebo

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Assessments of Improvement: Clinical Global Impression of Improvement (CGI-I) Week 24	For the Clinical Global Impression of Improvement (CGI-I), the investigator or rater is asked to rate the patient's total improvement, whether or not in his or her judgment it is due entirely to drug treatment, based on a 1-7 point weighted scale ranging from "very much improved" (1) to "very much worse" (7). A zero score is assigned if the score is not assessed. Scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. Tables show Treatment vs Placebo.	At Week 24
Patient Global Impression of Improvement (PGI-I) Week 24	For the Patient Global Impression of Improvement (PG-I), the patient is asked to rate the total improvement of their Parkinson's Disease, whether or not in the patient's judgment it is due entirely to drug treatment, based on a 1-7 point weighted scale. "very much improved" (1) to "very much worse" (7). A zero score is assigned if the score is not assessed. Scale: 1 = Normal, not at all ill, 2 = Borderline ill, 3 = Mildly ill, 4 = Moderately ill, 5 = Markedly ill, 6 = Severly ill, 7 = Among the most extremely ill. Tables show Treatment vs Placebo.	At Week 24

Collaborators and Investigators

• Sponsor: Biotie Therapies Inc.
• Investigators: Study Director: Christopher Kenney, MD, Biotie Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): January 12, 2018
• Study Completion (Actual): January 12, 2018

Study Registration Dates

• First Submitted: May 21, 2015
• First Submitted That Met QC Criteria: May 21, 2015
• First Posted (Estimate): May 25, 2015

Study Record Updates

• Last Update Posted (Actual): April 3, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Motor fluctuations; Dyskinesia; Off time; On time
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: TOZ-CL05; 2014-005630-60 (EudraCT Number)