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Safety and Tolerability of Tozadenant as Adjunctive Therapy in Levodopa-Treated Patients With Parkinson's Disease.

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ClinicalTrials.gov Identifier: NCT03051607
Recruitment Status : Terminated (New Safety Information)
First Posted : February 13, 2017
Results First Posted : May 3, 2019
Last Update Posted : May 3, 2019
Sponsor:
Collaborator:
Acorda Therapeutics
Information provided by (Responsible Party):
Biotie Therapies Inc.

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Idiopathic Parkinson Disease
Intervention Drug: Tozadenant
Enrollment 66
Recruitment Details The disposition of study patients. A total of 66 patients were enrolled in 27 study centers across 6 countries: USA, United Kingdom, Italy, Canada, Spain and Hungary, and were included in the Safety Set (SS) as well as the Full Analysis Set (FAS).
Pre-assignment Details  
Arm/Group Title Tozadenant
Hide Arm/Group Description

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Period Title: Overall Study
Started 66
Completed 0
Not Completed 66
Reason Not Completed
Adverse Event             66
Arm/Group Title Tozadenant
Hide Arm/Group Description

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Overall Number of Baseline Participants 66
Hide Baseline Analysis Population Description
Planned patient enrollment numbers were not achieved as this study and the tozadenant development program were terminated early, based on an unexpected emerging safety signal. A total of 60 out of 66 enrolled patients completed up to Week 2, 44 completed Week 4, 22 completed Week 12, and 4 completed Week 24.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 66 participants
<=18 years
0
   0.0%
Between 18 and 65 years
27
  40.9%
>=65 years
39
  59.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 66 participants
65.8  (8.14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 66 participants
Female
16
  24.2%
Male
50
  75.8%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 66 participants
Caucasian
61
  92.4%
Black or African American
1
   1.5%
Asian
3
   4.5%
American Indian or Alaska Native
1
   1.5%
Hispanic or Latino
6
   9.1%
Not Hispanic or Latino
60
  90.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 66 participants
United States
51
  77.3%
United Kingdom
6
   9.1%
Canada
1
   1.5%
Spain
1
   1.5%
Hungary
1
   1.5%
Italy
6
   9.1%
Weight at Screening  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 66 participants
80.4  (17.18)
1.Primary Outcome
Title To Evaluate the Safety and Tolerability of Tozadenant in Levodopa-treated PD Patients Experiencing Motor Fluctuations.
Hide Description The primary objective of this study was to evaluate the safety and tolerability of tozadenant in levodopa-treated Parkinson's Disease (PD) patients experiencing motor fluctuations, based on assessment of treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms (ECGs), and clinical laboratory tests. A total of 66 patients were enrolled in 27 study centers across 6 countries: USA, United Kingdom, Italy, Canada, Spain and Hungary, and were included in the Safety Set (SS).
Time Frame Up to 28 Weeks including safety follow-up visit.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety evaluation was based on Safety Set which included all 66 patients enrolled in the study.
Arm/Group Title Tozadenant
Hide Arm/Group Description:

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Overall Number of Participants Analyzed 66
Measure Type: Count of Participants
Unit of Measure: Participants
Subjects with at least one treatment-emergent AE
46
  69.7%
Subjects with at least one related TEAE
33
  50.0%
Subjects discontinuing study drug due to an AE
7
  10.6%
Subjects with at least one SAE
5
   7.6%
Subjects with at least one life-threatening SAE
5
   7.6%
Subjects with AE leading to death
2
   3.0%
2.Secondary Outcome
Title To Evaluate the Effects of Tozadenant on the Occurrences of Daytime Drowsiness by Using the Epworth Sleepiness Scale.
Hide Description The Epworth Sleepiness Scale (ESS) is a scale intended to measure daytime sleepiness that is measured by use of a short questionnaire. Minimum range is 0 - Maximum range is 24. A score within the range 0-9 is considered to be normal while a score within the range of 10-24 would indicate that medical help should be solicited.
Time Frame Up to 28 Weeks including safety follow-up visit.
Hide Outcome Measure Data
Hide Analysis Population Description
Planned patient enrollment numbers were not achieved as this study and the tozadenant development program were terminated early, based on an unexpected emerging safety signal. No patient completed the 52 Week study treatment period prior to Sponsor termination of the study.
Arm/Group Title Tozadenant
Hide Arm/Group Description:

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Overall Number of Participants Analyzed 66
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 66 participants
7.9  (5.32)
Week 2 Number Analyzed 59 participants
7.4  (5.29)
Week 6 Number Analyzed 44 participants
8.5  (4.72)
Week 12 Number Analyzed 22 participants
10.0  (3.53)
Week 24 Number Analyzed 4 participants
12.0  (4.08)
Early Termination Number Analyzed 61 participants
7.9  (5.08)
Safety Follow-up Number Analyzed 56 participants
7.3  (4.95)
3.Secondary Outcome
Title To Evaluate the Effects of Tozadenant on the Number of Participants With Suicidal Ideation or Behavior Using the Columbia-Suicide Severity Scale (C-SSRS) Summarized by Visit.
Hide Description

The Columbia Suicide Severity Rating Scale (C-SSRS) is a standardized suicidality rating system. The interview measures presence of suicidality and consists of 4 categories: suicidal ideation, intensity of ideation, suicidal behavior, and actual/potential lethality.

Suicidal Ideation - A series of 1 -5 questions with 5 types of ideation of increasing severity. Score of Yes = 1, No= 0. A positive answer to question 4 (active suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific plan and intent) indicates that the individual has some intent to act on suicidal thoughts and will need further evaluation.

Suicidal Behavior - Different types of suicidal behavior are scored (Yes=1, No=0) and identify the occurrence of actual, interrupted, or aborted attempts; preparatory behaviors; and suicide. The total number of each type of suicidal behavior show the density of suicide, (more behaviors represent a higher degree of risk).

Time Frame Up to 28 Weeks including safety follow-up visit.
Hide Outcome Measure Data
Hide Analysis Population Description
Planned patient enrollment numbers were not achieved as this study and the tozadenant development program were terminated early, based on an unexpected emerging safety signal. No patient completed the 52 Week study treatment period prior to Sponsor termination of the study.
Arm/Group Title Tozadenant
Hide Arm/Group Description:

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Overall Number of Participants Analyzed 66
Measure Type: Count of Participants
Unit of Measure: Participants
Screening - Lifetime: Actual attempts
2
   3.0%
Screening - Lifetime: Interrupted attempts
2
   3.0%
Screening - Lifetime: Aborted attempts
3
   4.5%
Screening - Past 5 years: Actual attempts
2
   3.0%
Screening - Past 5 years: Interrupted attempts
2
   3.0%
Screening - Past 5 years: Aborted attempts
2
   3.0%
Screening - Past 6 months: Actual attempts
2
   3.0%
Screening - Past 6 months: Interrupted attempts
2
   3.0%
Screening - Past 6 months: Aborted attempts
2
   3.0%
Baseline - Since last visit: Actual attempts
3
   4.5%
Baseline - Since last visit: Interrupted attempts
2
   3.0%
Baseline - Since last visit: Aborted attempts
3
   4.5%
Week 2 - Since last visit: Actual attempts
3
   4.5%
Week 2 - Since last visit: Interrupted attempts
3
   4.5%
Week 2 - Since last visit: Aborted attempts
3
   4.5%
Week 6 - Since last visit: Actual attempts
1
   1.5%
Week 6 - Since last visit: Interrupted attempts
1
   1.5%
Week 6 - Since last visit: Aborted attempts
1
   1.5%
Week 12 - Since last visit: Actual attempts
1
   1.5%
Week 12 - Since last visit: Interrupted attempts
1
   1.5%
Week 12 - Since last visit: Aborted attempts
1
   1.5%
Week 24 - Since last visit: Actual attempts
1
   1.5%
Week 24 - Since last visit: Interrupted attempts
1
   1.5%
Week 24 - Since last visit: Aborted attempts
1
   1.5%
Early Termination: Actual attempts
10
  15.2%
Early Termination: Interrupted attempts
10
  15.2%
Early Termination: Aborted attempts
10
  15.2%
Safety Follow-up: Actual attempts
8
  12.1%
Safety Follow-up: Interrupted attempts
8
  12.1%
Safety Follow-up: Aborted attempts
11
  16.7%
4.Secondary Outcome
Title To Evaluate the Effects of Tozadenant on the Number of Participants With Occurrence of Impulsive Behavior - Modified Minnesota Impulse Disorder Interview (mMIDI)
Hide Description

The Minnesota Impulsive Disorders Interview (MIDI) 8 is a global instrument that includes questions for compulsive gambling, buying, and sexual behavior (as well as other disorders not reported to occur in PD).

The mMIDI consists of 5 modules: compulsive buying, compulsive gambling, compulsive eating, hypersexuality and punding.

Positive Answer: Any answer other than "no" on any question is considered a "yes"/positive answer.

Negative Module: A module is considered negative if the patient's answer to a gateway (initial) question is "no" or if a patient answers "yes" to a gateway question and "no" to all of the remaining answers after the gateway question in that module.

Positive Module: A module is considered positive if a patient gives a positive answer (No = 0, rarely = 1, occasionally = 2, frequently = 3) to any question after the gateway (initial) question in one or more of the 5 modules.

Time Frame Up to 28 Weeks including safety follow-up visit.
Hide Outcome Measure Data
Hide Analysis Population Description
Planned patient enrollment numbers were not achieved as this study and the tozadenant development program were terminated early, based on an unexpected emerging safety signal. No patient completed the 52 Week study treatment period prior to Sponsor termination of the study. .
Arm/Group Title Tozadenant
Hide Arm/Group Description:

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

Overall Number of Participants Analyzed 66
Measure Type: Count of Participants
Unit of Measure: Participants
Buying Disorder - Screening Number Analyzed 66 participants
Negative
66
 100.0%
Positive
0
   0.0%
Buying Disorder - Week 2 Number Analyzed 60 participants
Negative
59
  98.3%
Positive
1
   1.7%
Buying Disorder - Week 6 Number Analyzed 44 participants
Negative
43
  97.7%
Positive
1
   2.3%
Buying Disorder - Week 12 Number Analyzed 22 participants
Negative
22
 100.0%
Positive
0
   0.0%
Buying Disorder - Week 24 Number Analyzed 4 participants
Negative
4
 100.0%
Positive
0
   0.0%
Buying Disorder - Early Termination Number Analyzed 62 participants
Negative
60
  96.8%
Positive
2
   3.2%
Buying Disorder - Safety Follow-up Number Analyzed 57 participants
Negative
56
  98.2%
Positive
1
   1.8%
Compulsive Gambling - Screening Number Analyzed 66 participants
Negative
65
  98.5%
Positive
1
   1.5%
Compulsive Gambling - Week 2 Number Analyzed 60 participants
Negative
59
  98.3%
Positive
1
   1.7%
Compulsive Gambling - Week 6 Number Analyzed 44 participants
Negative
44
 100.0%
Positive
0
   0.0%
Compulsive Gambling - Week 12 Number Analyzed 22 participants
Negative
22
 100.0%
Positive
0
   0.0%
Compulsive Gambling - Week 24 Number Analyzed 4 participants
Negative
4
 100.0%
Positive
0
   0.0%
Compulsive Gambling - Early Termination Number Analyzed 62 participants
Negative
61
  98.4%
Positive
1
   1.6%
Compulsive Gambling - Safety Follow-up Number Analyzed 57 participants
Negative
56
  98.2%
Positive
1
   1.8%
Compulsive Sexual Behavior - Screening Number Analyzed 66 participants
Negative
66
 100.0%
Positive
0
   0.0%
Compulsive Sexual Behavior - Week 2 Number Analyzed 60 participants
Negative
60
 100.0%
Positive
0
   0.0%
Compulsive Sexual Behavior - Week 6 Number Analyzed 44 participants
Negative
44
 100.0%
Positive
0
   0.0%
Compulsive Sexual Behavior - Week 12 Number Analyzed 22 participants
Negative
22
 100.0%
Positive
0
   0.0%
Compulsive Sexual Behavior - Week 24 Number Analyzed 4 participants
Negative
4
 100.0%
Positive
0
   0.0%
Compulsive Sexual Behavior - Early Termination Number Analyzed 62 participants
Negative
60
  96.8%
Positive
2
   3.2%
Compulsive Sexual Behavior - Safety Follow-up Number Analyzed 57 participants
Negative
56
  98.2%
Positive
1
   1.8%
Compulsive Eating Module - Screening Number Analyzed 66 participants
Negative
66
 100.0%
Positive
0
   0.0%
Compulsive Eating Module - Week 2 Number Analyzed 60 participants
Negative
60
 100.0%
Positive
0
   0.0%
Compulsive Eating Module - Week 6 Number Analyzed 44 participants
Negative
43
  97.7%
Positive
1
   2.3%
Compulsive Eating Module - Week 12 Number Analyzed 22 participants
Negative
22
 100.0%
Positive
0
   0.0%
Compulsive Eating Module - Week 24 Number Analyzed 4 participants
Negative
4
 100.0%
Positive
0
   0.0%
Compulsive Eating Module - Early Termination Number Analyzed 62 participants
Negative
61
  98.4%
Positive
1
   1.6%
Compulsive Eating Module - Safety Follow-up Number Analyzed 57 participants
Negative
57
 100.0%
Positive
0
   0.0%
Punding Behavior - Screening Number Analyzed 66 participants
Negative
66
 100.0%
Positive
0
   0.0%
Punding Behavior - Week 2 Number Analyzed 60 participants
Negative
60
 100.0%
Positive
0
   0.0%
Punding Behavior - Week 6 Number Analyzed 44 participants
Negative
44
 100.0%
Positive
0
   0.0%
Punding Behavior - Week 12 Number Analyzed 22 participants
Negative
22
 100.0%
Positive
0
   0.0%
Punding Behavior - Week 24 Number Analyzed 4 participants
Negative
4
 100.0%
Positive
0
   0.0%
Punding Behavior - Early Termination Number Analyzed 62 participants
Negative
62
 100.0%
Positive
0
   0.0%
Punding Behavior - Safety Follow-up Number Analyzed 57 participants
Negative
57
 100.0%
Positive
0
   0.0%
Time Frame This study and the tozadenant development program were terminated early, based on an unexpected emerging safety signal. Due to Sponsor termination of the study, Adverse Events were collected up to Week 24.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tozadenant
Hide Arm/Group Description

120 mg twice daily. At Week 2 or thereafter doses of 60 mg BID and 120 mg BID will be permitted.

Tozadenant: 1 Year Open Label, 120 mg BID tozadenant, with dose modification to 60 mg BID tozadenant permitted.

All-Cause Mortality
Tozadenant
Affected / at Risk (%)
Total   2/66 (3.03%) 
Hide Serious Adverse Events
Tozadenant
Affected / at Risk (%)
Total   5/66 (7.58%) 
Blood and lymphatic system disorders   
Agranulocytosis  1  2/66 (3.03%) 
Gastrointestinal disorders   
Colitis ischaemic  1  1/66 (1.52%) 
Hepatobiliary disorders   
Gallbladder disorder  1  1/66 (1.52%) 
Infections and infestations   
Abdominal abscess  1  1/66 (1.52%) 
Atypical pneumonia  1  1/66 (1.52%) 
Diverticulitis  1  1/66 (1.52%) 
Septic shock  1  1/66 (1.52%) 
Injury, poisoning and procedural complications   
Tibia fracture  1  1/66 (1.52%) 
Respiratory, thoracic and mediastinal disorders   
Pneumonia aspiration  1  1/66 (1.52%) 
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Tozadenant
Affected / at Risk (%)
Total   46/66 (69.70%) 
Blood and lymphatic system disorders   
Agranulocytosis  1  2/66 (3.03%) 
Gastrointestinal disorders   
Nausea  1  6/66 (9.09%) 
Diarrhea  1  3/66 (4.55%) 
Abdominal pain  1  2/66 (3.03%) 
Constipation  1  2/66 (3.03%) 
Infections and infestations   
Upper respiratory tract infection  1  4/66 (6.06%) 
Nasopharyngitis  1  3/66 (4.55%) 
Urinary tract infection  1  2/66 (3.03%) 
Injury, poisoning and procedural complications   
Fall  1  7/66 (10.61%) 
Contusion  1  2/66 (3.03%) 
Drug administration error  1  2/66 (3.03%) 
Investigations   
Blood creatinine increased  1  2/66 (3.03%) 
Blood glucose increased  1  2/66 (3.03%) 
Blood pressure increased  1  2/66 (3.03%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  2/66 (3.03%) 
Joint Swelling  1  2/66 (3.03%) 
Nervous system disorders   
Dyskinesia  1  17/66 (25.76%) 
Parkinson's Disease  1  3/66 (4.55%) 
Headache  1  2/66 (3.03%) 
Tremor  1  2/66 (3.03%) 
Psychiatric disorders   
Hallucination  1  3/66 (4.55%) 
Anxiety  1  2/66 (3.03%) 
Insomnia  1  2/66 (3.03%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  2/66 (3.03%) 
Vascular disorders   
Hypertension  1  2/66 (3.03%) 
Orthostatic hypotension  1  2/66 (3.03%) 
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding the study results for a period up to 30 days from the date the communication is submitted to the sponsor. The sponsor shall have the right to defer proposed publication an additional 60 days from the end of the review period. The sponsor cannot require changes to the communication and cannot unilaterally extend the embargo.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Christopher Kenney, Senior Vice President - Medical Affairs
Organization: Acorda Therapeutics
Phone: 9143265775
EMail: ckenney@acorda.com
Layout table for additonal information
Responsible Party: Biotie Therapies Inc.
ClinicalTrials.gov Identifier: NCT03051607    
Other Study ID Numbers: TOZ-CL06
First Submitted: February 9, 2017
First Posted: February 13, 2017
Results First Submitted: January 14, 2019
Results First Posted: May 3, 2019
Last Update Posted: May 3, 2019