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

• ClinicalTrials.gov Identifier: NCT03051607
• Recruitment Status: Terminated
• First Posted: February 13, 2017
• Results First Posted: May 3, 2019
• Last Update Posted: May 3, 2019
• Sponsor: Biotie Therapies Inc.
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Tozadenant
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
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)

Outcome Measures

1. Primary Outcome

Title	To Evaluate the Safety and Tolerability of Tozadenant in Levodopa-treated PD Patients Experiencing Motor Fluctuations.
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.

Outcome Measure Data

Analysis Population Description

Safety evaluation was based on Safety Set which included all 66 patients enrolled in the study.

Arm/Group Title	Tozadenant
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.
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.

Outcome Measure Data

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
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.
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.

Outcome Measure Data

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
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)
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.

Outcome Measure Data

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
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%

Adverse Events

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
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%)
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
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Christopher Kenney, Senior Vice President - Medical Affairs
• Organization: Acorda Therapeutics
• Phone: 9143265775
• EMail: ckenney@acorda.com

• 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